PHARMACEUTICAL COMPOSITION HAVING EXCELLENT DRUG ABSORPTION INTO THE LIVING BODY AND EXCELLENT CHEMICAL STABILITY

Abstract

A medicinal composition containing a scopolamine salt and/or a hydrate thereof, polyvinylpyrrolidone, and a base. The medicinal composition is excellent in terms of absorption of the drug into the living body and chemical stability thereof.

Claims

1. A pharmaceutical composition comprising a scopolamine salt and/or a hydrate thereof, polyvinylpyrrolidone, and a base.

2. The pharmaceutical composition according to claim 1, wherein the scopolamine salt and/or hydrate thereof is scopolamine hydrobromide and/or scopolamine hydrobromide hydrate.

3. The pharmaceutical composition according to claim 1, wherein a content of the scopolamine salt and/or hydrate thereof is 0.5 to 10 mass % with respect to a total mass of the pharmaceutical composition.

4. The pharmaceutical composition according to claim 1, wherein a content of the polyvinylpyrrolidone is 0.3 to 12 mass % with respect to a total mass of the pharmaceutical composition.

5. The pharmaceutical composition according to claim 1, wherein the base comprises at least one amine compounds.

6. The pharmaceutical composition according to claim 1, wherein a content of the base is 0.3 to 10 mass % with respect to a total mass of the pharmaceutical composition.

7. The pharmaceutical composition according to claim 5, wherein the amine compound is a copolymer of methyl methacrylate, butyl methacrylate, and dimethylaminoethyl methacrylate.

8. A matrix-type patch comprising a support, a drug-containing adhesive layer, and a release liner wherein the drug-containing adhesive layer contains a pharmaceutical composition according to claim 1.

9. The patch according to claim 8, wherein the drug-containing adhesive layer comprises one or more selected from the group consisting of an acrylic adhesive, a rubber adhesive, and a silicone adhesive.

10. The patch according to claim 8, wherein the drug-containing adhesive layer comprises an acrylic adhesive.

11. The patch according to claim 10, wherein the acrylic adhesive comprises one or more selected from the group consisting of a hydroxyl group-containing adhesive and a non-polar adhesive.

Description

EXAMPLES

[0041] Production examples are shown below to explain the present invention more specifically. However, the present invention is not limited to these production examples, and various modifications can be made without departing from the technical idea of the present invention.

Production Example 1

[0042] Scopolamine hydrobromide hydrate, isopropyl myristate, and dodecylamine were dissolved in a mixture of ethyl acetate and methanol according to the blending ratios shown in Table 1, and acrylic adhesive components (trade name: DURO-TAK 87-4287, manufactured by Henkel) were added and mixed and stirred to obtain a homogeneous solution. Next, this solution was spread on a release film using a doctor-knife coating machine so that the thickness after drying was 100 μm, dried to form a drug-containing adhesive layer, and then adhered to a support. Then, it was cut to the desired size to obtain a patch

Production Example 2

[0043] A patch was obtained in the same manner as in Production Example 1, except that diethylamine was added in place of dodecylamine according to the blending ratios described in Table 1 so that the amount of scopolamine free base was equivalent to that in Production Example 1.

Production Example 3

[0044] A patch was prepared in the same manner as in Production Example 1, except that a copolymer of methyl methacrylate, butyl methacrylate, and dimethylaminoethyl methacrylate (trade name: EUDRAGIT EPO, manufactured by Evonik) was added in place of dodecylamine according to the blending ratios shown in Table 1 so that the amount of scopolamine free base was equivalent to that in Production Example 1.

Production Example 4

[0045] A patch was obtained in the same manner as in Production Example 1, except that sodium hydroxide was added in place of dodecylamine, and further polyvinylpyrrolidone (trade name: Kollidon30, manufactured by BASF SE) was added in accordance with the blending ratios described in Table 1 so that the amount of scopolamine free base was equivalent to that in Production Example 1.

Production Example 5

[0046] A patch was obtained in the same manner as in Production Example 1, except that Eudragit EPO was added in place of dodecylamine, and further polyvinylpyrrolidone was added according to the blending ratios described in Table 1 so that the amount of scopolamine free base was equivalent to that in Production Example 1.

Production Example 6

[0047] Scopolamine hydrobromide hydrate, Eudragit EPO, and polyvinylpyrrolidone were dissolved in a mixture of ethyl acetate and methanol in accordance with the blending ratio described in Table 1, and KURO-TAK 87-4287 was added thereto and mixed and stirred to obtain a homogeneous solution. Next, this solution was spread on a release film using a doctor-knife coating machine so that the thickness after drying was 100 μm, dried to form a drug-containing adhesive layer, and then adhered to a support. Then, it was cut to the desired size to obtain a patch.

Production Example 7

[0048] A patch was obtained in the same manner as in Production Example 6, except that the amount of polyvinyl pyrrolidone was increased according to the blending amount shown in Table 1

Production Example 8

[0049] Scopolamine hydrobromide hydrate, isopropyl myristate, Eudragit EPO, and polyvinylpyrrolidone were dissolved in a mixture of ethyl acetate and methanol in accordance with the blending ratios described in Table 1, and KURO-TAK 87-4287 was added and mixed and stirred to obtain a homogeneous solution. Next, this solution was spread on a release film using a doctor-knife coating machine so that the thickness after drying was 100 μm, dried to form a drug-containing adhesive layer, and then adhered to a support. Then, it was cut to the desired size to obtain a patch.

Production Example 9

[0050] Scopolamine hydrobromide hydrate, isopropyl myristate, Eudragit EPO, and polyvinylpyrrolidone were dissolved in a mixture of ethyl acetate and methanol in accordance with the blending ratios described in Table 1, and KURO-TAK 87-4287 was added and mixed and stirred to obtain a homogeneous solution. Next, using a doctor-knife coating machine, the solution was spread on a release film so that the thickness after drying became 50 μm, dried to form a drug-containing adhesive layer, and then adhered to a support. Then, it was cut to the desired size to obtain a patch.

Production Example 10

[0051] A patch was obtained in the same manner as in Production Example 9, except that the amount of isopropyl myristate was increased according to the blending amounts shown in Table 1.

Production Example 11

[0052] A patch was obtained in the same manner as in Production Example 1, except that sodium hydroxide was added in place of dodecylamine according to the blending ratio described in Table 1 so that the amount of scopolamine free base was equivalent to that in Production Example 1.

Production Example 12

[0053] A patch was obtained in the same manner as in Production Example 6, except that polyvinyl pyrrolidone was not added according to the blending ratio shown in Table 1.

Production Example 13

[0054] A patch was obtained in the same manner as in Production Example 1, except that dodecylamine was not added according to the blending ratios shown in Table 1.

TABLE-US-00001 TABLE 1 Prod. Prod. Prod. Prod. Prod. Prod. Prod. Prod. Prod. Prod. Prod. Prod. Prod. Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12 Ex. 13 scopolamine hydrobromide 3 3 3 3 3 3 3 3 6 6 3 3 3 hydrate acrylic adhesive component*.sup.1 91  91.6 90.5 89.3 88 95  91  81  71  66  91.8 96  92  sodium hydroxide — — — 0.2 — — — — — — 0.2 — — dodecylamine 1 — — — — — — — — — — — — diethylamine — 0.4 — — — — — — — — — — — methyl-methacrylate/butyl — — 1.5 — 1.5 1 1 2 5 5 — 1 — methacrylate/dimethylaminoethyl methacrylate copolymer*.sup.2 polyvinylpyrrolidone — — — 2.5 2.5 1 5 4 8 8 — — — isopropyl myristate 5 5 5 5 5 — — 10  10  15  5 — 5 *.sup.1DURO-TAK 87-4287 *.sup.2EUDRAGIT EPO

Test Example 1

Chemical Stability Test 1

[0055] Each of the patches obtained in Production Examples 1 to 13 was packed in a bag of a composite film (an aluminum-laminated film of the innermost layer heat-sealed PET, manufactured by Maywapax), stored in a thermo-hygrostat (temperature: 60° C., CSH-110, manufactured by Tabai Espec) for three days or 28 days, and the amount of optical isomer, which was major decomposition products, was measured. The three sheets of patches, with the liners removed, were placed in a 10 mL centrifuge tube, 1 mL of tetrahydrofuran and 0.5 mL of methanol were added, and were shaken for 10 minutes to dissolve the paste completely. 1 mL of water was added to this liquid, and the mixture was shaken for 10 minutes to flocculate and precipitate the adhesive base component completely. The supernatant liquid was used as the sample solution, and the content was measured by high-performance liquid chromatography (wavelength: 210 nm). The amounts of optical isomers after storage measured by the method are shown in Tables 2 and 3.

Test Example 2

Chemical Stability Test 2

[0056] Each of the patches obtained in Production Examples 1 to 13 was filled in a bag of a composite film (an aluminum-laminated film of the innermost layer heat-sealed PET, manufactured by Maywapax), stored in a thermo-hygrostat (temperature: 60° C., CSH-110, manufactured by Tabai Espec) for three days or 28 days, and the amount of aposcopolamine, which was the main decomposition product, was measured. Three sheets of patches, with the liners removed, were placed in a 10 mL centrifuge tube, 1 mL of tetrahydrofuran and 0.5 mL of methanol were added, and were shaken for 10 minutes to dissolve the paste completely. 1 mL of water was added to this liquid, and the mixture was shaken for 10 minutes to flocculate and precipitate the adhesive base component completely. The supernatant liquid was used as the sample solution, and the content was measured by high-performance liquid chromatography (wavelength: 220 nm). The amounts of aposcopolamine after storage measured by the method are shown in Tables 2 and 3.

Test Example 3

Release Test

[0057] For each patch obtained in Production Examples 5, 8, 9, 10, and 13, the release rate of scopolamine from the patch was measured. Each patch was cut with a leather punch of 15 mm in diameter, affixed to filter paper, covered with a cover tape, cut with a leather punch of 23 mm in diameter so that the test piece was at the center, and a release test was performed using a percutaneous absorption test apparatus (TRANS VIEW C.sub.12, manufactured by Cosmidi Pharmaceutical). In the operation of the percutaneous absorption test apparatus, a stirrer was placed in the diffusion cell, the test piece and the diffusion cell hole were set together, and a collar and a cap were attached thereon. A test liquid kept at 32° C. (3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in 1000 mL of water) was injected into the receiver tank of the diffusion cell. The diffusion cell was placed in a heat block thermostatic chamber (temperature: 32±2° C.). The sample solution was sampled after 24 hours. The amount was measured by high-performance liquid chromatography (measurement wavelength: 210 nm). The release rate of scopolamine after 24 hours in each patch measured by the method is shown in Table 4.

Test Example 4

Combination Study

[0058] A drug solution containing scopolamine free base and polyvinylpyrrolidone in a blending ratio of 1:0, 2:1, 1:1, 1:2 was prepared (Production Examples 14 to 17). Each drug solution thus obtained was taken into a 10 mL centrifuge tube, stored in a hot-air dryer (temperature: 70° C., LC 110, manufactured by Tabai Espec) for one day, and the amounts of optical isomers and aposcopolamine after storage were measured by high-performance liquid chromatography (measuring wavelengths: 210 nm and 220 nm). The amounts of optical isomers and the aposcopolamine after storage measured by the method are shown in Table 5.

TABLE-US-00002 TABLE 2 Amount of each decomposition product (%, 60° C. 3 days later) Optical isomer aposcopolamine total Prod. Ex. 11 8.88 0.87 9.75 Prod. Ex. 1 0.50 0.17 0.67 Prod. Ex. 2 4.80 0.70 5.50 Prod. Ex. 3 0.29 0.46 0.75 Prod. Ex. 4 1.61 0.51 2.12 Prod. Ex. 5 0.15 0.31 0.46

TABLE-US-00003 TABLE 3 Amount of each decomposition product (%, 60° C. 28 days later) Optical isomer aposcopolamine total Prod. Ex. 12 0.33 1.67 2.00 Prod. Ex. 6 0.18 0.95 1.13 Prod. Ex. 7 0.15 0.86 1.01 Prod. Ex. 8 0.54 0.86 1.40 Prod. Ex. 9 0.62 0.94 1.56 Prod. Ex. 10 0.46 0.90 1.36

TABLE-US-00004 TABLE 4 Release rate (%, 24 hours later) Prod. Ex. 13 3.4 Prod. Ex. 5 54.8 Prod. Ex. 6 38.6 Prod. Ex. 7 35.7 Prod. Ex. 8 82.0 Prod. Ex. 9 80.0 Prod. Ex. 10 82.2

TABLE-US-00005 TABLE 5 Amount of each decomposition Scopolamine product (%, 70° C. 1 day later) free base:poly- Optical vinylpyrrolidone isomer aposcopolamine total Prod. Ex. 14 1:0 6.93 12.81 19.74 Prod. Ex. 15 2:1 2.28 5.67 7.95 Prod. Ex. 16 1:1 1.64 4.37 6.01 Prod. Ex. 17 1:2 1.17 3.24 4.41

[0059] Compared with Production Example 11 (free base formation using sodium hydroxide), the amounts of optical isomers and aposcopolamine are low in Production Examples 1 (free base formation using dodecylamine), 2 (free base formation using diethylamine), Production Example 2 (free base formation using diethylamine), and Production Example 3 (free base formation using Eudragit EPO), in which an amine compound is used as a base for making scopolamine a free base. The above results have revealed that using an amine compound as a base for making a scopolamine salt and/or its hydrate a free base effectively improves the chemical stability of scopolamine.

[0060] In the blending test, blending polyvinylpyrrolidone (Production Examples 15 to 17) decreased the optical isomer and aposcopolamine compared to when polyvinylpyrrolidone was not blended (Production Example 14). As the ratio of polyvinylpyrrolidone to scopolamine free base increased, optical isomers and apospolamine decreased. The above results demonstrated that adding polyvinylpyrrolidone effectively improves the chemical stability of scopolamine.

[0061] Compared with Production Example 11, the amounts of optical isomers and aposcopolamine are smaller in Production Example 4, where polyvinylpyrrolidone is blended. Further, compared to Production Example 3, the amounts of optical isomers and aposcopolamine are smaller in Production Example 5, where polyvinylpyrrolidone is blended. Further, in comparison with Production Example 12, the amounts of optical isomers and aposcopolamine are smaller in Production Examples 6 and 7 in which polyvinylpyrrolidone is blended. The above results show that adding polyvinylpyrrolidone effectively improves the chemical stability of scopolamine even when a patch is used as the dosage form.

[0062] Production Example 8 is a formulation in which the amount of Eudragit EPO is increased so that the amount of scopolamine free base is twice as large as that in Production Example 12, and chemical stability is made under more severe conditions than that in Production Example 12. Further, Production Examples 9 and 10 are formulations in which the amounts of scopolamine hydrobromide hydrate and Eudragit EPO are increased so that the amount of scopolamine free base is 4.7 times that in Production Example 12, and the chemical stability is made under more severe conditions than in Production Example 12. Under these conditions, compared with Production Example 12, although the addition of polyvinylpyrrolidone could not suppress the increase in the amount of optical isomers, the amount of aposcopolamine decreased, and the total amount of decomposition products also decreased. The above results have shown that the addition of polyvinylpyrrolidone effectively improves the chemical stability of scopolamine even under severe conditions of chemical stability.

[0063] The release rate after 24 hours is higher in Production Examples 5, 6, 7, 8, 9, and 10 than in Production Example 13. The above results showed that using an amine compound as a base and scopolamine hydrobromide as a free base effectively improves absorption into a living body.

INDUSTRIAL APPLICABILITY

[0064] As described above, the composition of the present invention is a pharmaceutical composition produced by including polyvinylpyrrolidone and a base in a composition containing a scopolamine salt and/or a hydrate thereof and is a novel pharmaceutical composition having high absorption into the living body and excellent chemical stability of scopolamine. The composition of the present invention can effectively and continuously utilize the pharmacological effect of scopolamine.