TW446561B - Improved stabilization of prostaglandin drug - Google Patents

Abstract

The present invention relates to a stable solid type prostaglandin drug, particularly a Misoprostol (± methyl 7-[3(Α)-hydroxy-2-β-(4(RS)-4-hydroxy-4-methyl-trans-1-octen-1-yl)-oxycyclopenta-1Α-yl]heptanoate, which comprises an ammonio methacrylate copolymer. The ammonio methacrylate copolymer used in the stable solid type of the present invention comprises Eudragit RS series copolymers, Eudragit RL series copolymers, Eudragit S, Eudragit L, and a mixture thereof.

Description

Printed by the Central Labor Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, 44656 1 A7 ___B7_ V. Description of the Invention (1) Background of the Invention The present invention relates to a solid stable dosage form of a prostaglandin drug, particularly Misoprostol ((± ) Methyl 7- [3 (α) .Cyclo-2-p- (4 (RS) -4-Cyclo-4-methyl-trans-1-octen-1-yl) -oxycyclopentane -1α · yl] heptyl ester, (±) π ^ ΐΙιγ17- [3 (α) -1ψ < ΪΓ〇χγ-2 · β- (4 (Ε5) · 44 ^ (ΐΓ〇χγ · 4-ηΐ6υ ^ 1 -ί3η3-1-octen-l-yl) -oxycyclopent-la-yl] lieptanoate) is a sedative and stable dosage form, which uses fluonio methacrylate copolymer. Previous technology US patent No. 3,965,143 discloses the compound (±) methyl 7- [3 (α) -lightyl-2-p- (4 (RS) -4-Ethyl-4-methyl-trans-1-octane_1 _Yl) · Oxycyclopent-1a-yl] heptanol vinegar is a potent anti- gastric acid secretion agent. The above compound is also called Misoprostol, which is a prostaglandin e-type drug. Because The instability of misoprostol itself causes difficulties in the development of pharmaceutical formulations. Provided is a stabilizer composition of the above-mentioned anti-gastric acid secretion agent; in particular, the present invention provides a solid dosage form for increasing the stability of misoprostol and its manufacturing technology. SUMMARY OF THE INVENTION Therefore, one object of the present invention is to provide a prostaglandin A solid stabilizer dosage form of a drug, which comprises an aminomethylpropionate copolymer effective for stabilization. Another object of the present invention is to provide a misoprostol (Misprostol, (±) methyl 7- [3 (α) -Hydroxy-2-p- (4 (RS) -4-Hydroxy_4_methyl-trans4722S.DOC-4-This paper ΛΑϋϋ 财 财 鲜 {CNS) A4 * Ufr (21GX297 mm ) '~ I --- Γ, --.------- (Please read the note on the back Ϋ-item before filling out this page) Order by the Ministry of Economic Affairs and the Central Bureau of Quasi-Bureau Shellfish Consumer Cooperative Printed 446561 A7 ___ B7 V. Description of the invention (2) A solid stabilizer of the formula -1-octyl-1-yl) -oxycyclopentyl-1α-yl] heptyl ester), which comprises a gas methyl acrylic ester copolymer (ammonio methacry 丨 ate copolymer) to increase stability and overcome the above problems. A secondary object of the present invention is to provide a solid stabilizer of misoprostol, which has a slow release effect and is a long-acting tablet. Another object of the present invention is to provide a method for preparing a solid stabilizer of a prostaglandin drug, particularly misoprostol, which is manufactured by using an organic solvent removal method. The formula is briefly explained. The present invention will be further illustrated by the following diagrams, in which FIG. 1 shows the dissociation curve of the sustained-release homogeneous particles prepared by Misoprostol and Eudragit in Example 7; FIG. 2 shows the rice food in Example 10. Dissolution profile of the long-acting bond of prolonged-release misoprostol prepared by Prostaglandol and Eu ^ agit; and 囷 3 represents the dissolution profile of the fast-acting lozenges of commercially available misoprostol. Detailed description of the invention. The present invention belongs to a solid stable dosage form of a prostaglandin drug, which composition comprises about 1 to about 1,000 times parts of ammonia methacrylate copolymer (ammoniomethacrylate copolymer) in 1 part. The prostaglandin drug is calculated; preferably, the solid stable dosage form of the prostaglandin drug in the present invention comprises about 10 to about 450 times parts of the aminomethacrylate copolymer β. The prostaglandin drug is a slow release type. The prostaglandin drug is, for example, misoprostol (Misoprost〇1, (±) methyl 7 _ [3 (a) -hydroxy-2-p_ (4 (RS) -4 -hydroxy · 4-methyl · trans式 ·！ _octene-This paper size is applicable to the Chinese national standard (CNS) Α4 affinity (2 丨 0X297). --- I Γ. I-(Please read the note I on the back before filling in this 苋) Revision. 4 4 6 5 Luo 8 Ming No. 09178 Patent Application Chinese Revised Page (August 86) Printed by the Shell Standard Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of Invention (3) 1-based)- Oxycyclopentan-1α-yl] heptyl vinegar 'find) 11 ^ 1! ^?-! ^^)-! ^^ :. : ^) ^ · ^-(4 (RS) -4-hydroxy-4-methyl-trans-1 -octen-1 -yl) -oxycyclopent-1 a-yl] heptanoate). To the best of this skill, misoprostol has a molecular weight of 382.5 and 4 stereoisomers. U.S. Patent No. 3,965,143 relates to misoprostol, which is incorporated herein by reference in its entirety. Furthermore, the present invention is capable of stabilizing any medicinal active compound, especially one having properties similar to misoprostol. According to the invention, the anunonio methacrylate copolymer is a copolymer selected from the Eudragit RS series (aminomethacrylic acid copolymer, type B, USP), and the Eudragit RL series copolymer (ammonia Methacrylate copolymer, Type A, USP), and mixtures thereof. It should be understood that the amino methacrylate copolymer used in the present invention is not limited to copolymers of Eudragit RS series and copolymers of Eudragit RL series 歹 1 丨. The copolymers of Eudragit RS series are ethyl propionate Terpolymers of esters, methyl methacrylate, and trimethylaminoethyl methacrylate vapors, in which the molar ratio of the three is 1: 2: 0.1, and the average molecular weight is about 150,000 ° The Eudragit RS may contain any molar ratio of the linker and the neutral methylpropionate; preferably, the Eudragit RS contains the molar ratio of the linker and the neutral methylpropionate to 1 : 40. In the present invention, Eudragit RS is selected from Eudragit RSPM, Eudragit RSPO, Eudragit RS100, Eudragit RSH.5, and mixtures thereof; wherein “Eudragit RSPM” represents Eudragit RS powder that has not been generally ground, and “Eudragit RSPO” represents milled Passed Eudragit RS fine powder, "Eudragit RS 100" represents the granules of Eudragit RS, and "Eudragit RS 12.5" represents a solution product dissolved in an organic solvent => Similarly, the copolymer of Eudragit RL series is ethyl acrylate Ester, methacrylic acid 4122J.DOC — 6 ~ This paper size is free to use Chinese attention rate (CNS) A4 size (210X297 mm) (-read the note on the back of the first item and then sand 4 pages) 4 4 6 5 Revised page of Chinese manual for Patent Application No. 109178 (August 86) Printed by Shellfish Consumer Cooperative of Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of Inventions (4) L ~ Price Acid Methyl Ester, and Top Three A terpolymer of amino aminoethyl methacrylate vapors, wherein the molar ratio of the three is 1: 2: 0.2, and the average molecular weight is about 150.000. The Eudragit RL may contain ammonium groups and neutral methylpropionate S groups in any proportion; preferably, the Eudragit RJL has a molar ratio of 1 and neutral methylpropionate groups: 20. In the present invention, Eudragit RL is selected from Eudragit RLPM, Eudragit RLPO, Eudragit RL [00] Eudragit RL12.5, and mixtures thereof; wherein " PM ",,, P0", " 100 " and " 12.5 " The definition is as described above. A mixture of Eudragit RS series copolymer and Eudragit RL series copolymer in any proportion can be used as the aminomethylpropionate copolymer of the present invention. The amino methacrylate copolymer used in the solid stabilizer dosage form of the prostaglandin drug of the present invention can also be selected from Eudragit S (fluorenyl acrylic copolymer, type B, USP), Eudragit L (methacrylic copolymer, A Type, USP), and mixtures thereof. Eudragit S is a copolymer of methacrylic acid and methyl methacrylate, in which the molar ratio of the two is 1: 2, and its average molecular weight is about 135,000. Eudragit L is a copolymer of methacrylic acid and methyl methacrylate, in which the molar ratio of the two is 1: 1, and the average molecular weight is about 135.000. A mixture of Eudragit S and Eudragit L in any ratio can also be used as the aminomethacrylate copolymer of the present invention. The present invention also provides a method for preparing a solid stabilizer of a prostaglandin medicine, which comprises the following steps: ⑴ dissolving the prostaglandin medicine in an organic solvent to form a solution; ⑵ adding amino non-methyl methacrylate copolymer Until a mixture is formed in the solution, and the mixture is stirred for a period of time; U223.DOC _ 7-This paper size is in accordance with China Standard (CNS) A4 specification (210XM7 mm >

446561 Printed by A7 ____B7______ of the Central Cooperative Bureau of the Ministry of Economic Affairs. Η ___ B7______ V. Description of the Invention (5) ⑶ Remove the organic solvent by volatilization and blow dry the volatilized residue to obtain a solid stabilizer; ⑷ Dry solid stabilizer; The Schindza stabilizer was ground and passed to obtain the final product. In the present invention, the prostaglandin drug is exemplified by Misoprostol ((iso) stol, (±) methyl 7- [3 (α) -hydroxy- 2-p- (4 (RS) -4 · hydroxy-4- Methyl-trans-1 -octene-1 · yl) -oxocyclopentan-1α-yl] heptyl ester, (n) methyl 7-[3 (a)-hydroxy-2-β-(4 (RS )-4-hydroxy-4-methyl-trans-1 octen _ 1-yl) _ oxycyclopent lex · yl] heptanoate). Furthermore, the method of the present invention can stabilize any medicinal active compound, especially one having properties similar to misoprostol. The organic solvent used in step (1) of the method of the present invention can be a person skilled in the art and can be used in any amount. Organic solvents suitable for the present invention include ethyl alcohol, such as ethanol 200 proof grade, ethanol 3A grade, ethyl fermentation USP grade, absolute ethanol (GR grade), and mixtures thereof; and digas methane, such as digas methane AR grade; And mixtures of ethanol and digas methane in any ratio. The preferred organic solvent in the present invention is anhydrous ethanol ((^^)). In the method of the present invention, the ammonio methacryiate copolymer used as a solid stabilizer for the prostaglandin drug is about 1 to About 1,000 times the aminomethacrylate copolymer, based on 1 part of the prostaglandin drug; preferably, about 10 to about 450 times the aminomethacrylate copolymer. The prostaglandin obtained by the method of the present invention According to the preparation method of the present invention, the aminomethacrylate copolymer 47223 .DOC _ β _ (〇NS) A4 * Μί · (210X297 ^ *) — --- -'44656 ί Α7 Β7 5. Description of the invention (6) is a copolymer selected from Eudragit RS series (aminomethylpropionate copolymer, type b, USP), Eudragit RL series copolymer (aminomethylpropane) Phosphonate copolymer, type A, USP), and mixtures thereof. Furthermore, the aminomethyl acrylate copolymer used may also be selected from Eudragit S (methacrylic acid copolymer, beta type, USP), Eudragit L (methylpropionic acid copolymer, type A, USP), and The definition and description of Eudragit RS series copolymers, Eudragit RL series copolymers, Eudragit S and Eudragit L are as described above. According to the present invention, the mixture is stirred in step (2) for about 1 to 3 hours 'It is preferably about 2 hours. The stirring is performed under a cap. In step (3) of the method of the present invention, nitrogen or other suitable gas can be used to blow dry the residue. In step (4) of the method, Guyi The stabilizer is dried at a temperature between about 40 ° C and 50 ° C for about 1 to 3 hours. After that, the obtained solid stabilizer can be stored at a temperature of from 80 ° C to 30 ° C, preferably It is stored at a temperature from -2TC to + 5 ° C, and it is stored in an air-tight container with a silicone moisture-proofing agent for storage before use. Printed by the Central Samples and Standards Bureau of the Ministry of Economic Affairs, another industrial consumer cooperative. --1¾—— (Please read the notes on the back before filling this page) Therefore, the present invention provides a method for preparing Misoprostol (Misoprostol, (±) methyl 7 · [3 (α) .hydroxyl · 2- Solid stability of β · (4 (ί ^)-4-hydroxy-4 -methyl · trans-1β octenen-1-yl) -oxocyclopentyl-lot-yl] heptyl ester The method comprises the following steps: ⑴ dissolving misoprost in an organic solvent to form a solution; ⑵ adding an amino methacrylate copolymer (anunonio methacrylate copolymer) to the solution to form a mixture, and stirring the mixture for a period of time; ⑶ volatilization Remove the organic solvent and blow dry the volatilized residue to obtain a solid stabilizer; 47223.DOC _ 9-This standard is used in the domestic standard rate (CNS > Α4ΛΜΜ 210X297 male f · 4 4656 ί Α7 Β7 five 2. Description of the invention (7) ⑷ dried solid stabilizer; and ⑸ ground and sieved the solid stabilizer to obtain the final product. The solid stabilizer homogeneous granules prepared by the method of the present invention can be directly taken as a powdery tincture, and can also be filled in capsules with or without pharmaceutical excipients, or with or without Adding excipients to compress into tablets for taking. The homogeneous granules of the solid stabilizer can also be coated in core granules with or without effective main ingredients to make round granules for administration, or the solid can be directly taken. Stabilizer homogeneous granules are made into round granules for administration. The following examples are further illustrated to make the applicant of the present invention more courteous. These examples only enable the skilled person to clearly understand the technical content of the method of the present invention, so that it can be implemented based on it, rather than to limit the scope of protection that the present invention should receive. Printed (please read the notes on the back before filling this page) This example is used to prepare a kind of misoprostol, (±) methyl 7-[3 (α) -qudi-2-β · ( 4 (RS) · 4-acid · 4-methyl-trans-l-octyl-oxyl) -oxocyclopenta-la-yl] heptyl ester) slow-release solid stabilizer, which contains misoprost Alcohol and Eudragit RS (amino methacrylate copolymer, type b, USP) were prepared at a ratio of 1: 150. First, 66.7 mg of misoprostol was dissolved in 47 ml of absolute ethanol, and 20 grams of Eudragit RS was added to the misoprostol-ethanol solution to form a ratio of misoprostol to Eudragit RS of 1: 150. Covered and stirred miso forefront 47323.DOG-1〇- {CNS) A4 «Ufr (210X297 ^ *) " --- ^ 44656 1 Printed by Male Workers Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 11 A7 B7 V. Description of the invention ( 8) Alcohol-Eudragit-ethanol solution mixture for 2 hours. The ethanol organic solvent is then removed by volatilization, and the residue is blown dry with nitrogen, and the remaining solid residue (that is, solid male stabilizer) is dried at 4 (rc for 2 hours, and then the solid residue is dried). Grinded and passed through a No. 40 sieve. The obtained powdery solid stabilizer stabilizer particles must be stored in an air-tight container, which not only increases stability but also has a slow-release effect. Example 2: Follow the steps of Example 1. Sample manufacturing, in which 40 grams and 60 grams of Eudragit RS were added to the misoprostol · ethanol solution to form a slow-release solid solution of misoprostol and Eudragit RS in a ratio of 1: 300 and 1: 450. Stabilizer, which has added stability and has a slow release effect. Example 3: Manufactured according to the procedure of Example 1, in which 47ml of organic solvent containing 90% anhydrous ethanol and 10% digas methane was used, and 40 grams of Eudragit RS to form a slow-release solid stabilizer with a ratio of 1: 300 of misoprostol and Eudragit RS, which has increased stability and has a slow release effect. Example 4:

Manufactured in accordance with the step of Example 1 in which 47 ml of digas methane was used as an organic solvent and 40 g of Eudragit RS to form a slow-release solid cross-linking stabilizer with a ratio of 1: 300 of misoprostol and Eudragit RS. With increased stability and slow release effect. 471i3.DOC — 11 Table 1 uses the household starvation rate of CNH (CNS) A4 * U ^ (210X297 mm) ^ ~ (please read the note t on the back before filling in this note)

446 561 A7 B7 V. Description of the invention (9) Example 5: Manufactured according to the steps of Example 1, in which three different amounts of Eudragit RS were used, namely 1.33 g, 2.67 g, and 5.34 g of Eudragit RS to form Misoprostol and Eudragit RS have a ratio of 1:10, 1:20, and 1:40 respectively. And the solid residue (that is, the solid stabilizer) was dried at a temperature of 40 ° C for 2 hours, and then a sieve No. 100 was used to obtain a sustained-release solid stabilizer at the time of sieving. The fine powdered solid stabilizer was obtained. Homogeneous granules are placed in an air-tight container containing silicone before use, and stored at a low temperature of -27 ° C. The resulting homogeneous stabilizer stabilizer granules have increased stability and have a slow release effect. Example Stone ·· Economy Central Government Bureau of Standards and Administration®; Industrial and Consumer Cooperation Du Yin 11 I ---:! --.----- (Please read the note on the back before filling this page) Follow the steps in Example 5 Two different amounts of Eudragit RL, 6.67 grams and 60 grams of Eudragit RL, were added to misoprost. Ethanol solution to form misoprostol and Eudragit RL at a ratio of 1:50 and i: 450. Shiguxiong stabilizer, which has increased stability and slow release effect. Example 7: Manufactured according to the snail of Example 5, wherein 6.67 grams of Eudragit RS was added to the misoprostol · ethanol solution to form Sustained-release Gu Zhao Zhao in a ratio of 1:50 to misoprostol and blood red Zhao RS A fixed agent, which has increased stability and has a slow release effect. 47223, DOC — 12 — This paper size is in use •, home sample (CNS > A4 * UM 210X297 mm) '---- 446561 A7 B7 V. Description of the invention (10) Example 8: Use the stable and stable release solid stabilizer homogeneous particles prepared in Example 7 with misoprostol and Eudragit RS in a ratio of 1:50. Seven different medicinal excipients are used to prepare seven different uniform powdery mixtures. The types and mixing ratios of the used medicinal excipients are stated as follows: In terms of weight ratio, 1 Parts of the solid stabilizer homogeneous granules are mixed with five times parts of Avicel pH102 (Microcrystalline Cellulose), Eudragit RS, Corn Starch, or Mannitol. Based on silicon, by weight, Fifty times the homogeneous granules of Guli stabilizer are mixed with two times the Talc, Magnesium Stearate or Hydrogenated Castor Oil. Please read the note above first. Fill in this page Example 9: The stable and stable solid stabilizer homogeneous particles prepared in Example 7 produced by the local shellfish consumer cooperative, with a ratio of 1:50 of misoprostol and Eudragit RS, used in the preparation of long Effective Misoprostol capsule. 20.4 mg of the homogeneous granules of the solid stabilizer prepared in Example 7 were weighed and filled into a No. 2 capsule to prepare it. Each capsule contains 400 pg of misoprostol. Example 10: The stable and stable release stable solid stabilizer prepared in Example 7 is homogeneous 47223.DOC — ^ 3 A paper size using 11 Chinese companies Feng Feng (Café) (210 > < 297 cm) ) 44656 Printed by A7, B7, Male Workers' Cooperatives of the Central Bureau of Procurement, Ministry of Economic Affairs 5. Description of the invention (11) Granules with a ratio of 1:50 of misoprostol to Eudragit RS, used to prepare long-acting misoprost Alcohol tablets. According to the amount of each ingredient in the following lozenge formulation: 20 · 4 mg of the solid stabilizer homogeneous granules prepared in Example 7, 167.6 mg of Avicel pH102 (microcrystalline cellulose), and 10,0 mg of starch glycol. (Sodium Starch Glycolate), and 2.0mg of Hydrogenated Castor Oil, to obtain long-acting misoprostol health tablets. A total of 2,000 long-acting misoprostol tablets, each of which contains 400 micrograms of misoprostol. Example 11: Various samples prepared in Examples 1 to 10 were subjected to accelerated stability experiments under different temperature conditions. After different incubation times, various samples were taken out and chemically analyzed by high-efficiency liquid chromatography (RP 丄 .C) for the isoprostol contained in long-acting homogeneous particles. The results of the stability analysis are listed in Table 1 (including the stability data of Examples 1-4), Table 2 (including the stability data of Examples 5 and 6), Table 3 (including the stability data of Example 8), and Table 4 (Including the stability data of Examples 7, 9 and 10). All stability quantitative analysis uses Spectra-Physics Liquid Chromatography, and is equipped with P2000-type power electronics, AS3000-type automatic sampling device, UV1000-type ultraviolet light detector, IMS1000-type integrator And SN4000 type data processing controller "and the ultraviolet light wavelength is 210nm, the moving speed of the recording circle is 0.5 cm / min, and the type of the separation column is Lichrospher 100, RP-8, the length and the inside of the column June Fen 4722 ^ .D〇C — 14 ~ This paper size is in use. _ Home sample rate (QNS) Α4Λ grid (21〇 × 297 mm) ) J ---: · --.----- (Please read the note ^ on the back before filling out this page) Order 44656 1 A7 B7 V. Description of the invention (12) (acetonitrile) and phosphoric acid at pH 2.81 Buffer, using a flow rate of 1 ml / min. Table 1. Chemical stability of homogenous particles of misoprostol and solid stabilizers prepared by various misoprostol and Eudragit under separate conditions (remaining active ingredient in%) Storage temperature Storage time (weeks)

5eC

30 ° C

50 ° C

70 ° C 3 6 3 6 3 6 1 Misoprostol alone 100000 94 94 22.2 82.7 93.9 91.7 64 81.2 Example 1 (1 Example 2 (1 Example 2 (1 Example 3 (1 Example 4 (1 150 homogeneous particles) 100 99.2 99.5 95.8 97 · 7 97.1 91.4 80.1 89.8 300 homogeneous particles) 100 99.2 98.6 94.2 95.8 95.6 90.7 81.5 88.5 450 homogeneous particles) 100 100 100 100 100 100 93 83.3 83 300 homogeneous particles) 100 100 100 100 100 99.7 95.3 95.8 92.4 300 Homogeneous particles) 100 100 99.7 100 100 99.5 96.1 91.7 85.9 (please read the note on the back and fill in this page first) Samples in the Ministry And chemical stability of homogeneous particles of solid stabilizers prepared by various misoprostol and Eudragit _ Qualitative (represents active ingredient residue in%) _ Storage temperature 30 ° C 50 ° C 70aC Storage time (weeks) 0 3 6 12 1 3 6 12 1 2 100 92.2 82.7 14.4 93.9 91.7 64 10.9 81.2 41.5 100 99.5 102.2 93.0 97.0 97.2 94.8 91.8 1-100 99.1 98.1 95.6 102 95.8 95.0 93.7 93.9 88.6 100 98.S 100.4 97.5 100.7 99.7 98.3 96.5 95.0 92.3 100 96.5 94.5 96 .6 96.5 97.0 93.0 93.0 94.5 90.5 100 102.9 101.5 97 97.9 95.3 95.2 95.7 97.6 92.3 47223.DOC-X5 — This paper is a scale-free order Beta β Family Standard (CNS) A4 ^ | (210X297 mm) Misoprostol alone Example 5 (1 Example 5 (1 Example 5 (1 Example 6 (1 Example 6 (1 10 Homogeneous particles) 20 Homogeneous particles) 40 Homogeneous particles) 50 Homogeneous particles) 450 Homogeneous particles) 446561 A7 _____ B7 (U) The chemical stability of the mixture of homogeneous granules of misoprostol solid stabilizer and seven medicinal excipients in Example 8 of Table 3, printed by the cooperative of the Ministry of Economic Affairs of the Central Bureau of Quasi-Staff of the Ministry of Economic Affairs (expressed as%) Residual active ingredients) _ ---- ratio (homogeneous particles: excipient = 1: 5) (homogeneous particles: excipient = 50: 2) excipient Avicel Eudragit corn temple powder Mannitol talc powder magnesium stearate Sesame oil pH 102 RS Com Starch TaJc Magnesium Hydrogenatch Stearate Castor Oil Stored in 70 1 102.6 97.7 100.6 «97.3 98.4 99.9 100.0 Table 4 Example 7 1:50 ratio of misoprostol extended-release solid stabilizer Tablets, Example 10 Chemical stability of misoprostol long-acting tablets prepared from 1:50 misoprostol homogeneous granules, and misoprostol long-acting capsules of Example 9 (active ingredients are expressed in%) Residual)》 Storage relative humidity (RH) and temperature 75% RH + 37 ° C 75% RH + 43 ° C 75% RH + 50 ° C Storage time (month) I 3 6 1 3 6 1 3 6 Misoprostol -Eudragit sustained release are 95.1 95.9 92.1 96.0 94.7 90.1 93.5 90.7 76 granules (1:50 ratio) long-acting misoprostol tablets (sustained release homogeneity at a ratio of 1.50 · 100.0 96.6 97.3 100.0 96.4 91.6 93.8 89.6 56.8 granules Manufacturing) Long-acting Misoprostol Capsules 97.9-95.4 95.3 — 92.2 92.8-68.8 47223.DOC ~ 16-This paper has a standard scale ¥ + «« Sample Rate (CNS > A4 «Employment (210X297) ^ * Used The container is an air-tight PE plastic bottle containing a dream gel moisture-proofing agent (please read the note on the back of the item Ϋ-item before filling out this page) 4 4 6 5 6 each 86109178 Patent Application Chinese Manual Correction Page (86 August)

V. Description of the invention () 'The solid stabilizer of misoprostol in the method of the present invention, and the misoprostol long-acting capsules and misoprostol long-acting lozenges prepared therefrom, are placed at different temperatures and After different holding times, chemical stability experiments were performed. It was found that the present invention can provide a solid stable dosage form of prostaglandin, especially misoprostol (MiSopröStd, (±) methyl 7- [3 (α) • hydroxy_2p_ (4 (Rs) _4 meridian- 4-Methyl-trans-1-octen-1-yl) solid oxide formulation of oxepin-1-alpha] heptyl ester. Furthermore, according to the present invention, a solid stabilizer formulation of misoprostol is filled. Both misoprostol long-acting capsules and misoprostol long-acting mosquitoes made from the solid stabilization formulation of misoprostol, both have increased stability and have a slow release effect. (Please read the search first) Note on the back (item $ _ 本页) on this page). Packing. Example 12: Dissolution curve of homogeneous particles of slow-release solid stabilizer with a ratio of 1 to 50 in Example 7 and Example 10 of a long-acting tablet of misoprostol The dissolution curves are shown in Figure 1 and Figure 2. The slow release rate is shown in Figure 1. The conditions of each dissolution experiment are to use a paddle dissolution tester of the United States Pharmacopeia and a stirring speed of 37 ° C and a stirring speed of 75 rpm. The dissolution curve in Figure 1 is based on a dissolution experiment in 0.2% sodium lauryl sulfate (SLS). Figure 2 The solvents used in the dissolution test in 囷 and 囷 3 are respectively marked in 圏. The dissolution samples at each sampling point were quantified using the high-precision liquid chromatography (HPLC) described in Example 11. For easy comparison, the solvent curve of the commercially available misoprostol fast-acting lozenge is also shown in Figure 3; at a rate of $, the commercial name of the commercial misoprostol fast-acting lozenge is Cyt〇tec. The tablet contains 0.2mg misoprostol. 47223.DOC-17 A paper size in use BB home kneading rate (CNS) A4 # t (210X297 gong) Order printed by the Central Standards Bureau of the Ministry of Economic Affairs Consumer Cooperatives 44446 1 A7 B7 V. Explanation of the invention (u) It can be seen from Figures 1'2 and 3 that the solid troches of misoprostol in the present invention have a slower release effect than the commercially available misoprostol fast-acting drum. Therefore, according to the present invention, the long-acting capsules and long-acting lozenges prepared from the solid stabilizer of misoprostol need only one dosage per day. The features and methods of the present invention will be more apparent through the above examples. It should be understood that 'any modification that does not depart from the spirit of the present invention Or change, as both the intent protector of the present invention I I t I n ^ n.. (Read the back of the note -? Items curse reloading the page)

'1T Printed by Zhengong Consumer Cooperative of the Central Bureau of Quasi-Ministry of Economic Affairs «.

Claims (1)

44656 1 A8 B8 C8 08 Patent Application No. 86109178 Chinese Patent Amendment for Patent Application (March 89) VI. Scope of Patent Application 1. A solid and stable pharmaceutical composition of prostaglandin medicine, containing 1 to 0. 〇 times the amount of ammonio methacrylate copolymer (ammonio methacrylate copolymer), based on 1 part of the prostaglandin drug, of which the prostaglandin drug is misoprostol (Misoprostol, (±) methyl 7- [3 ( α) -Hydroxy-2-p- (4 (RS) -4-hydroxy-4-methyl-trans-1-octen-1-yl) -oxocyclopenta-fluorene alpha-yl] heptyl). 2. The solid and stable pharmaceutical composition according to the item of the patent application park, which contains 10 to 450 times the amount of the aminomethacrylate copolymer. 3. The solid stable pharmaceutical composition according to item 1 of the patent application park, which is a slow release type. 4. The solid stable pharmaceutical composition according to item 1 of the patent application scope, in which the amino methacrylate copolymer is selected Copolymers from Eudragit RS series (aminomethacrylate copolymer, type B, USP), Eudragit RL series copolymers (aminomethacrylate copolymer, type A, USP), and mixtures thereof. Printed by Zhengong Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 11 (please read the notes on the back before filling this page) ") · According to Item 4 of the scope of patent application for a solid stable pharmaceutical composition, Eudragit RS is selected from Eudragit RSPM, Eudragit RSPO, Eudragit RS100, Eudragit RS 12.5, and mixtures thereof β 6. The solid stable pharmaceutical composition according to item 4 of the patent application park, wherein Eudragit RS contains any mole ratio of ammonium group and methacrylate group 7. The solid stable pharmaceutical composition according to item 4 of the scope of patent application, wherein the molar ratio of Eudragit RS containing ammonium groups and methacrylate groups is 1: 40. 5. The solid stable pharmaceutical group according to item 4 of the patent application park Spare parts, in which Eudragit RL is selected from Eudragit RLPM 'Eudragit RLPO, Eudragit RL100 «12J3.DOC _ 1 — This paper wave standard is applicable« National Slope (CNS) A4 specification (210X297 mm) 44656 1 ABCD Central Kneading Printed by the Bureau of Shellfish Consumer Cooperatives 6. Scope of patent application, Eudragit RL12.5, and mixtures thereof. 9. Solid according to item 4 of scope of patent application "Medical composition" wherein Eudragit RL contains any molybdenum group and methyl propionate group. 10. The solid stable pharmaceutical composition according to item 4 of the patent application scope, wherein Eudragit RL contains an ammonium group and a methyl group The molar ratio of the acrylate group is 1: 20. 11. The solid stable pharmaceutical composition according to item 1 of the patent application scope, wherein the amino methacrylate copolymer is selected from Eudragit S (methacrylic copolymer, type B) , USP), Eudragit L (methacrylic acid copolymer, type A USP), and mixtures thereof. 12. A method for preparing a solid stable pharmaceutical composition of a prostaglandin drug, comprising the following steps: (1) the prostate The medicinal solution is dissolved in an organic solvent to form a solution, wherein the prostaglandin is Misoprostol ((±) methyl 7-[3 (α)-meridian-2- (J- (4 (RS) -4 -Hydroxy-4 -methyl-trans-1-octene-fluorenyl) -oxy% pentyl-lot-yl] heptyl)), ⑵ added methyl acrylic copolymer (amm〇ni. methacfyiate copolymer) to form a mixture in the solution, and stir the mixture for a period of time; ⑶ volatilize to remove the organic solvent And drying the volatilized residue to obtain a solid diazepam pharmaceutical composition; (4) drying the solid diazepam pharmaceutical composition; and (5) grinding and sieving the solid diazepam pharmaceutical composition to obtain the final product β 13_ according to the applied patent The method according to item 12, wherein the organic solvent is selected from the group consisting of ethanol, digas methane, and mixtures thereof. 2 < 7223 The paper size of the table is applicable to the country's national standard (CNS) Α4 specification (210X297 mm) {Please read the precautions on the back before filling this page) Order m --- 4 46 5 6 1 ABCD Central Samples printed by the staff consumer cooperative of the Bureau of Standards VI. Patent application scope M. According to the order, the method of patent No. 13 is applied, where the ethanol is selected from ethanol 200 proof grade ethanol 3A grade, ethanol usp grade, absolute ethanol (GR grade) , And mixtures thereof. 15. The method according to item 12 of the scope of patent application, wherein the organic solvent is anhydrous ethanol (GR grade). 16. The method according to item 13 of the patent application, in which the digas methane is a digas A tiger AR grade. 17. The method according to item 12 of the applied patent circle, which is added to 1000 times parts of aminomethylpropionate copolymer, based on 丨 parts of prostaglandin ^ 18. According to the patent application The method of solid item 17 wherein the aminomethylpropionate copolymer is added in an amount of from 0 to 45 times. 19. The method according to item 12 of the patent application scope, wherein the aminomethacrylate copolymer is selected from Eudragit Copolymers of the RS series (aminomethylpropionate copolymer, type B, USP), Eudragit RL series of copolymers (aminomethacrylate copolymer 'type A, (JSP), and mixtures thereof. 2 ( 1 The method according to item 19 of the scope of patent application, wherein Eudragit RS is selected from the group consisting of Eudragit RSPM, Eudragit RSPO, Eudragit RS100, Eudragit RS 12.5, and mixtures thereof. Π. The method according to Item 19 of the patent application park, wherein Eudragit RL is selected from Eudragit RLPM, Eudragit RLP0, Eudragit RL100, Eudragit RJL12.5, and mixtures thereof. This is in accordance with the method of claim 12 in which the aminomethylpropionate copolymer is selected from Eudragit S (A Base Acid copolymer, type B, USP), Eudragit L (methacrylic acid copolymer, type A 'USP), and their blends 47223.DOC _ 3 _ This paper uses ta® standard (CNS) A4 specifications ( 210X297 male thin 1 (please read the note on the back before filling in this page)-order 446561 A7 B7 V. Invention Description (23) Method according to item 12 of the scope of patent application, where the mixture is in step Township (2) Stirring for 1 to 3 hours "24 Method according to item 23 of Shenqing Patent Fanyuan, wherein the mixture is stirred for 2 hours in step (2). 25. According to item 12 of the scope of patent application Method, wherein the solid stabilizer is dried at a temperature between 40 ° C and 50 ° C. 26. The method according to item 12 of the scope of the Shen Qing patent, wherein the solid stabilizer is dried for 1 to 3 hours. 27 The method according to item 12 of the scope of patent application, wherein the obtained solid stabilizer is stored at a temperature of -80eC to 30 ° C, and is stored in an air-tight container before use. 28. According to the scope of patent application scope, Method 27 of the method, wherein the solid stabilizer obtained is stored at -27 ° C to + 5 ° C ≪ 丨 I! Iy binding f Jingxian K1 Read the notes on the back side and fill in this page) The Central Procurement Bureau of the Ministry of Economic Affairs, the staff consumer cooperatives, print the appropriate rule paper, the sample rate, the country, the country, the country, and the country. INS ) Centimeter