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Showing content from https://patents.google.com/patent/TWI492937B/en below:

TWI492937B - Tianeptine sulfate salt forms and methods of making and using the same

Publication number

TWI492937B

TWI492937B TW098136937A TW98136937A TWI492937B TW I492937 B TWI492937 B TW I492937B TW 098136937 A TW098136937 A TW 098136937A TW 98136937 A TW98136937 A TW 98136937A TW I492937 B TWI492937 B TW I492937B

Authority

TW

Taiwan

Prior art keywords

tianeptine

monohydrate

hemisulfate

methyldibenzo

chloro

Prior art date

2008-10-31

• Espacenet
• Global Dossier
• Discuss

• 238000000034 method Methods 0.000 title claims description 72
• 229960005138 tianeptine Drugs 0.000 title description 402
• JICJBGPOMZQUBB-UHFFFAOYSA-N 7-[(3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino]heptanoic acid Chemical compound O=S1(=O)N(C)C2=CC=CC=C2C(NCCCCCCC(O)=O)C2=CC=C(Cl)C=C21 JICJBGPOMZQUBB-UHFFFAOYSA-N 0.000 claims description 344
• -1 3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepine-11-yl Chemical group 0.000 claims description 99
• 239000008194 pharmaceutical composition Substances 0.000 claims description 80
• 239000000203 mixture Substances 0.000 claims description 71
• 238000000634 powder X-ray diffraction Methods 0.000 claims description 70
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 58
• 238000013270 controlled release Methods 0.000 claims description 57
• 241000124008 Mammalia Species 0.000 claims description 47
• 239000003826 tablet Substances 0.000 claims description 40
• 239000003814 drug Substances 0.000 claims description 39
• 239000002904 solvent Substances 0.000 claims description 34
• VCSZKSHWUBFOOE-UHFFFAOYSA-N dioxidanium;sulfate Chemical compound O.O.OS(O)(=O)=O VCSZKSHWUBFOOE-UHFFFAOYSA-N 0.000 claims description 32
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 30
• 239000007937 lozenge Substances 0.000 claims description 28
• 238000004458 analytical method Methods 0.000 claims description 26
• 230000036470 plasma concentration Effects 0.000 claims description 25
• 150000001875 compounds Chemical class 0.000 claims description 20
• 159000000000 sodium salts Chemical class 0.000 claims description 20
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• 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 14
• UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 14
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
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• HLKOWEUTUIOPFA-UHFFFAOYSA-N 3-chloro-6-methyl-11H-benzo[c][2,1]benzothiazepine Chemical compound ClC1=CC2=C(CC3=C(N(S2)C)C=CC=C3)C=C1 HLKOWEUTUIOPFA-UHFFFAOYSA-N 0.000 claims description 4
• ZTHVLZXTYSAELD-UHFFFAOYSA-N 7-[(3-chloro-6-methyl-11h-benzo[c][2,1]benzothiazepin-11-yl)amino]heptanoic acid Chemical compound CN1SC2=CC(Cl)=CC=C2C(NCCCCCCC(O)=O)C2=CC=CC=C12 ZTHVLZXTYSAELD-UHFFFAOYSA-N 0.000 claims description 4
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• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 103
• 229910019142 PO4 Inorganic materials 0.000 description 97
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• 239000010452 phosphate Substances 0.000 description 97
• VALUNVMGXVWSGM-UHFFFAOYSA-N 7-[(3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][2,1]benzothiazepin-11-yl)amino]heptanoic acid hydrochloride Chemical compound Cl.O=S1(=O)N(C)C2=CC=CC=C2C(NCCCCCCC(O)=O)C2=CC=C(Cl)C=C21 VALUNVMGXVWSGM-UHFFFAOYSA-N 0.000 description 79
• KVVMXNNJBVTOSX-UHFFFAOYSA-N 7-[(3-chloro-6-methyl-5,5-dioxo-11H-benzo[c][2,1]benzothiazepin-11-yl)amino]heptanoic acid sulfuric acid dihydrate Chemical compound O.O.OS(O)(=O)=O.O=S1(=O)N(C)C2=CC=CC=C2C(NCCCCCCC(O)=O)C2=CC=C(Cl)C=C21.O=S1(=O)N(C)C2=CC=CC=C2C(NCCCCCCC(O)=O)C2=CC=C(Cl)C=C21 KVVMXNNJBVTOSX-UHFFFAOYSA-N 0.000 description 43
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• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
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本發明係關於噻萘普汀的鹽類，特別是一具增進性能的噻萘普汀硫酸鹽，更特別為噻萘普汀單水半硫酸鹽。本發名也提供了使用噻萘普汀硫酸鹽於口服醫藥組合物的方法，以及使用噻萘普汀硫酸鹽治療的相關方法。The present invention relates to salts of tianeptine, in particular a tianeptine sulphate having improved properties, more particularly tianeptine monohydrate hemisulfate. This publication also provides methods for the use of tianeptine sulfate in oral pharmaceutical compositions, as well as related methods of treatment with tianeptine sulfate.

噻萘普汀是三環類化合物，其化學名稱為7-[(3-氯-6,11-二氫-6-甲基二苯並[c,f][1,2]硫氮雜卓-11-基)氨基]庚酸，S,S-二氧化物。噻萘普汀是抗憂鬱藥物。噻萘普汀的自由態為兩性的，並於技術領域中有一已知的非結晶型鈉鹽。Thiapeptin is a tricyclic compound with the chemical name 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepine -11-yl)amino]heptanoic acid, S,S-dioxide. Xirapaptine is an antidepressant drug. The free state of tianeptine is amphoteric and there is a known amorphous sodium salt in the technical field.

美國專利第3758528號揭露了合成噻萘普汀及其鈉鹽的方法。噻萘普汀鈉(即STABLON、Coaxil或Tatinol)近來已於一些國家如歐洲，拉丁美洲，亞洲和部分中東被核准使用於治療一個或多種抑鬱症。噻萘普汀鈉(即STABLON、Coaxil或Tatinol)會被迅速且完全地吸收，並有一個很短的終端半衰期，故有效的治療往往需要於一天內多次給藥。A method of synthesizing tianeptine and its sodium salt is disclosed in U.S. Patent No. 3,758,528. Sennalpeptin sodium (STABLON) Coaxil Or Tatinol Recently, it has been approved for the treatment of one or more depressions in some countries such as Europe, Latin America, Asia and parts of the Middle East. Sennalpeptin sodium (STABLON) Coaxil Or Tatinol ) will be absorbed quickly and completely, and has a short terminal half-life, so effective treatment often requires multiple doses within one day.

目前，噻萘普汀鈉鹽的醫藥組合物一般口服劑量高達每天3次。這樣頻繁的口服可能導致遵守建議用藥量的順應性降低。一控釋的噻萘普汀醫藥組合物應能有更好的控制釋放曲線，因此能有較低的建議用藥量。此種噻萘普汀硫酸鹽之優點在於其可用於製備控制釋放含有噻萘普汀的醫藥組合物。Currently, pharmaceutical compositions of tianeptine sodium salt are generally administered orally in an oral dose up to three times a day. Such frequent oral administration may result in reduced compliance with the recommended dosage. A controlled release tianeptine pharmaceutical composition should have a better controlled release profile and therefore a lower recommended dosage. An advantage of such tianeptine sulfate is that it can be used to prepare a controlled release pharmaceutical composition containing tianeptine.

本發明係關於一種新穎的噻萘普汀硫酸鹽，特別是具改進效能的噻萘普汀單水半硫酸鹽。此種改進的效能可包含但不限於吸濕性，物理穩定性及溶解度。本發明也提供了含有噻萘普汀硫酸鹽之新穎醫藥組合物、製備噻萘普汀硫酸鹽的方法以及相關的治療方法。舉例來說，噻萘普汀單水半硫酸鹽提供了現今市售醫藥組合物劑型(噻萘普汀鈉)的一種替代選擇。This invention relates to a novel tianeptine sulfate, particularly tianeptine monohydrate hemisulfate having improved performance. Such improved performance can include, but is not limited to, hygroscopicity, physical stability, and solubility. The present invention also provides novel pharmaceutical compositions containing tianeptine sulfate, methods of preparing tianeptine sulfate, and related methods of treatment. For example, tianeptine monohydrate hemisulfate provides an alternative to the commercially available pharmaceutical composition dosage form (tianapeptin sodium).

噻萘普汀的自由態具有以下結構(I)：The free state of tianeptine has the following structure (I):

噻萘普汀硫酸鹽可用於醫藥組合物中來治療技術領域中習知的病徵，如一或多種的抑鬱症、腸躁症(IBS)、注意力缺陷過動症(ADHD)，一或多種的神經退化疾病以及哮喘。The tianeptine sulphate can be used in pharmaceutical compositions to treat conditions well known in the art, such as one or more of depression, intestinal tract (IBS), attention deficit hyperactivity disorder (ADHD), one or more Neurodegenerative diseases and asthma.

本發明的一些具體實施例中，提供了7-[(3-氯-6,11-二氫-6-甲基二苯並[c,f][1,2]硫氮雜卓-11-基)氨基]庚酸，S,S-二氧化物單水半硫酸鹽，表現如下式(II)：In some embodiments of the invention, 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepine-11- Amino]heptanoic acid, S,S-dioxide monohydrate hemisulfate, which behaved as follows (II):

而在本發明的其他一些具體實施例，提供結晶的7-[(3-氯-6,11-二氫-6-甲基二苯並[c,f][1,2]硫氮雜卓-11-基)氨基]庚酸，S,S-二氧化物單水半硫酸鹽，其特徵為粉末X射線繞射圖中，在2-θ包括有著約8.97，約11.49，約14.73，約20.59，約22.83和約23.27度的波峰。In still other embodiments of the invention, crystalline 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepine is provided. -11-yl)amino]heptanoic acid, S,S-dioxide monohydrate hemisulfate, characterized by a powder X-ray diffraction pattern comprising about 8.97, about 11.49, about 14.73, in 2-theta. 20.59, about 22.83 and a peak of about 23.27 degrees.

本發明之其他一些具體實施例中，提供了一種製備式(II)的7-[(3-氯-6,11-二氫-6-甲基二苯並[c,f][1,2]硫氮雜卓-11-基)氨基]庚酸，S,S-二氧化物單水半硫酸鹽的方法，包括步驟：(a)溶解7-[(3-氯-6,11-二氫-6-甲基二苯並[c，f][1，2]硫氮雜卓-11-基)氨基]庚酸，S,S-二氧化物或其鈉鹽於水和醋酸的混合物中；加入一溶劑單獨為水或結合了醋酸的硫酸溶液於步驟(a)之反應混合物，及(c)結晶出式(II)的化合物。In other specific embodiments of the invention, there is provided a 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2) formula (II) a method for the preparation of sulphur azepine-11-yl)amino]heptanoic acid, S,S-dioxide monohydrate hemisulfate, comprising the steps of: (a) dissolving 7-[(3-chloro-6,11-di) a mixture of hydrogen-6-methyldibenzo[c,f][1,2]thiazepin-11-yl)amino]heptanoic acid, S,S-dioxide or its sodium salt in water and acetic acid Adding a solvent to the reaction mixture of step (a) in water alone or in combination with acetic acid in sulfuric acid, and (c) crystallizing the compound of formula (II).

在本發明的另一些具體實施例中，提供了一種控制釋放的基質錠劑，其包含了一醫藥上有效量的7-[(3-氯-6,11-二氫-6-甲基二苯並[c，f][1，2]硫氮雜卓-11-基)氨基]庚酸，S,S-二氧化物單水半硫酸鹽，及一或多種控釋的聚合物，其中此錠劑於施與病人口服時，可提供平均最高血漿濃度(C_max )的7-[(3-氯-6,11-二氫-6-甲基二苯並[c，f][1，2]硫氮雜卓-11-基)氨基]庚酸，S,S-二氧化物約由100ng/ml至150ng/ml。In still other embodiments of the present invention, there is provided a controlled release matrix lozenge comprising a pharmaceutically effective amount of 7-[(3-chloro-6,11-dihydro-6-methyldi Benzo[c,f][1,2]thiazepine-11-yl)amino]heptanoic acid, S,S-dioxide monohydrate hemisulfate, and one or more controlled release polymers, wherein This tablet provides the highest average plasma concentration (C _max ) of 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1] when administered orally to a patient. 2]thiazepine-11-yl)amino]heptanoic acid, S,S-dioxide is from about 100 ng/ml to 150 ng/ml.

為了更好地了解本發明，連同其他及進一步具體實施例，並伴有圖式和發明詳細說明做為參考。For a better understanding of the present invention, reference should be made to the accompanying drawings.

本發明係相關一種新穎的噻萘普汀硫酸鹽，更特別是噻萘普汀單水半硫酸鹽。相較於一種或多種已知的噻萘普汀型式，如噻萘普汀自由鹼或噻萘普汀鈉(當前所使用的噻萘普汀型式)，噻萘普汀硫酸鹽有增進的功效。此硫酸鹽可做成多種形式，其包括但不限於水合物、溶劑合物以及各種不同化學當量比的離子噻萘普汀的硫酸鹽相對離子。本發明還包括其他形式的噻萘普汀硫酸鹽，其包括不限於多形體，共晶體和無定形體。本發明還提供了包含這些形式之新穎醫藥組合物及製備其之方法以及相關治療方法。The present invention relates to a novel tianeptine sulfate, more particularly tianeptine monohydrate hemisulfate. Compared with one or more known tianeptine types, such as tianeptine free base or tianeptine sodium (currently used tianeptine type), tianeptine sulfate has improved efficacy . The sulfate can be formed in a variety of forms including, but not limited to, hydrates, solvates, and sulfate counterions of ionic tianeptine in various stoichiometric ratios. The invention also includes other forms of tianeptine sulfate, including but not limited to polymorphs, co-crystals, and amorphous bodies. The invention also provides novel pharmaceutical compositions comprising these forms, methods of making the same, and related methods of treatment.

所有於此提到的「噻萘普汀硫酸鹽」特別意指噻萘普汀單水半硫酸鹽。All of the "tianapeptine sulfate" mentioned herein specifically means tianeptine monohydrate hemisulfate.

本發明的鹽類是一種噻萘普汀硫酸鹽。噻萘普汀自由鹼具有以下結構(I)：The salt of the present invention is a tianeptine sulfate. The tianeptine free base has the following structure (I):

在第一個具體實施例，本發明包括噻萘普汀硫酸鹽。In a first embodiment, the invention includes tianeptine sulfate.

在進一步的具體實施例中，噻萘普汀硫酸鹽可納入醫藥組合物。在其他的具體實施例，噻萘普汀硫酸鹽可納入控制釋放的醫藥物組合物。In a further embodiment, the tianeptine sulfate can be incorporated into a pharmaceutical composition. In other embodiments, tianeptine sulfate can be incorporated into a controlled release pharmaceutical composition.

在另一具體實施例，噻萘普汀硫酸鹽可納入包含一層或多層噻萘普汀硫酸鹽的醫藥物組合物，這樣在體內，一層可於另一層大量釋放前先行釋放。在另一項具體實施例，噻萘普汀硫酸鹽可納入含有顆粒的藥物組合物，其中的顆粒可有不同的範圍或化學成分的塗層，使噻萘普汀的釋放時間可大幅度的長於當前可使用的噻萘普汀(例如STABLON、Coaxil或Tatinol)。In another embodiment, the tianeptine sulfate can be incorporated into a pharmaceutical composition comprising one or more layers of tianeptine sulfate such that in vivo, one layer can be released prior to bulk release in another layer. In another embodiment, the tianeptine sulfate can be incorporated into a pharmaceutical composition comprising granules, wherein the granules can have coatings of different ranges or chemical compositions, such that the release time of tianeptine can be substantially increased. Longer than currently available tianeptine (eg STABLON) Coaxil Or Tatinol ).

在另一具體實施例，噻萘普汀硫酸鹽可以納入一個適合口服的滲透性活性藥物組合物。適合口服的滲透性活性藥物組合物、滲透泵、滲透給藥及其他滲透技術可以包括但不限於OROSPush-Pull及OROS三層藥物組合物。在另一項具體實施例，噻萘普汀硫酸鹽可以併入一OROS藥物輸送系統。這種控制釋放藥物組合物組成的噻萘普汀硫酸鹽，如適合口服的滲透性活性藥物組合物，可能較目前市售的形式的噻萘普汀鈉鹽有更持久的療效。In another embodiment, the tianeptine sulfate can be incorporated into a pharmaceutically active pharmaceutical composition suitable for oral administration. Permeable active pharmaceutical compositions suitable for oral administration, osmotic pumps, osmotic administration, and other infiltration techniques may include, but are not limited to, OROS Push-Pull and OROS A three-layer pharmaceutical composition. In another embodiment, the tianeptine sulfate can be incorporated into an OROS Drug delivery system. The stanopeptine sulfate of such a controlled release pharmaceutical composition, such as a osmotically active pharmaceutical composition suitable for oral administration, may have a more durable effect than the currently marketed form of tianeptine sodium salt.

本發明之另一具體實施例中，包括噻萘普汀單水半硫酸鹽。噻萘普汀單水半硫酸鹽具有以下結構(II)：In another embodiment of the invention, tianeptine monohydrate hemisulfate is included. The tianeptine monohydrate hemisulfate has the following structure (II):

在一些具體實施例，本發明是針對噻萘普汀單水半硫酸鹽結晶物的型式。In some embodiments, the invention is directed to a form of tianeptine monohydrate hemisulfate crystals.

在另一具體實施例中，噻萘普汀單水半硫酸鹽存在至少在一可檢測出的數量，如噻萘普汀單水半硫酸鹽結晶物。例如，在一些具體實施例中，噻萘普汀單水半硫酸鹽可能存在量約20%至約100%重量的噻萘普汀單水半硫酸鹽結晶。In another embodiment, the tianeptine monohydrate hemisulfate is present in at least one detectable amount, such as tianeptine monohydrate hemisulfate crystals. For example, in some embodiments, tianeptine monohydrate hemisulfate may be present in an amount from about 20% to about 100% by weight of tianeptine monohydrate hemisulfate crystals.

在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括一個2-θ為約8.97度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括一個2-θ為約8.25度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括一個2-θ為約11.49度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約8.25及約8.97度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約8.97及約11.49度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約13.91及約14.73度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約8.25、約8.97及約11.49度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約8.97、約14.73、約18.07及約19.39度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約8.25、約11.49、約13.91、約16.95及約20.59度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約16.95、約18.07、約19.39及約20.59度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約13.91、約14.73、約22.83及約23.27度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約8.25、約8.97、約11.49、約13.91及約14.73度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約16.95、約18.07、約19.39、約20.59、約21.99及約23.27度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約8.25、約8.97、約11.49、約13.91、約14.73、約16.95、約18.07、約19.39、約20.59、約21.99、約22.83及約23.27度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約8.25、約13.91及約14.73度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約8.97、約18.07、約19.39及約20.59度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖包括2-θ為約8.97、約11.49、約13.91、約18.07、約19.39及約20.59度的波峰。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的PXRD繞射圖基本上類似於圖1。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的DSC溫度記錄圖中，包含一約攝氏193度的吸熱轉性點。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現DSC溫度記錄圖基本上類似於圖2。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的TGA溫度記錄圖基本上類似於圖3。在另一具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽呈現的動態水份吸附分析(DVS)基本上類似於圖4。在另一項具體實施例，噻萘普汀單水半硫酸鹽可納入控制釋放藥物組合物。In another embodiment, the invention comprises tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a peak having a 2-theta of about 8.97 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a peak having a 2-theta of about 8.25 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a peak having a 2-theta of about 11.49 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a peak having a 2-theta of about 8.25 and about 8.97 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a peak having a 2-theta of about 8.97 and about 11.49 degrees. In another embodiment, the invention comprises tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a peak having a 2-theta of about 13.91 and about 14.73 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a peak having a 2-theta of about 8.25, about 8.97, and about 11.49 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a PXRD diffraction pattern comprising 2-theta of about 8.97, about 14.73, about 18.07, and about 19.39 degrees. The crest. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises 2-theta of about 8.25, about 11.49, about 13.91, about 16.95, and A peak of about 20.59 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by monohydrate hemisulfate comprises 2-theta of about 16.95, about 18.07, about 19.39, and about 20.59 degrees. The crest. In another embodiment, the invention comprises tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a PXRD diffraction pattern comprising 2-theta of about 13.91, about 14.73, about 22.83, and about 23.27 degrees. The crest. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises 2-theta of about 8.25, about 8.97, about 11.49, about 13.91, and A peak of about 14.73 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises 2-theta of about 16.95, about 18.07, about 19.39, about 20.59, A peak of about 21.99 and about 23.27 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a PXRD diffraction pattern comprising 2-theta of about 8.25, about 8.97, about 11.49, about 13.91, Peaks of about 14.73, about 16.95, about 18.07, about 19.39, about 20.59, about 21.99, about 22.83, and about 23.27 degrees. In another embodiment, the invention comprises tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises a peak having a 2-theta of about 8.25, about 13.91, and about 14.73 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a PXRD diffraction pattern comprising 2-theta of about 8.97, about 18.07, about 19.39, and about 20.59 degrees. The crest. In another embodiment, the invention comprises tianeptine monohydrate hemisulfate, wherein the PXRD diffraction pattern exhibited by the monohydrate hemisulfate comprises 2-theta of about 8.97, about 11.49, about 13.91, about 18.07, A peak of about 19.39 and about 20.59 degrees. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a PXRD diffraction pattern substantially similar to that of FIG. In another embodiment, the invention includes tianeptine monohydrate hemisulfate wherein the monohydrate hemisulfate exhibits a DSC thermogram comprising an endothermic transition point of about 193 degrees Celsius. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a DSC thermogram similar to that of FIG. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a TGA thermogram similar to that of FIG. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate exhibits a dynamic moisture adsorption analysis (DVS) substantially similar to that of FIG. In another specific embodiment, tianeptine monohydrate hemisulfate can be incorporated into a controlled release pharmaceutical composition.

在另一具體實施例中，本發明包括一個噻萘普汀硫酸鹽，其中，硫酸鹽為非吸濕性的。在另一項具體實施例，本發明包括一個噻萘普汀硫酸鹽，其中，硫酸鹽在約10%左右的相對濕度至約90%左右的相對濕度下為非吸濕性的。在另一項具體實施例，本發明包括噻萘普汀單水半硫酸鹽，其中，單水半硫酸鹽於DVS攝氏25度，約10%左右的相對濕度至約90%左右的相對濕度下為非吸濕性的。在另一項具體實施例，本發明包括一個噻萘普汀硫酸鹽，其中，硫酸鹽在約20%左右的相對濕度至約80%左右的相對濕度下為非吸濕性的。在另一項具體實施例，本發明包括一個噻萘普汀硫酸鹽，其中，硫酸鹽在約30%左右的相對濕度至約70%左右的相對濕度下為非吸濕性的。在另一項具體實施例，本發明包括一個噻萘普汀硫酸鹽，其中，硫酸鹽為完全穩定的。另一項具體實施例，本發明包括一個噻萘普汀硫酸鹽，其中，硫酸鹽在約10%左右的相對濕度至約90%左右的相對濕度下為完全穩定的。另一項具體實施例，本發明包括一個噻萘普汀硫酸鹽，其中，硫酸鹽在約20%左右的相對濕度至約80%左右的相對濕度下為完全穩定的。另一項具體實施例，本發明包括一個噻萘普汀硫酸鹽，其中，硫酸鹽在約30%左右的相對濕度至約70%左右的相對濕度下為完全穩定的。In another embodiment, the invention includes a tianeptine sulfate wherein the sulfate is non-hygroscopic. In another embodiment, the invention includes a tianeptine sulfate wherein the sulfate is non-hygroscopic at a relative humidity of from about 10% to about 90% relative humidity. In another embodiment, the invention includes tianeptine monohydrate hemisulfate, wherein the monohydrate hemisulfate is at a DVS of 25 degrees Celsius, a relative humidity of about 10% to a relative humidity of about 90%. It is non-hygroscopic. In another embodiment, the invention includes a tianeptine sulfate wherein the sulfate is non-hygroscopic at a relative humidity of from about 20% to about 80% relative humidity. In another embodiment, the invention includes a tianeptine sulfate wherein the sulfate is non-hygroscopic at a relative humidity of from about 30% to about 70% relative humidity. In another embodiment, the invention includes a tianeptine sulfate wherein the sulfate is completely stable. In another embodiment, the invention includes a tianeptine sulfate wherein the sulfate is fully stable at a relative humidity of from about 10% to about 90% relative humidity. In another embodiment, the invention includes a tianeptine sulfate wherein the sulfate is fully stable at a relative humidity of from about 20% to about 80% relative humidity. In another embodiment, the invention includes a tianeptine sulfate wherein the sulfate is fully stable at a relative humidity of from about 30% to about 70% relative humidity.

根據本發明，噻萘普汀硫酸鹽可有不同的離子化噻萘普汀(陽離子)對硫酸鹽相對離子(陰離子)的化學當量比。例如，陽離子：負離子的比率可為1:1或2:1。其他的當量比率也包括於本發明中。在一些具體實施例中，噻萘普汀單水半硫酸鹽包括一個離子噻萘普汀比硫酸比水約為2:1:2的比率。According to the present invention, tianeptine sulfate may have a different stoichiometric ratio of ionized tianeptine (cation) to sulfate relative ion (anion). For example, the ratio of cation: negative ions can be 1:1 or 2:1. Other equivalent ratios are also included in the present invention. In some embodiments, the tianeptine monohydrate hemisulfate comprises a ratio of ionic tianeptine to sulfuric acid to water of about 2:1:2.

在另一具體實施例，本發明包括噻萘普汀硫酸鹽及其製備與使用的方法。在另一具體實施例中，本發明包括了噻萘普汀硫酸鹽的水合物及其製備與使用的方法。在另一具體實施例中，本發明包括了的噻萘普汀硫酸鹽的溶劑合物。在另一項具體實施例，本發明由一個或多個噻萘普汀硫酸鹽多形體，或一個或多個多噻萘普汀硫酸鹽水合物或溶劑合物的多形體。在另一具體實施例中，本發明包括噻萘普汀硫酸鹽的共晶體。在另一具體實施例，本發明包括噻萘普汀硫酸鹽之無定形體及其製備與使用的方法。In another embodiment, the invention includes tianeptine sulfate and methods of making and using same. In another embodiment, the invention includes hydrates of tianeptine sulfate and methods of making and using same. In another embodiment, the invention includes a solvate of tianeptine sulfate. In another embodiment, the invention consists of one or more tianeptine sulphate polymorphs, or one or more polymorphs of thiapineptin sulfate hydrate or solvate. In another embodiment, the invention includes a co-crystal of tianeptine sulfate. In another embodiment, the invention includes an amorphous form of tianeptine sulfate and methods of making and using same.

在另一具體實施例中，一噻萘普汀硫酸鹽形式可以存在於，例如，但不限於，一無水形式，一水合物形式，一脫水形式或一溶劑合物的形式。這種水合物和溶劑合物形式可有不同噻萘普汀離子比上水或溶劑合物分子的化學當量，例如，但不限於約1:1、1:1.5、2:1或1:2。In another embodiment, the tianeptine sulfate form may be present, for example, but not limited to, in the form of an anhydrous form, a monohydrate form, a dehydrated form or a solvate. Such hydrate and solvate forms may have different stoichiometric equivalents of the tianeptine ion to the water or solvate molecule, such as, but not limited to, about 1:1, 1:1.5, 2:1, or 1:2. .

在另一具體實施例，本發明提供了一製備噻萘普汀硫酸鹽的方法，包括：In another embodiment, the invention provides a method of preparing tianeptine sulfate, comprising:

(a)提供噻萘普汀或其鈉鹽；及(a) providing tianeptine or a sodium salt thereof;

(b)噻萘普汀或其鈉鹽與硫酸作用，以形成結晶化的噻萘普汀硫酸鹽。(b) The tianeptine or its sodium salt acts with sulfuric acid to form a crystallized tianeptine sulfate.

在一個特定的具體實施例中，其中噻萘普汀的形式為鈉鹽。在另一具體實施例，於加入硫酸前先將一溶劑添加到噻萘普汀或其鈉鹽中。在另一項具體實施例，步驟(b)在溶劑存在下完成，使得溶液在硫酸鹽結晶前形成。在另一項具體實施例，步驟(b)在溶劑存在下完成，使得懸浮液在硫酸鹽結晶前形成。在某些具體實施例中，溶劑是選自由：丙酮，乙醇，硝基甲烷，甲醇，乙腈，二氯甲烷，水和四氫呋喃(THF)所組成的群組。在另一具體實施例中，一溶劑可為任何兩個或兩個以上溶劑所形成的混合物，其包括但不限於丙酮，乙醇，硝基甲烷，甲醇，乙腈，二氯甲烷，水和四氫呋喃。In a specific embodiment, wherein the form of tianeptine is a sodium salt. In another embodiment, a solvent is added to the tianeptine or its sodium salt prior to the addition of sulfuric acid. In another embodiment, step (b) is carried out in the presence of a solvent such that the solution forms prior to crystallization of the sulfate. In another embodiment, step (b) is carried out in the presence of a solvent such that the suspension forms prior to crystallization of the sulfate. In certain embodiments, the solvent is selected from the group consisting of: acetone, ethanol, nitromethane, methanol, acetonitrile, dichloromethane, water, and tetrahydrofuran (THF). In another embodiment, a solvent can be a mixture of any two or more solvents including, but not limited to, acetone, ethanol, nitromethane, methanol, acetonitrile, dichloromethane, water, and tetrahydrofuran.

在另一具體實施例，本發明提供了一種製備噻萘普汀單水半硫酸鹽的方法，包括步驟：In another embodiment, the present invention provides a method of preparing tianeptine monohydrate hemisulfate, comprising the steps of:

(a)將噻萘普汀或其鈉鹽溶解於水和醋酸的混合物中；(a) dissolving tianeptine or a sodium salt thereof in a mixture of water and acetic acid;

(b)加入一溶劑單獨為水或結合了醋酸的硫酸溶液於步驟(a)之反應混合物，及(b) adding a solvent to the reaction mixture of step (a), either alone or in combination with acetic acid in sulfuric acid;

(c)結晶出噻萘普汀單水半硫酸鹽。(c) Crystallization of tianeptine monohydrate hemisulfate.

在一些具體實施例中，該方法還可進一步的包含步驟：In some embodiments, the method may further comprise the steps of:

(d)由上述步驟(c)的反應混合物中分離出所獲得的噻萘普汀單水半硫酸鹽；(d) separating the obtained tianeptine monohydrate hemisulfate from the reaction mixture of the above step (c);

(e)以水和醋酸的混合物清洗噻萘普汀單水半硫酸鹽；(e) washing tianeptine monohydrate hemisulfate with a mixture of water and acetic acid;

(f)進一步清以水清洗噻萘普汀單水半硫酸鹽；及(f) further cleaning the tianeptine monohydrate hemisulfate with water; and

(g)乾燥噻萘普汀單水半硫酸鹽。(g) Drying tianeptine monohydrate hemisulfate.

在一些具體實施例中，實施此方法不包含分離如下所示的中間物：In some embodiments, implementing the method does not involve isolating the intermediates shown below:

噻萘普汀自由鹼及噻萘普汀鈉可於技術領域中可獲得的一個或多個方法來製備，其包括但不限於美國專利第3,758,528號的方法。The tianeptine free base and tianeptine sodium can be prepared by one or more methods available in the art including, but not limited to, the method of U.S. Patent No. 3,758,528.

在本發明的一個具體實施例中，一可調節哺乳動物的生理和/或治療哺乳動物的有效量噻萘普汀硫酸鹽被施予至所述哺乳動物。在另一方面，施予足以影響調節哺乳動物的生理和/或治療的有效量噻萘普汀硫酸鹽。In a specific embodiment of the invention, an effective amount of tianeptine sulfate, which modulates the physiological and/or therapeutic mammalian of the mammal, is administered to the mammal. In another aspect, an effective amount of tianeptine sulfate is administered sufficient to affect the physiology and/or treatment of the mammal.

在另一具體實施例中，提供一治療患有抑鬱症之哺乳動物的方法，包括施予所述哺乳動物有效量的噻萘普汀硫酸鹽。在另一具體實施例中，提供了一種治療治療患有腸躁症之哺乳動物的方法，包括施予所述哺乳動物有效量之噻萘普汀硫酸鹽。在另一具體實施例中，提供了一種治療患有注意力缺陷過動症之哺乳動物的方法，包括施與所述哺乳動物有效量之噻萘普汀硫酸鹽。在另一具體實施例中，提供了一種治療患有哮喘之哺乳動物的方法，包括施與所述哺乳動物有效量之噻萘普汀硫酸鹽。在另一項具體實施例中，所述之哺乳動物為人類。In another embodiment, a method of treating a mammal suffering from depression comprising administering an effective amount of tianeptine sulfate to the mammal is provided. In another embodiment, a method of treating a mammal suffering from intestinal fistula is provided, comprising administering to the mammal an effective amount of tianeptine sulfate. In another embodiment, a method of treating a mammal suffering from attention deficit hyperactivity disorder comprising administering an effective amount of tianeptine sulfate to the mammal is provided. In another embodiment, a method of treating a mammal having asthma comprising administering an effective amount of tianeptine sulfate to the mammal is provided. In another specific embodiment, the mammal is a human.

本發明之另一具體實施例中，包括了製備一藥劑，包含了噻萘普汀硫酸鹽。這種藥劑可用於需要此種治療的哺乳動物，用以治療抑鬱症，腸躁症，注意力缺陷過動症，一種或多種神經退化性疾病或哮喘等疾病。在另一項具體實施例中，所述哺乳動物是人。In another embodiment of the invention, the preparation of a medicament comprising tianeptine sulfate is included. Such agents are useful in mammals in need of such treatment for the treatment of depression, intestinal cramps, attention deficit hyperactivity disorder, one or more neurodegenerative diseases or asthma. In another specific embodiment, the mammal is a human.

噻萘普汀硫酸鹽的藥品劑型的可有多種施與的方法，其包括但不限於口服。口服醫藥物組合物和劑型的為模範劑型。又或口服劑型可為固體劑型，如錠劑，一易吞錠，一硬膠囊，一澱粉膠囊，一羥丙基甲基纖維素(HPMC)膠囊，或一軟彈性明膠膠囊。本發明之錠劑可由任何此領域已知之方法製造。錠劑製備的傳統方法，包括直接壓縮(「乾混合」)，乾燥造粒後壓縮和濕造粒後乾燥再壓縮。其他方法包括使用滾動壓實技術，如chilsonator或落差軋輥、或成型、或鑄造，或擠壓技術。所有這些方法皆為技術領域中習知，並有詳細描述，例如Lachman,et al.,“The Theory and Practice of Industrial Pharmacy,”Chapter 11,(3^rd Ed. 1986),於此併為參考。本發明也提供了液體劑型，其中包括不做為限制的例子如懸浮液、溶液、糖漿或乳劑。Pharmaceutical dosage forms of tianeptine sulfate may be administered in a variety of ways including, but not limited to, oral. Oral pharmaceutical compositions and dosage forms are exemplary dosage forms. Alternatively, the oral dosage form can be a solid dosage form such as a troche, an easy-to-swallow tablet, a hard capsule, a starch capsule, a hydroxypropyl methylcellulose (HPMC) capsule, or a soft elastic gelatin capsule. Tablets of the present invention can be made by any method known in the art. Conventional methods for the preparation of tablets include direct compression ("dry mixing"), dry granulation followed by compression and wet granulation followed by drying and compression. Other methods include the use of rolling compaction techniques such as chilsonator or drop rolls, or forming, or casting, or extrusion techniques. All of these methods are all conventional art, and described in detail, for example, Lachman, et al., "The Theory and Practice of Industrial Pharmacy," Chapter 11, (3 rd Ed. 1986), and by reference thereto. The invention also provides liquid dosage forms which include, without limitation, examples such as suspensions, solutions, syrups or emulsions.

噻萘普汀硫酸鹽以控制或延遲釋放的手段來投藥。控釋的醫藥產品通常都具有一改善其非控釋藥物的療效的一般目標。理想情況下，利用優化設計的控釋製劑在醫療上特點是以最低的API(活性藥物成分)物質釋放於最短的時間內來治癒或控制病情。優選的控釋醫藥組合物一般包括：1)延遲了API的活性；2)減少劑量的頻率；3)提高病人的順應性；4)較少總API的劑量；5)減少局部或全身性的副作用；6)API的積累最小化；7)減少血液濃度的波動；8)改善治療效果；9)降低增強效應或減低API活性；和10)改善控制疾病或徵狀的控制速度。(Kim,Cherng-ju,Controlled Release Dosage Form Design,2 Technomic Publishing,Lancaster,Pa.: 2000)。The tianeptine sulfate is administered by means of controlled or delayed release. Controlled release pharmaceutical products generally have a general goal of improving the efficacy of their non-controlled release drugs. Ideally, the use of an optimized design of a controlled release formulation is medically characterized by the release of the lowest API (active pharmaceutical ingredient) in the shortest amount of time to cure or control the condition. Preferred controlled release pharmaceutical compositions generally include: 1) delayed API activity; 2) reduced dose frequency; 3) improved patient compliance; 4) less total API dose; 5) reduced local or systemic Side effects; 6) Minimization of API accumulation; 7) Reduction of fluctuations in blood concentration; 8) Improvement of therapeutic effect; 9) Reduction of enhancement effect or reduction of API activity; and 10) Improvement of control rate of control of disease or symptoms. (Kim, Cherng-ju, Controlled Release Dosage Form Design, 2 Technomic Publishing, Lancaster, Pa.: 2000).

本發明之一些具體實施例中，典型的每日劑量包括噻萘普汀硫酸鹽，其劑量從約10.0毫克至50.0毫克左右，約12.5毫克至50.0毫克左右，約12.5毫克至37.5毫克，或約25.0毫克至37.5毫克。在一特定的具體實施例中，噻萘普汀硫酸鹽於此種組合中為噻萘普汀單水半硫酸鹽。在本文所述的劑量為噻萘普汀自由鹼的劑量，不包括相對離子(如硫酸)或任何水或溶劑分子的重量。In some embodiments of the invention, a typical daily dose comprises tianeptine sulfate at a dose of from about 10.0 mg to about 50.0 mg, from about 12.5 mg to about 50.0 mg, from about 12.5 mg to about 37.5 mg, or about 25.0 mg to 37.5 mg. In a specific embodiment, the tianeptine sulfate is tianeptine monohydrate hemisulfate in this combination. The dosages described herein are doses of tianeptine free base, excluding the weight of relative ions (such as sulfuric acid) or any water or solvent molecules.

在本發明之另一具體實施例，一醫藥組合物，包括口服噻萘普汀硫酸鹽必要的劑量，由約10.0毫克至50.0毫克左右，約12.5毫克至50.0毫克左右，約25.0毫克至50.0毫克左右，或約37.5毫克至50.0毫克左右的噻萘普汀。例如，約12.5毫克，約25.0毫克或約37.5毫克。在特定的具體實施例中，藥品成分包括可口服的噻萘普汀硫酸鹽，劑量約為25.0毫克或約37.5毫克。劑量總額可單一或分次施藥。在一些具體實施例中，該劑型為每天施藥一次。在一些具體實施例中，該劑型為每天施藥多次。在另一具體實施例中，每日劑量的醫藥組合物包括噻萘普汀硫酸鹽，其包括最多不超過50.0毫克的噻萘普汀。In another embodiment of the invention, a pharmaceutical composition, including oral tianeptine sulfate, is administered at a dose of from about 10.0 mg to about 50.0 mg, from about 12.5 mg to about 50.0 mg, and from about 25.0 mg to about 50.0 mg. Left and right, or about 37.5 mg to 50.0 mg of tianeptine. For example, about 12.5 mg, about 25.0 mg or about 37.5 mg. In a particular embodiment, the pharmaceutical composition comprises an orally available tianeptine sulfate at a dose of about 25.0 mg or about 37.5 mg. The total dose can be administered in a single or divided dose. In some embodiments, the dosage form is administered once a day. In some embodiments, the dosage form is administered multiple times per day. In another specific embodiment, the daily dose of the pharmaceutical composition comprises tianeptine sulfate comprising up to 50.0 mg of tianeptine.

在一些具體實施例，本發明的每日劑量形式包括噻萘普汀硫酸鹽，其劑量約25.0毫克至約200.0毫克，約25.0毫克至約150.0毫克，約25.0毫克至100.0毫克，或約25.0毫克至75.0毫克左右。在一個特定的具體實施例中，於組合物中的噻萘普汀硫酸鹽為噻萘普汀單水半硫酸鹽。在本文所述的劑量為噻萘普汀自由鹼的劑量，不包括相對離子(如硫酸)或任何水或溶劑分子的重量。In some embodiments, the daily dosage form of the invention comprises tianeptine sulfate at a dose of from about 25.0 mg to about 200.0 mg, from about 25.0 mg to about 150.0 mg, from about 25.0 mg to 100.0 mg, or about 25.0 mg. It is about 75.0 mg. In a specific embodiment, the tianeptine sulfate in the composition is tianeptine monohydrate hemisulfate. The dosages described herein are doses of tianeptine free base, excluding the weight of relative ions (such as sulfuric acid) or any water or solvent molecules.

在本發明之另一具體實施例中，一醫藥組合物，包括口服的噻萘普汀硫酸鹽，必要劑量約25.0毫克至約200.0毫克，約25.0毫克至約150.0毫克，約25.0毫克至約100.0毫克，約25.0毫克至75.0毫克左右，或約50.0毫克至75.0毫克左右的噻萘普汀。例如，約25.0毫克，約50.0毫克，或約75.0毫克。在特異的具體實施例中，醫藥組合物包括可口服的噻萘普汀硫酸鹽，劑量約為25.0毫克，約50.0毫克，或75.0毫克左右。在另一具體實施例，每日劑量的醫藥組合物，包括噻萘普汀硫酸鹽，其包括最多不超過100.0毫克的噻萘普汀。In another embodiment of the invention, a pharmaceutical composition comprising orally oral tianeptine sulfate, a necessary dose of from about 25.0 mg to about 200.0 mg, from about 25.0 mg to about 150.0 mg, from about 25.0 mg to about 100.0 Mg, about 25.0 mg to 75.0 mg, or about 50.0 mg to 75.0 mg of tianeptine. For example, about 25.0 mg, about 50.0 mg, or about 75.0 mg. In a specific embodiment, the pharmaceutical composition comprises an orally available tianeptine sulfate at a dose of about 25.0 mg, about 50.0 mg, or about 75.0 mg. In another embodiment, a daily dosage of a pharmaceutical composition comprising tianeptine sulfate comprises up to no more than 100.0 mg of tianeptine.

本發明的一些具體實施例中，每日劑量形式包括噻萘普汀硫酸鹽，劑量約30.0毫克至約200.0毫克，約30.0毫克至約150.0毫克，約30.0毫克至100.0毫克，或約30.0毫克至60.0毫克左右。在一個特定的具體實施例，於組合物中的噻萘普汀硫酸鹽為噻萘普汀單水半硫酸鹽。在本文所述的劑量為噻萘普汀自由鹼的劑量，不包括相對離子(如硫酸)或任何水或溶劑分子的重量。In some embodiments of the invention, the daily dosage form comprises tianeptine sulfate, at a dose of from about 30.0 mg to about 200.0 mg, from about 30.0 mg to about 150.0 mg, from about 30.0 mg to 100.0 mg, or from about 30.0 mg to About 60.0 mg. In a specific embodiment, the tianeptine sulfate in the composition is tianeptine monohydrate hemisulfate. The dosages described herein are doses of tianeptine free base, excluding the weight of relative ions (such as sulfuric acid) or any water or solvent molecules.

於本發明的另一具體實施例，一醫藥組合物，包括口服的噻萘普汀硫酸鹽，必要劑量約30.0毫克至約200.0毫克，約30.0毫克至約150.0毫克，約30.0毫克至約100.0毫克，約30.0毫克至60.0毫克左右的噻萘普汀。例如，約30.0毫克，60.0毫克左右，約100.0毫克。在特定的具體實施例，藥品成分包括可口服的噻萘普汀硫酸鹽，劑量約為30.0毫克，約60.0毫克，約100.0毫克。在另一具體實施例，每日劑量的醫藥組合物，包括噻萘普汀硫酸鹽，其包括最多不超過100.0毫克的噻萘普汀。In another embodiment of the invention, a pharmaceutical composition comprising orally oral tianeptine sulfate, a necessary dose of from about 30.0 mg to about 200.0 mg, from about 30.0 mg to about 150.0 mg, from about 30.0 mg to about 100.0 mg. , about 30.0 mg to 60.0 mg of tianeptine. For example, about 30.0 mg, about 60.0 mg, about 100.0 mg. In a specific embodiment, the pharmaceutical composition comprises an orally available tianeptine sulfate at a dose of about 30.0 mg, about 60.0 mg, and about 100.0 mg. In another embodiment, a daily dosage of a pharmaceutical composition comprising tianeptine sulfate comprises up to no more than 100.0 mg of tianeptine.

在本發明之另一具體實施例，一醫藥組合物，包括口服噻萘普汀硫酸鹽必要的劑量，由約10.0毫克至50.0毫克左右，約12.5毫克至50.0毫克左右，約25.0毫克至50.0毫克左右，或約37.5毫克至50.0毫克左右的噻萘普汀。例如，約12.5毫克，約25.0毫克或約37.5毫克。在一特定的具體實施例中，噻萘普汀硫酸鹽於此種組合中為噻萘普汀單水半硫酸鹽。在本文所述的劑量為噻萘普汀自由鹼的劑量，不包括相對離子(如硫酸)或任何水或溶劑分子的重量。In another embodiment of the invention, a pharmaceutical composition, including oral tianeptine sulfate, is administered at a dose of from about 10.0 mg to about 50.0 mg, from about 12.5 mg to about 50.0 mg, and from about 25.0 mg to about 50.0 mg. Left and right, or about 37.5 mg to 50.0 mg of tianeptine. For example, about 12.5 mg, about 25.0 mg or about 37.5 mg. In a specific embodiment, the tianeptine sulfate is tianeptine monohydrate hemisulfate in this combination. The dosages described herein are doses of tianeptine free base, excluding the weight of relative ions (such as sulfuric acid) or any water or solvent molecules.

在本發明之另一具體實施例，一醫藥組合物，包括口服噻萘普汀硫酸鹽必要的劑量，由約10.0毫克至50.0毫克左右，約12.5毫克至50.0毫克左右，約25.0毫克至50.0毫克左右，或約37.5毫克至50.0毫克左右的噻萘普汀。例如，約12.5毫克，約25.0毫克或約37.5毫克。在特定的具體實施例中，藥品成分包括可口服的噻萘普汀硫酸鹽，劑量約為25.0毫克或約37.5毫克。劑量總額可單一或分次施藥。在另一具體實施例中，每日劑量的醫藥組合物包括噻萘普汀硫酸鹽，其包括最多不超過50.0毫克的噻萘普汀。In another embodiment of the invention, a pharmaceutical composition, including oral tianeptine sulfate, is administered at a dose of from about 10.0 mg to about 50.0 mg, from about 12.5 mg to about 50.0 mg, and from about 25.0 mg to about 50.0 mg. Left and right, or about 37.5 mg to 50.0 mg of tianeptine. For example, about 12.5 mg, about 25.0 mg or about 37.5 mg. In a particular embodiment, the pharmaceutical composition comprises an orally available tianeptine sulfate at a dose of about 25.0 mg or about 37.5 mg. The total dose can be administered in a single or divided dose. In another specific embodiment, the daily dose of the pharmaceutical composition comprises tianeptine sulfate comprising up to 50.0 mg of tianeptine.

在一些具體實施例，本發明的每日劑量形式包括噻萘普汀硫酸鹽，其劑量約25.0毫克至約200.0毫克，約25.0毫克至約150.0毫克，約25.0毫克至100.0毫克，或約25.0毫克至75.0毫克左右。在一個特定的具體實施例中，於組合物中的噻萘普汀硫酸鹽為噻萘普汀單水半硫酸鹽。在本文所述的劑量為噻萘普汀自由鹼的劑量，不包括相對離子(如硫酸)或任何水或溶劑分子的重量。In some embodiments, the daily dosage form of the invention comprises tianeptine sulfate at a dose of from about 25.0 mg to about 200.0 mg, from about 25.0 mg to about 150.0 mg, from about 25.0 mg to 100.0 mg, or about 25.0 mg. It is about 75.0 mg. In a specific embodiment, the tianeptine sulfate in the composition is tianeptine monohydrate hemisulfate. The dosages described herein are doses of tianeptine free base, excluding the weight of relative ions (such as sulfuric acid) or any water or solvent molecules.

在本發明之另一具體實施例中，一醫藥組合物，包括口服的噻萘普汀硫酸鹽，必要劑量約25.0毫克至約200.0毫克，約25.0毫克至約150.0毫克，約25.0毫克至約100.0毫克，約25.0毫克至75.0毫克左右，或約50.0毫克至75.0毫克左右的噻萘普汀。例如，約25.0毫克，約50.0毫克，或約75.0毫克。在特異的具體實施例中，醫藥組合物包括可口服的噻萘普汀硫酸鹽，劑量約為25.0毫克，約50.0毫克，或75.0毫克左右。在另一具體實施例，每日劑量的醫藥組合物，包括噻萘普汀硫酸鹽，其包括最多不超過100.0毫克的噻萘普汀。In another embodiment of the invention, a pharmaceutical composition comprising orally oral tianeptine sulfate, a necessary dose of from about 25.0 mg to about 200.0 mg, from about 25.0 mg to about 150.0 mg, from about 25.0 mg to about 100.0 Mg, about 25.0 mg to 75.0 mg, or about 50.0 mg to 75.0 mg of tianeptine. For example, about 25.0 mg, about 50.0 mg, or about 75.0 mg. In a specific embodiment, the pharmaceutical composition comprises an orally available tianeptine sulfate at a dose of about 25.0 mg, about 50.0 mg, or about 75.0 mg. In another embodiment, a daily dosage of a pharmaceutical composition comprising tianeptine sulfate comprises up to no more than 100.0 mg of tianeptine.

本發明的一些具體實施例中，每日劑量形式包括噻萘普汀硫酸鹽，劑量約30.0毫克至約200.0毫克，約30.0毫克至約150.0毫克，約30.0毫克至100.0毫克，或約30.0毫克至60.0毫克左右。在一個特定的具體實施例，於組合物中的噻萘普汀硫酸鹽為噻萘普汀單水半硫酸鹽。在本文所述的劑量為噻萘普汀自由鹼的劑量，不包括相對離子(如硫酸)或任何水或溶劑分子的重量。In some embodiments of the invention, the daily dosage form comprises tianeptine sulfate, at a dose of from about 30.0 mg to about 200.0 mg, from about 30.0 mg to about 150.0 mg, from about 30.0 mg to 100.0 mg, or from about 30.0 mg to About 60.0 mg. In a specific embodiment, the tianeptine sulfate in the composition is tianeptine monohydrate hemisulfate. The dosages described herein are doses of tianeptine free base, excluding the weight of relative ions (such as sulfuric acid) or any water or solvent molecules.

於本發明的另一具體實施例，一醫藥組合物，包括口服的噻萘普汀硫酸鹽，必要劑量約30.0毫克至約200.0毫克，約30.0毫克至約150.0毫克，約30.0毫克至約100.0毫克，約30.0毫克至60.0毫克左右的噻萘普汀。例如，約30.0毫克，60.0毫克左右，約100.0毫克。在特定的具體實施例，藥品成分包括可口服的噻萘普汀硫酸鹽，劑量約為30.0毫克，約60.0毫克，約100.0毫克。在另一具體實施例，每日劑量的醫藥組合物，包括噻萘普汀硫酸鹽，其包括最多不超過100.0毫克的噻萘普汀。In another embodiment of the invention, a pharmaceutical composition comprising orally oral tianeptine sulfate, a necessary dose of from about 30.0 mg to about 200.0 mg, from about 30.0 mg to about 150.0 mg, from about 30.0 mg to about 100.0 mg. , about 30.0 mg to 60.0 mg of tianeptine. For example, about 30.0 mg, about 60.0 mg, about 100.0 mg. In a specific embodiment, the pharmaceutical composition comprises an orally available tianeptine sulfate at a dose of about 30.0 mg, about 60.0 mg, and about 100.0 mg. In another embodiment, a daily dosage of a pharmaceutical composition comprising tianeptine sulfate comprises up to no more than 100.0 mg of tianeptine.

在其他的具體實施例，本發明為針對一醫藥組合物其含有於此所述的噻萘普汀硫酸鹽及適合施與哺乳動物用以治療或預防一個或多個於此所述病徵的一個或多個稀釋劑、載體及/或賦形劑。於一些具體實施例中，一醫藥組合物包含噻萘普汀單水半硫酸鹽和醫藥上可接受的載體。在一些具體實施例中，醫藥組合為是控制釋放藥物組合物。在一個具體實施例中，一個噻萘普汀硫酸鹽控制釋放藥物組合物比起其他型式的噻萘普汀醫藥組合物，需要較少的賦形劑混合複合物。In other specific embodiments, the invention is directed to a pharmaceutical composition comprising the tianeptine sulfate described herein and one suitable for administration to a mammal for treating or preventing one or more of the symptoms described herein. Or a plurality of diluents, carriers and/or excipients. In some embodiments, a pharmaceutical composition comprises tianeptine monohydrate hemisulfate and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical combination is a controlled release pharmaceutical composition. In a specific embodiment, a stanopeptine sulfate controlled release pharmaceutical composition requires less excipient mixed complex than other types of tianeptine pharmaceutical compositions.

本發明的噻萘普汀硫酸鹽還可用於製備上述口服藥物以外的劑型，如局部劑型，注射劑型，穿皮吸收劑型和粘膜劑型。舉例來說，這些形式包括乳霜，乳液，溶液，懸浮液，乳劑，藥膏，粉末，貼片，栓劑等等。The tianeptine sulfate of the present invention can also be used in the preparation of dosage forms other than the above oral drugs, such as topical dosage forms, injectable dosage forms, transdermal absorption dosage forms and mucosal dosage forms. For example, these forms include creams, lotions, solutions, suspensions, emulsions, ointments, powders, patches, suppositories, and the like.

在其他的具體實施例，本發明係針對一個控制釋放錠劑，包括醫藥學上有效量的噻萘普汀硫酸鹽，特別是噻萘普汀單水半硫酸鹽，以及一個或多個控制釋放的聚合物，其中當施予病人口服錠劑時，可提供了一平均最高血漿濃度(C_max )的噻萘普汀約100ng/ml到150ng/ml。在一些具體實施例，其中當施予病人口服錠劑時，可提供了一平均最高血漿濃度(C_max )的噻萘普汀約100ng/ml到120ng/ml。錠劑可以包括25毫克劑量的噻萘普汀。In other embodiments, the present invention is directed to a controlled release lozenge comprising a pharmaceutically effective amount of tianeptine sulfate, particularly tianeptine monohydrate hemisulfate, and one or more controlled release A polymer wherein an average oral plasma concentration ( _Cmax ) of tianeptine is provided from about 100 ng/ml to 150 ng/ml when administered to a patient. In some embodiments, wherein an average oral plasma concentration ( _Cmax ) of tianeptine is provided from about 100 ng/ml to 120 ng/ml when administered to a patient. Tablets may include a 25 mg dose of tianeptine.

在一些具體實施例，當使用美國藥典溶解儀器第II型(槳型)，以100rpm於900毫升的模擬胃液，(pH值約1.2)37℃下，測試控釋錠劑於體外溶出度，一小時後釋放少於14%噻萘普汀單水半硫酸鹽，七小時後釋放了介於在45%至80%的，噻萘普汀單水半硫酸鹽，並在16小時候，釋放了超過90%的噻萘普汀單水半硫酸鹽以重量計算。In some embodiments, when the U.S. Pharmacopeia Dissolution Apparatus Type II (paddle type) is used, the controlled release lozenge is tested for dissolution in vitro at 100 rpm in 900 ml of simulated gastric fluid (pH about 1.2) at 37 °C. After less than 14% release of tianeptine monohydrate hemisulfate, after 7 hours released between 45% and 80% of tianeptine monohydrate hemisulfate, and at 16 hours, released more than 90% of tianeptine monohydrate hemisulfate is calculated by weight.

在其他具體實施例中，當以美國藥典溶解儀器第II型(槳型)在900mL的擬胃液(pH約1.2)中，在約37℃ 100rpm下，低於重量20%之噻萘普汀單水半硫酸鹽在2小時後釋放，約重量50%-80%之噻萘普汀單水半硫酸鹽在8小時後釋放，在14小時後，大於重量90%之噻萘普汀單水半硫酸鹽釋放出來。In other embodiments, when the U.S. Pharmacopeia Dissolution Apparatus Type II (paddle type) is in 900 mL of the gastric fluid (pH about 1.2), at about 37 ° C, 100 rpm, less than 20% by weight of tianeptine Water hemisulfate is released after 2 hours, about 50%-80% by weight of tianeptine monohydrate hemisulfate is released after 8 hours, after 14 hours, more than 90% by weight of tianeptine monohydrate half Sulfate is released.

在一些具體實施例中，當病人口服該錠劑，該錠劑可提供噻萘普汀之平均最大血漿濃度(T_max )的中位數時間約為2.5到3小時間。在具體實施例中，當病人口服該錠劑，該錠劑提供血漿濃度時間曲線之曲線下平均面積約為1170到1380ng.hr/mL。該錠劑包含25mg劑量之噻萘普汀。In some embodiments, when the patient takes the tablet orally, the tablet provides a median time to mean average plasma concentration ( _Tmax ) of tianeptine of about 2.5 to 3 hours. In a particular embodiment, when the patient orally takes the tablet, the tablet provides an average area under the curve of the plasma concentration time curve of about 1170 to 1380 ng.hr/mL. The tablet contains a 25 mg dose of tianeptine.

在一些具體實施例，內含在錠劑中之一種或多種控制釋放聚合物，其包含纖維素聚合物，如：羥丙甲基纖維素，但不限於此種。更進一步，一種或多種控制釋放聚合物包含：第一種具有黏度80到120cps(2%水溶液)之羥丙甲基纖維素，以及第二種具有黏度3,000到5,600cps(2%水溶液)之羥丙甲基纖維素。在具體實施例中，第一種與第二種羥丙甲基纖維素之比例約為2:1到4:1。In some embodiments, one or more controlled release polymers are included in the tablet comprising a cellulosic polymer such as, but not limited to, hydroxypropylmethylcellulose. Further, the one or more controlled release polymers comprise: a first hydroxypropylmethylcellulose having a viscosity of 80 to 120 cps (2% aqueous solution) and a second hydroxy having a viscosity of 3,000 to 5,600 cps (2% aqueous solution) Propyl methyl cellulose. In a particular embodiment, the ratio of the first to the second hydroxypropylmethylcellulose is from about 2:1 to about 4:1.

在一些具體實施例中，控制釋放基質錠劑更包含一種填充劑，如：微晶型纖維素該錠劑更包含一種賦形劑，如：硬脂酸鎂。在具體實施例中，該錠劑更包含矽酸膠。In some embodiments, the controlled release matrix tablet further comprises a filler such as microcrystalline cellulose. The tablet further comprises an excipient such as magnesium stearate. In a particular embodiment, the tablet further comprises a phthalic acid gel.

本發明之噻萘普汀硫酸鹽類型可以數據之資料為特徵，如：TGA、DSV、DVA、單晶X射線繞射儀數據或任何一種、任何兩種、任何三種、任何四種、任何五種、任何六種、任何七種、任何八種、任何九種、任何十種或任何PXRD-2θ角峰之單整數或任何以上所述所需之數據分析技術之任何組合。The type of tianeptine sulfate of the present invention can be characterized by data such as: TGA, DSV, DVA, single crystal X-ray diffractometer data or any one, any two, any three, any four, any Any combination of five, any six, any seven, any eight, any nine, any ten or any PXRD-2 theta peak or any combination of any of the above required data analysis techniques.

本發明亦關於一種新穎噻萘普汀鹽酸鹽。噻萘普汀鹽酸鹽之特性可被改善為一種或多種已知之噻萘普汀形式，如：噻萘普汀鈉游離鹼或噻萘普汀鈉(目前噻萘普汀可得之形式)。鹽酸鹽可包含但不限於以下幾種形式：水合物與溶劑合物，以及數種不同離子化噻萘普汀與氯相對離子之化學當量比率。本發明亦包含其他噻萘普汀鹽酸鹽之類型，如：多形體、共晶體與不定形體，但不限於以上幾種。本發明亦提供包含此類化合物之新穎醫藥組合物、製備此類化合物之方法與相關治療方法。The invention also relates to a novel tianeptine hydrochloride. The properties of tianeptine hydrochloride can be improved to one or more known forms of tianeptine, such as tianeptine sodium free base or tianeptine sodium (currently available in tianeptine) . Hydrochloride salts can include, but are not limited to, the following forms: hydrates and solvates, and the stoichiometric ratio of several different ionized tianeptine to chlorine counterions. The invention also encompasses other types of tianeptine hydrochloride, such as polymorphs, co-crystals and amorphous bodies, but is not limited to the above. The invention also provides novel pharmaceutical compositions comprising such compounds, methods of making such compounds, and related methods of treatment.

在具體施例中，本發明包含噻萘普汀鹽酸鹽。In a particular embodiment, the invention comprises tianeptine hydrochloride.

在進一步之具體實施例中，噻萘普汀鹽酸鹽可併入一個醫藥組合物中。在進一步之具體實施例中，噻萘普汀鹽酸鹽可併入一個控制釋放之醫藥組合物。In a further embodiment, tianeptine hydrochloride can be incorporated into a pharmaceutical composition. In further embodiments, tianeptine hydrochloride can be incorporated into a controlled release pharmaceutical composition.

在另一具體實施例中，噻萘普汀鹽酸鹽可併入一個包含兩層或多層噻萘普汀鹽酸鹽之醫藥組合物，使得在生物體內其中一層較另一層先釋放。在另一具體實施例中，噻萘普汀鹽酸鹽可併入一個醫藥組合物中，其為片狀，且具有不同包衣之範圍與成分，以使得噻萘普汀釋放之時間可較目前取得之噻萘普汀(如：STABLON)之釋放時間更長。In another embodiment, tianeptine hydrochloride can be incorporated into a pharmaceutical composition comprising two or more layers of tianeptine hydrochloride such that one of the layers is released prior to the other in the living body. In another embodiment, tianeptine hydrochloride can be incorporated into a pharmaceutical composition which is in the form of a tablet and has a range and composition of different coatings such that the release time of tianeptine can be compared Currently obtained tianeptine (eg: STABLON) ) The release time is longer.

在另一具體實施例中，噻萘普汀鹽酸鹽可併入一個適合口服之滲透性活性之醫藥組合物。滲透性活性之醫藥組合物、滲透泵、滲透藥物、滲透藥物釋放與其他適合口服之滲透技術可包含但不限於OROSPush-Pull與OROS三層醫藥組合物。在另一具體實施例中，噻萘普汀鹽酸鹽可併入一個OROS藥物釋放系統中。這種包含噻萘普汀鹽酸鹽的控制釋放醫藥組合物，如適合口服之滲透性活性的醫藥組合物，其治療效果可較目前銷售之噻萘普汀鈉鹽更為持久。In another embodiment, tianeptine hydrochloride can be incorporated into a pharmaceutical composition suitable for oral osmotic activity. Permeable active pharmaceutical compositions, osmotic pumps, osmotic drugs, osmotic drug release and other suitable oral permeation techniques may include, but are not limited to, OROS Push-Pull and OROS Three-layer pharmaceutical composition. In another specific embodiment, tianeptine hydrochloride can be incorporated into an OROS In the drug delivery system. Such controlled release pharmaceutical compositions comprising tianeptine hydrochloride, such as pharmaceutical compositions suitable for oral osmotic activity, are more durable than the currently sold tianeptine sodium salt.

在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為7.23度時包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為9.91度時包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為14.53度時包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為7.23度與9.91度時各包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為9.43度與14.53度時各包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為7.23度與10.53度時各包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為7.23度、9.91度與14.53度時各包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為9.43度、10.53度、14.53度與18.35度時各包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為7.23度、9.91度、18.35度、21.39度與23.93度時各包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為9.91度、14.53度、18.35度與21.39度時各包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為7.23度、9.43度、10.53度與18.35度時各包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為9.43度、9.91度、10.53度、14.53度與21.39度時各包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為7.23度、10.53度、14.53度、18.35度、21.39度與23.93度時各包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為7.23度、9.43度、9.91度、10.53度、14.53度、18.35度、21.39度與23.93度時各包含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽之PXRD繞射圖與圖5大體上相似。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在DSC溫度記錄圖中，其在約199℃包含一個吸熱轉移。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽之DSC溫度記錄圖與圖6大體上相似。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽之TGA溫度記錄圖與圖7大體上相似。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽在之動力蒸氣吸附(DVS)特性與圖8大體上相似。In another specific embodiment, the invention comprises tianeptine hydrochloride. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt comprises a wave front at a 2-theta of about 7.23 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt comprises a wave front at a 2-theta of about 9.91 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt comprises a wave front at a 2-theta of about 14.53 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt comprises a wave front at a 2-axis of about 7.23 degrees and 9.91 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt comprises a wave front in each of 2-theta at about 9.43 degrees and 14.53 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt comprises a wave front in each of the 2-theta at about 7.23 degrees and 10.53 degrees in the PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride comprises a wave in the PXRD diffraction pattern at a time of 2-theta of about 7.23 degrees, 9.91 degrees, and 14.53 degrees. Front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is in a PXRD diffraction pattern at a time of 2-theta of about 9.43 degrees, 10.53 degrees, 14.53 degrees, and 18.35 degrees. Contains a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt in the PXRD diffraction pattern is at about 2.23 degrees, 9.91 degrees, 18.35 degrees, 21.39 degrees, and 23.93 at 2-theta. Each time contains a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is in a PXRD diffraction pattern at a time of 2-theta of about 9.91 degrees, 14.53 degrees, 18.35 degrees, and 21.39 degrees. Contains a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is in a PXRD diffraction pattern at a time of 2-theta of about 7.23 degrees, 9.43 degrees, 10.53 degrees, and 18.35 degrees. Contains a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt in the PXRD diffraction pattern is about 9.43 degrees, 9.91 degrees, 10.53 degrees, 14.53 degrees, and 21.39 at 2-theta. Each time contains a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt in the PXRD diffraction pattern is at about 2.23 degrees, 10.53 degrees, 14.53 degrees, 18.35 degrees, 21.39 at 2-theta. The degree and the 23.93 degrees each contain a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt in the PXRD diffraction pattern is at about 2.23 degrees, 9.43 degrees, 9.91 degrees, 10.53 degrees, 14.53 at 2-theta. Degrees, 18.35 degrees, 21.39 degrees and 23.93 degrees each contain a wave front. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the PXRD diffraction pattern of the hydrochloride salt is substantially similar to that of Figure 5. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is in a DSC thermogram comprising an endothermic transfer at about 199 °C. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the DSC thermogram of the hydrochloride salt is substantially similar to that of Figure 6. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the TGA thermogram of the hydrochloride salt is substantially similar to that of Figure 7. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrous adsorption (DVS) characteristic of the hydrochloride salt is substantially similar to that of FIG.

在另一具體實施例中，噻萘普汀鹽酸鹽併入一個控制釋放之醫藥組合物。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽為防溼的。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽為防溼的，其相對濕度約10%到90%。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽為防溼的，其相對濕度約20%到80%。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽為防溼的，其相對濕度約30%到70%。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽為完全穩定的。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽為完全穩定的，其相對濕度約10%到90%。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽為完全穩定的，其相對濕度約20%到80%。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽，其中該鹽酸鹽為完全穩定的，其相對濕度約30%到70%。In another specific embodiment, tianeptine hydrochloride is incorporated into a controlled release pharmaceutical composition. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is moisture resistant. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is moisture resistant and has a relative humidity of from about 10% to about 90%. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is moisture resistant and has a relative humidity of from about 20% to about 80%. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is moisture resistant and has a relative humidity of from about 30% to about 70%. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is completely stable. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is fully stable and has a relative humidity of from about 10% to about 90%. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is fully stable and has a relative humidity of from about 20% to about 80%. In another embodiment, the invention comprises tianeptine hydrochloride, wherein the hydrochloride salt is fully stable and has a relative humidity of from about 30% to about 70%.

依據本發明所述，噻萘普汀鹽酸鹽可具有不同的離子化噻萘普汀(陽離子)對氯相對離子(陰離子)之化學當量比率。例如：陽離子：陰離子之比例約為1：1或2：1。According to the present invention, tianeptine hydrochloride may have a different stoichiometric ratio of ionized tianeptine (cation) to chlorine counter ion (anion). For example: the ratio of cation: anion is about 1:1 or 2:1.

本發明亦包括其他之化學量比率。在另一具體實施例中，本發明包含噻萘普汀鹽酸鹽及其製造與使用。在另一具體實施例中，本發明包含一種噻萘普汀鹽酸鹽之水合物。在另一具體實施例中，本發明包含一種噻萘普汀鹽酸鹽之溶劑合物。在另一具體實施例中，本發明包含一種或多種噻萘普汀鹽酸鹽之多形體或一種或多種噻萘普汀鹽酸鹽的水合物或溶劑合物之多形體。在另一具體實施例中，本發明包含一種噻萘普汀鹽酸鹽之共晶體。在另一具體實施例中，本發明包含一種噻萘普汀鹽酸鹽之非定型體及其製造與使用之方法。在另一具體實施例中，噻萘普汀鹽酸鹽類可為如無水形式或溶劑合物形式，但不限於以上形式。該水合或溶劑合物之形式具有不同之離子化噻萘普汀對水或溶劑合物分子之化學當量比率，約如：1：1、1：1.5、2：1或1：2，但不限於以上比例。The invention also includes other chemical amount ratios. In another embodiment, the invention comprises tianeptine hydrochloride and its manufacture and use. In another embodiment, the invention comprises a hydrate of tianeptine hydrochloride. In another embodiment, the invention comprises a solvate of tianeptine hydrochloride. In another embodiment, the invention comprises one or more polymorphs of tianeptine hydrochloride or a hydrate or solvate polymorph of one or more tianeptine hydrochloride. In another embodiment, the invention comprises a co-crystal of tianeptine hydrochloride. In another embodiment, the invention comprises a non-shaped form of tianeptine hydrochloride and a method of making and using same. In another specific embodiment, the tianeptine hydrochloride salt may be in the form of, for example, an anhydrous form or a solvate, but is not limited to the above form. The hydrated or solvated form has a stoichiometric ratio of different ionized tianeptine to water or solvate molecules, such as: 1:1, 1:1.5, 2:1 or 1:2, but not Limited to the above ratio.

在另一具體實施例中，本發明提供一種製造噻萘普汀鹽酸鹽之方法，其包含：In another embodiment, the invention provides a method of making narnatine hydrochloride comprising:

(c)提供噻萘普汀或其鈉鹽；以及(c) providing tianeptine or a sodium salt thereof;

(d)將該噻萘普汀或其鈉鹽接觸鹽酸，以使該噻萘普汀鹽酸鹽結晶。(d) contacting the tianeptine or a sodium salt thereof with hydrochloric acid to crystallize the tianeptine hydrochloride.

在一特定實施例中，該噻萘普汀為鈉鹽形式。在另一實施例中，在鹽酸處理前，先加入一種溶劑至該噻萘普汀或其鈉鹽中。在另一實施例中，步驟(b)為在溶劑存在下完成，使得一種溶液在鹽酸鹽結晶前形成。在另一實施例中，步驟(b)為在溶劑存在下完成，使得一種懸浮液在鹽酸鹽結晶前形成。在某些實施例中，一種溶劑係選自於以下群組，其包含：丙酮、乙醇、硝甲烷、甲醇、乙腈、二氯甲烷、水與四氫呋喃(THF)。在另一實施例中，一種溶劑包含一種任兩種或多種溶劑之混合物，其包含但不限於丙酮、乙醇、硝甲烷、甲醇、乙腈、二氯甲烷、水與四氫呋喃。In a particular embodiment, the tianeptine is in the form of a sodium salt. In another embodiment, a solvent is added to the tianeptine or its sodium salt prior to the hydrochloric acid treatment. In another embodiment, step (b) is carried out in the presence of a solvent such that a solution is formed prior to crystallization of the hydrochloride salt. In another embodiment, step (b) is carried out in the presence of a solvent such that a suspension is formed prior to crystallization of the hydrochloride salt. In certain embodiments, a solvent is selected from the group consisting of acetone, ethanol, methyl nitrate, methanol, acetonitrile, dichloromethane, water, and tetrahydrofuran (THF). In another embodiment, a solvent comprises a mixture of any two or more solvents including, but not limited to, acetone, ethanol, methyl nitrate, methanol, acetonitrile, dichloromethane, water, and tetrahydrofuran.

噻萘普汀自由鹼與噻萘普汀鈉可以一種或多種此領域之方法製備，包含但不限於美國專利第3,758,528號中之方法。The tianeptine free base and tianeptine sodium can be prepared by one or more methods in the art, including, but not limited to, the method of U.S. Patent No. 3,758,528.

在本發明之具體實施例中，哺乳類口服一調整哺乳類生理機能與/或治療哺乳類之有效量的噻萘普汀鹽酸鹽。在劑量部分，口服之噻萘普汀鹽酸鹽，其劑量足以影響哺乳類的生理機能與/或治療的調節。In a particular embodiment of the invention, the mammal is orally administered with an effective amount of tianeptine hydrochloride which modulates the physiological function of the mammal and/or treats the mammal. In the dosage portion, oral tianeptine hydrochloride is administered at a dose sufficient to affect the modulation of physiological functions and/or treatment of the mammal.

在另一實施例中，提供一種治療罹患抑鬱症的哺乳類之方法，其包含給該哺乳類服用一個有效劑量之噻萘普汀鹽酸鹽。在另一實施例中，提供一種治療罹患剌激性腸症候群的哺乳類之方法，其包含給該哺乳類服用一個有效劑量之噻萘普汀鹽酸鹽。在另一實施例中，提供一種治療罹患注意力不足過動症的哺乳類之方法，其包含給該哺乳類服用一個有效劑量之噻萘普汀鹽酸鹽。在另一實施例中，提供一種治療罹患氣喘的哺乳類之方法，其包含給該哺乳類服用一個有效劑量之噻萘普汀鹽酸鹽。在另一實施例中，該哺乳類為人類。In another embodiment, a method of treating a mammal suffering from depression comprising administering to the mammal an effective amount of tianeptine hydrochloride is provided. In another embodiment, a method of treating a mammal suffering from irritable bowel syndrome comprising administering to the mammal an effective amount of tianeptine hydrochloride is provided. In another embodiment, a method of treating a mammal suffering from attention deficit hyperactivity disorder comprising administering to the mammal an effective amount of tianeptine hydrochloride is provided. In another embodiment, a method of treating a mammal suffering from asthma comprising administering an effective amount of tianeptine hydrochloride to the mammal is provided. In another embodiment, the mammal is a human.

在另一實施例中，本發明包含一種包含噻萘普汀鹽酸鹽之藥劑的製備。該藥劑可用於治療抑鬱症、剌激性腸症候群、注意力不足過動症或氣喘，並用於需要該治療之哺乳類中。在另一實施例中，該哺乳類為人類。In another embodiment, the invention comprises the preparation of a medicament comprising tianeptine hydrochloride. The medicament can be used to treat depression, irritable bowel syndrome, attention deficit hyperactivity disorder or asthma, and is used in mammals in need of such treatment. In another embodiment, the mammal is a human.

噻萘普汀鹽酸鹽之醫藥劑型可以幾種方式服用，其包含但不限於口服。口服醫藥組合物與劑型為示範劑型。口服劑型可視需要為固態劑型，如：錠劑、橢圓形藥錠、硬明膠膠囊、澱粉膠囊、羥丙基甲基纖維素(HPMC)膠囊或軟且彈性的明膠膠囊。本發明亦提供液態劑型，包含但不限於懸浮液、溶液、糖漿或乳劑。The pharmaceutical dosage form of tianeptine hydrochloride can be administered in several ways including, but not limited to, oral. Oral pharmaceutical compositions and dosage forms are exemplary dosage forms. Oral dosage forms may be in the form of solid dosage forms such as lozenges, ellipses, hard gelatin capsules, starch capsules, hydroxypropyl methylcellulose (HPMC) capsules or soft and flexible gelatin capsules. The invention also provides liquid dosage forms including, but not limited to, suspensions, solutions, syrups or emulsions.

噻萘普汀鹽酸鹽以控制或延遲釋放方法服用。釋放控制醫藥產品通常有相同的目標，即藉由其釋放非控制的對應體部分來改善藥物的治療。在醫藥治療中，一種理想設計的釋放控制製備之特點為使用最少的API(活性醫藥成分)物質治療或控制病情，且在最短的時間內達成釋放控制醫藥組合物之優點通常包括：(1)API活性之延遲；(2)降低服藥次數；(3)增加病人之順應性；(4)總API使用較少；(5)降低局部或全身性的副作用；(6)減少API的累積；(7)減少血中濃度之波動；(8)改善治療之效力；(9)減少API活性之相乘作用或損失；與(10)改善疾病或狀態控制的速度(Kim,Cherng-ju,Controlled Release Dosage Form Design,2 Technomic Publishing,Lancaster,Pa.: 2000)。The tianeptine hydrochloride is administered as a controlled or delayed release method. Release Control Pharmaceutical products generally have the same goal of improving the treatment of drugs by releasing uncontrolled counterpart portions. In medical treatment, an ideally designed release control preparation is characterized by the use of minimal API (active pharmaceutical ingredient) substances to treat or control the condition, and the advantages of achieving release control pharmaceutical compositions in the shortest time usually include: (1) Delay in API activity; (2) reduce the number of doses; (3) increase patient compliance; (4) use less total API; (5) reduce local or systemic side effects; (6) reduce API accumulation; 7) reduce fluctuations in blood concentration; (8) improve the efficacy of treatment; (9) reduce the multiplication or loss of API activity; and (10) improve the speed of disease or state control (Kim, Cherng-ju, Controlled Release) Dosage Form Design, 2 Technomic Publishing, Lancaster, Pa.: 2000).

本發明之代表性每日劑量為約包含10.0mg到50.0mg、12.5mg到37.5mg或25.0mg到37.5mg之噻萘普汀鹽酸鹽。本發明所述之劑量表示噻萘普汀自由鹼之劑量，並不包含相對離子(如：氯)或任何水與溶劑分子之重量。A representative daily dose of the invention is about 10.0 mg to 50.0 mg, 12.5 mg to 37.5 mg or 25.0 mg to 37.5 mg of tianeptine hydrochloride. The doses described herein represent the dose of tianeptine free base and do not contain relative ions (e.g., chlorine) or any weight of water and solvent molecules.

在本發明之另一具體實施例中，給予口服所需劑量的一種含噻萘普汀鹽酸鹽的醫藥組合物，其劑量約為從10.0mg到50.0mg、12.5mg到50.0mg、25.0mg到50.0mg或37.5mg到50mg之噻萘普汀。例如：約12.5mg，25.0mg或37.5mg。在特定實施例中，可以給予口服包含噻萘普汀鹽酸鹽的醫藥組合物約25.0mg或37.5mg。該劑量可單次或分次投予。在本發明之另一具體實施例中，包含噻萘普汀鹽酸鹽之醫藥組合物的每日劑量最高約為50.0mg的噻萘普汀。在另一具體實施例中，本發明係關於包含如本文所述之噻萘普汀鹽酸鹽的組合物，以及適合哺乳類口服之一種或多種稀釋劑、載體與/或賦形劑，以治療或預防一種或多種本文所述之狀態。在具體實施例中，噻萘普汀鹽酸鹽之釋放控制醫藥組合物與其他含噻萘普汀不同形式的醫藥組合物相比，其需要一較不複雜之賦形劑混合物。In another embodiment of the present invention, a pharmaceutical composition comprising tianeptine hydrochloride in a dose required for oral administration is administered at a dose of from about 10.0 mg to 50.0 mg, from 12.5 mg to 50.0 mg, and from 25.0 mg. To 50.0 mg or 37.5 mg to 50 mg of tianeptine. For example: about 12.5 mg, 25.0 mg or 37.5 mg. In a particular embodiment, a pharmaceutical composition comprising narnatine hydrochloride can be administered orally in an amount of about 25.0 mg or 37.5 mg. This dose can be administered in a single or divided dose. In another embodiment of the invention, the daily dose of the pharmaceutical composition comprising tianeptine hydrochloride is about 50.0 mg of tianeptine. In another embodiment, the invention relates to a composition comprising tianeptine hydrochloride as described herein, and one or more diluents, carriers and/or excipients suitable for oral administration to mammals for treatment Or preventing one or more of the conditions described herein. In a particular embodiment, the release control pharmaceutical composition of tianeptine hydrochloride requires a less complex mixture of excipients than other pharmaceutical compositions containing different forms of tianeptine.

本發明之噻萘普汀鹽酸鹽除了上述之口服劑型，亦可用於製備其他醫藥劑型，如：局部劑型、非口服劑型、經皮劑型與黏膜劑型。該劑型舉例如下：乳油、洗劑、溶液、懸浮液、乳液、軟膏、粉末、貼劑與栓劑等。The tianeptine hydrochloride of the present invention can be used for the preparation of other pharmaceutical dosage forms in addition to the above oral dosage forms, such as topical dosage forms, parenteral dosage forms, transdermal dosage forms and mucosal dosage forms. Examples of such dosage forms are as follows: emulsifiable concentrates, lotions, solutions, suspensions, lotions, ointments, powders, patches, suppositories, and the like.

本發明之噻萘普汀硫酸鹽類型可以數據之資料為特徵，如：TGA、DSV、DVA、單晶X射線繞射儀數據或任何一種、任何兩種、任何三種、任何四種、任何五種、任何六種、任何七種、任何八種、任何九種、任何十種或任何PXRD-2θ角峰之單整數與任何以上所述所需之數據分析技術之任何組合。The type of tianeptine sulfate of the present invention can be characterized by data such as: TGA, DSV, DVA, single crystal X-ray diffractometer data or any one, any two, any three, any four, any Any combination of five, any six, any seven, any eight, any nine, any ten or any PXRD-2 theta peaks and any of the above required data analysis techniques.

本發明係關於一種新穎之噻萘普汀磷酸鹽。相較於一種或多種已知之噻萘普汀類型，可改良噻萘普汀磷酸鹽之特性，如：噻萘普汀自由鹼或噻萘普汀鈉(目前噻萘普汀可得之類型)。該磷酸鹽可包含以下幾種類型：水合物與溶劑合物，以及數種不同離子化噻萘普汀與氯相對離子之化學計量比率，但不限於以上幾種本發明亦包含其他噻萘普汀磷酸鹽之類型，其包含但不限於同素異形體、共結晶與非晶型類。本發明亦提供包含此類化合物之新穎醫藥組合物、製備此類化合物之方法與相關治療方法。This invention relates to a novel tianeptine phosphate. Compared to one or more known tianeptine types, the properties of tianeptine phosphate can be improved, such as tianeptine free base or tianeptine sodium (currently available from tianeptine) . The phosphate may comprise the following types: hydrates and solvates, and stoichiometric ratios of several different ionized tianeptine to chlorine counter ions, but are not limited to the above. The invention also includes other tian naproxes. Types of phosphonates, including but not limited to allotropes, co-crystals, and amorphous forms. The invention also provides novel pharmaceutical compositions comprising such compounds, methods of making such compounds, and related methods of treatment.

在具體施例中，本發明包含噻萘普汀磷酸鹽。In a particular embodiment, the invention comprises tianeptine phosphate.

在進一步之具體實施例中，噻萘普汀磷酸鹽可併入一個醫藥組合物中。在進一步之具體實施例中，噻萘普汀磷酸鹽可併入一個釋放控制之醫藥組合物。In further embodiments, tianeptine phosphate can be incorporated into a pharmaceutical composition. In a further embodiment, the tianeptine phosphate can be incorporated into a release controlled pharmaceutical composition.

在另一具體實施例中，噻萘普汀磷酸鹽可併入一個包含兩層或多層噻萘普汀磷酸鹽之醫藥駔合物，在生物體內其中一層較另一層先釋放。在另一具體實施例中，噻萘普汀磷酸鹽可併入一個醫藥組合物中，其為片狀，且具有不同包衣之範圍與成分，以使得噻萘普汀釋放之時間可較目前取得之噻萘普汀(如：STABLON)之釋放時間更長。In another embodiment, the tianeptine phosphate can be incorporated into a pharmaceutical composition comprising two or more layers of tianeptine phosphate in which one layer is released prior to the other. In another embodiment, the tianeptine phosphate can be incorporated into a pharmaceutical composition that is in the form of a tablet and has a range and composition of different coatings such that the release of tianeptine can be compared to current The tianeptine obtained (eg: STABLON) ) The release time is longer.

在另一具體實施例中，噻萘普汀磷酸鹽可併入一個具滲透活性之醫藥組合物中，其適合口服。滲透性活性之醫藥組合物、滲透泵、滲透藥物、滲透藥物釋放與其他適合口服之滲透技術可包含但不限於OROSPush-Pull與OROS三層醫藥組合物。在另一具體實施例中，噻萘普汀磷酸鹽可併入一個OROS藥物釋放系統中。包含噻萘普汀磷酸鹽的控制釋放醫藥組合物，如：適合口服之具滲透活性的醫藥組合物，使其治療效果可較目前銷售之噻萘普汀鈉鹽更為持久。In another embodiment, the tianeptine phosphate can be incorporated into an osmotically active pharmaceutical composition suitable for oral administration. Permeable active pharmaceutical compositions, osmotic pumps, osmotic drugs, osmotic drug release and other suitable oral permeation techniques may include, but are not limited to, OROS Push-Pull and OROS Three-layer pharmaceutical composition. In another embodiment, the tianeptine phosphate can be incorporated into an OROS In the drug delivery system. A controlled release pharmaceutical composition comprising tianeptine phosphate, such as an osmotically active pharmaceutical composition suitable for oral administration, provides a longer lasting therapeutic effect than the currently sold tianeptine sodium salt.

在另一具體實施例中，本發明包含噻萘普汀磷酸鹽。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為6.83度時含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為9.27度時含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為11.95度時含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為6.83度與9.27度時各含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該鹽酸鹽在PXRD繞射圖中，在2-θ約為11.95度與13.53度時各含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為16.31度與17.35度時各含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為6.83度、11.95度與13.53度時各含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為16.31度、17.35度、18.47度與20.93度時各含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為6.83度、9.27度、11.95度、13.53度與16.31度時各含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為20.93度、21.49度、22.77度與23.67度時各含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為6.83度、13.83度、17.35度與18.47度時各含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為9.27度、11.95度、13.53度、16.31度與18.47度時各含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為6.83度、11.95度、16.31度、17.35度、20.93度與22.77度時各含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在PXRD繞射圖中，在2-θ約為6.83度、9.27度、11.95度、13.53度、13.83度、15.93度、16.31度、17.35度、18.47度、20.93度、21.49度、22.77度與23.67度時各含一個波鋒。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽之PXRD繞射圖與圖9大體上相似。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在DSC溫度記錄圖中，其在約211℃包含一個吸熱轉移。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽之DSC溫度記錄圖與圖10大體上相似。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽之TGA溫度記錄圖與圖11大體上相似。在另一具體實施例中，本發明包含噻萘普汀磷酸鹽，其中該磷酸鹽在之動力蒸氣吸附(DVS)特性與圖12大體上相似。In another embodiment, the invention comprises tianeptine phosphate. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate contains a wave front at a 2-axis of about 6.83 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine phosphate wherein the phosphate contains a wave front at a 2-axis of about 9.27 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate comprises a wave front at a 2-axis of about 11.95 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate comprises a wave front at a 2-axis of about 6.83 degrees and 9.27 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine phosphate, wherein the hydrochloride salt has a wave front in the PXRD diffraction pattern at 2-theta of about 11.95 degrees and 13.53 degrees. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate comprises a wave front in the PXRD diffraction pattern at 2-theta of about 16.31 degrees and 17.35 degrees. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate comprises a wave front at each of 2-theta at about 6.83 degrees, 11.95 degrees, and 13.53 degrees in a PXRD diffraction pattern. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate comprises one in each of the 2-theta at about 16.31 degrees, 17.35 degrees, 18.47 degrees, and 20.93 degrees in the PXRD diffraction pattern. Wave front. In another embodiment, the invention comprises tianeptine phosphate wherein the phosphate is in the PXRD diffraction pattern at about 2.83 degrees, 9.27 degrees, 11.95 degrees, 13.53 degrees, and 16.31 degrees at 2-theta. Each contains a wave front. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate comprises one in each of the 2-theta at about 20.93 degrees, 21.49 degrees, 22.77 degrees, and 23.67 degrees in the PXRD diffraction pattern. Wave front. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate comprises one in each of the 2-theta at about 6.83 degrees, 13.83 degrees, 17.35 degrees, and 18.47 degrees in the PXRD diffraction pattern. Wave front. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate is in the PXRD diffraction pattern at a time of 2-theta of about 9.27 degrees, 11.95 degrees, 13.53 degrees, 16.31 degrees, and 18.47 degrees. Each contains a wave front. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate is in the PXRD diffraction pattern at about 2.83 degrees, 11.95 degrees, 16.31 degrees, 17.35 degrees, 20.93 degrees at 2-theta At 22.77 degrees each contains a wave front. In another embodiment, the invention comprises tianeptine phosphate, wherein the phosphate is in the PXRD diffraction pattern at about 2.83 degrees, 9.27 degrees, 11.95 degrees, 13.53 degrees, 13.83 degrees at 2-theta, 15.93 degrees, 16.31 degrees, 17.35 degrees, 18.47 degrees, 20.93 degrees, 21.49 degrees, 22.77 degrees and 23.67 degrees each contain a wave front. In another embodiment, the invention comprises tianeptine phosphate, wherein the PXRD diffraction pattern of the phosphate is substantially similar to that of FIG. In another embodiment, the invention comprises tianeptine phosphate wherein the phosphate comprises an endothermic transfer at about 211 ° C in a DSC thermogram. In another embodiment, the invention comprises tianeptine phosphate wherein the DSC temperature record of the phosphate is substantially similar to that of FIG. In another embodiment, the invention comprises tianeptine phosphate, wherein the TGA temperature record of the phosphate is substantially similar to that of FIG. In another embodiment, the invention comprises tianeptine phosphate wherein the phosphate has a dynamic vapor sorption (DVS) characteristic substantially similar to that of FIG.

在另一具體實施例中，噻萘普汀磷酸鹽併入一個控制釋放之醫藥組合物。在另一項具體實施例，本發明包括一個噻萘普汀磷酸鹽，其中磷酸鹽是完全穩定的。在另一具體實施例，本發明包括一個噻萘普汀磷酸鹽，其中磷酸鹽在約10%左右的相對濕度到約90%左右的相對濕度下是完全穩定的。在另一項具體實施例，本發明包括一個噻萘普汀磷酸鹽，其中磷酸鹽在約20%左右的相對濕度到約80%左右的相對濕度下是完全穩定的。在另一項具體實施例，本發明包括一個噻萘普汀磷酸鹽，其中磷酸鹽在約30%左右的相對濕度到約70%左右的相對濕度下是完全穩定的。In another specific embodiment, the tianeptine phosphate is incorporated into a controlled release pharmaceutical composition. In another embodiment, the invention includes a tianeptine phosphate wherein the phosphate is fully stable. In another embodiment, the invention includes a tianeptine phosphate wherein the phosphate is fully stable at a relative humidity of from about 10% to about 90% relative humidity. In another embodiment, the invention includes a tianeptine phosphate wherein the phosphate is fully stable at a relative humidity of from about 20% to about 80% relative humidity. In another embodiment, the invention includes a tianeptine phosphate wherein the phosphate is completely stable at a relative humidity of from about 30% to about 70% relative humidity.

根據本發明，噻萘普汀磷酸鹽可有不同的離子化噻萘普汀(陽離子)對磷酸鹽相對離子(陰離子)的化學當量比。陽離子：負離子的比率可為1:1或2:1。其他的當量比率也包括於本發明中。According to the present invention, tianeptine phosphate may have a different stoichiometric ratio of ionized tianeptine (cation) to phosphate relative ion (anion). Cation: The ratio of negative ions can be 1:1 or 2:1. Other equivalent ratios are also included in the present invention.

在另一項具體實施例，本發明包括噻萘普汀磷酸鹽及其製備與使用的方法。在另一項具體實施例中，本發明包括了噻萘普汀磷酸鹽的水合物及其製備與使用的方法。在另一具體實施例中，本發明包括了的噻萘普汀磷酸鹽的溶劑合物。在另一項具體實施例，本發明由一個或多個噻萘普汀磷酸鹽多形體，或一個或多個多噻萘普汀磷酸鹽水合物或溶劑化物的多形體。在另一具體實施例中，本發明包括噻萘普汀磷酸鹽的共晶體。在另一具體實施例，本發明包括噻萘普汀磷酸鹽之無定形體及其製備與使用的方法。In another embodiment, the invention includes tianeptine phosphate and methods of making and using same. In another specific embodiment, the invention includes hydrates of tianeptine phosphate and methods of making and using same. In another embodiment, the invention includes a solvate of tianeptine phosphate. In another embodiment, the invention consists of one or more tianeptine phosphate polymorphs, or one or more polymorphs of domiodapline phosphate hydrate or solvate. In another embodiment, the invention includes a co-crystal of tianeptine phosphate. In another embodiment, the invention includes an amorphous form of tianeptine phosphate and methods of making and using same.

在另一具體實施例中，一噻萘普汀磷酸鹽形式可以存在於，例如，但不限於，一無水形式，一水合物形式，一脫水形式或一溶劑化物的形式。這種水合物和溶劑化物形式可有不同噻萘普汀離子比上水或溶劑化物分子的化學當量，例如，但不限於約1:1，1:1.5，2:1或1:2。In another embodiment, a tianeptine phosphate form may be present, for example, but not limited to, in the form of an anhydrous form, a monohydrate form, a dehydrated form or a monosolvate. Such hydrate and solvate forms may have different stoichiometric equivalents of the tianeptine ion to the water or solvate molecule, such as, but not limited to, about 1:1, 1:1.5, 2:1 or 1:2.

在另一項具體實施例，本發明提供了一製備噻萘普汀磷酸鹽的方法，包括：In another embodiment, the invention provides a method of preparing tianeptine phosphate, comprising:

(e)提供噻萘普汀或其鈉鹽；及(e) providing tianeptine or a sodium salt thereof;

(f)噻萘普汀或其鈉鹽與磷酸作用，以形成結晶化的噻萘普汀磷酸鹽。(f) The tianeptine or its sodium salt acts with phosphoric acid to form a crystallized tianeptine phosphate.

在一個特定的具體實施例中，其中噻萘普汀的形式為鈉鹽。在另一具體實施例，於加入鹽酸前先將一溶劑添加到噻萘普汀或其鈉鹽中。在另一項具體實施例中，在溶劑存在下完成步驟(b)，使得該磷酸鹽結晶前會形成溶液。在另一項具體實施例中，在溶劑存在下完成步驟(b)，使得該磷酸鹽結晶前會形成懸浮液。在某些具體實施例中，溶劑是選自由：丙酮，乙醇，硝基甲烷，甲醇，乙腈，二氯甲烷，水和四氫呋喃(THF)所組成的群組。在另一具體實施例中，一溶劑可為任何兩個或兩個以上溶劑所形成的混合物，其包括但不限於丙酮，乙醇，硝基甲烷，甲醇，乙腈，二氯甲烷，水和四氫呋喃。In a specific embodiment, wherein the form of tianeptine is a sodium salt. In another embodiment, a solvent is added to the tianeptine or its sodium salt prior to the addition of hydrochloric acid. In another specific embodiment, step (b) is carried out in the presence of a solvent such that the solution forms a solution prior to crystallization of the phosphate. In another specific embodiment, step (b) is carried out in the presence of a solvent such that the phosphate forms a suspension prior to crystallization. In certain embodiments, the solvent is selected from the group consisting of: acetone, ethanol, nitromethane, methanol, acetonitrile, dichloromethane, water, and tetrahydrofuran (THF). In another embodiment, a solvent can be a mixture of any two or more solvents including, but not limited to, acetone, ethanol, nitromethane, methanol, acetonitrile, dichloromethane, water, and tetrahydrofuran.

噻萘普汀自由鹼及噻萘普汀鈉可於技術領域中可獲得的一個或多個方法來製備，其包括但不限於美國專利第3,758,528號的方法。The tianeptine free base and tianeptine sodium can be prepared by one or more methods available in the art including, but not limited to, the method of U.S. Patent No. 3,758,528.

在本發明的一個具體實施例中，一可調節哺乳動物的生理和/或治療哺乳動物有效量的噻萘普汀磷酸鹽被施予至所述哺乳動物。在另一方面，施予足以影響調節哺乳動物的生理和/或治療的有效量噻萘普汀磷酸鹽。In a specific embodiment of the invention, an physiologic and/or therapeutically effective amount of tianeptine phosphate in a mammal is administered to the mammal. In another aspect, an effective amount of tianeptine phosphate is administered sufficient to affect modulating the physiology and/or treatment of the mammal.

在另一具體實施例中，提供一種治療患有抑鬱症之哺乳動物的方法，包括施予所述哺乳動物有效量的噻萘普汀磷酸鹽。在另一具體實施例中，提供了一種治療患有腸躁症之哺乳動物的方法，包括施予所述哺乳動物有效量之噻萘普汀磷酸鹽。在另一具體實施例中，提供了一種治療患有注意力缺陷過動症之哺乳動物的方法，包括施與所述哺乳動物有效量之噻萘普汀磷酸鹽。在另一具體實施例，提供了一種治療患有哮喘之哺乳動物的方法，包括施與所述哺乳動物有效量之噻萘普汀磷酸鹽。在另一項具體實施例，所述之哺乳動物為人類。In another embodiment, a method of treating a mammal suffering from depression comprising administering an effective amount of tianeptine phosphate to the mammal is provided. In another embodiment, a method of treating a mammal suffering from intestinal tract, comprising administering an effective amount of tianeptine phosphate in said mammal, is provided. In another embodiment, a method of treating a mammal having attention deficit hyperactivity disorder comprising administering an effective amount of tianeptine phosphate to the mammal is provided. In another embodiment, a method of treating a mammal having asthma comprising administering an effective amount of tianeptine phosphate to the mammal is provided. In another specific embodiment, the mammal is a human.

本發明之另一具體實施例中，包括了製備一藥劑，包含了噻萘普汀磷酸鹽。這種藥劑可用於需要此種治療的哺乳動物，用以治療抑鬱症，腸躁症，注意力缺陷過動症或哮喘等疾病。在另一項具體實施例，所述哺乳動物是人。In another embodiment of the invention, the preparation of a medicament comprising tianeptine phosphate is included. Such agents are useful in mammals in need of such treatment for the treatment of depression, intestinal cramps, attention deficit hyperactivity disorder or asthma. In another specific embodiment, the mammal is a human.

噻萘普汀磷酸鹽的藥品劑型的可有多種施與的方法，其包括但不限於口服。口服醫藥組合物和劑型為示範劑型。口服劑型可視需要為固體劑型，如錠劑，一易吞錠，一硬膠囊，一澱粉膠囊，一羥丙基甲基纖維素(HPMC)膠囊，或一軟彈性明膠膠囊。本發明也提供了液體劑型，其中包括不做為限制的例子如懸浮液、溶液、糖漿或乳劑。Pharmaceutical dosage forms of tianeptine phosphate may be administered in a variety of ways including, but not limited to, oral. Oral pharmaceutical compositions and dosage forms are exemplary dosage forms. The oral dosage form may be in the form of a solid dosage form such as a tablet, an easy-to-swallow tablet, a hard capsule, a starch capsule, a monohydroxypropyl methylcellulose (HPMC) capsule, or a soft elastic gelatin capsule. The invention also provides liquid dosage forms which include, without limitation, examples such as suspensions, solutions, syrups or emulsions.

噻萘普汀磷酸鹽以控制或延遲釋放的手段來投藥。控釋的醫藥產品通常都具有一改善其非控釋藥物的療效的一般目標。理想情況下，利用視需要設計的控釋製劑在醫療上特點是以最低的API(活性藥物成分)物質釋放於最短的時間內來治癒或控制病情。控釋醫藥組合物的優點一般包括：1)延遲了API的活性；2)減少劑量的頻率；3)提高病人的順應性；4)較少總API的劑量；5)減少局部或全身性的副作用；6)API的積累最小化；7)減少血液濃度的波動；8)改善治療效果；9)降低增強效應或減低API活性；和10)改善控制疾病或徵狀的控制速度。(Kim,Cherng-ju,Controlled Release Dosage Form Design,2 Technomic Publishing,Lancaster,Pa.: 2000)。The tianeptine phosphate is administered by means of controlled or delayed release. Controlled release pharmaceutical products generally have a general goal of improving the efficacy of their non-controlled release drugs. Ideally, the use of controlled release formulations designed as needed is medically characterized by the release of the lowest API (active pharmaceutical ingredient) in the shortest amount of time to cure or control the condition. The advantages of controlled release pharmaceutical compositions generally include: 1) delayed API activity; 2) reduced dose frequency; 3) improved patient compliance; 4) less total API dose; 5) reduced local or systemic Side effects; 6) Minimization of API accumulation; 7) Reduction of fluctuations in blood concentration; 8) Improvement of therapeutic effect; 9) Reduction of enhancement effect or reduction of API activity; and 10) Improvement of control rate of control of disease or symptoms. (Kim, Cherng-ju, Controlled Release Dosage Form Design, 2 Technomic Publishing, Lancaster, Pa.: 2000).

本發明之典型的每日劑量包括噻萘普汀磷酸鹽，其劑量從約10.0mg至50.0mg左右，約12.5mg至37.5mg，或約25.0mg至37.5mg。在本文所述的劑量為噻萘普汀自由鹼的劑量，不包括相對離子(如磷)或任何水或溶劑分子的重量。A typical daily dose of the invention comprises tianeptine phosphate at a dose of from about 10.0 mg to about 50.0 mg, from about 12.5 mg to 37.5 mg, or from about 25.0 mg to 37.5 mg. The doses described herein are doses of tianeptine free base, excluding the weight of relative ions (such as phosphorus) or any water or solvent molecules.

在本發明之另一具體實施例中，給予口服一種包含噻萘普汀磷酸鹽的醫藥組合物，所需劑量由約10.0mg至50.0mg左右，約12.5mg至50.0mg左右，約25.0mg至50.0mg左右，或約37.5mg至50.0mg左右的噻萘普汀。例如，約12.5mg，約25.0mg或約37.5mg。在特定的具體實施例中，藥品成分包括可口服的噻萘普汀磷酸鹽，劑量約為25.0mg或約37.5mg。劑量總額可單一或分次施藥。在另一具體實施例中，每日劑量的醫藥組合物包括噻萘普汀磷酸鹽，其包括最多不超過50.0毫克的噻萘普汀。在其他的具體實施例中，本發明為針對包含本文中所述噻萘普汀磷酸鹽的醫藥組合物，及適合施予哺乳動物用以治療或預防一個或多個於本文中所述病徵的一個或多個稀釋劑、載體及/或賦形劑。在一個具體實施例中，一個噻萘普汀磷酸鹽控制釋放醫藥組合物比起其他型式的噻萘普汀醫藥組合物，需要較不複雜的賦形劑混合物。In another embodiment of the present invention, a pharmaceutical composition comprising tianeptine phosphate is administered orally at a dose of from about 10.0 mg to about 50.0 mg, from about 12.5 mg to about 50.0 mg, and about 25.0 mg to About 70.0 mg, or about 37.5 mg to 50.0 mg of tianeptine. For example, about 12.5 mg, about 25.0 mg or about 37.5 mg. In a particular embodiment, the pharmaceutical composition comprises an orally available tianeptine phosphate at a dose of about 25.0 mg or about 37.5 mg. The total dose can be administered in a single or divided dose. In another specific embodiment, the daily dose of the pharmaceutical composition comprises tianeptine phosphate comprising up to 50.0 mg of tianeptine. In other specific embodiments, the invention is directed to a pharmaceutical composition comprising the tianeptine phosphate described herein, and to a mammal for use in the treatment or prevention of one or more of the conditions described herein. One or more diluents, carriers and/or excipients. In one embodiment, a stanopeptine phosphate controlled release pharmaceutical composition requires a less complex excipient mixture than other types of tianeptine pharmaceutical compositions.

本發明的噻萘普汀硫酸鹽還可用於製備上述口服藥物以外的劑型，如局部劑型，注射劑型，穿皮吸收劑型和粘膜劑型。舉例來說，這些形式包括乳霜，乳液，溶液，懸浮液，乳劑，藥膏，粉末，貼片，栓劑等等。The tianeptine sulfate of the present invention can also be used in the preparation of dosage forms other than the above oral drugs, such as topical dosage forms, injectable dosage forms, transdermal absorption dosage forms and mucosal dosage forms. For example, these forms include creams, lotions, solutions, suspensions, emulsions, ointments, powders, patches, suppositories, and the like.

本發明之噻萘普汀磷酸鹽形式可被表徵為，例如，藉由TGA，DSC，DVS，單晶X-射線繞射儀數據，或藉由任一，任二，任三，任四，任五，任六，任七，任八，任九，任十，或任何單整數之PXRD 2-θ角峰，或藉由任何得自上述分析技術之數據之結合。The tianeptine phosphate form of the present invention can be characterized, for example, by TGA, DSC, DVS, single crystal X-ray diffractometer data, or by any, any two, any three, any four, Any of five, six, seven, eight, nine, ten, or any single integer PXRD 2-theta peak, or a combination of data from any of the above analytical techniques.

雖然本發明已以各方面之具體實施例揭露如下，在不脫離本發明之精神和後附之申請專利範圍內，本發明還能夠多種多樣的進一步具體實施。While the invention has been described in terms of various embodiments, the invention can be embodied in various embodiments without departing from the scope of the invention.

15 STABLON(噻萘普汀鈉)錠劑在一研缽中被杵磨碎，並與15mL之四氫呋喃(THF)混合以萃取噻萘普汀。以震盪和超聲處理來混合這些混合物。以布氏漏斗過濾非溶解成分。自經過濾之乾淨溶液蒸發THF溶劑，再將其餘組成溶解在1.5mL去離子水。添加四當量之硫酸以結晶噻萘普汀半硫酸鹽單水合物。15 STABLON The (tianapeptin sodium) lozenge was mashed in a mortar and mixed with 15 mL of tetrahydrofuran (THF) to extract tianeptine. These mixtures were mixed by shaking and sonication. The non-dissolved components were filtered through a Buchner funnel. The THF solvent was evaporated from the filtered clean solution, and the remaining composition was dissolved in 1.5 mL of deionized water. Four equivalents of sulfuric acid were added to crystallize the tianeptine hemisulfate monohydrate.

在50℃下將噻萘普汀鈉(1054.16克)溶解於醋酸：水(4升)50:50中，以產生一個無色溶液。熱過濾此溶液，並在95℃的情況下於大約三分鐘內加入硫酸(66毫升)。此溶液在95℃的情況下，一小時內會產生結晶狀之噻萘普汀半硫酸鹽單水合物。接著將溫度逐漸調整至104℃，100分鐘，80℃，220分鐘，25℃40分鐘，以及5℃，100分鐘。然後讓混合物於5℃攪拌過夜(約20小時)。過濾固體，並使用醋酸：水50:50(2×1升)，水(3×1升)，丙酮(1×600毫升)洗淨。40℃下乾燥固體在真空中。Sennalpeptin sodium (1054.16 g) was dissolved in acetic acid:water (4 L) at 50:50 at 50 ° C to give a colorless solution. The solution was filtered hot and sulfuric acid (66 mL) was added over approximately three minutes at 95 °C. This solution produced crystalline tianeptine hemisulfate monohydrate in one hour at 95 °C. The temperature was then gradually adjusted to 104 ° C, 100 minutes, 80 ° C, 220 minutes, 25 ° C for 40 minutes, and 5 ° C, 100 minutes. The mixture was then stirred at 5 ° C overnight (about 20 hours). The solid was filtered and washed with acetic acid: water 50: 50 (2 x 1 L), water (3 x 1 L), acetone (1 x 600 mL). The dried solid was dried under vacuum at 40 °C.

在室溫下將噻萘普汀鈉(100克)溶解於異丙醇：水(500毫升)50:50中，以產生一個無色溶液。過濾此溶液，並加入45.4%硫酸溶液(73.2毫升)。當混合物被過濾，此時結晶狀之噻萘普汀半硫酸鹽單水合物在兩個小時內會完全結晶。使用50:50異丙醇：水(500毫升)和水(300毫升)洗淨固體，然後在周圍環境下乾燥固體過夜。Sennalpeptin sodium (100 g) was dissolved in isopropanol:water (500 ml) 50:50 at room temperature to give a colorless solution. This solution was filtered and a 45.4% sulfuric acid solution (73.2 ml) was added. When the mixture is filtered, the crystalline tianeptine hemisulfate monohydrate will crystallize completely within two hours. The solid was washed with 50:50 isopropanol: water (500 ml) and water (300 ml), and then the solid was dried overnight under ambient conditions.

噻萘普汀半硫酸鹽單水合物包括一個噻萘普汀離子比硫酸鹽反離子比水為1:0.5:1的比率。The tianeptine hemisulfate monohydrate comprises a ratio of a tianeptine ion to a sulfate counterion ratio of 1:0.5:1.

噻萘普汀半硫酸鹽單水合物結晶代表了藉由完成任何描述於實施例1a到1c中之方法之所得，其特性可使用PXRD、DSC、TGA、Dynamic vapor sorption(DVS)、單晶X-光繞射儀、紫外/吸收光譜、傅立葉變換紅外光譜(FTIR)和拉曼光譜來表徵。噻萘普汀半硫酸鹽單水合物呈現的PXRD繞射圖包括2-θ為約8.25、8.97、11.49、13.91、14.73、16.95、18.07、19.39、20.59、21.99、22.83及約23.27度的繞射峰(見圖一)。DSC在攝氏約193度表現一個吸熱轉移(見圖二)。TGA分析表明，噻萘普汀半硫酸鹽單水合物在大約室溫到攝氏約160度之間失去約百分之5.0之重量(見圖三)。The tianeptine hemisulfate monohydrate crystals represent the properties obtained by performing any of the methods described in Examples 1a to 1c, and the characteristics thereof can be PXRD, DSC, TGA, Dynamic vapor sorption (DVS), single crystal X. - Characterization by light diffractometer, UV/absorption spectroscopy, Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy. The PXRD diffraction pattern exhibited by tianeptine hemisulfate monohydrate includes diffraction of 2-theta of about 8.25, 8.97, 11.49, 13.91, 14.73, 16.95, 18.07, 19.39, 20.59, 21.99, 22.83, and about 23.27 degrees. Peak (see Figure 1). The DSC exhibits an endothermic transfer at approximately 193 degrees Celsius (see Figure 2). TGA analysis indicated that tianeptine hemisulfate monohydrate lost about 5.0 percent by weight between about room temperature and about 160 degrees Celsius (see Figure 3).

動態氣相吸附(DVS)完成了在25℃左右，相對濕度從大約零至90%左右之噻萘普汀半硫酸鹽單水合物的分析(見圖四)。DVS分析顯示噻萘普汀半硫酸鹽單水合物在約10%左右的相對濕度到約90%左右的相對濕度下是穩定的。這是典型的非吸濕性材料。低於10%相對濕度，水團已失去。Dynamic gas phase adsorption (DVS) completes the analysis of tianeptine hemisulfate monohydrate at about 25 ° C and relative humidity from about zero to about 90% (see Figure 4). DVS analysis showed that tianeptine hemisulfate monohydrate was stable at a relative humidity of about 10% to a relative humidity of about 90%. This is a typical non-hygroscopic material. Below 10% relative humidity, the water mass has been lost.

單晶數據：2(碳₂₁ æ°«₂₇ ClN₂ æ°§₄ ç¡«₁ )‧(ç¡«æ°§₄ )‧2(æ°«₂ æ°§)；M=503.99；單斜晶體的，P2(1)/n;a=9.3816(4)埃；b=25.2869(10)埃；c=19.9621(7)埃；α=90度；β=103.144(2)度；γ=90度；V=4611.6(3)立方埃；T=100(2)K;Z=8;D _c =1.452克/立方埃；λ=0.71073埃。Single crystal data: 2 (carbon ₂₁ hydrogen ₂₇ ClN ₂ oxygen ₄ sulfur ₁ ) ‧ (sulfur oxygen ₄ ) ‧ 2 (hydrogen ₂ oxygen); M = 503.99; monoclinic crystal, P2 (1) / n; a = 9.3816 (4) angstrom; b = 25.2869 (10) angstrom; c = 19.9631 (7) angstrom; α = 90 degrees; β = 103.144 (2) degrees; γ = 90 degrees; V = 4611.6 (3) cubic angstroms; 100(2)K; Z=8; D _c = 1.452 g/cm Å; λ=0.71073 angstroms.

噻萘普汀半硫酸鹽單水合物呈現出一紫外/吸收光譜，包含一最大吸光度(λ最大值)，例如，在約208nm，以及一弱吸光度，例如，在約275nm(見圖13)。The tianeptine hemisulfate monohydrate exhibits an ultraviolet/absorption spectrum comprising a maximum absorbance (lambda maximum), for example, at about 208 nm, and a weak absorbance, for example, at about 275 nm (see Figure 13).

噻萘普汀半硫酸鹽單水合物呈現出一FTIR光譜，包含繞射峰，例如，在約1351、1713、1732、2855、2916、2939、3193以及3540cm^-1 (見圖14)。The tianeptine hemisulfate monohydrate exhibits an FTIR spectrum comprising diffraction peaks, for example, at about 1351, 1713, 1732, 2855, 2916, 2939, 3193, and 3540 cm ^-1 (see Figure 14).

噻萘普汀半硫酸鹽單水合物呈現出一拉曼光譜，包含峰波，例如，在約286、339、582、672、695、1053、1099、1163、1182、1300以及1586cm^-1 (見圖15)。The tianeptine hemisulfate monohydrate exhibits a Raman spectrum comprising peak waves, for example, at about 286, 339, 582, 672, 695, 1053, 1099, 1163, 1182, 1300, and 1586 cm ^-1 (see Figure 15).

以下為所使用之分析技術。The following are the analytical techniques used.

各樣本之DSC分析之進行使用一Q1000掃描式熱差分儀(TA儀器，德拉瓦州新堡，美國)，其使用優勢QW-系列，版本1.0.0.78，熱優勢發布2.0(2001 TA儀器-水公司)，以及下列組成：QDdv.exe版本1.0.0.78建設78.2；RHBASE.DLL版本1.0.0.78建設78.2；RHCOMM.DLL版本1.0.0.78建設78.0；RHDLL.DLL版本1.0.0.78建設78.1；一TGA.DLL版本1.0.0.78建設78.1。另外，使用之分析軟體為通用分析2000針對Windows 95/95/2000/NT，版本3.1E；建設3.1.0.40(2001 TA儀器-水公司)，或者本發明中圖示或其他處所指定之其他版本。The DSC analysis of each sample was performed using a Q1000 scanning thermal differential (TA instrument, Newcastle, Delaware, USA), which used the advantage QW-series, version 1.0.0.78, thermal advantage release 2.0 ( 2001 TA Instruments - Water Company), and the following components: QDdv.exe version 1.0.0.78 build 78.2; RHBASE.DLL version 1.0.0.78 build 78.2; RHCOMM.DLL version 1.0.0.78 build 78.0; RHDLL.DLL version 1.0.0.78 build 78.1; A TGA.DLL version 1.0.0.78 builds 78.1. In addition, the analysis software used is Universal Analysis 2000 for Windows 95/95/2000/NT, version 3.1E; build 3.1.0.40 ( 2001 TA Instruments - Water Company), or other versions specified in the illustrations of the invention or elsewhere.

針對所有的DSC分析，皆使用一可整除的樣本，在一個標準的鋁秤盤(秤盤部分# 900786.091；蓋子部分# 900779.901)或一密封鋁秤盤(秤盤部分# 900793.901；蓋子部分# 900794.901(TA儀器，新堡，德拉瓦，美國))中秤重。非溶劑化樣品被裝入標準盤中並使用皺縮壓製密封乾燥樣品，使用壓接方式密封濕樣品(如泥漿)。溶劑樣本(包括水合物)被裝進密封盤和密封。樣品秤盤被裝入Q1000掃描式熱差分儀，其配備有一自動取樣器，並藉由控制軟件相同地單獨加熱以得到一熱像圖，加熱速率為10℃/分鐘自T_min (一般為30℃)至T_max (t通常為300℃)，使用空鋁秤盤作為參考。使用乾燥的氮氣(壓縮氮氣，4.8級(BOC氣體，默里山，新澤西州，美國))作為樣本淨化氣體，並將流速訂為50mL/分鐘。利用儀器提供之分析軟件觀察和分析熱轉移。For all DSC analyses, use a divisible sample in a standard aluminum weighing pan (weighing pan section #900786.091; lid section #900779.901) or a sealed aluminum weighing pan (scale pan section #900793.901; cover section #900794.901 (TA Instruments, Newcastle, Delaware, USA)) Weighing in the middle. The unsolvated sample is loaded into a standard pan and the dried sample is sealed using crimping, and the wet sample (such as mud) is sealed using crimping. Solvent samples (including hydrates) are loaded into a sealing disk and sealed. The sample pan is loaded into a Q1000 scanning thermal differential equipped with an autosampler and heated separately by control software to obtain a thermal image at a heating rate of 10 ° C / min from T _min (typically 30 °C) to T _max (t is usually 300 ° C), using an empty aluminum weighing pan as a reference. Dry nitrogen (compressed nitrogen, grade 4.8 (BOC gas, Murray Hill, NJ, USA)) was used as a sample purge gas and the flow rate was set at 50 mL/min. Thermal transfer was observed and analyzed using analytical software provided by the instrument.

樣品的熱重分析(TGA)使用一Q500熱重分析儀(TA儀器，新堡，德拉瓦，美國)，其使用優勢QW-系列，版本1.0.0.78，熱優勢發布2.0(2001 TA儀器-水公司)。另外，使用之分析軟體為Universal Analysis 2000針對Windows 95/95/2000/NT，版本3.1E；建設3.1.0.40(2001 TA儀器-水公司)，或者本發明中圖示或其他處所指定之其他版本。The thermogravimetric analysis (TGA) of the sample uses a Q500 thermogravimetric analyzer (TA Instruments, Newcastle, Delaware, USA), which uses the dominant QW-series, version 1.0.0.78, and thermal advantage release 2.0 ( 2001 TA Instruments - Water Company). In addition, the analysis software used is Universal Analysis 2000 for Windows 95/95/2000/NT, version 3.1E; build 3.1.0.40 ( 2001 TA Instruments - Water Company), or other versions specified in the illustrations of the invention or elsewhere.

針對TGA實驗，使用乾燥的氮氣作為淨化氣體，平衡淨化氣體為40mL/分鐘氮₂ ，樣品淨化氣體為60mL/分鐘氮₂ 。For the TGA experiment, dry nitrogen was used as the purge gas, the equilibrium purge gas was 40 mL/min of nitrogen ₂ , and the sample purge gas was 60 mL/min of nitrogen ₂ .

將一噻萘普汀硫酸鹽放置於一白金秤盤中以進行TGA。起始溫度一般約為攝氏20度，加熱速率為攝氏10度/分鐘，結束溫度為攝氏300度。A tianeptine sulfate was placed in a platinum weighing pan for TGA. The initial temperature is generally about 20 degrees Celsius, the heating rate is 10 degrees Celsius per minute, and the end temperature is 300 degrees Celsius.

利用一D/最大快速x射線繞射儀以獲得粉末x射線繞射圖樣(Rigaku/MSC，伍德蘭德斯，德州，美國)。A D/maximum fast x-ray diffractometer was used to obtain a powder x-ray diffraction pattern (Rigaku/MSC, Woodlands, Texas, USA).

D/最大快速x射線繞射儀配備有一銅源(銅/鉀_α 1.5406)，手動x-y鏡台，以及0.3mm準直儀。藉由切片關閉毛細管封閉端，並於一粉末狀樣品層或於一打漿樣品沉積物上輕叩小的毛細管開口端，將樣品放入一0.3mm石英毛細管(查爾斯晚餐公司，納提克，邁阿密，美國)。置入的毛細管被放於一安裝在x-y鏡台上之支架內。一繞射圖樣需要控制軟件(RINT快速控制軟件，Rigaku快速/XRD，版本1.0.0(1999 Rigaku Co.))，環境條件為傳輸模式之功率設置在40mA為46kV，而關於歐米茄-軸之振盪從0-5度為1度/秒，關於phi-軸之旋轉則超過360度，以2度/秒之速度。曝光時間為15分鐘，除非另有說明。D / maximum fast x-ray diffractometer equipped with a copper source (copper / potassium _α 1.5406 ), manual xy stage, and 0.3mm collimator. The sample was placed in a 0.3 mm quartz capillary by slicing the closed end of the capillary and tapping the open end of the capillary on a powdered sample layer or on a beating sample deposit (Charles Dinner Company, Natick, Miami) ,United States). The placed capillary is placed in a holder mounted on the xy stage. A diffractive pattern requires control software (RINT Rapid Control Software, Rigaku Express/XRD, version 1.0.0 ( 1999 Rigaku Co.)), the environmental condition is that the power of the transmission mode is set to 46kV at 40mA, and the oscillation of the Omega-axis is from 0-5 degrees to 1 degree/second, and the rotation of the phi-axis is more than 360 degrees. 2 degrees / second speed. The exposure time is 15 minutes unless otherwise stated.

獲得之繞射圖是集成自2-40度之2-θ以及自0-36度，步長為0.02度之chi(1段)，並使用由Rigaku儀器提供之RINT快速顯示軟體(RINT快速顯示軟體，版本1.18(Rigaku/MSC))中的cyllnt 效用。按照Rigaku之各系統校準將暗計數的值設置為8。整合沒有使用正常化或歐米茄、chi或phi抵銷。本文所包含的繞射圖顯示原始數據(沒有減去背景)。The obtained diffraction pattern is integrated from 2-40 degrees of 2-θ and from 0-36 degrees, with a step size of 0.02 degrees chi (1 segment), and uses RINT fast display software provided by Rigaku instrument (RINT fast display) Software, cyllnt utility in version 1.18 (Rigaku/MSC). Set the value of the dark count to 8 according to the system calibration of Rigaku. Integration does not use normalization or offset by OMEGA, chi or phi. The diffraction diagrams included in this article show raw data (without subtracting the background).

一繞射圖中的繞射峰相對強度並不一定是PXRD模式的限制，因為峰值強度會隨著樣品變化，例如，由於結晶雜質。此外，每一繞射峰之也會有所不同角度，大約+/-0.1度，或大約+/-0.05。由於不同的校準，設置和儀器之間及操作者之間的不同因素，整個模式或大部分模式之繞射峰也可能改變大約+/-0.1度至約+/-0.2度。在圖示，實施例，以及本說明書其他處中所有報告之PXRD繞射峰都具有2-θ大約±0.1度之誤差。除非另有說明，所有繞射圖皆於室溫(約攝氏24度至攝氏25度)中完成。The relative intensity of the diffraction peaks in a diffraction pattern is not necessarily a limitation of the PXRD mode because the peak intensity varies with the sample, for example, due to crystalline impurities. In addition, each diffraction peak will have a different angle, approximately +/- 0.1 degrees, or approximately +/- 0.05. The diffraction peaks for the entire mode or most modes may also vary by about +/- 0.1 degrees to about +/- 0.2 degrees due to different calibrations, settings, and different factors between the instruments and the operator. All of the reported PXRD diffraction peaks in the figures, the examples, and elsewhere in this specification have an error of 2-theta of about ±0.1 degrees. All diffraction patterns are done at room temperature (approximately 24 degrees Celsius to 25 degrees Celsius) unless otherwise stated.

使用在一Bruker KAPPA APEX II電荷耦合元件區域偵測系統上之100(2)K來測量X射線強度數據，此偵測系統配備有石墨單色器和MoKαfine-重點密封管(λ=0.71073)，操作功率為1.5千瓦(50kV,30mA)。八分子噻萘普汀組成單位細胞。硫酸根離子形成在兩個噻萘普汀分子之二級胺上形成一個鹽。兩個噻萘普汀分子和一水分子之羧酸尾和硫酸根離子之間可以發現氫鍵。X-ray intensity data was measured using a 100(2)K on a Bruker KAPPA APEX II CCD device. The detection system is equipped with a graphite monochromator and a MoKαfine-focus seal tube (λ=0.71073). ), operating power is 1.5 kW (50kV, 30mA). Eight molecules of tianeptine constitute unit cells. Sulfate ions form a salt on the secondary amines of the two tianeptine molecules. Hydrogen bonds can be found between the two tianeptine molecules and the carboxylic acid tail and sulfate ion of one water molecule.

利用一卡萊50紫外/可見光分析儀(Vankel，帕羅奧多，加州)測量紫外/吸收光譜。將噻萘普汀半硫酸鹽單水合物溶解於甲醇：水(0.150mg/mL) 50:50中)，通過一個過濾0.45um之注射過濾器，然後以相同溶劑(終濃度0.075mg/mL)稀釋2倍。將1.0mL樣品添加到一個具有光徑1.0cm之石英比色管。The UV/absorption spectra were measured using a Carlisle 50 UV/Vis spectrometer (Vankel, Palo Alto, Calif.). The tianeptine hemisulfate monohydrate was dissolved in methanol:water (0.150 mg/mL) 50:50) through a filtered 0.45 um syringe filter followed by the same solvent (final concentration 0.075 mg/mL) Dilute 2 times. A 1.0 mL sample was added to a quartz colorimetric tube having a light path of 1.0 cm.

FTIR分析是利用熱電公司之一奈克瑟斯470 FTIR儀器(賓州，費城)。噻萘普汀半硫酸鹽單水合物和溴化鉀一起被研磨並壓縮成一個半透明的圓平面。在E.S.P.模式使用32次掃描進行分析。在樣本分析前收集一清新背景測量值。FTIR analysis is the use of one of the thermoelectric companies Nexus 470 FTIR instruments (Pennsylvania, Philadelphia). The tianeptine hemisulfate monohydrate and potassium bromide are ground together and compressed into a translucent circular plane. The analysis was performed using 32 scans in the E.S.P. mode. A fresh background measurement was collected prior to sample analysis.

拉曼光譜表徵是利用熱電公司之一尼可萊拉曼系統進行，其配備有一785nm激光顯微鏡裝置和一10倍物鏡。利用每次曝光4秒窗口之30次曝光來收集分散的拉曼光譜。在樣本分析前收集一清新背景測量值。Raman spectroscopy is performed using the Nicolai Raman system, one of the thermoelectric companies, equipped with a 785 nm laser microscope device and a 10x objective lens. The dispersed Raman spectra were collected using 30 exposures of a 4 second window per exposure. A fresh background measurement was collected prior to sample analysis.

31 STABLON(噻萘普汀鈉)錠劑在一研缽中被杵磨碎，並與23mL之四氫呋喃(THF)混合以萃取噻萘普汀。以震盪和超聲處理來混合這些混合物。以布氏漏斗過濾非溶解成分。自經過濾之乾淨溶液蒸發THF溶劑，再將其餘組成溶解在4mL去離子水。添加四當量之鹽酸以結晶噻萘普汀鹽酸鹽。31 STABLON The (tianapeptin sodium) lozenge was mashed in a mortar and mixed with 23 mL of tetrahydrofuran (THF) to extract tianeptine. These mixtures were mixed by shaking and sonication. The non-dissolved components were filtered through a Buchner funnel. The THF solvent was evaporated from the filtered clean solution, and the remaining composition was dissolved in 4 mL of deionized water. Four equivalents of hydrochloric acid were added to crystallize tianeptine hydrochloride.

結晶代表了藉由完成上述方法之所得，其特性可使用PXRD、DSC、TGA，動態水份吸附分析(DVS)來表徵。噻萘普汀鹽酸鹽呈現的PXRD繞射圖包括2-θ為約7.23、9.43、9.91、10.53、14.53、18.35、21.39及約23.93度的繞射峰(見圖5)。DSC在攝氏約199度表現一個吸熱轉移(見圖6)。TGA分析表明，噻萘普汀鹽酸鹽在大約室溫到攝氏約140度之間失去約百分之2.9的重量(見圖7)。Crystallization represents the result obtained by performing the above method, and its characteristics can be characterized using PXRD, DSC, TGA, dynamic moisture adsorption analysis (DVS). The PXRD diffraction pattern exhibited by tianeptine hydrochloride includes a diffraction peak of 2-theta of about 7.23, 9.43, 9.91, 10.53, 14.53, 18.35, 21.39, and about 23.93 degrees (see Figure 5). The DSC exhibits an endothermic transfer at approximately 199 degrees Celsius (see Figure 6). TGA analysis indicated that tianeptine hydrochloride lost about 2.9 percent by weight between about room temperature and about 140 degrees Celsius (see Figure 7).

動態水份吸附分析(DVS)在攝氏25度下自相對濕度約0到約90%之噻萘普汀鹽酸鹽(見圖8)。動態水份吸附分析(DVS)顯示噻萘普汀鹽酸鹽在相對濕度直到大約90%都是穩定的。在整個濕度範圍內，噻萘普汀鹽酸鹽吸收不到2.5%的水重量。Dynamic moisture adsorption analysis (DVS) of tianeptine hydrochloride at a relative humidity of from about 0 to about 90% at 25 degrees Celsius (see Figure 8). Dynamic moisture adsorption analysis (DVS) showed that tianeptine hydrochloride was stable at relative humidity up to about 90%. The tianeptine hydrochloride absorbs less than 2.5% of the water weight over the entire humidity range.

15 STABLON(噻萘普汀鈉)錠劑在一研缽中被杵磨碎，並與15mL之四氫呋喃混合以萃取噻萘普汀。以震盪和超聲處理來混合這些混合物。以布氏漏斗過濾非溶解成分。自經過濾之乾淨溶液蒸發THF溶劑，再將其餘組成再溶解於2.5mL THF。添加五當量之磷酸以結晶噻萘普汀磷酸鹽。15 STABLON The (tianapeptin sodium) lozenge was mashed in a mortar and mixed with 15 mL of tetrahydrofuran to extract tianeptine. These mixtures were mixed by shaking and sonication. The non-dissolved components were filtered through a Buchner funnel. The THF solvent was evaporated from the filtered clean solution and the remaining mixture was redissolved in 2.5 mL THF. Five equivalents of phosphoric acid were added to crystallize the tianeptine phosphate.

結晶代表了藉由完成上述方法之所得，其特性可使用PXRD、DSC、TGA、動態水份吸附分析(DVS)來表徵。噻萘普汀磷酸鹽呈現的PXRD繞射圖包括2-θ為約6.83、9.27、11.95、13.53、13.83、15.93、16.31、17.35、18.47、20.93、21.49、22.77及約23.67度的繞射峰(見圖9)。DSC在攝氏約193度表現一個吸熱轉移(見圖10)。TGA分析表明，噻萘普汀磷酸鹽在大約室溫到攝氏約199度之間失去約百分之3.7的重量(見圖11)。Crystallization represents the result obtained by performing the above method, and its characteristics can be characterized using PXRD, DSC, TGA, dynamic moisture adsorption analysis (DVS). The PXRD diffraction pattern exhibited by tianeptine phosphate includes diffraction peaks of 2-theta of about 6.83, 9.27, 11.95, 13.53, 13.83, 15.93, 16.31, 17.35, 18.47, 20.93, 21.49, 22.77, and about 23.67 degrees ( See Figure 9). The DSC exhibits an endothermic transfer at approximately 193 degrees Celsius (see Figure 10). TGA analysis indicated that tianeptine phosphate lost about 3.7 percent by weight between about room temperature and about 199 degrees Celsius (see Figure 11).

動態水份吸附分析(DVS)在攝氏25度下自相對濕度約0到約90%之噻萘普汀磷酸鹽(見圖12)。動態水份吸附(DVS)分析顯示噻萘普汀磷酸鹽在相對濕度約90%時吸收了大約按重量為25%的水。Dynamic moisture adsorption analysis (DVS) is from about 0 to about 90% tianeptine phosphate at 25 degrees Celsius (see Figure 12). Dynamic moisture adsorption (DVS) analysis showed that tianeptine phosphate absorbed about 25% by weight of water at a relative humidity of about 90%.

圖16顯示噻萘普汀鈉之相對DVS數據(在約攝氏25度)和圖4中之噻萘普汀半硫酸鹽單水合物之DVS數據之比較。噻萘普汀鈉在相對濕度約60%時開始潮解，並在相對濕度約90%時吸收了大約38%的水(按重量)。Figure 16 shows a comparison of the relative DVS data for tianeptine sodium (at about 25 degrees Celsius) and the DVS data for tianeptine hemisulfate monohydrate of Figure 4. The tianeptine sodium begins to deliquesce at a relative humidity of about 60% and absorbs about 38% of water (by weight) at a relative humidity of about 90%.

添加過量的噻萘普汀半硫酸鹽單水合物(來自實施例1)到溶液中並在持續混合下平衡24小時，然後在室溫下測量噻萘普汀半硫酸鹽單水合物的水性溶解度。三種溶液被使用，包括10mM HCl溶液、pH值為6.5(50mM磷酸鈉)的緩衝溶液及去離子水。從每個溶液中移除剩餘固體並進行固態形式分析。噻萘普汀半硫酸鹽單水合物並未顯示出有任何轉換為自由兩性離子形式。在全部三種溶液中，噻萘普汀半硫酸鹽單水合物的溶解度少於1mg/mL圖17顯示噻萘普汀半硫酸鹽單水合物、噻萘普汀鹽酸鹽及噻萘普汀磷酸鹽的溶解度比較。An excess of tianeptine hemisulfate monohydrate (from Example 1) was added to the solution and equilibrated for 24 hours with continuous mixing, then the aqueous solubility of tianeptine hemisulfate monohydrate was measured at room temperature. . Three solutions were used, including a 10 mM HCl solution, a buffer solution with a pH of 6.5 (50 mM sodium phosphate), and deionized water. The remaining solids were removed from each solution and analyzed in solid form. The tianeptine hemisulfate monohydrate did not show any conversion to a free zwitterionic form. The solubility of tianeptine hemisulfate monohydrate in less than 1 mg/mL in all three solutions. Figure 17 shows tianeptine hemisulfate monohydrate, tianeptine hydrochloride and tianeptine phosphate The solubility of the salt is compared.

製造三種噻萘普汀硫酸鹽的配方。組合物描述如下。Formulation of three tianeptine sulfates. The composition is described below.

測量下列噻萘普汀形式的pH值溶解度曲線：噻萘普汀鹽酸鹽；噻萘普汀半硫酸鹽單水合物；甲苯磺酸噻萘普汀；噻萘普汀自由形式(型II兩性離子，如美國公開號US2008/0221081 A1中所描述並鑑定，其PXRD繞射圖描繪於圖18中)；及噻萘普汀鈉。The pH solubility curves of the following tianeptine forms were measured: tianeptine hydrochloride; tianeptine hemisulfate monohydrate; tianeptine tosylate; tianeptine free form (type II) Ions, as described and identified in U.S. Publication No. US 2008/0221081 A1, the PXRD diffraction pattern of which is depicted in Figure 18; and tianeptine sodium.

以下述程序製備在此實施例中所使用的甲苯磺酸噻萘普汀。將噻萘普汀自由形式II(2.072克)與對甲苯磺酸(0.923克)結合。在該固體混合物中添加乙腈(50.0毫升)。將該混合物加熱以產出一清澈溶液。允許該溶液冷卻至室溫，然後種入甲苯磺酸噻萘普汀(約5毫克)。允許該溶液攪拌一整夜以產出完整的產物結晶。接著將懸浮液冷卻至0℃並過濾以分離出白色結晶固體。The tianeptine tosylate used in this example was prepared by the following procedure. The tianeptine free form II (2.072 grams) was combined with p-toluenesulfonic acid (0.923 grams). Acetonitrile (50.0 mL) was added to the solid mixture. The mixture is heated to produce a clear solution. The solution was allowed to cool to room temperature and then tianeptine tosylate (about 5 mg) was added. The solution was allowed to stir overnight to yield the complete product crystals. The suspension was then cooled to 0 ° C and filtered to isolate a white crystalline solid.

下面提供另一個可製備甲苯磺酸噻萘普汀的程序。將噻萘普汀鈉(442.0毫克)與對甲苯磺酸(199.3毫克)結合。添加醋酸乙酯及甲苯為1：1的溶液(共10毫升)到該固體混合物中。將該混合物進行短暫的超音波震盪以產出溶液，接著攪拌約15分鐘。攪拌的整個過程中，觀察到形成白色懸浮體的明顯結晶。藉由過濾收集該固體，然後在75℃真空下乾燥60小時。Another procedure for preparing tianeptine tosylate is provided below. Sennalpeptin sodium (442.0 mg) was combined with p-toluenesulfonic acid (199.3 mg). A solution of ethyl acetate and toluene in a ratio of 1:1 (total 10 ml) was added to the solid mixture. The mixture was subjected to brief ultrasonic vibration to produce a solution, followed by stirring for about 15 minutes. During the entire agitation, significant crystallization of the white suspension was observed. The solid was collected by filtration and then dried under vacuum at 75 ° C for 60 hours.

下面更提供另一個可製備甲苯磺酸噻萘普汀的程序。將噻萘普汀自由形式II(45.5毫克)與對甲苯磺酸(21.5毫克)結合。添加乙腈(1.0毫升)到該固體混合物中。將該混合物溫和加熱以產出溶液，允許該溶液冷卻至室溫並放置1小時。用玻璃棒刮含該溶液之玻璃瓶的內面。結晶被誘導並在約15分鐘後接近完成。藉由過濾收集該固體，其並被定性為甲苯磺酸噻萘普汀。Another procedure for preparing tianeptine tosylate is provided below. The tianeptine free form II (45.5 mg) was combined with p-toluenesulfonic acid (21.5 mg). Acetonitrile (1.0 mL) was added to the solid mixture. The mixture was gently heated to yield a solution which was allowed to cool to room temperature and allowed to stand for 1 hour. The inner surface of the glass bottle containing the solution was scraped with a glass rod. Crystallization was induced and nearly completed after about 15 minutes. The solid was collected by filtration and characterized as tianeptine tosylate.

每個噻萘普汀形式都被添加至玻璃瓶裡的緩衝液中。加入攪拌棒並關閉該玻璃瓶。將密封的玻璃瓶培養在37℃下並持續混合24到36小時。培養後，透過使用0.2um孔徑過濾器的離心過濾移除溶液中的剩餘固體。測量每個濾液的pH值，然後將該溶液稀釋2到10倍並用HPLC(UV偵測)分析噻萘普汀的含量。藉由粉末x射線繞射定性該剩餘固體以測定每個玻璃瓶中所產生的固體形式(均衡形式)。下面的表1到表5可以找到每個噻萘普汀形式的數據。Each tianeptine form was added to the buffer in a glass vial. Add a stir bar and close the glass bottle. The sealed glass bottles were incubated at 37 ° C and mixed for 24 to 36 hours. After the cultivation, the residual solids in the solution were removed by centrifugal filtration using a 0.2 um pore size filter. The pH of each filtrate was measured, then the solution was diluted 2 to 10 times and the content of tianeptine was analyzed by HPLC (UV detection). The remaining solids were characterized by powder x-ray diffraction to determine the solid form (equal form) produced in each glass vial. Data for each form of tianeptine can be found in Tables 1 through 5 below.

表5中所述的噻萘普汀鈉樣品在3種pH值條件(初始pH值1、2和3)下重複試驗並具有不同的藥物目標濃度。舉例來說，在pH值為1的條件下，添加60到70mg的噻萘普汀鈉至100mM HCl中。對第2個樣品而言，則是添加60到70mg的噻萘普汀鈉至100mM HCl中，然後再加入額外的噻萘普汀鈉鹽直到懸浮體出現。這樣做是為了達到藥物的過飽和。因此，因為在第2個樣品中的噻萘普汀鈉濃度較高，在噻萘普汀鈉鹽轉換為均衡形式後，最終pH值便不同。最終pH值及形式會影響溶解度。The tianeptine sodium samples described in Table 5 were tested repeatedly under three pH conditions (initial pH 1, 2 and 3) and had different drug target concentrations. For example, 60 to 70 mg of tianeptine sodium to 100 mM HCl is added at a pH of 1. For the second sample, 60 to 70 mg of tianeptine sodium was added to 100 mM HCl, followed by the addition of additional tianeptine sodium salt until the suspension appeared. This is done to achieve supersaturation of the drug. Therefore, since the concentration of tianeptine sodium in the second sample is high, the final pH value is different after the tianeptine sodium salt is converted into a balanced form. The final pH and form will affect the solubility.

不同形式噻萘普汀的pH值溶解度數據繪製於圖19中。The pH solubility data for different forms of tianeptine is plotted in Figure 19.

如圖19所示，噻萘普汀半硫酸鹽單水合物從pH 1到pH 7具有大致上平緩的溶解度曲線，相較之下，其他形式的噻萘普汀則在低於pH 4.5時有顯著較高的溶解度並在高於pH 4.5後溶解度大幅下降。對於口服控制釋放劑型而言，在胃腸道的全部pH範圍具有一致的溶解度是較佳的。如果在胃中的延長滯留時間為高變異性(這是可能的，特別是食物存在時)，這樣的溶解度曲線可能減少噻萘普汀吸收的變異性。例如在噻萘普汀鹽酸鹽的案例中，數據顯示在胃中的延長滯留時間可能造成較快的溶解和吸收。相反地，腸中溶解度的大幅下降可能接著限制其溶解，因此限制吸收。噻萘普汀半硫酸鹽單水合物具有相對一致的溶解度曲線，能夠減少這種變異性，對於控制釋放劑型可能是有利的。溶解度能顯著影響觀察到的吸收變異性。As shown in Figure 19, the tianeptine hemisulfate monohydrate has a substantially gradual solubility curve from pH 1 to pH 7, compared to other forms of tianeptine at pH 4.5. Significantly higher solubility and a significant decrease in solubility above pH 4.5. For oral controlled release dosage forms, it is preferred to have a consistent solubility throughout the pH range of the gastrointestinal tract. If the extended residence time in the stomach is highly variable (which is possible, especially in the presence of food), such a solubility profile may reduce the variability in the absorption of tianeptine. For example, in the case of tianeptine hydrochloride, the data show that prolonged residence time in the stomach may result in faster dissolution and absorption. Conversely, a large drop in solubility in the intestine may then limit its dissolution, thus limiting absorption. The tianeptine hemisulfate monohydrate has a relatively consistent solubility profile that can reduce this variability and may be advantageous for controlled release dosage forms. Solubility can significantly affect the observed absorption variability.

使用來自實施例6定義為F1、F2和F3的三種配方(除了省略矽酸膠)製造包含噻萘普汀半硫酸鹽單水合物的錠劑。也使用類似實施例6中F1、F2和F3的配方製造錠劑，除了省略矽酸膠及使用噻萘普汀鈉鹽作為取代噻萘普汀半硫酸鹽單水合物的活性分子。在美國藥典II溶離儀器中測試這些錠劑以評估鹽的形式對藥物釋放的影響。A tablet containing tianeptine pentasulfate monohydrate was produced using three formulations defined from Example 6 as F1, F2 and F3 except that the citric acid gel was omitted. Tablets were also prepared using a formulation similar to F1, F2 and F3 in Example 6, except that the citrate gel was omitted and the tianeptine sodium salt was used as the active molecule for the substituted tianeptine hemisulfate monohydrate. These tablets were tested in a US Pharmacopoeia II dissolution apparatus to assess the effect of salt form on drug release.

將F1、F2和F3配方中所需量的噻萘普汀半硫酸鹽單水合物、艾維素(Avicel)PH200及美多秀(Methocel)K4M和/或美多秀(Methocel)K100分別於大小合適的玻璃瓶中使用特卜拉(Turbula)摻合機混合10分鐘。然後加入硬脂酸鎂並將摻合物額外混合5分鐘。典型的粉末摻合物批量大小為4克。The required amounts of tianeptine hemisulfate monohydrate, Avicel PH200, and Methocel K4M and/or Methocel K100 in the F1, F2 and F3 formulations, respectively A properly sized glass bottle was mixed for 10 minutes using a Turbula blender. Magnesium stearate was then added and the blend was additionally mixed for 5 minutes. A typical powder blend has a batch size of 4 grams.

使用具有8-mm平面圓形模具的卡弗(Carver)壓機手動壓縮錠劑(200±5mg)，典型壓縮力約為650kgf(約130MPa)。The tablet (200 ± 5 mg) was manually compressed using a Carver press with an 8-mm planar circular die with a typical compression force of approximately 650 kgf (about 130 MPa).

同樣地製備包含噻萘普汀鈉鹽(來自位於匈牙利布達佩斯的CF製藥公司(批號為HAT-357AB))的錠劑。A lozenge containing tianeptine sodium salt (from CF Pharmaceuticals, Inc., Budapest, Hungary (batch number HAT-357AB)) was prepared in the same manner.

進行兩個單獨的溶解實驗。在一個實驗中，測量包含噻萘普汀半硫酸鹽單水合物之錠劑(F1、F2及F3)的藥物釋放。在第二個實驗中，測量包含噻萘普汀鈉鹽之錠劑(F1、F2及F3)的藥物釋放。在每個實驗中，使用美國藥典溶離儀器II型(槳式)測量錠劑的藥物釋放，具體的該儀器為瓦里安(Varian) VK 7000美國藥典溶離儀器II(旋轉槳)。使用瓦里安卡里(Varian Cary)50紫外線分光光度計以定量樣品。自動泵取的樣品管線中使用10um PE全流過濾器。Two separate dissolution experiments were performed. In one experiment, drug release was carried out containing lozenges (F1, F2 and F3) of tianeptine hemisulfate monohydrate. In the second experiment, the drug release of the tablets containing tianeptine sodium salt (F1, F2 and F3) was measured. In each experiment, the drug release of the tablet was measured using the United States Pharmacopoeia Dissolve Instrument Type II (paddle), specifically the Varian VK 7000 United States Pharmacopoeia Dissolving Instrument II (rotary paddle). A Varian Cary 50 UV spectrophotometer was used to quantify the sample. A 10um PE full flow filter was used in the sample line for automatic pumping.

溶解條件如下：The dissolution conditions are as follows:

介質及量：900mL模擬胃液(SGF)，pH值約1.2Medium and amount: 900mL simulated gastric juice (SGF), pH value about 1.2

900mL模擬腸液(SIF)，pH值約6.5900mL simulated intestinal fluid (SIF), pH about 6.5

去氣：無去氣Degas: no degassing

容器種類：尖底容器1Container type: sharp bottom container 1

溫度：37.3±0.5℃Temperature: 37.3 ± 0.5 ° C

槳高度：槳底到容器尖端約10mmPaddle height: about 10mm from the bottom of the paddle to the tip of the container

攪拌速率：100rpmStirring rate: 100rpm

偵檢：管線中連續式，在208nm的紫外線吸收Detection: continuous in the pipeline, UV absorption at 208nm

時間點：每6分鐘直到2小時，然後每12分鐘直到3小時，然後每30分鐘直到30小時或直到最大吸收高原建立。Time point: every 6 minutes until 2 hours, then every 12 minutes until 3 hours, then every 30 minutes until 30 hours or until the maximum absorption plateau is established.

添加2.0g的NaCl及7.0ml的濃縮HCl至足夠水中以作出1000ml溶液，接著秤重適當量以製備SGF溶解介質。2.0 g of NaCl and 7.0 ml of concentrated HCl were added to sufficient water to make a 1000 ml solution, and then an appropriate amount was weighed to prepare an SGF dissolution medium.

添加6.8g的磷酸二氫鉀(KH₂ PO₄ )及0.66g的氫氧化鈉(NaOH)至足夠水中以作出1000ml溶液(產生的pH值約6.5)，接著秤重適當量以製備SIF溶解介質。Add 6.8 g of potassium dihydrogen phosphate (KH ₂ PO ₄ ) and 0.66 g of sodium hydroxide (NaOH) to sufficient water to make a 1000 ml solution (resulting in a pH of about 6.5), and then weigh the appropriate amount to prepare a SIF dissolution medium. .

根據下面計算標準化釋放曲線：(吸光度)/(在最後時間點的吸光度)×100%=標準化溶解的百分比The normalized release profile was calculated according to the following: (absorbance) / (absorbance at the last time point) × 100% = percentage of normalized dissolution

噻萘普汀半硫酸鹽單水合物的實驗結果顯示於下面表6中。平均每個配方在每個介質中的三重複實驗結果，以獲得表6中的「釋放百分比」值。The experimental results of tianeptine hemisulfate monohydrate are shown in Table 6 below. The results of the three replicates of each recipe in each medium were averaged to obtain the "release percentage" values in Table 6.

噻萘普汀鈉鹽的實驗結果顯示於下面表7中。以每個配方在每個介質中的一重複實驗結果作為表7中的「釋放百分比」值。The experimental results of tianeptine sodium salt are shown in Table 7 below. The results of a repeated experiment in each medium for each formulation are taken as the "release percentage" values in Table 7.

如這些結果所示，鈉鹽(非晶質)在SGF和在SIF中比半硫酸鹽單水合物鹽類更為可溶。具體如圖20及21所顯示，其描繪了包含噻萘普汀半硫酸鹽單水合物之錠劑與包含噻萘普汀鈉鹽之錠劑的比較結果，用鈉鹽製備的錠劑釋放較迅速，尤其在溶解時間的早期。As shown by these results, the sodium salt (amorphous) is more soluble in SGF and in SIF than the hemisulfate monohydrate salt. Specifically, as shown in FIGS. 20 and 21, it depicts a comparison result between a tablet containing tianeptine sulphate monohydrate and a tablet containing tianeptine sodium salt, and a tablet prepared by using a sodium salt is released. Quickly, especially in the early stages of dissolution time.

為了進一步強調用噻萘普汀鈉鹽製備的錠劑和用噻萘普汀半硫酸鹽單水合物鹽類製備的錠劑在釋放動力學中的不同，自對應的釋放曲線數據中取關於時間的一階導數以計算出釋放速率。如圖22(使用每個鹽類的錠劑配方F2作為範例)所示，以半硫酸鹽單水合物鹽類為基礎的配方在整個溶解實驗期間的釋放速率比起以鈉鹽為基礎的配方會穩定的多。當x軸(時間)以對數坐標呈現時特別能看出這種差異，如圖23所示。In order to further emphasize the difference in release kinetics between tablets prepared with tianeptine sodium salt and tablets prepared with tianeptine sulphate monohydrate salt, time is taken from the corresponding release curve data. The first derivative is calculated to calculate the release rate. As shown in Figure 22 (using the tablet formulation F2 for each salt as an example), the formulation based on the hemisulfate monohydrate salt has a release rate throughout the dissolution experiment compared to the sodium salt based formulation. It will be much more stable. This difference is particularly seen when the x-axis (time) is presented in logarithmic coordinates, as shown in FIG.

小鼠中的行為絕望測試，又稱為強迫游泳實驗，是一種偵測測試化合物抗抑鬱活性的急性體內檢定。The behavioral despair test in mice, also known as forced swimming test, is an acute in vivo assay that detects the antidepressant activity of test compounds.

偵測抗抑鬱活性的該方法依照波爾首特(Porsolt)等人所述(Behavioural Despair in Mice: A Primary Screening Test for Antidepressants,Arch. Int. Pharmacodyn.,229,327-336,1977 )。在一種小鼠無法快速逃脫的情況下被強迫游泳的小鼠會變的不動。抗抑鬱劑會減少持續不動的時間。This method of detecting antidepressant activity is described by Porsolt et al. ( Behavioural Despair in Mice: A Primary Screening Test for Antidepressants, Arch. Int. Pharmacodyn., 229, 327-336, 1977 ). Mice that are forced to swim in a situation where a mouse cannot escape quickly will become immobile. Antidepressants reduce the amount of time that persists.

運來體重範圍在20到28克之間的雄性Rj NMRI小鼠(購自法國的Elevage Janvier)並在運送後將其置於鋪有木頭墊料且可自由取用水及食物的模克隆(MACROLON)籠(25×19×13cm，每籠中10隻動物)中穩定至少5天(SAFE的守則11-3)。將這些動物安置在人工照明(12小時)下21±3℃的控制環境溫度，且相對濕度在30%到80%之間。Male Rj NMRI mice (purchased from Elevage Janvier, France) weighing between 20 and 28 grams were transported and placed on wood pulp and freely available for water and food (MACROLON) after shipment. The cage (25 x 19 x 13 cm, 10 animals per cage) was stable for at least 5 days (SAFE Code 11-3). The animals were placed under controlled illumination at 21 ± 3 °C under artificial lighting (12 hours) with a relative humidity between 30% and 80%.

試驗後，藉由暴露於O₂ /CO₂ (20%/80%)的混合物中並接著用CO₂ 或斷頸將所有動物犧牲。After the test, all animals were sacrificed by exposure to a mixture of O ₂ /CO ₂ (20%/80%) followed by CO ₂ or a broken neck.

在研究A中，將白色粉末狀噻萘普汀半硫酸鹽單水合物溶解於生理食鹽水中。將白色粉末狀的噻萘普汀鈉(市面上有售)溶解於生理食鹽水中，並調整pH值為8.62。控制組為媒液，即生理食鹽水。將作為參考化合物的白色粉末狀鹽酸伊米胺(購自西格瑪(Sigma))溶解於生理食鹽水中。In Study A, white powdered tianeptine hemisulfate monohydrate was dissolved in physiological saline. The white powdered tianeptine sodium (commercially available) was dissolved in physiological saline and adjusted to a pH of 8.62. The control group is a vehicle, that is, physiological saline. White powdered imiamine hydrochloride (purchased from Sigma) as a reference compound was dissolved in physiological saline.

在研究B中，將白色粉末狀噻萘普汀半硫酸鹽單水合物溶解於生理食鹽水中，並調整pH值為8.71(研究B)。控制組為媒液，即生理食鹽水。將作為參考化合物的白色粉末狀鹽酸伊米胺(購自西格瑪(Sigma))溶解於生理食鹽水中。In Study B, white powdered tianeptine hemisulfate monohydrate was dissolved in physiological saline and adjusted to a pH of 8.71 (Study B). The control group is a vehicle, that is, physiological saline. White powdered imiamine hydrochloride (purchased from Sigma) as a reference compound was dissolved in physiological saline.

添加的配方賦形劑包括1N鹽酸、2M氫氧化鈉及生理食鹽水(購自阿奎坦製藥公司(Laboratoire Aguettant))。Formulation excipients added included 1N hydrochloric acid, 2M sodium hydroxide, and physiological saline (purchased from Laboratoire Aguettant).

在環境溫度(接近+20℃)下儲存噻萘普汀半硫酸鹽單水合物、噻萘普汀鈉及鹽酸伊米胺的配方。將媒液儲存在接近+4℃下。給予試驗動物施用10毫升/公斤體重的測試化合物、參考化合物及媒液。所有配方皆以10毫升/公斤體重的量給予施用。The formulation of tianeptine hemisulfate monohydrate, tianeptine sodium and imiamine hydrochloride was stored at ambient temperature (close to +20 ° C). The vehicle was stored at approximately +4 °C. Test animals were administered 10 ml/kg body weight of test compound, reference compound and vehicle. All formulations were administered in an amount of 10 ml/kg body weight.

在檢定一開始，進入游泳室的30分鐘前，給予每組中的小鼠單一劑量的媒液、參考化合物、噻萘普汀半硫酸鹽單水合物或噻萘普汀鈉，劑量如下面所詳述。30分鐘後，將小鼠個別放置在含有10公分水(22℃)的圓筒中(高=24公分；直徑13公分)，從該圓筒中小鼠無法逃脫。將小鼠置於水中6分鐘並測量後4分鐘的持續不動時間。每組研究10隻小鼠。該試驗以盲方式進行。利用視點動態影像追蹤軟體紀錄不動的時間。At the beginning of the test, 30 minutes before entering the swimming room, a single dose of vehicle, reference compound, tianeptine hemisulfate monohydrate or tianeptine sodium was administered to each group of mice at the dose as follows Detailed. After 30 minutes, the mice were individually placed in a cylinder containing 10 cm of water (22 ° C) (height = 24 cm; diameter 13 cm) from which the mice could not escape. Mice were placed in water for 6 minutes and the duration of 4 minutes after the measurement was measured. Ten mice were studied in each group. The test was conducted in a blind manner. Use the viewpoint dynamic image to track the time when the software records are not moving.

在兩個行為絕望檢定的研究中評估噻萘普汀半硫酸鹽單水合物，如下面所詳述。The tianeptine hemisulfate monohydrate was evaluated in two studies of behavioral despair assays as detailed below.

在研究A中，六組中的每一組都分配10隻動物。三組以噻萘普汀半硫酸鹽單水合物處理，分別給予100mg/kg、150mg/kg及200mg/kg。在試驗30分鐘前以腹腔注射給予噻萘普汀半硫酸鹽單水合物，並與給予媒液的動物作比較。一組以噻萘普汀鈉處理，在試驗30分鐘前以腹腔注射給予150mg/kg。一組以參考化合物(鹽酸伊米胺)處理，在試驗30分鐘前以腹腔注射給予32mg/kg，第六組以控制媒液處理，在試驗30分鐘前以腹腔注射給予。In Study A, 10 animals were assigned to each of the six groups. The three groups were treated with tianeptine, hemisulfate monohydrate, and administered at 100 mg/kg, 150 mg/kg, and 200 mg/kg, respectively. The tianeptine pentasulfate monohydrate was administered by intraperitoneal injection 30 minutes before the test and compared with the animals to which the vehicle was administered. One group was treated with tianeptine sodium, and 150 mg/kg was administered intraperitoneally 30 minutes before the test. One group was treated with a reference compound (imamine hydrochloride), and 32 mg/kg was administered intraperitoneally 30 minutes before the test, and the sixth group was treated with a control vehicle, and administered intraperitoneally 30 minutes before the test.

在研究B中，四組中的每一組都分配10隻動物。兩組以噻萘普汀半硫酸鹽單水合物處理，分別給予30mg/kg及60mg/kg。在試驗30分鐘前以腹腔注射給予噻萘普汀半硫酸鹽單水合物，並與給予媒液的動物作比較。第三組的動物以參考化合物(鹽酸伊米胺)處理，在試驗30分鐘前以腹腔注射給予32mg/kg，第四組以控制媒液處理，在試驗30分鐘前以腹腔注射給予。In Study B, 10 animals were assigned to each of the four groups. The two groups were treated with tianeptine hemisulfate monohydrate and given 30 mg/kg and 60 mg/kg, respectively. The tianeptine pentasulfate monohydrate was administered by intraperitoneal injection 30 minutes before the test and compared with the animals to which the vehicle was administered. The animals in the third group were treated with the reference compound (imamine hydrochloride), and 32 mg/kg was administered intraperitoneally 30 minutes before the test, and the fourth group was treated with control vehicle, and administered intraperitoneally 30 minutes before the test.

根據上述的程序測試動物，測量持續不動的時間並列於下表。使用司徒頓t字檢定評估測量結果，帶有*的值表示在統計上有顯著差異，其p值小於0.001。Animals were tested according to the procedure described above and the duration of the measurements was measured and listed in the table below. The measurement results were evaluated using the Stuart t-character test, with a value of * indicating a statistically significant difference with a p-value less than 0.001.

100mg/kg、150mg/kg及200mg/kg的噻萘普汀半硫酸鹽單水合物，與給予媒液的動物相比，減少了持續不動的時間(-59%、-43%及-46%，p分別小於0.001)。所有動物顯現出史特勞布(Straub)舉尾反應、高活動性及繞圈行為。幾隻動物有游泳困難；兩隻動物被淹死，一隻在100mg/kg組，另一隻在200mg/kg組。這些動物的數據並未包含在該結果中。100 mg/kg, 150 mg/kg, and 200 mg/kg of tianeptine hemisulfate monohydrate reduced the duration of immobility (-59%, -43%, and -46%) compared to animals given vehicle. , p is less than 0.001). All animals showed a Straub tail reaction, high activity and circling behavior. Several animals had difficulty swimming; two animals were drowned, one in the 100 mg/kg group and the other in the 200 mg/kg group. The data for these animals are not included in the results.

150mg/kg的噻萘普汀鈉，與給予媒液的動物相比，同樣減少了持續不動的時間(-50%，p小於0.001)。所有動物顯現出史特勞布(Straub)舉尾反應、高活動性及繞圈行為。幾隻動物有游泳困難；兩隻動物被淹死，而這些動物的數據並未包含在該結果中。150 mg/kg of tianeptine sodium also reduced the duration of immobility (-50%, p less than 0.001) compared to animals given vehicle. All animals showed a Straub tail reaction, high activity and circling behavior. Several animals had difficulty swimming; two animals were drowned and the data for these animals were not included in the results.

相較之下，以鹽酸伊米胺(32mg/kg)處理的動物，與給予媒液的控制組相比，也減少了持續不動的時間(-68%，p小於0.001)。In contrast, animals treated with imamine hydrochloride (32 mg/kg) also reduced the duration of onset (-68%, p less than 0.001) compared to the vehicle-administered control group.

根據上述的程序測試動物，測量持續不動的時間並列於下表。使用司徒頓t字檢定評估測量結果，帶有*的值表示在統計上有顯著差異，其p值小於0.001。Animals were tested according to the procedure described above and the duration of the measurements was measured and listed in the table below. The measurement results were evaluated using the Stuart t-character test, with a value of * indicating a statistically significant difference with a p-value less than 0.001.

30mg/kg及60mg/kg的噻萘普汀半硫酸鹽單水合物，與給予媒液的動物相比，減少了持續不動的時間(-86%及-83%，p分別小於0.001)。在兩個劑量中，試驗前均觀察在所有10隻小鼠中有異常行為(包括史特勞布(Straub)舉尾反應及繞圈行為)。30 mg/kg and 60 mg/kg of tianeptine hemisulfate monohydrate reduced the duration of persistence (-86% and -83%, p less than 0.001, respectively) compared to animals given vehicle. In both doses, abnormal behavior was observed in all 10 mice before the test (including Straub's tail-tailing and circling behavior).

相較之下，以鹽酸伊米胺(32mg/kg)處理的動物，與給予媒液的控制組相比，也減少了持續不動的時間(-88%，p小於0.001)。In contrast, animals treated with imamine hydrochloride (32 mg/kg) also reduced the duration of persistence (-88%, p less than 0.001) compared to the vehicle-administered control group.

研究A及B的結果顯示，腹腔注射劑量範圍在30mg/kg到200mg/kg間的噻萘普汀半硫酸鹽單水合物存在有類抗抑鬱劑活性。The results of studies A and B show that there is an antidepressant activity in the tianeptine hemisulfate monohydrate administered intraperitoneally at doses ranging from 30 mg/kg to 200 mg/kg.

下述臨床試驗評估了在配方篩選中單一劑量的藥物動力學(PK)，其為雙盲、隨機、四處理順序、四期交叉同齡群，每個處理順序(樣本數為3)基於電腦產生的隨機排程，以隨機順序接受三個噻萘普汀半硫酸鹽單水合物控制釋放(CR)錠劑配方各25mg及一個25mg劑量(兩個12.5mg錠劑)的市售噻萘普汀鈉STABLON立即釋放(IR)配方。The following clinical trials evaluated a single dose of pharmacokinetics (PK) in a formulation screen that was double-blind, random, four-processing sequence, four-phase cross-age group, and each processing sequence (sample number 3) was computer-generated A random schedule of commercially available tianeptine in a random order of three 25 mg of each of the tianeptine monosulfate monohydrate controlled release (CR) lozenge formulations and one 25 mg dose (two 12.5 mg lozenges) Sodium STABLON Immediate release (IR) recipe.

募集12名受試者至試驗中。受試者為從21歲一直到55歲的健康男性或健康非哺乳中女性。臨床化學、血液學及尿分析法測試皆在正常可允許的界限內(如果超出範圍，應視為其臨床上意義被排除)，並在接受第一劑研究藥物的21天內進行。身體質量指數從18kg/m² 一直到30kg/m² 。在以仰臥姿休息5分鐘後，生命徵象正常(95mm<收縮壓<140mm Hg、50mm Hg<舒張壓<90mm Hg、45bpm<心跳速率<90bpm)。12-導程自動心電圖(ECG；非完全性右束枝傳導阻滯可被接受)正常：120ms<PR<210ms、QRS<120ms、QTc(巴澤特(Bazett))男性小於等於430msec且女性小於等於450msec。若受試者在給予研究藥物後一開始的6小時未經歷嘔吐、完成所有計畫的評估、未達到退出標準、並且在四處理期間均完成24小時PK血液樣本採集，則視為該受試者完成該研究。Twelve subjects were recruited to the trial. The subjects were healthy males or healthy non-lactating women from 21 years old to 55 years old. Clinical chemistry, hematology, and urinalysis tests are within normal allowable limits (if they are out of range, they should be considered clinically excluded) and are performed within 21 days of receiving the first study drug. The body mass index is from 18 kg/m ^{2 up} to 30 kg/m ² . After resting for 5 minutes in a supine position, the signs of life were normal (95 mm < systolic blood pressure < 140 mm Hg, 50 mm Hg < diastolic blood pressure < 90 mm Hg, 45 bpm < heart rate < 90 bpm). 12-lead automatic electrocardiogram (ECG; incomplete right bundle branch block can be accepted) normal: 120ms<PR<210ms, QRS<120ms, QTc (Bazett) male is less than or equal to 430msec and female is less than Equal to 450msec. If the subject does not experience vomiting 6 hours after the administration of the study drug, completes the evaluation of all plans, does not meet the exit criteria, and completes the 24-hour PK blood sample collection during the four treatment periods, the subject is considered to be the subject Complete the study.

包含噻萘普汀半硫酸鹽單水合物的臨床配方一天服用一次，控制釋放基質錠劑由作為速度控制聚合物的羥丙基甲基纖維素及作為可侵蝕填料的微晶型纖維素所組成。研究中使用三種CR錠劑配方(如表6中所提供的F1、F2及F3，其體外釋放曲線分別在接近9、12及15小時時顯示出90%的藥物釋放)。除了釋放控制聚合物美多秀(Methocel)特級K100 LV CR比上美多秀(Methocel)特級K4M CR的比率以外，這三種配方的組成物大致相同。三種CR配方都是白色到接近白色的圓形錠劑，包含25mg的噻萘普汀(相當於28.84mg的噻萘普汀半硫酸鹽單水合物)。安慰劑錠劑係不含噻萘普汀的配合錠劑。STABLONIR錠劑(購自澳洲)為兩個12.5mg白色到接近白色的錠劑(總共25mg)，為銷售中的產品。將全部的噻萘普汀半硫酸鹽單水合物研究性產品儲存於適當的上鎖房間，溫度在15℃到25℃之間，並由該研究者負責。STABLONIR錠劑則根據銷售包裝儲存：不要在高於25℃下儲存；避免光照。The clinical formulation containing tianeptine hemisulfate monohydrate is administered once a day, and the controlled release matrix tablet consists of hydroxypropyl methylcellulose as a rate controlling polymer and microcrystalline cellulose as an erosable filler. . Three CR lozenge formulations were used in the study (such as F1, F2, and F3 provided in Table 6, which showed 90% drug release at approximately 9, 12, and 15 hours, respectively). The composition of the three formulations was approximately the same except for the ratio of the release control polymer Methocel premium K100 LV CR to the Methocel premium K4M CR. The three CR formulations were white to nearly white round lozenges containing 25 mg of tianeptine (equivalent to 28.84 mg of tianeptine hemisulfate monohydrate). The placebo tablet is a flavonoid-free lozenge. STABLON IR lozenges (purchased from Australia) were two 12.5 mg white to nearly white lozenges (25 mg total) and were on sale. The entire tianeptine hemisulfate monohydrate research product was stored in a suitable locked room at a temperature between 15 ° C and 25 ° C and was the responsibility of the investigator. STABLON IR tablets are stored according to the sales package: do not store above 25 ° C; avoid light.

所有研究藥物都是在第1、4、7及10天接近早上8點到10點之間時，在禁食條件下以240mL的非碳酸水被服用。為了保持給予的處理是看不見的，受試者被要求閉上眼睛及張開嘴巴，將所述兩個錠劑(2個12.5mg的STABLON錠劑或1個25mg的CR配方加上1個配合的安慰劑錠劑)放置在他們的舌頭上並要求他們吞下。研究藥物被整個吞入，而沒有被咀嚼、分割、溶解或壓碎。從給予研究藥物開始一直到給予研究藥物4小時後，受試者均維持直立姿勢。給藥後約2小時時(但不早於)，受試者喝一杯水(約240mL)；從這時開始一直到之後，喝水都是被允許的。攝入藥物4小時後，第一天供應標準化的午餐給所有的受試者。所有給藥天的午餐都相同。在CRF中紀錄午餐及晚餐確切開始的時間(給藥後9小時)，以及任何關於午餐及晚餐時間的偏差。在研究期間，禁止使用研究藥物以外的處方或非處方藥(包括維生素及草藥輔助物)，除了乙醯胺苯酚。乙醯胺苯酚被允許使用到每個研究藥物開始給予的3天前。在研究期間，允許使用每天最高3劑的500-mg乙醯胺苯酚治療頭痛或其他疼痛，但每週不得超過3克。All study medications were taken at 240 mL of non-carbonated water under fasting conditions on days 1, 4, 7 and 10, between 8 am and 10 am. In order to keep the treatment given invisible, the subject was asked to close the eyes and open the mouth, the two lozenges (2 12.5 mg STABLON) A lozenge or a 25 mg CR formula plus a combined placebo lozenge was placed on their tongue and asked to swallow. The study drug was swallowed entirely without being chewed, divided, dissolved or crushed. Subjects maintained an upright position from the time the study drug was administered until 4 hours after the study drug was administered. At about 2 hours after dosing (but not earlier than), the subject drank a glass of water (about 240 mL); from this point on until after, drinking water was allowed. Four hours after the ingestion of the drug, a standardized lunch was served to all subjects on the first day. The lunch is the same on all days of dosing. Record the exact start time for lunch and dinner in the CRF (9 hours after dosing) and any deviations from lunch and dinner time. Prescription or over-the-counter medications (including vitamins and herbal supplements) other than research medications, except acetaminophen, are prohibited during the study period. Acetamine phenol was allowed to be used 3 days before the start of each study drug. During the study period, up to 3 doses of 500-mg acetaminophen per day were allowed to treat headache or other pain, but not more than 3 grams per week.

在第1、4、7及10天給予受試者用藥；在第17±2天內進行後續視察。Subjects were administered on days 1, 4, 7 and 10; follow-up visits were performed within 17 ± 2 days.

在第1、4、7及10天給予受試者用藥，並在第1、2、4、5、7、8、10及11天採集血液樣本(每次4.5mL以獲得約2mL的血漿)作為PK評估。具體來說，在每個給藥天的給藥前(t=0)及給藥後第0.25、0.5、1.0、1.5、2.0、2.5、3.0、4.0、6.0、8.0、10.0、12.0、14.0、16.0、24.0、28.0、32.0及36.0小時採集樣本。將這些樣本儲存在-20℃下。Subjects were administered on days 1, 4, 7 and 10 and blood samples were taken on days 1, 2, 4, 5, 7, 8, 10 and 11 (4.5 mL each time to obtain approximately 2 mL of plasma) As a PK assessment. Specifically, before administration (t=0) on each administration day and at 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, 14.0, after administration, Samples were taken at 16.0, 24.0, 28.0, 32.0, and 36.0 hours. These samples were stored at -20 °C.

在ICON發展解決方案(曼徹斯特，英國)的監督下，使用經過驗證且敏感的液相層析質譜儀/質譜儀(LC-MS/MS)生物分析法分析血漿樣本以測定噻萘普汀濃度。噻萘普汀的定量極限(LoQ)為5ng/mL。Plasma samples were analyzed using a validated and sensitive liquid chromatography mass spectrometer/mass spectrometer (LC-MS/MS) bioassay to determine the tianeptine concentration under the supervision of the ICON Development Solutions (Manchester, UK). The quantitative limit (LoQ) of tianeptine was 5 ng/mL.

所有可得的數據都包含在數據列表中。All available data is included in the data list.

PK分析組包含所有接受過至少一劑研究藥物且關於研究藥物的攝入沒有主要偏差的受試者。所有可得的PK數據都被使用。該分析中包括在一些期間(但不是全部期間)缺失數據的受試者。The PK analysis group included all subjects who had received at least one dose of study drug and had no major deviations in the intake of the study drug. All available PK data is used. Subjects with missing data during some (but not all) periods were included in the analysis.

基於個別的血漿濃度-時間數據，使用實際採樣時間估計每個處理中的下列噻萘普汀PK參數：The following tianeptine PK parameters in each treatment were estimated using actual sampling times based on individual plasma concentration-time data:

C_max =觀察到的最大血漿濃度(ng/mL)C _max = maximum plasma concentration observed (ng/mL)

T_max =達到觀察到的最大血漿濃度的時間(小時)T _max = time to reach the maximum plasma concentration observed (hours)

T_lag =在給藥時間及第一個分析物濃度超過定量極限的時間之間的間隔(小時)T _lag = interval between the time of administration and the time when the first analyte concentration exceeds the limit of quantitation (hours)

AUC_24h =在給藥間隔(24小時，只有CR配方)使用梯形法計算血漿濃度相對時間曲線下的面積(ng.h/mL)AUC _24h = area under the plasma concentration versus time curve (ng.h/mL) using the trapezoidal method at the dosing interval (24 hours, CR formulation only)

AUC_last =血漿濃度-時間曲線下從給藥後0到t_last 小時的面積，以線性梯形求和法計算AUC _last = area under the plasma concentration-time curve from 0 to t _last hour after administration, calculated by linear trapezoidal summation

AUC_∞ =血漿濃度-時間曲線下從給時間0到無限時間的面積，根據下列方程式計算：AUC_∞ =AUC_last +C_last /λ_z (ng.h/mL)；若t_1/2,λ 可評估則報導AUC_∞ AUC _∞ = area from time 0 to infinite time under the plasma concentration-time curve, calculated according to the following equation: AUC _∞ = AUC _last + C _last / λ _z (ng.h/mL); if t _{1/2, λ} Evaluable to report AUC _∞

%AUC_∞,ex =用外推法得到的AUC∞百分比，以下列方程式計算：%AUC _{∞, ex} = percentage of AUC∞ obtained by extrapolation, calculated by the following equation:

λ_z =與曲線終端部分相關的第一反應速率常數，由藥物濃度-時間曲線終端對數-線性階段的負斜率所決定λ _z = the first reaction rate constant associated with the terminal portion of the curve, determined by the negative slope of the log-linear phase of the drug concentration-time curve

t_1/2,λ =與半對數藥物濃度-時間曲線終端斜率(λ_z )相關的消除半衰期，計算為0.693/λ_z t _1/2,λ = elimination half-life associated with the semi-log drug concentration-time curve terminal slope (λ _z ), calculated as 0.693/λ _z

F_rel =相對生物利用度：給予的藥物劑量能達到全身的百分比，計算為：[(AUC_∞(test) /AUC∞_(ref) )*(D_(ref) /D_(test) )]*100，參考處理為非靜脈內給藥。試驗：F1、F2及F3 CR配方；參考：IR配方。F _rel = relative bioavailability: The dose of the drug administered can reach the percentage of the whole body, calculated as: [(AUC _∞(test) /AUC∞ _(ref) )*(D _(ref) /D _(test) )]*100 The reference treatment is non-intravenous administration. Test: Formulations for F1, F2 and F3 CR; Reference: IR formulation.

使用非隔室分析計算噻萘普汀的PK參數。實際的處理後血液採樣時間被使用於所有的最終PK分析中。使用每個流程時間計算平均血漿濃度以作為圖形顯示。使用經過驗證的藥物動力學及統計軟體進行PK分析及敘述統計。The PK parameters of tianeptine were calculated using non-compartmental analysis. The actual post-treatment blood sampling time was used in all final PK analyses. The mean plasma concentration was calculated using each process time as a graphical display. PK analysis and narrative statistics were performed using validated pharmacokinetics and statistical software.

直接從數據中取C_max 及T_max 值。計算血漿濃度-時間曲線終端對數-線性階段的負斜率以作為消除速率常數λ_z 。目視檢查濃度相對時間的半對數圖以決定每個受試者及劑量所使用的數據範圍。至少使用三個數據點來估計λ_z 。用上述方法計算其他的PK參數。Take the C _max and T _max values directly from the data. The negative slope of the log-linear phase of the plasma concentration-time curve is calculated as the elimination rate constant λ _z . A semi-logarithmic plot of concentration versus time was visually inspected to determine the range of data used for each subject and dose. Use at least three data points to estimate λ _z . Calculate other PK parameters using the above method.

在募集的12位受試者中，12位都完成了該研究。平均年齡為37.7歲，範圍在23歲到55歲間。12位受試者均為白種人且半數(50.0%)為男性。在4個處理順序中，12位受試者的人口及基線特徵是相似的。沒有流程偏差干擾研究數據的解讀，也沒有受試者因為偏差而被排除在分析外。Of the 12 subjects recruited, 12 completed the study. The average age is 37.7 years and ranges from 23 to 55 years old. Twelve subjects were all Caucasian and half (50.0%) were male. The population and baseline characteristics of the 12 subjects were similar in the 4 treatment sequences. No process deviations interfered with the interpretation of the study data, and no subjects were excluded from the analysis due to bias.

所有的給藥前樣本均在給予研究藥物約12到22分鐘前取得，並限制處理後實際採樣時間與排程採樣時間之間的(相對)差異，該差異不被視作是排除理由。只有當用於估計終端消除階段的決定係數(R² _adj )高於0.80時，才計算消除速率常數λ_z 及半衰期t_1/2,λ 。若AUC_∞,ex 的百分比超過20%，則計算AUC_∞ ，但其不包括在敘述統計學中。All pre-dose samples were taken approximately 12 to 22 minutes prior to administration of the study drug and limited the (relative) difference between the actual sampling time after processing and the scheduled sampling time, which is not considered a reason for exclusion. The elimination rate constant λ _z and the half-life t _{1/2, λ} are calculated only when the decision coefficient (R ² _adj ) for estimating the terminal elimination phase is higher than 0.80. If AUC _∞, the percentage of _ex exceeds 20%, then AUC _∞ is calculated, but it is not included in the narrative statistics.

4種處理的平均血漿濃度-時間曲線顯示於圖24中，濃度尺度為線性。下面表10列出分別給予如同STABLONIR錠劑配方的25mg噻萘普汀以及噻萘普汀半硫酸鹽單水合物CR錠劑配方F1、F2及F3後的平均(±SD)噻萘普汀藥物動力學參數。The mean plasma concentration-time curves for the four treatments are shown in Figure 24, and the concentration scale is linear. Table 10 below is given separately as STABLON Mean (±SD) tianeptine pharmacokinetic parameters after formulation of 25 mg of tianeptine and narnatristine hemisulfate monohydrate CR tablet formulations of IR tablets.

C_max 為最大血漿濃度；T_max 為達到最大血漿濃度的時間；AUC_∞ 為血漿濃度-時間曲線下到無限時間的面積；AUC_last 為血漿濃度-時間曲線下從給藥後0到t_last 小時的面積；為消除半衰期；F_rel 為相對生物利用度；BQL指低於定量極限；T_max ：中位數(最小值－最大值)C _max is the maximum plasma concentration; T _max is the time to reach the maximum plasma concentration; AUC _∞ is the area under the plasma concentration-time curve to infinity; AUC _last is the plasma concentration-time curve from 0 to t _last hour after administration Area To eliminate half-life; F _rel is relative bioavailability; BQL means below quantitative limit; T _max : median (min - max)

這項研究的結果可以歸納如下。在口服STABLONIR錠劑配方後，噻萘普汀被快速吸收並在給予用藥後的1到2小時顯示出血漿濃度峰值。噻萘普汀血漿濃度隨著約3小時的終端半衰期而衰減。The results of this study can be summarized as follows. Oral STABLON After the IR tablet formulation, tianeptine was rapidly absorbed and showed a peak plasma concentration 1 to 2 hours after administration. The tianeptine plasma concentration decays with a terminal half-life of about 3 hours.

所有三種噻萘普汀半硫酸鹽單水合物CR配方(F1、F2及F3)在0.3到0.4小時的延遲時間後顯示出血漿濃度程度，在約2.5到3小時有峰值(F3比F1及F2稍遲)。F1的最大噻萘普汀濃度約比STABLONIR配方的低3倍，而F2及F3的噻萘普汀血漿濃度峰值比STABLONIR配方的低4到5倍。噻萘普汀血漿濃度衰減到約8小時，然後逐步上升到第二個濃度峰值，其約在給藥後12小時被觀察到。這個第二血漿濃度峰值約為F1初始C_max 的0.4倍，以及F2及F3C_max 的0.5到0.6倍。在這個第二峰值後，血漿濃度進一步隨著估計的半衰期衰減，其在F1計算為5.3小時、F2計算為5.7小時且F3計算為5.9小時，直到給予用藥後36小時。F1的平均24小時濃度為C_max 的0.13倍、F2的為C_max 的0.20倍、且F3的為C_max 的0.16倍，預測了F2在QD重複給藥後最有限的峰谷比。與STABLONIR配方相比，F1的噻萘普汀相對生物有效度為91%、F2的為90%、且F3的為73%。暴露在噻萘普汀下的個體間變異性(以CV百分比表示)從CR配方F1到F2到F3有增加的趨勢。All three tianeptine hemisulfate monohydrate CR formulations (F1, F2 and F3) showed a plasma concentration level after a delay time of 0.3 to 0.4 hours with a peak at about 2.5 to 3 hours (F3 vs. F1 and F2) A little later). The maximum tianeptine concentration of F1 is about the same as STABLON The IR formulation is 3 times lower, while the peak concentrations of tianeptine in F2 and F3 are higher than STABLON. The IR formula is 4 to 5 times lower. The tianeptine plasma concentration was attenuated to about 8 hours and then gradually increased to a second concentration peak, which was observed about 12 hours after administration. This second peak is about 0.4 times the plasma concentration C _max is the initial F1, F2, and 0.5 and 0.6 times the F3C _max. After this second peak, the plasma concentration further attenuated with the estimated half-life, which was calculated to be 5.3 hours at F1, 5.7 hours at F2, and 5.9 hours at F3 until 36 hours after administration. The average 24-hour concentration of F1 was 0.13 times _Cmax , F2 was 0.20 times _Cmax , and F3 was 0.16 times _Cmax , and the most limited peak-to-valley ratio of F2 after repeated administration of QD was predicted. With STABLON Compared to the IR formulation, the relative bioavailability of tianeptine in F1 was 91%, 90% in F2, and 73% in F3. The inter-individual variability (expressed as a percentage of CV) exposed to tianeptine has an increasing tendency from CR formulations F1 to F2 to F3.

STABLONIR錠劑配方顯示出與文獻中已知一致的PK特徵：快速被吸收、在給藥後1到2小時顯示出血漿濃度峰值、以及隨著約3小時的半衰期衰減。STABLON The IR lozenge formulation showed PK characteristics consistent with known in the literature: rapid absorption, peak plasma concentration 1 to 2 hours after administration, and half-life decay with about 3 hours.

在給藥後約2.5到3小時的中位數時間，噻萘普汀半硫酸鹽單水合物CR配方(F1、F2及F3)顯示出比STABLONIR配方低的多的血漿濃度峰值(F3比F1及F2稍遲)。F1 CR配方的噻萘普汀濃度峰值要比F2及F3 CR配方的來的高。在C_max 後，噻萘普汀持續從CR配方(F1、F2及F3)中被吸收，造成在給藥後約10到16小時的第二個峰值。第一及第二峰值間的差異在F1中(第二峰值約C_max 的0.4倍)比在F2及F3中(第二峰值為C_max 的0.5到0.6倍)大。血漿濃度隨著5到6小時的半衰期衰減。C_24h 與C_max 間的差異在F1及F3中(C_24h /C_max 比率分別為0.13及0.16)比起在F2中(C_24h /C_max 比率為0.20)較大，其預測了F2在重複給藥後最小的峰谷比。CR配方F2顯示了最有限的峰谷比以及高生物利用度。The median time of about 2.5 to 3 hours after administration, the tianeptine hemisulfate monohydrate CR formula (F1, F2 and F3) showed a better than STABLON The IR formula has a much lower plasma concentration peak (F3 is slightly later than F1 and F2). The peak concentration of tianeptine in the F1 CR formulation was higher than that in the F2 and F3 CR formulations. After _Cmax , tianeptine was continuously absorbed from the CR formulations (F1, F2 and F3), resulting in a second peak of about 10 to 16 hours after administration. The difference between the first and second peaks is greater in F1 (the second peak is about 0.4 times _Cmax ) than in F2 and F3 (the second peak is 0.5 to 0.6 times _Cmax ). Plasma concentrations decay with a half-life of 5 to 6 hours. The difference between C _24h and C _max is larger in F1 and F3 (C _24h / C _max ratios are 0.13 and 0.16, respectively) than in F2 (C _24h / C _max ratio is 0.20), which predicts that F2 is repeated. The smallest peak-to-valley ratio after administration. CR Formula F2 shows the most limited peak-to-valley ratio and high bioavailability.

總之，噻萘普汀半硫酸鹽單水合物CR配方(F1、F2及F3)比起STABLONIR配方，在用藥後顯示了較為平緩的吸收，如較晚的峰值時間、較低的C_max 、及較平緩的衰減所證實。與STABLONIR配方相比，在第一次C_max 後，噻萘普汀自CR配方中持續被吸收，造成在給藥後約10到16小時的第二個峰值。In summary, the tianeptine hemisulfate monohydrate CR formula (F1, F2 and F3) is compared to STABLON The IR formulation showed a more gradual absorption after administration, as evidenced by later peak times, lower _Cmax , and more gradual attenuation. With STABLON Compared to the IR formulation, tianeptine was continuously absorbed from the CR formulation after the first _Cmax , resulting in a second peak of about 10 to 16 hours after administration.

圖1-噻萘普汀單水半硫酸鹽的PXRD繞射圖。Figure 1 - PXRD diffraction pattern of tianeptine monohydrate hemisulfate.

圖2-噻萘普汀單水半硫酸鹽的DSC溫度記錄圖。Figure 2 - DSC temperature chart of tianeptine monohydrate hemisulfate.

圖3-噻萘普汀單水半硫酸鹽的TGA溫度記錄圖。Figure 3 - TGA temperature chart of tianeptine monohydrate hemisulfate.

圖4-噻萘普汀單水半硫酸鹽的DVS數據。Figure 4 - DVS data for tianeptine monohydrate hemisulfate.

圖5-噻萘普汀鹽酸鹽的PXRD繞射圖。Figure 5 - PXRD diffraction pattern of tianeptine hydrochloride.

圖6-噻萘普汀鹽酸鹽的DSC溫度記錄圖。Figure 6 - DSC thermogram of tianeptine hydrochloride.

圖7-噻萘普汀鹽酸鹽的TGA溫度記錄圖。Figure 7 - TGA thermogram of tianeptine hydrochloride.

圖8-噻萘普汀鹽酸鹽的DVS數據。Figure 8 - DVS data for tianeptine hydrochloride.

圖9-噻萘普汀磷酸鹽的PXRD繞射圖。Figure 9 - PXRD diffraction pattern of tianeptine phosphate.

圖10-噻萘普汀磷酸鹽的DSC溫度記錄圖。Figure 10 - DSC thermogram of tianeptine phosphate.

圖11-噻萘普汀磷酸鹽的TGA溫度記錄圖。Figure 11 - TGA thermogram of tianeptine phosphate.

圖12-噻萘普汀磷酸鹽的DVS數據。Figure 12 - DVS data for tianeptine phosphate.

圖13-噻萘普汀單水半硫酸鹽的紫外/吸收光譜。Figure 13 - Ultraviolet/absorption spectra of tianeptine monohydrate hemisulfate.

圖14-噻萘普汀單水半硫酸鹽的紅外光譜。Figure 14 - Infrared spectrum of tianeptine monohydrate hemisulfate.

圖15-噻萘普汀單水半硫酸鹽的拉曼光譜。Figure 15 - Raman spectrum of tianeptine monohydrate hemisulfate.

圖16-噻萘普汀鈉的DVS數據。Figure 16 - DVS data for tianeptine sodium.

圖17-不同噻萘普汀鹽的溶解度。Figure 17 - Solubility of different tianeptine salts.

圖18-噻萘普汀式(II)的PXRD繞射圖。Figure 18 - PXRD diffraction pattern of tianeptine formula (II).

圖19-各種形式的噻萘普汀於37℃下各種緩衝液的溶解度數據。Figure 19 - Solubility data for various buffers of various forms of tianeptine at 37 °C.

圖20-噻萘普汀鈉鹽及噻萘普汀單水半硫酸鹽製成錠劑之藥物釋放(於SGF中)。Figure 20 - Drug release (in SGF) of a tablet made from tianeptine sodium salt and tianeptine monohydrate hemisulfate.

圖21-噻萘普汀鈉鹽及噻萘普汀單水半硫酸鹽製成錠劑之藥物釋放(於SIF中)。Figure 21 - Drug release (in SIF) of tablets made from tianeptine sodium and tianeptine monohydrate hemisulfate.

圖22-噻萘普汀鈉鹽及噻萘普汀單水半硫酸鹽製成錠劑之藥物釋放速率(於SGF中)。Figure 22 - Drug release rate (in SGF) of a tablet made from tianeptine sodium salt and tianeptine monohydrate hemisulfate.

圖23-噻萘普汀鈉鹽及噻萘普汀單水半硫酸鹽製成錠劑之藥物釋放速率(以對數座標，於SGF中)。Figure 23 - Drug release rate (in logarithmic coordinates, in SGF) of tablets made from tianeptine sodium salt and tianeptine monohydrate hemisulfate.

圖24-STABLON藥錠與噻萘普汀單水半硫酸鹽錠劑相比之線性平均血漿濃度時間曲線。Figure 24-STABLON A linear mean plasma concentration time curve of the tablet compared to the tianeptine monohydrate hemisulfate tablet.

一種如式(II)所示之7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物： 其中所述半硫酸鹽單水合物之特徵為X射線粉末繞射圖包含尖峰位於2-θ 角度約8.97、約11.47、約13.91、約18.07、約19.39及約20.59度。a 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepine-11-yl) as shown in formula (II) Amino]heptanoic acid S,S-dioxide hemisulfate monohydrate: Wherein the hemisulfate monohydrate is characterized by an X-ray powder diffraction pattern comprising peaks at a 2- theta angle of about 8.97, about 11.47, about 13.91, about 18.07, about 19.39, and about 20.59 degrees. 根據申請專利範圍第1項之7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物，其係結晶型。 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl)amine according to item 1 of the scope of application Base] heptanoic acid S, S-dioxide hemisulfate monohydrate, which is a crystalline form. 根據申請專利範圍第1項之7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物，其中所述半硫酸鹽單水合物係呈現為至少有可測量的結晶7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物。 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl)amine according to item 1 of the scope of application a heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate exhibits at least measurable crystals of 7-[(3-chloro-6,11-dihydrogen) -6-Methyldibenzo[c,f][1,2]thiazepin-11-yl)amino]heptanoic acid S,S-dioxide hemisulfate monohydrate. 根據申請專利範圍第3項之7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物，其中所述結晶半硫酸鹽單水合物的重量為所述半硫酸鹽單水合物重量的約20%到約100%。 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl)amine according to item 3 of the patent application A heptanoic acid S,S-dioxide hemisulfate monohydrate wherein the crystalline hemisulfate monohydrate has a weight of from about 20% to about 100% by weight of the hemisulfate monohydrate. 根據申請專利範圍第1項之7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物，其中所述半硫酸鹽單水合物之特徵為X射線粉末繞射圖包含尖峰位於2-θ角度約8.25、約8.97、約11.49、約13.91、約14.73、約16.95、約18.07、約19.39、約20.59、約21.99、約22.83及約23.27度。 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl)amine according to item 1 of the scope of application a heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate is characterized by an X-ray powder diffraction pattern comprising a peak at a 2-theta angle of about 8.25, about 8.97, about 11.49, about 13.91, about 14.73, about 16.95, about 18.07, about 19.39, about 20.59, about 21.99, about 22.83, and about 23.27 degrees. 根據申請專利範圍第1項之7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物，其中所述半硫酸鹽單水合物之特徵為大致上如圖1所示之X射線粉末繞射圖。 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl)amine according to item 1 of the scope of application Heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate is characterized by an X-ray powder diffraction pattern substantially as shown in FIG. 根據申請專利範圍第1項之7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物，其中所述半硫酸鹽單水合物之特徵為掃描式熱差分儀溫度記錄圖包含一吸熱過渡位於約193℃處。 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl)amine according to item 1 of the scope of application Heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein the hemisulfate monohydrate is characterized by a scanning thermal differential temperature record comprising an endothermic transition at about 193 °C. 根據申請專利範圍第1項之7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化 物半硫酸鹽單水合物，其中所述半硫酸鹽單水合物以動態水分吸附分析測量出在25℃下從相對濕度約10%到約90%係防濕的。 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl)amine according to item 1 of the scope of application Base] heptanoic acid S, S-dioxide A hemisulfate monohydrate wherein the hemisulfate monohydrate is moisture resistant from a relative humidity of from about 10% to about 90% at 25 ° C as measured by dynamic moisture adsorption analysis. 根據申請專利範圍第1項之7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物，其中7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物比上硫酸比上水的比率約為2：1：2。 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl)amine according to item 1 of the scope of application H]heptanoic acid S,S-dioxide hemisulfate monohydrate, wherein 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2 The ratio of S,S-dioxide to heptanoic acid to water is about 2:1:2. 一種結晶7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物，其特徵為X射線粉末繞射圖包含尖峰位於2-θ角度約8.97、約11.49、約14.73、約20.59、約22.83及約23.27度。 a crystalline 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl)amino]heptanoic acid S, S-dioxide hemisulfate monohydrate characterized in that the X-ray powder diffraction pattern comprises peaks at about 2-87 angles of about 8.97, about 11.49, about 14.73, about 20.59, about 22.83, and about 23.27 degrees. 一種製造如式(II)之7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物的方法： 其包含步驟(a)在水和醋酸的混合物中溶解7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物或其鈉鹽；(b)添加僅包含水或包含水結合醋酸的溶劑之硫酸溶液到步驟(a)的反應混合物中；(c)結晶式(II)的化合物。A 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl)amine of formula (II) Method for the formation of heptanoic acid S,S-dioxide hemisulfate monohydrate: It comprises the step (a) of dissolving 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepine in a mixture of water and acetic acid. -11-yl)amino]heptanoic acid S,S-dioxide or a sodium salt thereof; (b) adding a sulfuric acid solution containing only water or a solvent comprising water in combination with acetic acid to the reaction mixture of step (a); c) Crystallizing the compound of formula (II). 根據申請專利範圍第11項之方法，其更進一步包含步驟：(d)分離在步驟(c)的反應混合物中所得到之式(II)化合物；(e)以水和醋酸的混合物清洗式(II)化合物；(f)進一步用水清洗式(II)化合物；及(g)乾燥式(II)化合物。 According to the method of claim 11, further comprising the steps of: (d) separating the compound of the formula (II) obtained in the reaction mixture of the step (c); (e) washing the mixture with a mixture of water and acetic acid ( II) a compound; (f) further washing the compound of the formula (II) with water; and (g) drying the compound of the formula (II). 根據申請專利範圍第11項之方法，其中該方法實施時未分離下式之中間產物： According to the method of claim 11, wherein the method does not separate the intermediate product of the formula: 一種如申請專利範圍第1項之7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物的用途，係用於製備治療患有抑鬱症之哺乳動物的藥物。 A 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepine-11-yl) as claimed in claim 1 The use of amino]heptanoic acid S,S-dioxide hemisulfate monohydrate is used to prepare a medicament for treating a mammal suffering from depression. 一種包含申請專利範圍第1項之7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物及醫藥上可接受載體的醫藥組合物。 A 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepine-11-yl) containing the first item of the patent application scope A pharmaceutical composition of an amino]heptanoic acid S,S-dioxide hemisulfate monohydrate and a pharmaceutically acceptable carrier. 根據申請專利範圍第15項之組合物，其中所述醫藥組合物係控制釋放醫藥組合物。 The composition of claim 15 wherein the pharmaceutical composition is a controlled release pharmaceutical composition. 一種控制釋放間質錠劑，其包含：醫藥上有效量的7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物；及一個或多個釋放控制聚合物，其中當該錠劑給予患者口服時，其7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物的平均最高血漿濃度(C_max )為約100ng/mL到約150ng/mL。A controlled release interstitial lozenge comprising: a pharmaceutically effective amount of 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepine a heterologous 11-yl)amino]heptanoic acid S,S-dioxide hemisulfate monohydrate; and one or more release controlling polymers, wherein when the tablet is administered orally to a patient, its 7-[ (3-Chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepin-11-yl)amino]heptanoic acid S,S-dioxide The average maximum plasma concentration ( _Cmax ) is from about 100 ng/mL to about 150 ng/mL. 根據申請專利範圍第17項之錠劑，其中所述錠劑使用美國藥典溶離儀器II型(槳式)在約37℃、100rpm下、900mL模擬胃液(pH值約為1.2)中所測量的體外溶 離速率在釋放1小時後少於14%重量的7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物，釋放7小時後在45%到80%重量的7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物之間，並在釋放16小時後多於90%重量的7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物半硫酸鹽單水合物。 A lozenge according to claim 17, wherein the tablet is in vitro in the form of a U.S. Pharmacopoeia Dissolving Apparatus Type II (paddle) at about 37 ° C, 100 rpm, 900 mL of simulated gastric fluid (pH of about 1.2). Dissolve Less than 14% by weight of 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepine - after 1 hour of release 11-yl)amino]heptanoic acid S,S-dioxide hemisulfate monohydrate, after 7 hours of release, in 45% to 80% by weight of 7-[(3-chloro-6,11-dihydro- 6-Methyldibenzo[c,f][1,2]thiazepine-11-yl)amino]heptanoic acid S,S-dioxide hemisulfate monohydrate, and is released More than 90% by weight of 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f][1,2]thiazepine-11-yl) after 16 hours Amino]heptanoic acid S,S-dioxide hemisulfate monohydrate. 根據申請專利範圍第17項之錠劑，其中所述錠劑當給予患者口服時，其7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物的平均最高血漿濃度(C_max )為約100ng/mL到約120ng/mL。A lozenge according to item 17 of the patent application, wherein the tablet is 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f] when administered orally to a patient. The average maximum plasma concentration ( _Cmax ) of [1,2]thiazepin-11-yl)amino]heptanoic acid S,S-dioxide is from about 100 ng/mL to about 120 ng/mL. 根據申請專利範圍第17項之錠劑，其中所述錠劑當給予患者口服時，其7-[(3-氯-6,11-二氫-6-甲基二苯并[c,f][1,2]硫氮雜卓-11-基)胺基]庚酸S,S-二氧化物達到平均最高血漿濃度的中位數時間(T_max )範圍從約2.5小時到約3.0小時。A lozenge according to item 17 of the patent application, wherein the tablet is 7-[(3-chloro-6,11-dihydro-6-methyldibenzo[c,f] when administered orally to a patient. The median time ( _Tmax ) for [1,2]thiazepin-11-yl)amino]heptanoic acid S,S-dioxide to achieve an average maximum plasma concentration ranges from about 2.5 hours to about 3.0 hours. 根據申請專利範圍第17項之錠劑，其中所述錠劑當給予患者口服時，其血漿濃度時間曲線的曲線下平均面積範圍從約1170ng.hr/mL到約1380ng.hr/mL。 A lozenge according to claim 17, wherein the lozenge, when administered orally to a patient, has an average area under the curve of the plasma concentration time curve ranging from about 1170 ng.hr/mL to about 1380 ng.hr/mL. 根據申請專利範圍第17項之錠劑，其中所述一個或多個釋放控制聚合物包含羥丙基甲基纖維素。 A lozenge according to item 17 of the patent application, wherein the one or more release controlling polymers comprise hydroxypropyl methylcellulose. 根據申請專利範圍第17項之錠劑，其中所述一個或多個釋放控制聚合物包含黏度80到120cps的第一羥丙基甲基纖維素(溶於水中的2%溶液)及黏度3,000到5,600cps的第二羥丙基甲基纖維素(溶於水中的2%溶液)。 The tablet according to claim 17, wherein the one or more release controlling polymers comprise first hydroxypropyl methylcellulose (2% solution dissolved in water) having a viscosity of 80 to 120 cps and a viscosity of 3,000 to 5,600 cps of second hydroxypropyl methylcellulose (2% solution in water). 根據申請專利範圍第23項之錠劑，其中所述第一羥丙基甲基纖維素及所述第二羥丙基甲基纖維素之比率為約2：1到約4：1。A lozenge according to claim 23, wherein the ratio of the first hydroxypropylmethylcellulose to the second hydroxypropylmethylcellulose is from about 2:1 to about 4:1.

• 2009
  • 2009-10-29 JO JO2009398A patent/JO2844B1/en active
  • 2009-10-30 TW TW098136937A patent/TWI492937B/en not_active IP Right Cessation
  • 2009-10-30 AR ARP090104204 patent/AR075295A1/en unknown
  • 2009-10-30 UY UY32216A patent/UY32216A/en unknown

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