Pharmaceutical composition including sertraline or salt thereof

Abstract

The present invention relates to a pharmaceutical composition including sertraline or a salt thereof. The pharmaceutical composition according to the present invention can achieve excellent stability and safety by inhibiting the generation of impurities of nitrosamines.

Description

[0001]

Description of the invention

Title of the invention

Technical field

Background art

Prior Art Documents

Patent Documents

Non-Patent Documents

Summary of the invention

Technical problem

Technical solution

[0002] <MS / MS 조건> Equipment: Waters XEVO TQ-MS Ionization Mode: ESI Positive (MRM mode) Capillary Voltage: 1.75 kV Cone Gas Flow: 350 L / Hr Desolvation Gas Flow: 900 L / Hr Desolvation temp: 450 ℃ Table 2 Analysis Comparative Example 1 Conduct Conduct Conduct Conduct Conduct Conduct Conduct Conduct Conduct Material Initial After 4 weeks Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 N-nitroso sertraline 0.13 7.10 0.47 0.34 1.06 0.73 0.68 0.57 0.41 0.87 1.05 0.41 (ppm) Referring to Table 2, under accelerated conditions, comparative examples The tablets according to Example 1 showed an increase of NNS generation by more than 54 times compared to the initial value after 4 weeks. On the other hand, it was confirmed that the compositions of Examples 1 to 10 according to the present invention significantly suppressed NNS generation compared to the comparative example. Experimental Example 2 Preparation of Tablets Examples 11 to 13 Tablets were prepared in substantially the same manner as the preparation method of the tablets of Examples 1 to 10 and Comparative Example 1, except that each tablet was prepared in the weight (mg) shown in Table 3 below. In Table 3 량 (mg) 원료명 분류Comparative Example 1 Example 11 Example 12 Example 13 Sertraline hydrochloride Main ingredient 56.0 28.0 56.0 111.9 Microcrystalline cellulose Excipient 49.1 23.0 46.1 92.1 Calcium hydrogen phosphate hydrate Excipient 24.0 12.0 24.0 48.0 Sodium starch glycolate Disintegrant 15.0 7.5 15.0 30.0 Hydroxypropyl cellulose Binder 4.5 2.3 4.5 9.0 Magnesium stearate Lubricant 1.5 0.8 1.5 3.0 Magnesium oxide Alkalizer - 1.5 3.0 6.0 Total (mg) 150.0 75.0 150.0 300.0 The tablet of Comparative Example 1 is shown in Table 1. The content of each component was described instead of the weight % for the same tablet as that of Comparative Example 1. Stability Evaluation 2 The amount of NNS was measured for the tablets of Examples 11 to 13 in substantially the same manner as in Stability Evaluation 1, and compared with the value measured for Comparative Example 1 in Stability Evaluation 1, and the results are shown in Table 4 and Figure 2 below. Table 4 Analyte Comparative Example 1 Example 11 Example 12 Example 13 N-nitroso sertraline (ppm) 7.10 0.55 0.47 0.43 As confirmed in Table 4, it was found that the tablets of Examples 11 to 13 according to the present invention maintained a lower content of N-nitroso-sertraline compared to Comparative Example 1 in the contents of various main components. Therefore, the tablet according to the present invention has excellent stability and can suppress the increase of flexible substances, and specifically, can suppress the generation of N-nitroso sertraline, thereby achieving excellent safety. Experimental Example 3 Examples 14 to 16 - Preparation of tablets Tablets of Examples 14 to 17 were prepared in substantially the same manner as the preparation method of the tablets of Examples 1 to 10 and Comparative Example 1, except that the composition ratios (weight %) described in Table 5 below were prepared.Table 5 Composition ratio (weight%) Raw material name Classification Comparative example Example Example Example Example Example 1 1 14 15 16 2 Sertraline hydrochloride Main ingredient 37.3 37.3 37.3 37.3 37.3 37.3 Microcrystalline cellulose Excipient 32.7 31.7 30.7 27.7 22.7 17.7 Calcium hydrogen phosphate hydrate Excipient 16.0 16.0 16.0 16.0 16.0 16.0 16.0 Sodium starch glycolate Disintegrant 10.0 10.0 10.0 10.0 10.0 10.0 Hydroxypropyl cellulose. 오스 Binder 3.0 3.0 3.0 3.0 3.0 3.0 Magnesium stearate Lubricant 1.0 1.0 1.0 1.0 1.0 Al 칼리 산화마그네슘 fury 제 - 1.0 2.0 5.0 10.0 15.0 Stability Evaluation 3 The amount of NNS was measured for the tablets of Examples 14 to 16 in substantially the same manner as in Stability Evaluation 1, and compared with the values ​​measured for Comparative Example 1, Example 1, and Example 2 measured in Stability Evaluation 1, and the results are shown in Table 6 and Figure 3 below. Table 6 Example Example Analyte Comparative Example 1 Example 1 실시예 14 실시예 2 15 16 N-nitroso sertraline ( ppm)As confirmed in Table 6, it was found that the tablets of Examples 14 to 16 according to the present invention maintained a low content of N-nitroso-sertraline at various contents of the alkalizing agent. Therefore, the tablets according to the present invention have excellent stability and can suppress the increase of related substances, and specifically, can suppress the generation of N-nitroso-sertraline, thereby achieving excellent safety. Experimental Example 4 Preparation of Tablets Examples 17 to 19 Tablets The tablets of Examples 17 to 19 were prepared in substantially the same manner as the preparation methods of the tablets of Examples 1 to 10 and Comparative Example 1, except that the composition ratios (weight %) described in Table 7 below were prepared. Table 7 Composition ratio (weight%) Raw material name Classification Comparative example Example Example Example Example Example 1 3 17 18 19 4 Sertraline hydrochloride Main ingredient 37.3 37.3 37.3 37.3 37.3 37.3 Microcrystalline cellulose Excipient 32.7 31.7 30.7 27.7 22.7 17.7 Calcium hydrogen phosphate hydrate Excipient 16.0 16.0 16.0 16.0 16.0 16.0 Sodium starch glycolate Disintegrant 10.0 10.0 10.0 10.0 10.0 10.0 Hydroxypropyl cellulose 스 Binder 3.0 3.0 3.0 3.0 3.0 3.0 Magnesium stearate Lubricant 1.0 1.0 1.0 1.0 1.0 1.0 Carbon 산마그네슘 알칼리화 -1.0 2.0 5.0 10.0 15.0 제Total (%) 100.0 100.0 100.0 100.0 100.0 100.0 Stability Evaluation 4 The amount of NNS was measured for the tablets of Examples 17 to 19 in substantially the same manner as in Stability Evaluation 1, and compared with the values ​​measured for Comparative Example 1, Example 3, and Practical Example 4 measured in Stability Evaluation 1, and the results are shown in Table 8 and Figure 4 below. Table 8 Comparative examples of analytes Example 1 Example 3 Example 17 Example 18 Example 19 Example 4 N-nitroso sertraline (ppm) 7.10 1.06 0.5 0.49 0.53 0.73 As confirmed in Table 8, it was found that the tablets of Examples 17 to 19 according to the present invention maintained a low content of N-nitroso-sertraline at various contents of the alkalizing agent. Therefore, the tablets according to the present invention have excellent stability and can suppress the increase of related substances, and specifically, can suppress the generation of N-nitroso-sertraline, thereby achieving excellent safety. Experimental Example 5 Preparation of capsules for Examples 20 and 21 Capsules Capsules (Examples 20 and 21) were prepared with the composition ratios (weight %) described in Table 9 below. All the ingredients were mixed according to the ingredients and contents described in Table 9 below and filled into gelatin capsules (Example 20) and HPMC capsules (Example 21), respectively, to manufacture capsules according to Example 20 and capsules according to Example 21, respectively. The tablet according to Example 12 of Table 9 below is a tablet substantially the same as the tablet of Table 3, except that the contents are expressed as a composition ratio (weight %). Table 9 성비 (중량%) 원료명 분류Comparative Example 1 Example 12 Example 20 Example 21 Sertraline hydrochloride Active ingredient 37.3 37.3 37.3 37.3 Microcrystalline cellulose Excipient 32.7 30.7 30.7 30.7 Calcium hydrogen phosphate hydrate Excipient 16.0 16.0 16.0 16.0 Sodium starch glycolate Disintegrant 10.0 10.0 10.0 10.0 Hydroxypropyl cellulose Binder 3.0 3.0 3.0 3.0 Magnesium stearate Lubricant 1.0 1.0 1.0 1.0 Magnesium oxide Alkalizer - 2.0 2.0 2.0 Gelatin capsule - - O - Cap 슐HPMC Capsules - - - O Tablets OO - - Total (%) 100.0 100.0 100.0 100.0 Stability Evaluation 5 The amount of NNS was measured for the tablets according to Example 12 in substantially the same manner as in Stability Evaluation 1, and compared with the value measured for Comparative Example 1 measured in Stability Evaluation 1. Meanwhile, the amount of NNS was measured for the capsules according to Examples 20 and 21. For the capsules according to Examples 20 and 21, each was stored under accelerated conditions (40°C, relative humidity 75%), taken out after a specified period (initially and after 4 weeks), and the entire contents of about 10 capsules or more were taken out to make a homogeneous mixture, and an amount equivalent to 150 mg of sertraline (free base basis) was precisely taken, and 10 mL of 80% methanol aqueous solution as a diluent was added and stirred. This solution was centrifuged at 4000 rpm for 10 minutes, and then the supernatant was filtered through a 0.2 μm syringe filter (PVDF). The first filtrate was discarded and the next filtrate was used. The amount of NNS in the obtained test solution was measured using LC-MS / MS under the same conditions as in stability evaluation 1. The results are shown in Table 10 and Fig. 5 below. Table 10 Analyte Comparative Example 1 Example 12 Example 20 Example 21 N-nitroso sertraline (ppm) 7.10 0.42 0.40 0.34 As confirmed in Table 10, it was found that the tablet of Example 12 and the capsules according to Examples 20 and 21 according to the present invention, which are various solid preparations such as tablets and capsules, maintained a low content of N-nitroso-sertraline. Therefore, the tablet according to the present invention has excellent stability and can suppress the increase of flexible substances, and specifically, can suppress the generation of N-nitroso sertraline, thereby achieving excellent safety.Experimental Example 6 Examples 20 to 27 / Comparative Examples 2 to 4 - Preparation of tablets and / or capsules Capsules of Comparative Examples 3 and 4, Examples 23, 24, 26 and 27 were prepared in substantially the same manner as the capsules of Examples 20 and 21, except that they were prepared in the composition ratios (weight %) described in Table 11 below. In addition, tablets of Comparative Examples 2, 22 and 25 were prepared in substantially the same manner as the tablets of Examples 1 to 10 and Comparative Example 1, except that they were prepared in the ingredients and composition ratios (weight %) described in Table 11 below. The tablets of Comparative Example 2, Practical Example 22 and Example 25 used lactose monohydrate instead of microcrystalline cellulose, mannitol instead of calcium hydrogen phosphate, crospovidone and croscarmellose sodium instead of sodium starch glycolate, and povidone instead of hydroxypropyl cellulose, compared to the tablet of Example 1. Table 11 Composition ratio (weight%) Raw material name Classification Comparison Comparison Comparison Example Example Example Example Example Example Example Example 2 Example 3 Example 4 22 23 24 25 26 27 Sertraline hydrochloride Main ingredient 37.3 37.3 37.3 37.3 37.3 37.3 37.3 37.3 Lactose monohydrate Excipient 32.7 32.7 32.7 27.7 27.7 27.7 27.7 27.7 27.7 Mannitol Excipient 16.0 16.0 16.0 16.0 16.0 16.0 16.0 16.0 Crospovidone Disintegrant 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Crosscarmelos. 나트륨 Disintegrant 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 Povidone binder 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 Magnesium stearate glidant 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 산화마그네슘 알칼리 - - - 5.0 5.0 5.0 - - - Magnesium Carbonate Topical Agent - - - - - - - 5.0 5.0 5.0 Gelatin Cap슐 - O - - O - - O -Capsule HPMC Cap 슐 - - O - - O - - O Tablet O - O - O - - Total (%) 100 100 100 100 100 100 100 100 100 100 Stability Evaluation 6 The amount of NNS was measured in substantially the same manner as in Stability Evaluation 1 for the tablets according to Comparative Examples 2, Example 22 and Example 25, while the amount of NNS was measured in substantially the same manner as in Stability Evaluation 5 for the capsules according to Comparative Examples 3 and 4, and Examples 23, 24, 26 and 27. The results are shown in Table 12 and Fig. 6 below. Table 12 Non 교 Comparison Comparison Example Example Example Example Example Example Example 석물질 Example 2 Example 3 Example 4 22 23 24 25 26 27 N-nitroso sertraline (ppm) 8.60 10.38 3.39 0.28 0.21 0.21 0.40 0.48 0.28 As confirmed in Table 12, it was found that the solid preparations according to Examples 22 to 27 according to the present invention maintained a low content of N-nitroso-sertraline in combinations of various excipients, disintegrants and / or binders. Therefore, the solid preparation according to the present invention has excellent stability and can suppress the increase of related substances, and specifically, can suppress the generation of N-nitroso-sertraline, thereby achieving excellent safety.

Claims

【Scope of Claims】

1. A pharmaceutical composition comprising sertraline or a pharmaceutically acceptable salt thereof; and an alkalizing agent. 【

2. In claim 1, the pharmaceutically acceptable salt of sertraline comprises at least one selected from the group consisting of hydrochloride salt, hydrobromide salt, hydroiodide salt, sulfate, bisulfate, phosphate, acetate, lactate, maleate, fumarate, citrate, tartrate, bitartrate, succinate, gluconate, and saccharate. [

3. A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of sertraline is a hydrochloride salt. Claim 4] In claim 1, the alkalizing agent can inhibit the production of N-nitroso-sertraline. Pharmaceutical composition. 【

5. A pharmaceutical composition according to claim 1, wherein the alkalizing agent comprises at least one selected from the group consisting of magnesium oxide, magnesium carbonate, magnesium hydroxide, calcium hydroxide, and meglumine.

6. A pharmaceutical composition according to claim 1, wherein the alkalizing agent is contained in an amount of 0.1 wt% to 15 wt% of the total 100 wt% of the pharmaceutical composition.

7. A pharmaceutical composition according to claim 1, wherein N-nitroso-sertraline production is inhibited.

8. A pharmaceutical composition according to claim 1, wherein, when stored at 40°C and 75% relative humidity for 4 weeks, N-nitroso-sertraline is present at a concentration of 1.5 ppm or less. Claim 9】 A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises at least one additive selected from among an excipient, a binder, a disintegrant, a lubricant, and a glidant.

10. In claim 9, the excipient comprises lactose or a hydrate thereof, starch, cell lactose, dextrin, microcrystalline cellulose, potassium hydrogen phosphate or a hydrate thereof, calcium hydrogen phosphate or a hydrate thereof, sugar, sugar alcohol, alginate, alkaline earth metal salt, clay, polyethylene glycol, or a mixture thereof, a pharmaceutical composition. 【

11. A pharmaceutical composition according to claim 9, wherein the excipient comprises lactose or a hydrate thereof, starch, cellactose, dextrin, microcrystalline cellulose, potassium hydrogen phosphate or a hydrate thereof, calcium hydrogen phosphate or a hydrate thereof, mannitol, glucose, alginate, alkaline earth metal salt, clay, polyethylene glycol, or a mixture thereof.

12. A pharmaceutical composition according to claim 9, wherein the excipient comprises lactose or a hydrate thereof, microcrystalline cellulose, calcium hydrogen phosphate or a hydrate thereof, mannitol or a mixture thereof.

13. A pharmaceutical composition according to claim 9, wherein the disintegrant comprises crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropylmethylcellulose, sodium starch glycolate, croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, alginic acid or a sodium salt thereof, or a mixture thereof.

14. A pharmaceutical composition according to claim 9, wherein the disintegrant comprises crospovidone, sodium starch glycolate, croscarmellose sodium, or a mixture thereof. Claim 15】 A pharmaceutical composition in claim 9, wherein the binder comprises a polyvinylpyrrolidone derivative, methylcellulose, hydroxypropylcellulose, ethylcellulose, starch, gelatin, or a mixture thereof.

16. A pharmaceutical composition according to claim 9, wherein the binder comprises hydroxypropyl cellulose, povidone, or a mixture thereof. Claim 17】 A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is an oral formulation. 【

18. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a tablet or capsule.

19. In claim 9, the pharmaceutical composition comprises 30 to 45 wt% of sertraline or a salt thereof, 25 to 55 wt% of an excipient, 1 to 15 wt% of a disintegrant, 1 to 10 wt% of a binder, 0.1 to 3 wt% of a lubricant, and 0.1 to 15 wt% of an alkalizing agent, based on 100 wt% of the pharmaceutical composition. Claim 20] The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a pharmaceutical composition for treating or preventing one or more diseases selected from depression; panic disorder; social anxiety disorder and social phobia; adult and pediatric obsessive-compulsive disorder; and post-traumatic stress disorder.

21. A solid preparation comprising sertraline or a pharmaceutically acceptable salt thereof; and an alkalizing agent including at least one selected from the group consisting of magnesium oxide, magnesium carbonate, magnesium hydroxide, calcium hydroxide, and meglumine, wherein the solid preparation contains N-nitroso-sertraline at a concentration of 1.5 ppm or less when stored for 4 weeks at 40°C and a relative humidity of 75%. 【

22. A solid preparation according to claim 21, wherein the alkalizing agent is magnesium oxide or magnesium carbonate.

23. A solid preparation according to claim 21 or 22, wherein the alkalizing agent is contained in an amount of 0.1 wt% to 15 wt% of the total 100 wt% of the solid preparation.

24. A solid preparation according to claim 21 or 22, wherein the solid preparation is a tablet or a capsule.

25. In claim 21 or 22, the solid preparation comprises 30 to 45 wt% of sertraline or a salt thereof, 25 to 55 wt% of an excipient, 1 to 15 wt% of a disintegrant, 1 to 10 wt% of a binder, 0.1 to 3 wt% of a lubricant, and 0.1 to 15 wt% of an alkalizing agent, based on 100 wt% of the solid preparation. A pharmaceutical composition comprising:

26. A method for preventing or treating one or more diseases selected from depression; panic disorder; social anxiety disorder and social phobia; adult and childhood obsessive-compulsive disorder; and post-traumatic stress disorder by administering the pharmaceutical composition according to claim 1 or the solid preparation according to claim 21 to a subject in need thereof.

27. Use of the pharmaceutical composition according to claim 1 or the solid preparation according to claim 21 for preventing or treating one or more diseases selected from depression; panic disorder; social anxiety disorder and social phobia; adult and pediatric obsessive-compulsive disorder; and post-traumatic stress disorder. Claim 28] Use of a pharmaceutical composition according to claim 1 or a solid preparation according to claim 21 for the manufacture of a medicament for preventing or treating one or more diseases selected from depression; panic disorder; social anxiety disorder and social phobia; obsessive-compulsive disorder in adults and children; and post-traumatic stress disorder.

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