Drug composition and soft capsule drug sealing the drug composition

Abstract

A drug composition in a liquid form sealed within a soft capsule containing succinylated gelatin as a principal component thereof, the composition including (a) one kind of phenol derivative or a mixture of multiple kinds thereof and (b) a succinylated-gelatin insolubilizing agent; and a soft capsule drug including a capsule shell containing succinylated gelatin as a principal component thereof, the shell sealing therein a drug composition in a liquid form including (a) one kind of phenol derivative or a mixture of multiple kinds thereof; and (b) a succinylated-gelatin insolubilizing agent.

Claims

1. A drug composition in a liquid form sealed within a soft capsule shell containing succinylated gelatin as a principal component thereof, the shell having a water content of 6 to 9% by weight, the composition comprising: (a) wood creosote, wherein the wood creosote is in liquid form at room temperature; and (b) a succinylated-gelatin insolubilizing agent; the succinylated-gelatin insolubilizing agent is selected from the group consisting of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, glycerin-fatty acid ester, polyglycerin-fatty acid ester, polyethylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxylated castor oil, polyoxyethylene cetylether, polyoxyethylene stearylether, polyoxyethylene nonylphenyl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan acid monolaurate, a polysorbate, sorbitan monooleate, glyceride monostearate, monooxyethyelene sorbitan monopalminate, monooxyethyelene sorbitan monostearate, polyoxyethylene sorbitan monooleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polyoxyethylene polyoxypropylene block copolymer, a macrogol, sucrose fatty acid ester, medium chain triglyceride, tri (caprylic/capric) glyceride, propyleneglycol fatty acid ester, and a combination thereof, wherein the succinylated-gelatin insolubilizing agent (b) is present in an amount of 0.3 to 10 parts by weight, per one part by weight of the wood creosote, wherein the wood creosote is the only drug ingredient that is contained in the drug composition.

2. A soft capsule drug comprising a soft capsule shell containing succinylated gelatin, the shell having a water content of 6 to 9% by weight and the shell sealing therein a drug composition in a liquid form comprising: (a) wood creosote or a constituent of the wood creosote, wherein the wood creosote or constituent of the wood creosote is in liquid form at room temperature; and (b) a succinylated-gelatin insolubilizing agent; the succinylated-gelatin insolubilizing agent is selected from the group consisting of polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, glycerin-fatty acid ester, polyglycerin-fatty acid ester, polyethylene glycol fatty acid ester, sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxylated castor oil, polyoxyethylene cetylether, polyoxyethylene stearylether, polyoxyethylene nonylphenyl ether, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan acid monolaurate, a polysorbate, sorbitan monooleate, glyceride monostearate, monooxyethyelene sorbitan monopalminate, monooxyethyelene sorbitan monostearate, polyoxyethylene sorbitan monooleate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polyoxyethylene polyoxypropylene block copolymer, a macrogol, sucrose fatty acid ester, medium chain triglyceride, tri (caprylic/capric) glyceride, propyleneglycol fatty acid ester, and a combination thereof, wherein the succinylated-gelatin insolubilizing agent (b) is present in an amount of 0.3 to 10 parts by weight, per one part by weight of the wood creosote or a constituent of the wood creosote, wherein the wood creosote or constituent of the wood creosote is the only drug ingredient that is contained in the drug composition.

3. The drug composition according to claim 1, wherein a content of repeats of an oxyethylene group represented by Chemical Formula 1 below in the succinylated-gelatin insolubilizing agent (b) is 45 weight % or more relative to the total weight of the succinylated-gelatin insolubilizing agent (b),
(—CH.sub.2—CH.sub.2—O—).  [Chemical Formula 1]

4. The soft capsule drug according to claim 2, wherein a content of repeats of an oxyethylene group represented by Chemical Formula 1 below in the succinylated-gelatin insolubilizing agent (b) is 45 weight % or more relative to the total weight of the succinylated-gelatin insolubilizing agent (b),
(—CH.sub.2—CH.sub.2—O—).  [Chemical Formula 1]

5. The soft capsule drug according to claim 2, wherein the constituent of the wood creosote comprises guaiacol, cresol, phenol, p-cresol, 4-ethylguaiacol, o-cresol, or a combination thereof.

6. The soft capsule drug according to claim 2, wherein the capsule shell further comprises glycerin.

7. The drug composition according to claim 1, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and a combination thereof.

8. The soft capsule drug according to claim 2, wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and a combination thereof.

Description

EXAMPLES

(1) Next, one embodiment of the present invention will be explained. It should be noted however that the present invention is not limited thereto.

Formulation Examples 1-2 (Soft Capsule Shell Formulations)

(2) The respective components shown in Table 1 below were mixed by the ratios (weight parts, may be referred to simply as “parts” hereinafter) indicated therein and soft capsule raw sheets were made by the conventional method (Formulation Examples 1, 2-1, 2-2).

(3) TABLE-US-00001 TABLE 1 for- for- for- mulation mulation mulation example example example 1 2-1 2-2 capsule succinylated gelatin 100 parts 100 parts 100 parts drug shell concentrated glycerin 20 parts 20 parts 20 parts mixing D-sorbitol solution 20 parts 20 parts 20 parts ratio caramel 0.3 parts 0.3 parts 0.3 parts crystalline cellulose 0 parts 0 parts 10 parts purified water 105 parts 105 parts 95 parts drug shell water content (%) 8.6 8.5 8.7

Examples 1-3, Comparison Example 1 (Formulation of Drug Composition, Manufacture of Soft Capsule Drug)

(4) The respective components shown in Table 2 below were mixed by ratios indicated therein and clear drug compositions containing wood creosote and a succinylated-gelatin insolubilizing agent such as a surface active agent were prepared. And, with using the soft capsule raw sheets obtained as described above, soft capsule drugs (soft capsules) encapsulating the drug composition were made by the standard method. It is noted that the drug shell water contents (%) shown in Table 1 above are water contents of the capsule drug shells (matrices) of the soft capsule drugs as measured at this timing (at the timing of completion of charging and drying process).

(5) TABLE-US-00002 TABLE 2 Comparison Example 1 Example 2 Example 3 Example 1 employed soft capsule raw sheet formulation formulation formulation formulation example 1 example 2-1 example 2-2 example 2-1 formulation of wood creosote 45 parts 45 parts 45 parts 45 parts drug composition HLB value Polysorbate 80 15 35 parts 35 parts 35 parts polyoxyl 35 castor oil 12~14 20 parts glycerin fatty acid ester (*1) 10.3 20 parts 20 parts sesame oil 55 parts *1 tetraglycerin monolaurate (SY-Glyster ML-310, manufactured by Sakamoto Yakuhin Kogyo Co., Ltd. HLB10.3)

(6) The respective soft capsule drugs obtained as above were subjected to stability test (50° C., 30 days). The results are shown in Table 3 below.

(7) TABLE-US-00003 TABLE 3 Comparison Example 1 Example 2 Example 3 Example 1 results of No No No Dissolution stability test dissolution dissolution dissolution of capsule (50° C., of capsule of capsule of capsule drug shell 30 days) drug shell drug shell drug shell confirmed observed observed observed

(8) As may be understood from Table 3 above, in a soft capsule drug sealing (charged with) wood creosote, the contents did not dissolve the capsule drug shell only when a succinylated-gelatin insolubilizing agent such as a surface active agent was employed in combination.

Formulation Examples 3-4 (Formulation of Soft Capsule Drug)

(9) The respective components shown in Table 4 below were mixed by ratios indicated therein and soft capsule raw sheets were made by the conventional method (Formulation Examples 3-1˜3-3, 4-1˜4-3).

(10) TABLE-US-00004 TABLE 4 formulation formulation formulation formulation formulation formulation example 3-1 example 3-2 example 3-3 example 4-1 example 4-2 example 4-3 capsule drug shell succinylated gelatin 100 parts 100 parts 100 parts 100 parts 100 parts 100 parts mixing ratio concentrated glycerin 10 parts 10 parts 10 parts 15 parts 15 parts 15 parts D-sorbitol solution 20 parts 20 parts 20 parts 20 parts 20 parts 20 parts caramel 0.3 parts 0.3 parts 0.3 parts 0.3 parts 0.3 parts 0.3 parts purified water 105 parts 105 parts 105 parts 105 parts 105 parts 105 parts drug shell water content (%) 6% 7% 8% 6% 7% 8%

Examples 4-9 (Formulation of Drug Composition, Manufacture of Soft Capsule Drug)

(11) With using the soft capsule raw sheets obtained as described above, soft capsule drugs (soft capsules) were made by the standard method. The drug compositions sealed (charged) in these soft capsule drugs are as shown in Table 5 below. It is noted that the drug shell water contents (%) shown in Table 4 above are water contents of the manufactured soft capsule drug shells (measured at this timing). The water content is adjustable by lengthening or shortening the drying process during the formulation. And, if it is desired to obtain a drug shell having water content of 8% for example, a standard drying process should be effected for about 48 hours. If it is desired to obtain a drug shell having water content of 6% for example, a standard drying process should be effected for about 100 hours.

(12) The respective soft capsule drugs obtained as above were subjected to stability test (50° C., 30 days). The results are shown also in Table 5 below.

(13) TABLE-US-00005 TABLE 5 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 employed soft capsule raw sheet formulation formulation formulation formulation formulation formulation example 3-1 example 3-2 example 3-3 example 4-1 example 4-2 example 4-3 formulation of wood creosote 45 parts 45 parts 45 parts 45 parts 45 parts 45 parts drug composition Polysorbate 80 30 parts 30 parts 30 parts 30 parts 30 parts 30 parts polyoxyl 35 castor oil 25 parts 25 parts 25 parts 25 parts 25 parts 25 parts results of stability test No dissolution No dissolution No dissolution No dissolution No dissolution No dissolution (40° C., 6 months) of capsule of capsule of capsule of capsule of capsule of capsule drug shell drug shell drug shell drug shell drug shell drug shell HLB value Polysorbate 80 15 polyoxyl 35 castor oil 12~14

Collapsibility Test after Storage

(14) Separately, with using the wood creosote soft capsule drug (Example 7), stability and collapsibility after storage at 40° C. (6 months storage period in sealed glass bottle) were checked. The results are shown in Table 6 below.

(15) TABLE-US-00006 TABLE 6 storage period at 40° C. 0 month (control) after 6 months guaiacol amount 100 101.7 (control ratio) guaiacol content 28.7% 29.2% collapse test (min.) 5-7 6-7 ※ guaiacol content in the used wood creosote: 29.4%

(16) From Table 6 above, it was found that the inventive soft capsule has high solubility and high resistance against collapse delay.

Other Examples 10-38 (Dissolution Preventing Effect Tests)

(17) In order to check the shell dissolution preventing effects when using different ratios of the succinylated-gelatin insolubilizing agent such as a surface active agent or using other substances, dissolution preventing effect tests using components shown in the tables below were conducted. As the soft capsule raw sheet, the one obtained in Formulation Example 3-1 was employed. That is, the soft capsule raw sheet obtained in Formulation Example 3-1 was placed within the glass bottle and mixtures of wood creosote and various kinds of succinylated-gelatin insolubilizing agent (drug compositions in liquid form) were collected in a screw tube. Then, in these mixtures (drug compositions), the soft capsule raw sheet in the glass bottle was submerged and then sealed and stored under the condition of 40° C. After storage for two weeks, changes if any in the soft capsule raw sheets were checked with eyes. The molecular weights and HLB values of the used succinylated-gelatin insolubilizing agents are shown in Table 7 below and the results are shown in Tables 8-12 below (∘ indicates no change; Δ indicates slight dissolution of the sheet, but not problematic; and X indicates dissolution).

(18) TABLE-US-00007 TABLE 7 list of surface active agent used (general name/commercial name) HLB value Polysorbate 80 15 polyoxyl 35 castor oil Cremophor EL 12~14 triethyl citrate Citroflex plasticizing agent, coating agent propylene glycol fatty acid ester Miglyol 840 medium chain fatty acid triglyceride Panasate 810 7~9 medium chain fatty acid triglyceride Panasate 810S 7~9 tri (caprylic/capric) glyceride Myritol 325 molecular weight 465 glycerin-fatty acid ester SY Glyster ML-310 10.3 glycerin-fatty acid ester SY Glyster MO-5S 11.6 diglycerin monolaurate Sunsoft Q-12D 8.5 decaglyceryl laurate/ Sunsoft Q-12S 15.5 decaglyerin monolaurate decaglycerin monomyristate Sunsoft Q-14S 14.5 decaglycerin monooleate Sunsoft Q-17S 12.0 pentaglycerin monolaurate Sunsoft A-121E 10.9 pentaglycerin monomyristate Sunsoft A-141E 12.2 pentaglycerin monomyristate Sunsoft A-171E 13.0 polyglycerin-fatty acid ester NIKKOL Hexaglyn1-M 11.0 polyglycerin-fatty acid ester NIKKOL Decaglyn1-LN 12.0 polyglycerin-fatty acid ester NIKKOL ODM-100 ※1 ※1: No HLB value as being not surface active agent. Required HLB value at time of O/W emulsification is 11-13.

(19) TABLE-US-00008 TABLE 8 Ex. 10 Ex. 11 Ex. 12 for 1 part of wood creosote ratio two times three times four times Polysorbate 80 Δ Δ ◯ Cremophor EL Δ Δ ◯

(20) TABLE-US-00009 TABLE 9 Ex. 13 Ex. 14 Ex. 15 Ex. 16 Ex. 17 wood creosote 45 45 45 45 45 Polysorbate 80 100 Cremophor EL 50 100 150 200 triethyl citrate 50 50 50 50 50 total 195 145 195 245 295 result ◯ Δ ◯ ◯ ◯

(21) TABLE-US-00010 TABLE 10 formulation Ex. 18 Ex. 19 Ex. 20 Ex. 21 Ex. 22 wood creosote 45 45 45 45 45 Polysorbate 80 50 50 50 50 50 Cremophor EL 25 25 25 25 25 triethyl citrate 30 Miglyol 840 30 Panasate 810 30 Panasate 810S 30 Myritol 325 30 total 150 150 150 150 150 result ◯ ◯ ◯ ◯ ◯

(22) TABLE-US-00011 TABLE 11 formulation Ex. 23 Ex. 24 Ex. 25 Ex. 26 Ex. 27 Ex. 28 Ex. 29 Ex. 30 Ex. 31 Ex. 32 Ex. 33 wood creosote 45 45 45 45 45 45 45 45 45 45 45 Polysorbate 80 20 20 20 20 20 20 20 20 20 20 20 SY Glyster ML-310 20 SY Glyster MO-5S 20 Sunsoft Q-12D 20 Sunsoft Q-12S 20 Sunsoft Q-14S 20 Sunsoft Q-17S 20 Sunsoft A-121E 20 Sunsoft A-141E 20 Sunsoft A-171E 20 NIKKOL Hexaglyn1-M 20 NIKKOL Decaglyn1-LN 20 total 85 85 85 85 85 85 85 85 85 85 85 result ◯ ◯ ◯ ◯ ◯ ◯ ◯ ◯ ◯ ◯ ◯

(23) TABLE-US-00012 TABLE 12 Ex. 34 Ex. 35 Ex. 36 Ex. 37 Ex. 38 for 1 part of wood creosote 1 time 2 times 3 times 4 times 5 times SY Glyster Δ ◯ ◯ ◯ ◯ ML-310 SY Glyster not used ◯ ◯ ◯ ◯ MO-5S Sunsoft Q-12D not used ◯ ◯ ◯ ◯ Sunsoft Q-12S Δ ◯ ◯ ◯ ◯ Sunsoft Q-14S not used ◯ ◯ ◯ ◯ Sunsoft Q-17S not used ◯ ◯ ◯ ◯ Sunsoft A-121E ◯ ◯ ◯ ◯ ◯ Sunsoft A-141E ◯ ◯ ◯ ◯ ◯ Sunsoft A-171E not used ◯ ◯ ◯ ◯ NIKKOL not used ◯ ◯ ◯ ◯ Hexaglyn1-M NIKKOL not used ◯ ◯ ◯ ◯ Decaglyn1-LN

Examples 39-40 (Formulation of Drug Composition, Manufacture of Soft Capsule Drug)

(24) With using the soft capsule raw sheets obtained in formulation example 4-2 above, soft capsule drugs (soft capsules) were made by the standard method. The drug compositions sealed (charged) in these soft capsule drugs are as shown in Table 13 below. It is noted that the drug shell water contents (%) of the used soft capsule raw sheets (obtained in formulation example 4-2) are water contents of the manufactured capsule drug shells (measured at this timing). The respective soft capsule drugs obtained as above were subjected to stability test (50° C., 30 days). The results are shown also in Table 13 below.

(25) TABLE-US-00013 TABLE 13 Ex. 39 Ex. 40 formulation formulation employed soft capsule raw sheet example 4-2 example 4-2 formulation wood creosote 45 parts 45 parts of drug Polysorhate 80 25 parts 0 parts composition Polyethylene glycol 400 30 parts 55 parts results of stability test No dissolution No dissolution (50° C., 30 days) of capsule of capsule drug shell drug shell observed observed

Collapsibility Test after Storage

(26) Separately, with using the wood creosote soft capsule drugs (Examples 39 and 40), stability and collapsibility after storage at 40° C. (6 months storage period in sealed glass bottle) were checked. The results are shown in Table 14 below

(27) TABLE-US-00014 TABLE 14 storage period at 40° C. 0 month (control) after 6 months guaiacol amount 100 101.7 (control ratio) guaiacol content 28.7% 29.2% collapse test (min.) about 6 min. about 6 min. ※ guaiacol content in the used wood creosote: 29.4%

(28) From Table 14 above, it was found that the inventive soft capsule has high solubility and high resistance against collapse delay.

INDUSTRIAL APPLICABILITY

(29) The drug composition of the present invention is applicable as a drug composition in a liquid (solution) form that is stored inside a soft capsule whose capsule shell contains a succinylated-gelatin as a principal component thereof and also as a soft capsule drug sealed in a soft capsule whose capsule shell contains a succinylated-gelatin as a principal component thereof.