JP4048389B2 - Cyclosporine soft capsule - Google Patents
Cyclosporine soft capsule Download PDFInfo
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- JP4048389B2 JP4048389B2 JP30491797A JP30491797A JP4048389B2 JP 4048389 B2 JP4048389 B2 JP 4048389B2 JP 30491797 A JP30491797 A JP 30491797A JP 30491797 A JP30491797 A JP 30491797A JP 4048389 B2 JP4048389 B2 JP 4048389B2
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- cyclosporine
- parts
- fatty acid
- soft capsule
- Prior art date
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- 108010036949 Cyclosporine Proteins 0.000 title claims description 45
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 title claims description 44
- 229960001265 ciclosporin Drugs 0.000 title claims description 44
- 229930182912 cyclosporin Natural products 0.000 title claims description 43
- 239000007901 soft capsule Substances 0.000 title claims description 16
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 15
- 239000000194 fatty acid Substances 0.000 claims description 15
- 229930195729 fatty acid Natural products 0.000 claims description 15
- -1 fatty acid ester Chemical class 0.000 claims description 12
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 12
- 239000008158 vegetable oil Substances 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 8
- 229930105110 Cyclosporin A Natural products 0.000 claims description 7
- 239000007903 gelatin capsule Substances 0.000 claims description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 229920000223 polyglycerol Polymers 0.000 claims description 5
- NPTLAYTZMHJJDP-KTKRTIGZSA-N [3-[3-[3-[3-[3-[3-[3-[3-[3-(2,3-dihydroxypropoxy)-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropyl] (z)-octadec-9-enoate Chemical group CCCCCCCC\C=C/CCCCCCCC(=O)OCC(O)COCC(O)COCC(O)COCC(O)COCC(O)COCC(O)COCC(O)COCC(O)COCC(O)COCC(O)CO NPTLAYTZMHJJDP-KTKRTIGZSA-N 0.000 claims description 4
- CUNWUEBNSZSNRX-RKGWDQTMSA-N (2r,3r,4r,5s)-hexane-1,2,3,4,5,6-hexol;(z)-octadec-9-enoic acid Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O.CCCCCCCC\C=C/CCCCCCCC(O)=O CUNWUEBNSZSNRX-RKGWDQTMSA-N 0.000 claims description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- 229960005078 sorbitan sesquioleate Drugs 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims 1
- 229920000159 gelatin Polymers 0.000 claims 1
- 239000008273 gelatin Substances 0.000 claims 1
- 235000019322 gelatine Nutrition 0.000 claims 1
- 235000011852 gelatine desserts Nutrition 0.000 claims 1
- 239000002775 capsule Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 150000004667 medium chain fatty acids Chemical class 0.000 description 5
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000002156 mixing Methods 0.000 description 2
- 239000002736 nonionic surfactant Substances 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- PPWHTZKZQNXVAE-UHFFFAOYSA-N Tetracaine hydrochloride Chemical compound Cl.CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 PPWHTZKZQNXVAE-UHFFFAOYSA-N 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 1
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 108010025899 gelatin film Proteins 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- DTOSIQBPPRVQHS-PDBXOOCHSA-M linolenate Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC([O-])=O DTOSIQBPPRVQHS-PDBXOOCHSA-M 0.000 description 1
- 229940040452 linolenate Drugs 0.000 description 1
- 229960004488 linolenic acid Drugs 0.000 description 1
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 229920001281 polyalkylene Polymers 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
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- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【０００１】
本発明の背景
本発明は、免疫抑制剤として知られているシクロスポリン（別名サイクロスポリンＡ）の軟カプセル剤に関する。
【０００２】
シクロスポリンは、メタノール、エタノールなどには極めて溶け易く、水には殆ど溶けない。そのため結晶状態では経口投与による生体利用率は非常に低いので、これを高めるために製剤化に工夫を必要とする。
【０００３】
このような工夫の一つとして、特公昭６２−７８９１には、シクロスポリンを、エタノール、植物油および天然植物油トリグリセリドとポリアルキレンポリオールのエステル交換生成物からなる担体に配合した経口および非経口液体製剤が提案されている。この液剤はカプセルに充填できることも記載されているが、担体中のエタノールはゼラチン皮膜を透過して揮発し、シクロスポリンの全量を担体中に溶解状態で留めることが不可能になる。このためカプセルは例えば両面アルミニウムＰＴＰ包袋とし、服用直前までカプセル内部のエタノールの揮発を厳重に防止しなければならない。それでもなおエタノールの揮発を完全に防止するのは困難である上、包装を開封して取出したカプセルは独特の異臭を放つ。
【０００４】
従ってエタノールを含まない上記欠点を克服できるシクロスポリン軟カプセル剤が要望される。
【０００５】
本発明の開示
シクロスポリンは、ポリグリセリン脂肪酸エステルと植物油の混合物、またはポリグリセリン脂肪酸エステルとポリエチレングリコールおよび／またはプロピレングリコールの混合物よりなる液体担体中によく溶けることがわかった。
【０００６】
本発明はこの知見を基にし、この液体担体中に溶解したシクロスポリンの溶液をゼラチンカプセルに充填したシクロスポリン軟カプセル剤を提供する。
【０００７】
ポリグリセリン脂肪酸エステルは、脂肪酸がオレイン酸またはリノレン酸であり、ＨＬＢが３〜１６であることが好ましい。好ましい具体例としては、ＨＬＢ７．０のトリオレイン酸デカグリセリル、ＨＬＢ１２．０のモノオレイン酸デカグリセリル、および対応するリノレン酸デカグリセリルなどがある。
【０００８】
液体担体の他の成分の一つは植物油である。任意の植物油を使用し得るが、中鎖脂肪酸のトリグリセリドを主成分とする植物油が好ましい。ここで中鎖脂肪酸とは炭素数６〜１０の脂肪酸を意味する。そのような植物油の例はヤシ油である。
【０００９】
液体担体の他の成分は、植物油の代わりにポリエチレングリコール、プロピレングリコールまたは両者の混合物であってもよい。
【００１０】
液体担体は、任意の成分として、ポリグリセリン脂肪酸エステル以外の非イオン界面活性剤を含むことができる。その好ましい例はモノオレイン酸ポリオキシエチレンソルビタンおよびセスキオレイン酸ソルビタンである。
【００１１】
液体担体の配合割合はシクロスポリンの各成分に対する重量比に基いて決めることができる。この重量比は、ポリグリセリン脂肪酸に対し１：０．１〜１０および植物油に対し１：１〜２０である。植物油を含まない場合シクロスポリンの重量比は、ポリグリセリン脂肪酸エステルに対し１：０．０５〜５、ポリエチレングリコールおよび／またはプロピレングリコールに対し１：１〜２０の範囲にある。含有する場合、ポリグリセリン脂肪酸エステル以外の非イオン界面活性剤の配合量は、シクロスポリンのこの界面活性剤に対する重量比が１：０．０１〜５の範囲であるのが好ましい。
【００１２】
軟カプセルは、液体担体の各成分をあらかじめ均一に混合し、これへ所要量のシクロスポリンを溶解し、得られた溶液を常法によりゼラチンカプセルへ充填することによって得られる。
【００１３】
実施例１
シクロスポリン １．０重量部
トリオレイン酸デカグリセリル（ＨＬＢ７．０） １．０重量部
中鎖脂肪酸トリグリセリド ８．０重量部
────────────────────────────────
合計 １０．０重量部
【００１４】
トリオレイン酸デカグリセリルおよび中鎖脂肪酸トリグリセリドを均一に混合し、これへシクロスポリンを加えて完全に溶解する。この溶液をゼラチンカプセルへ充填し、シクロスポリンとして２５ｍｇ／カプセルを含有する軟カプセルを得た。
【００１５】
実施例２
シクロスポリン １．０重量部
トリオレイン酸デカグリセリル（ＨＬＢ７．０） １．０重量部
セスキオレイン酸ソルビタン ０．１重量部
中鎖脂肪酸トリグリセリド ８．０重量部
────────────────────────────────
合計 １０．１重量部
【００１６】
実施例１と同様にシクロスポリン以外の成分を均一に混合し、これへシクロスポリンを加えて完全に溶解し、ゼラチンカプセルへシクロスポリンとして２５ｍｇ／カプセルに充填する。
【００１７】
実施例３
シクロスポリン １．０重量部
モノオレイン酸デカグリセリル（ＨＬＢ１２．０） ０．１重量部
プロピレングリコール ２．０重量部
ポリエチレングリコール４００ ８．０重量部
────────────────────────────────
合計 １１．１重量部
【００１８】
実施例１と同様にシクロスポリン以外の成分を均一に混合し、これへシクロスポリンを加えて完全に溶解し、シクロスポリンとして２５ｍｇ／カプセルを含有する軟カプセルを得た。
【００１９】
実施例４
シクロスポリン １．０重量部
モノオレイン酸デカグリセリル（ＨＬＢ１２．０） ０．１重量部
モノオレイン酸ポリオキシエチレンソルビタン ０．５重量部
プロピレングリコール ２．０重量部
ポリエチレングリコール ８．０重量部
────────────────────────────────
合計 １１．６重量部
【００２０】
実施例１と同様にシクロスポリン以外の成分を均一に混合し、これへシクロスポリンを加えて完全に溶解し、シクロスポリンとして２５ｍｇ／カプセルを含有する軟カプセルを得た。
【００２１】
溶解性試験
実施例１〜４の軟カプセル中のシクロスポリンの水に対する溶解性を日本薬局方溶出試験法第２法（パドル法）に従って試験し、図１に示す結果を得た。対照としてシクロスポリンの原末について同じ方法により試験した。溶出量は高速液体クロマトグラフィー（ＨＬＰＣ）によって求めた。
【図面の簡単な説明】
【図１】実施例１〜４の本発明のシクロスポリン軟カプセル剤の中のシクロポリンの水に対する溶解性を示すグラフである。[0001]
Background of the invention The present invention relates to a soft capsule of cyclosporine (also known as cyclosporin A) known as an immunosuppressant.
[0002]
Cyclosporine is extremely soluble in methanol, ethanol, etc. and hardly soluble in water. Therefore, since the bioavailability by oral administration is very low in the crystalline state, ingenuity is required for formulation in order to increase this.
[0003]
As one of such devices, Japanese Examined Patent Publication No. 62-7891 proposes oral and parenteral liquid preparations in which cyclosporine is blended with a transesterification product of ethanol, vegetable oil and natural vegetable oil triglyceride and polyalkylene polyol. Has been. It is also described that this solution can be filled in a capsule, but ethanol in the carrier permeates through the gelatin film and volatilizes, making it impossible to keep the entire amount of cyclosporine dissolved in the carrier. For this reason, for example, the capsule should be a double-sided aluminum PTP bag, and ethanol in the capsule must be volatilized strictly until just before taking the capsule. Nevertheless, it is difficult to completely prevent the volatilization of ethanol, and the capsules taken out after opening the package give off a unique odor.
[0004]
Therefore, there is a need for a cyclosporine soft capsule that does not contain ethanol and can overcome the above-mentioned drawbacks.
[0005]
DISCLOSURE OF THE INVENTION Cyclosporine has been found to be well soluble in liquid carriers consisting of a mixture of polyglycerin fatty acid ester and vegetable oil, or a mixture of polyglycerin fatty acid ester and polyethylene glycol and / or propylene glycol.
[0006]
Based on this finding, the present invention provides a cyclosporine soft capsule in which a gelatin capsule is filled with a solution of cyclosporin dissolved in the liquid carrier.
[0007]
In the polyglycerol fatty acid ester, the fatty acid is preferably oleic acid or linolenic acid, and the HLB is preferably from 3 to 16. Preferred examples include decaglyceryl trioleate with HLB 7.0, decaglyceryl monooleate with HLB 12.0, and the corresponding decaglyceryl linolenate.
[0008]
One other component of the liquid carrier is vegetable oil. Although any vegetable oil can be used, vegetable oils based on triglycerides of medium chain fatty acids are preferred. Here, the medium chain fatty acid means a fatty acid having 6 to 10 carbon atoms. An example of such a vegetable oil is coconut oil.
[0009]
Other components of the liquid carrier may be polyethylene glycol, propylene glycol or a mixture of both instead of vegetable oil.
[0010]
The liquid carrier can contain a nonionic surfactant other than polyglycerin fatty acid ester as an optional component. Preferred examples thereof are polyoxyethylene sorbitan monooleate and sorbitan sesquioleate.
[0011]
The blending ratio of the liquid carrier can be determined based on the weight ratio of cyclosporine to each component. This weight ratio is 1: 0.1-10 for polyglycerin fatty acids and 1: 1-20 for vegetable oils. When vegetable oil is not included, the weight ratio of cyclosporine is in the range of 1: 0.05 to 5 for polyglycerol fatty acid ester and 1: 1 to 20 for polyethylene glycol and / or propylene glycol. When it contains, it is preferable that the compounding quantity of nonionic surfactants other than polyglycerol fatty acid ester is the range whose weight ratio with respect to this surfactant of cyclosporine is 1: 0.01-5.
[0012]
A soft capsule can be obtained by uniformly mixing each component of a liquid carrier in advance, dissolving a required amount of cyclosporine therein, and filling the resulting solution into a gelatin capsule by a conventional method.
[0013]
Example 1
Cyclosporine 1.0 part by weight Decaglyceryl trioleate (HLB 7.0) 1.0 part by weight Medium chain fatty acid triglyceride 8.0 parts by weight ──────────────────── ────────────
Total 10.0 parts by weight [0014]
Decaglyceryl trioleate and medium chain fatty acid triglyceride are mixed uniformly, and cyclosporine is added to this and completely dissolved. This solution was filled into gelatin capsules to obtain soft capsules containing 25 mg / capsule as cyclosporine.
[0015]
Example 2
Cyclosporine 1.0 part by weight Decaglyceryl trioleate (HLB 7.0) 1.0 part by weight sorbitan sesquioleate 0.1 part by weight Medium chain fatty acid triglyceride 8.0 part by weight ─────────── ─────────────────────
Total 10.1 parts by weight [0016]
Ingredients other than cyclosporine are uniformly mixed in the same manner as in Example 1, and cyclosporine is added and completely dissolved therein. The gelatin capsule is filled with 25 mg / capsule as cyclosporine.
[0017]
Example 3
Cyclosporine 1.0 parts by weight Decaglyceryl monooleate (HLB12.0) 0.1 parts by weight Propylene glycol 2.0 parts by weight Polyethylene glycol 400 8.0 parts by weight ────────────── ──────────────────
Total 11.1 parts by weight [0018]
Ingredients other than cyclosporin were uniformly mixed in the same manner as in Example 1, and cyclosporine was added and completely dissolved therein to obtain soft capsules containing 25 mg / capsule as cyclosporine.
[0019]
Example 4
Cyclosporine 1.0 parts by weight Decaglyceryl monooleate (HLB12.0) 0.1 parts by weight Polyoxyethylene sorbitan monooleate 0.5 parts by weight Propylene glycol 2.0 parts by weight Polyethylene glycol 8.0 parts by weight ─────────────────────────────
Total 11.6 parts by weight [0020]
Ingredients other than cyclosporin were uniformly mixed in the same manner as in Example 1, and cyclosporine was added and completely dissolved therein to obtain soft capsules containing 25 mg / capsule as cyclosporine.
[0021]
Solubility test The solubility of cyclosporine in the soft capsules of Examples 1 to 4 in water was tested according to the Japanese Pharmacopoeia dissolution test method 2 (paddle method), and the results shown in Fig. 1 were obtained. As a control, cyclosporine bulk powder was tested by the same method. The amount of elution was determined by high performance liquid chromatography (HLPC).
[Brief description of the drawings]
1 is a graph showing the solubility of cycloporin in water in the cyclosporin soft capsules of the present invention of Examples 1 to 4. FIG.
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30491797A JP4048389B2 (en) | 1997-10-20 | 1997-10-20 | Cyclosporine soft capsule |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP30491797A JP4048389B2 (en) | 1997-10-20 | 1997-10-20 | Cyclosporine soft capsule |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH11124339A JPH11124339A (en) | 1999-05-11 |
| JP4048389B2 true JP4048389B2 (en) | 2008-02-20 |
Family
ID=17938869
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP30491797A Expired - Fee Related JP4048389B2 (en) | 1997-10-20 | 1997-10-20 | Cyclosporine soft capsule |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP4048389B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5788256B2 (en) * | 2010-07-29 | 2015-09-30 | 富士カプセル株式会社 | Seamless capsule filling composition |
| CN114755346A (en) * | 2022-05-10 | 2022-07-15 | 丽珠集团丽珠制药厂 | A kind of determination method of cyclosporine soft capsule related substances |
| CN118356481A (en) * | 2023-01-19 | 2024-07-19 | 华北制药股份有限公司 | Cyclosporin soft capsule and preparation method thereof |
-
1997
- 1997-10-20 JP JP30491797A patent/JP4048389B2/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| JPH11124339A (en) | 1999-05-11 |
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