Pharmaceutical JAK kinase inhibitor and diethylene glycol composition for topical administration and preparation method therefor

Abstract

A pharmaceutical composition for topical administration and a preparation method therefor are described. In particular, a pharmaceutical composition comprising (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide, or a pharmaceutically acceptable salt thereof, and diethylene glycol monoethyl ether is described.

Claims

1. A pharmaceutical composition comprising (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, and diethylene glycol monoethyl ether wherein a content of the diethylene glycol monoethyl ether is 0.5% to 20% based on the total weight of the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises a matrix, and the matrix is a water-soluble matrix.

3. The pharmaceutical composition according to claim 2, wherein the matrix contains polyethylene glycol 400 and polyethylene glycol 4000.

4. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition has a content of the matrix of 40% to 90%, based on a total weight of the pharmaceutical composition.

5. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has a content of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or the pharmaceutically acceptable salt thereof of 0.1% to 20% based on a total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition further comprises at least one additive selected from the group consisting of preservatives, humectants, and antioxidants.

7. The pharmaceutical composition according to claim 6, wherein the preservative is at least one selected from the group consisting of methylparaben, ethylparaben, benzoic acid, sorbic acid, phenoxyethanol, trichloro-tert-butylalcohol, phenylmercuric acetate, phenol, cresol and benzalkonium chloride.

8. The pharmaceutical composition according to claim 6, wherein the humectant is at least one selected from the group consisting of glycerol, propylene glycol, 1,3-butanediol, sorbitol, xylitol, hyaluronic acid and trehalose.

9. The pharmaceutical composition according to claim 6, wherein the antioxidant is at least one selected from the group consisting of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and tocopherol.

10. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises: i) 0.1% w/w to 20% w/w of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or the pharmaceutically acceptable salt thereof, ii) 0.5% w/w to 20% w/w of diethylene glycol monoethyl ether, iii) 40% w/w to 90% w/w of a water-soluble matrix, wherein the water-soluble matrix contains polyethylene glycol 400 and polyethylene glycol 4000, and iv) 20% w/w to 60% w/w of a humectant, wherein the humectant is at least one selected from the group consisting of glycerol, propylene glycol, 1,3-butanediol, sorbitol, xylitol, hyaluronic acid and trehalose.

11. A pharmaceutical composition comprising: i) 0.1% w/w to 20% w/w of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or a pharmaceutically acceptable salt thereof, 2) 0.5% w/w to 20% w/w diethylene glycol monoethyl ether, and 3) 40% w/w to 90% w/w of a water-soluble matrix, wherein the water-soluble matrix contains polyethylene glycol 400 and polyethylene glycol 4000.

12. The pharmaceutical composition according to claim 1, wherein the (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide has a particle size of not greater than 50 μm.

13. A method for preparing the pharmaceutical composition according to claim 1 comprising: i) mixing (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or the pharmaceutically acceptable salt thereof, diethylene glycol monoethyl ether, and at least one pharmaceutical excipient selected from the group consisting of matrices, antioxidants and preservatives, to obtain a mixture, and ii) filling the mixture obtained in step i).

14. The pharmaceutical composition according to claim 2, wherein the water-soluble matrix comprises a polyethylene glycols macromolecular compound.

15. The pharmaceutical composition according to claim 3, wherein the matrix has a weight ratio of the polyethylene glycol 400 to the polyethylene glycol 4000 of 1:10 to 10:1.

16. The pharmaceutical composition according to claim 4, wherein the content of the matrix is 50% to 80% based on the total weight of the pharmaceutical composition.

17. The pharmaceutical composition according to claim 5, wherein the content of (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide or the pharmaceutically acceptable salt thereof is 1% to 10% based on the total weight of the pharmaceutical composition.

18. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition has a content of the preservative of 0.05% to 0.5% based on a total weight of the pharmaceutical composition.

19. The pharmaceutical composition according to claim 8, Wherein the pharmaceutical composition has a content of the humectant of 20% to 60% based on a total weight of the pharmaceutical composition.

20. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition has a content of the antioxidant of 0.05% to 0.5% based on a total weight of the pharmaceutical composition.

21. The pharmaceutical composition according to claim 12, wherein the particle size is not greater than 30 μm.

Description

DETAILED DESCRIPTION OF EMBODIMENTS

(1) The present disclosure will be explained in detail through the following embodiments. The embodiments of the present disclosure are only used to describe the technical solutions of the present disclosure, and do not limit the essence and scope of the present disclosure.

Embodiments 1-4

(2) An active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole- 2(1H)-carboxamide was slowly added to propylene glycol, which was then mixed with caprylocaproyl macrogolglycerides, diethylene glycol monoethyl ether, and isopropyl myristate, respectively, and then polyethylene glycol 400 (PEG400), polyethylene glycol 4000 (PEG4000), glycerol, and butylated hydroxytoluene (BHT) were added. The resulting mixtures were stirred to dissolution and were rapidly cooled. The specific data is shown in Table 1.

(3) TABLE-US-00001 TABLE 1 Embodiment Ingredient 1 2 3 4 Active  2 g  2 g  2 g  2 g Ingredient Penetration Caprylocaproyl Diethylene glycol Isopropyl — Enhancer macrogolglycerides monoethyl ether myristate  2 g  2 g  2 g Glycerol 17.9 g  17.9 g  17.9 g  17.9 g  Propylene 18.0 g  18.0 g  18.0 g  20.0 g  glycol PEG400 40.0 g  40.0 g  40.0 g  40.0 g  PEG4000 20.0 g  20.0 g  20.0 g  20.0 g  BHT  0.1 g  0.1 g  0.1 g  0.1 g Ethylparaben  0.2 g  0.2 g  0.2 g  0.2 g Total amount 100 g 100 g 100 g 100 g

(4) The ointments obtained in Embodiment 1-4 were subjected to an in vitro transdermal test to investigate the ability of the active ingredient of different formulations to penetrate the skin barrier and stay in the skin.

(5) Preparation of excised skin: the skins of the Bama pigs in the same region were selected as the test model, hairs were shaved and the subcutaneous excess fat was peeled off. The skins were washed with PBS, and stored at −70° C. for later use.

(6) In vitro transdermal test: the pig's skins were restored to room temperature and mounted on a Franz diffusion cell. About 0.300 g of the ointment was accurately measured, disposed in the supplying chamber, and spread evenly. A rotor and 4 mL of phosphate buffer solution (pH=7.4) were added to the receiving chamber. A multi-functional transdermal diffusion tester was used, with temperature set to 32.0° C. and a rotation speed set to 500 rpm. The sampling was carried out at 2, 4, 6, 8, 10, 12 h with a volume of 2 mL, and a phosphate buffer solution with the same volume and temperature was added at the same time. The drug contents of the samples were detected by LC-MS, and the cumulative drug transdermal amount was calculated. After completion of the test, the residual active ingredient in the supplying chamber was collected by cotton swab wiping method, the active ingredient in the stratum corneum was collected by tape peeling method, the remaining skin was shredded to collect the active ingredient, the obtained three samples containing the active ingredient were dissolved in a suitable solvent and adjusted to a constant volume, the active ingredient content was measured by HPLC method, and the recovery rate was calculated. The content of the active ingredient in the supplying chamber was referred to as residual amount, the content of the active ingredient in the stratum corneum and the skin were referred to as stratum corneum retention amount and epidermal retention amount respectively, and the cumulative transdermal amount of the active ingredient in the receiving chamber was referred to as transdermal amount. The above test was performed in 12 replicates, and the results are shown in Table 2.

(7) TABLE-US-00002 TABLE 2 Embodiment Data 1 2 3 4 Transdermal amount (%) 0.0067 0.0061 0.0059 0.0034 Stratum corneum 1.54 2.36 1.76 1.08 retention amount (%) Epidermal retention 1.86 1.60 1.60 0.80 amount (%) Total skin retention 3.375 4.019 3.324 1.880 amount (%) Enhancing ratio 1.80 2.14 1.77 1 Note: the total skin retention amount = the stratum corneum retention amount + the epidermal retention amount; the enhancing ratio refers to the ratio of the total skin retention amount of the formulation with the penetration enhancer to the total skin retention amount of the formulation without the penetration enhancer.

(8) It can be known from the above data that the active ingredient in embodiment 2 has the largest total skin retention amount and optimal enhancing ratio, which indicates that diethylene glycol monoethyl ether has better effect on enhancing the transdermal delivery of the active ingredient.

Embodiments 5-6

(9) An active ingredient (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole- 2(1H)-carboxamide was slowly added to propylene glycol, and diethylene glycol monoethyl ether was added and mixed, then PEG400, PEG4000, glycerol and BHT were added, the resulting mixture was stirred for dissolving and rapidly cooled. The specific data are shown in Table 3.

(10) TABLE-US-00003 TABLE 3 Embodiment Ingredient 5 6 Active ingredient  2 g  2 g Diethylene glycol  2 g  2 g monoethyl ether Glycerol 17.9 g  10.0 g  Propylene glycol 18.0 g  25.9 g  PEG400 30.0 g  40.0 g  PEG4000 30.0 g  20.0 g  BHT  0.1 g  0.1 g Total amount 100 g 100 g

(11) In vitro transdermal test: the method was the same as embodiment 1, and the results are shown in Table 4.

(12) TABLE-US-00004 TABLE 4 Embodiment Data 5 6 Transdermal amount (%) 0.0018 0.0021 Stratum corneum 2.25 0.90 retention amount (%) Epidermal retention 1.16 0.77 amount (%) Residual amount (%) 96.59 98.33 Recovery rate (%) 103.23 97.66

(13) Conclusion:

(14) It is seen that when the ratio of PEG400 to PEG4000 is 2:1, the active ingredient has the larger epidermal retention amount, which is beneficial to the active ingredient in the pharmaceutical composition to exert its effect in skin, by comparing embodiment 5 with embodiment 2.

(15) It is seen that when the ratio of glycerol to propylene glycol is 1:1, the active ingredient has the larger epidermal retention amount, which is beneficial to the active ingredient in the pharmaceutical composition to exert its effect in skin, by comparing embodiment 6 with embodiment 2.

Embodiment 7: Stability Study

(16) The samples obtained in embodiment 2 were placed under an accelerated condition (30° C.±2° C./RH65%±5%) and a long-term condition (25° C.±2° C./RH60%±5%) to study their stability. The appearance, content, viscosity, and related substances were evaluated, and the viscosity was determined by the cone penetration method of general principle 0983 in Chinese Pharmacopoeia 2015 edition (Volume IV). The results are shown in Table 5.

(17) TABLE-US-00005 TABLE 5 stability study results Related substances (%) Maximum single Index Cone unknown Total Evaluation Time Content penetration Impurity impurity impurities conditions (month) Appearance (%) (mm) D (%) (%) (%) 30° C. ± 2° C./ Original Off-white 98.2 28.3 0.12 0.04 0.18 RH65% ± 5% state ointment 1M Off-white 97.6 26.2 0.11 0.03 0.16 ointment 2M Off-white 96.8 27.4 0.12 0.04 0.17 ointment 3M Off-white 96.8 27.3 0.13 0.04 0.19 ointment 6M Off-white 100.5 27.4 0.12 0.03 0.16 ointment 25° C. ± 2° C./ Original Off-white 101.5 35.0 0.12 0.04 0.19 RH60% ± 5% state ointment 3M Off-white 96.2 28.5 0.13 0.04 0.20 ointment 6M Off-white 98.7 28.2 0.10 0.04 0.16 ointment 9M Off-white 99.0 28.4 0.12 0.04 0.18 ointment 12M Off-white 100.3 28.2 0.10 0.02 0.15 ointment

(18) The results indicate that the product obtained in embodiment 2 shows good physical stability and chemical stability under the accelerated condition (30° C.±2° C./RH65%±5%) and the long-term condition (25° C.±2° C./RH60%±5%).