JP4370451B2 - Pharmaceutical composition - Google Patents

Description

【０１４４】
表１中の各数値は、ラット４匹〜１１匹を用いた mean±S.E.値である。
【０１４５】
表１から、次のことがわかる。
【０１４６】
スペルミン（ポリアミン）を含有する溶液ＰＢ（コントロール２）は、スペルミン（ポリアミン）を含有しない溶液ＰＡ（コントロール１）に比し、ＰＲの吸収率が殆ど変化がなく、また蛋白質漏出量も同レベルであった。このことから、スペルミン自身は、薬理活性物質の吸収及びラットの大腸粘膜になんら影響を与えていないことが分かる。
【０１４７】
タウロデオキシコール酸ナトリウム（溶解補助剤）を低濃度で含有する溶液ＰＤ（比較例２）は、タウロデオキシコール酸ナトリウム（溶解補助剤）を含有しない溶液ＰＡ（コントロール１）及びスペルミン（ポリアミン）を含有する溶液ＰＢ（コントロール２）に比し、ＰＲの吸収率は低下しているものの、蛋白質漏出量は殆ど変わらなかった。ＰＲの吸収率が低下した原因としては、タウロデオキシコール酸ナトリウム（溶解補助剤）が形成するミセル中にＰＲが取り込まれたため、ＰＲが腸管から吸収されなかったことが考えられる。
【０１４８】
タウロデオキシコール酸ナトリウム（溶解補助剤）を高濃度で含有する溶液ＰＣ（比較例１）は、タウロデオキシコール酸ナトリウム（溶解補助剤）を低濃度で含有する溶液ＰＤ（比較例２）に比し、ＰＲの吸収率が向上しているが、蛋白質漏出量が著しく増加し、ラットの大腸に損傷を与えた。
【０１４９】
低濃度のタウロデオキシコール酸ナトリウム（溶解補助剤）と共にスペルミン（ポリアミン）を含有する溶液ＰＥ（実施例１）は、ＰＲの吸収率を大幅に向上させ、しかも、蛋白質漏出量に殆ど影響を与えておらず、ラットの大腸に損傷を与えなかった。
【０１５０】
（２）溶解補助剤としてラウリン酸ナトリウムを用いた試験
試験動物としてＳＤ系雄性ラット（体重約２５０ｇ）を用いた。ラットの大腸上部に５ｃｍのループを作製し、そのループ内へ上記で調製した各種溶液（溶液ＰＡ、溶液ＰＦ又は溶液ＰＧ）を２．５ｍｌ投与した。投与から１．５時間後に、ループ内に残存している溶液を回収した。
【０１５１】
回収した溶液中のＰＲの残存量を求め、ラットの大腸から吸収されたＰＲの吸収率（％）を求めた。
【０１５２】
また、ラット大腸から漏出（溶出）した蛋白質の量(mg)を測定した。この蛋白質漏出量が大腸損傷の目安となる。
【０１５３】
結果を表２に示す。
【０１５４】
【表２】

【０１５５】
表２中の各数値は、ラット４匹〜１１匹を用いた mean±S.E.値である。
【０１５６】
表２から、次のことがわかる。
【０１５７】
ラウリン酸ナトリウム（溶解補助剤）を含有する溶液ＰＦ（コントロール３）は、ラウリン酸ナトリウム（溶解補助剤）を含有しない溶液ＰＡ（コントロール１）に比し、ＰＲの吸収率が向上しているが、蛋白質漏出量が著しく増加し、ラットの大腸に損傷を与えた。
【０１５８】
ラウリン酸ナトリウム（溶解補助剤）と共にスペルミン（ポリアミン）を含有する溶液ＰＧ（実施例２）は、ラウリン酸ナトリウム（溶解補助剤）のみを含有する溶液ＰＦ（コントロール３）に比し、ＰＲの吸収率を大幅に向上させ、しかも、蛋白質漏出量に殆ど影響を与えておらず、ラットの大腸に損傷を与えなかった。
【０１５９】
以上の表１及び表２の結果から、医薬組成物に溶解補助剤及びポリアミンを配合することで、腸管粘膜障害の生じない低濃度の溶解補助剤量で、腸管粘膜障害の生じる高濃度の溶解補助剤量と同等もしくはそれ以上の薬物吸収増強作用を発現でき、安全性が向上することがわかる。
【０１６０】
試験例２
吸収に関するモデル化合物として、レバミピド（商品名：ムコスタ、大塚製薬（株）製）を使用し、次の４種類の溶液を調製した。
溶液ＰＨ（コントロール４）：
レバミピドが２．０ｍｇ／ｍｌ及びヒドロキシプロピルメチルセルロース（商品名：ＴＣ−５Ｅ、信越化学（株）製）が１重量％となるように、トリス−塩酸緩衝液（ｐＨ７．４）にレバミピド及びヒドロキシプロピルメチルセルロースを加え、溶液状態になるように２Ｎ−ＮａＯＨを滴下して、溶液ＰＨを調製した。溶液ＰＩ（コントロール５）：
レバミピドが２．０ｍｇ／ｍｌ、ヒドロキシプロピルメチルセルロースが１重量％及びタウロコール酸ナトリウム（溶解補助剤）が５ｍＭとなるように、トリス−塩酸緩衝液（ｐＨ７．４）にレバミピド、ヒドロキシプロピルメチルセルロース及びタウロコール酸ナトリウムを加え、溶液状態になるように２Ｎ−ＮａＯＨを滴下して、溶液ＰＩを調製した。
溶液ＰＪ（実施例３）：
レバミピドが２．０ｍｇ／ｍｌ、ヒドロキシプロピルメチルセルロースが１重量％、タウロコール酸ナトリウム（溶解補助剤）が５ｍＭ及びスペルミン（ポリアミン）が１０ｍＭとなるように、トリス−塩酸緩衝液（ｐＨ７．４）にレバミピド、ヒドロキシプロピルメチルセルロース、タウロコール酸ナトリウム及びスペルミン（ポリアミン）を加え、溶液状態になるように２Ｎ−ＮａＯＨを滴下して、溶液ＰＪを調製した。
溶液ＰＫ（実施例４）：
レバミピドが２．０ｍｇ／ｍｌ、ヒドロキシプロピルメチルセルロースが１重量％及びスペルミン（ポリアミン）が１０ｍＭとなるように、トリス−塩酸緩衝液（ｐＨ７．４）にレバミピド、ヒドロキシプロピルメチルセルロース及びスペルミン（ポリアミン）を加えて、溶液ＰＫを調製した。
【０１６１】
試験動物としてＳＤ系雄性ラット（体重約２５０ｇ）を用いた。ラットの大腸上部に５ｃｍのループを作製し、そのループ内へ上記で調製した各種溶液（溶液ＰＨ、溶液ＰＩ、溶液ＰＪ又は溶液ＰＫ）を２．５ｍｌ投与した。投与から５分後、１５分後、３０分後、４５分後、６０分後及び９０分後に、ラット頸静脈から採血した。また、投与から９０分後に、ループ内に残存している溶液を回収した。
【０１６２】
投与から９０分以内の全レバミピド吸収量(ng.hr/ml)を求め、ＡＵＣ_1.5hrとして表３に示す。また、投与から５〜９０分後におけるレバミピドの最高血中濃度(ng/ml)を求め、Ｃ_maxとして表３に示す。更に、ラット大腸から漏出（溶出）したリン脂質の量を測定し、表３に示す。
【０１６３】
【表３】

【０１６４】
表３中の各数値は、ラット４匹を用いた mean±S.E.値である。
【０１６５】
表３から、次のことがわかる。
【０１６６】
タウロコール酸ナトリウム（溶解補助剤）を低濃度含有する溶液ＰＩ（コントロール５）は、タウロコール酸ナトリウム（溶解補助剤）を含有しない溶液ＰＨ（コントロール４）に比し、レバミピドの吸収率は低下しているものの、リン脂質漏出量は殆ど変わらなかった。レバミピドの吸収率が低下した原因としては、タウロコール酸ナトリウム（溶解補助剤）が形成するミセル中にレバミピドが取り込まれたため、レバミピドが腸管から吸収されなかったことが考えられる。
【０１６７】
低濃度のタウロコール酸ナトリウム（溶解補助剤）と共にスペルミン（ポリアミン）を含有する溶液ＰＪ（実施例３）は、レバミピドの吸収率を大幅に向上させ、しかも、リン脂質漏出量に殆ど影響を与えておらず、ラットの大腸に損傷を与えなかった。
【０１６８】
スペルミン（ポリアミン）を含有する溶液ＰＫ（実施例４）は、レバミピドの吸収を増加させた。上記試験例１においてＰＲにスペルミン（ポリアミン）を用いた場合にはＰＲの吸収増加効果が認められなかったことから、スペルミン（ポリアミン）は、難溶性薬理活性物質に対して特異的に作用し、吸収増加効果を発揮することがわかった。
【０１６９】
実施例４の溶液ＰＫにおいて、レバミピドの代わりにシロスタゾールを用いた場合にも、上記と同様の結果が得られた。
【０１７０】
また、実施例４の溶液ＰＫにおいて、スペルミン以外のポリアミンを用いた場合にも、上記と同様の結果が得られた。[0001]
The present invention relates to a pharmaceutical composition.
[0002]
[Prior art]
For the purpose of improving absorption promotion of a pharmacologically active substance, a drug absorption accelerator is usually added to a drug containing the pharmacologically active substance (for example, Crit. Rev. Ther. Drug Carrier Syst., S .Muranishi, 7, p1-33 (1990) etc.).
[0003]
However, a medicament containing a pharmacologically active substance and a drug absorption promoter has a side effect of damaging the intestinal mucosa such as the small intestine, large intestine, and rectum (for example, Pharm. Res., ESSwenson, WBMilisen, W. Curatolo, 11 (8), p1132-1142 (1994) etc.). This side effect is due to drug absorption accelerators.
[0004]
In order to suppress the expression of the above side effects, it is necessary to reduce the amount of the drug absorption promoter. However, when the blending amount of the drug absorption accelerator is reduced, there arises a disadvantage that the effect of promoting absorption of the pharmacologically active substance is lowered.
[0005]
In order to improve such a problem, an attempt has been made to add an amino acid such as arginine to a pharmaceutical composition containing a pharmacologically active substance and a drug absorption accelerator (Biol. Pharm. Bull., Y. Kinouchi, N. Yata, 19 (3), p375-378 (1996)).
[0006]
However, although the damage of the intestinal mucosa can be suppressed to some extent by adding an amino acid, the effect is insufficient. And development of the pharmaceutical composition which can suppress the damage of an intestinal mucosa further is desired.
[0007]
On the other hand, polyamines have an action to promote maturation of the digestive tract of infants (Japanese Patent Laid-Open No. 10-262607, Patent Document 1), and polyamines inhibit gastric acid secretion and have a gastric mucosal protective action (Japanese Patent Laid-Open No. Sho). No. 58-131914, Patent Document 2) is known. However, the publication does not mention or suggest that polyamines increase the absorption of low molecular weight pharmacologically active substances having a molecular weight of about 1000 or less. Furthermore, to date no examples of polyamines used to increase intestinal pharmacologically active substance absorption are known.
[0008]
[Patent Document 1]
JP-A-10-262607
[0009]
[Patent Document 2]
JP 58-131914 A
[0010]
[Problems to be solved by the invention]
An object of the present invention is to provide a pharmaceutical composition that hardly damages the intestinal mucosa.
[0011]
[Means for Solving the Problems]
As a result of intensive studies to solve the above problems, the present inventor has found that the above object of the present invention can be achieved by blending a polyamine with a pharmaceutical composition containing a pharmacologically active substance and a drug absorption accelerator. It was. That is, the present inventor has the effect that the polyamine has an effect of enhancing the drug absorption promoting effect of the drug absorption accelerator. As a result, it has been found that damage to the intestinal mucosa due to side effects of the drug absorption promoter can be suppressed or prevented. The present invention has been completed based on such findings.
1. The present invention provides a pharmaceutical composition comprising a pharmacologically active substance, a drug absorption accelerator and a polyamine.
2. The present invention provides the pharmaceutical composition according to the above 1, wherein the drug absorption accelerator is a solubilizing agent.
3. In the present invention, the pharmacologically active substance is theophylline, cilostazol, grepafloxacin, carteolol, procaterol, rebamipide, aripiprazole, 5-fluorouracil, diclofenac, cyclosporine, nifedipine, phenol red, tolpabutane, interferon α, interferon β, vesnarinone, Nadifloxacin, tobonone, pranidipine, cefazoline, buprenorphine, probucol, γ-oryzanol, 1- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-methoxy-3,4-dihydro-2 (1H ) -Quinolinone monomethanesulfonate, 4- (N-methyl-2-phenylethylamino) -1- (3,5-dimethyl-4-propionylaminobenzoyl) piperidine high Drochloride monohydrate, (±) -5-dimethylamino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine hydrochloride, 6- [2 -(3,4-diethoxyphenyl) thiazol-4-yl] pyridine-2-carboxylic acid, mevalotin, loxonin, probreth, basin, takepron, pansporine, serta, carlotnorbasque, lipitol, cardenaline, viagra, clabit, vanaldin , Gaster, Harnal, Perdipine, Celbex, Graque, Aricept, Lipovas, Neurotan, Renibase, Fromox, Fullmarine, Kefler, Sajiten, Rasimir, Epogin, Cefzon, Intal, and Nivazir Provides a pharmaceutical composition according to claim 1 is at least one kind.
4). The present invention provides the pharmaceutical composition according to 1 above, wherein the drug absorption accelerator is an alkali metal salt of bile acid.
5). The present invention provides the pharmaceutical composition according to 4 above, wherein the drug absorption accelerator is at least one selected from the group consisting of an alkali metal salt of taurocholic acid and an alkali metal salt of taurodeoxycholic acid.
6). The present invention provides the pharmaceutical composition according to the above 1, wherein the polyamine is spermine.
7. The present invention provides a drug absorption enhancer that is used in combination with a pharmaceutical composition containing a pharmacologically active substance and a drug absorption enhancer and contains a polyamine.
8). The present invention provides the drug absorption enhancer according to 7 above, wherein the drug absorption accelerator is a solubilizing agent.
9. The present invention provides the drug absorption enhancer according to 7 or 8 above, wherein the polyamine is spermine.
10. The present invention provides an intestinal mucosal protective agent that is used in combination with a pharmaceutical composition containing a pharmacologically active substance and a drug absorption promoter and contains a polyamine.
11. The present invention provides the intestinal mucosa protective agent as described in 10 above, wherein the drug absorption accelerator is a solubilizing agent.
12 The present invention provides the intestinal mucosa protective agent according to 10 or 11 above, wherein the polyamine is spermine.
13. The present invention provides a method for improving the absorption of a pharmacologically active substance by blending a polyamine with a pharmaceutical composition containing a pharmacologically active substance and a drug absorption accelerator.
14 The present invention provides a method for inhibiting or preventing intestinal mucosa damage by blending a polyamine with a pharmaceutical composition containing a pharmacologically active substance and a drug absorption promoter.
15. The present invention provides a method for improving the absorption of a pharmacologically active substance by using a pharmaceutical composition containing a pharmacologically active substance and a drug absorption enhancer in combination with a drug absorption enhancer containing a polyamine.
16. The present invention provides a method for suppressing or preventing intestinal mucosal damage by using a pharmaceutical composition containing a pharmacologically active substance and a drug absorption promoter together with a drug absorption enhancer containing a polyamine.
17. The present invention provides a pharmaceutical composition containing a hardly soluble pharmacologically active substance and a polyamine and containing no drug absorption promoter.
18. The present invention provides the pharmaceutical composition according to the above 17, wherein the drug absorption accelerator is a solubilizing agent.
19. The present invention provides the pharmaceutical composition according to the above 17, wherein the poorly soluble pharmacologically active substance is at least one selected from the group consisting of cilostazol, rebamipide, cyclosporine and nifedipine.
20. The present invention provides the pharmaceutical composition according to the above 17, wherein the polyamine is spermine.
21. The present invention provides a drug absorption improver that is used in combination with a pharmaceutical composition that contains a poorly soluble pharmacologically active substance and does not contain a drug absorption accelerator, and that contains a polyamine To do.
22. The present invention provides a method for improving absorption of a pharmacologically active substance by blending a polyamine with a pharmaceutical composition containing a hardly soluble pharmacologically active substance and not containing a drug absorption promoter.
[0012]
DETAILED DESCRIPTION OF THE INVENTION
Polyamine-containing pharmaceutical composition A
The pharmaceutical composition containing a polyamine will be described below.
[0013]
The pharmaceutical composition of the present invention contains a pharmacologically active substance, a drug absorption accelerator and a polyamine. Polyamine has the effect | action which raises the absorption promotion effect of a drug absorption promoter. In this specification, the drug absorption promoter is a compound that promotes absorption of a pharmacologically active substance.
[0014]
The pharmacologically active substance is not particularly limited as long as it is a pharmacologically active substance absorbed from the intestinal mucosa, and a wide variety of known substances can be used. Examples of such pharmacologically active substances include respiratory preparations, digestive organ preparations, circulatory organ preparations, central nervous system preparations, peripheral nerve preparations, antibiotic preparations, chemotherapeutic agents, antitumor agents, and platelet aggregation. Examples include normal pharmacologically active substances that are blended in various preparations such as inhibitors, antiallergic agents, vitamins, and diagnostic agents.
[0015]
Specific examples of such pharmacologically active substances include, for example, theophylline, cilostazol, grepafloxacin, carteolol, procaterol, rebamipide, aripiprazole, 5-fluorouracil, diclofenac, cyclosporine, nifedipine, phenol red, tolpabutane, interferon α, Interferon β, vesnarinone, nadifloxacin, tobonone, pranidipine, cefazoline, buprenorphine, probucol, γ-oryzanol, 1- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-methoxy-3,4- Dihydro-2 (1H) -quinolinone monomethanesulfonate, 4- (N-methyl-2-phenylethylamino) -1- (3,5-dimethyl-4-propionylaminoben Yl) piperidine hydrochloride monohydrate, (±) -5-dimethylamino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine hydrochloride, 6 -[2- (3,4-diethoxyphenyl) thiazol-4-yl] pyridine-2-carboxylic acid, mevalotin, loxonin, probres, basin, takepron, pansporin, serta, carlotnorbasque, lipitol, cardenaline, viagra, Cravit, Vanardine, Gaster, Harnal, Perdipine, Selvex, Graquet, Aricept, Lipovas, Neurotan, Renibase, Frommox, Fullmarine, Kefler, Sajiten, Rasimir, Epogin, Cefzon, Intal, Nivaji Etc. The.
[0016]
Preferred pharmacologically active substances are, for example, theophylline, cilostazol, grepafloxacin, carteolol, procaterol, rebamipide, aripiprazole, 5-fluorouracil, diclofenac, cyclosporine, nifedipine, phenol red, tolpabutane, interferon α, interferon β, vesnarinone, nadifloxacin , Tobonone, pranidipine, cefazoline, buprenorphine, probucol, γ-oryzanol, 1- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-methoxy-3,4-dihydro-2 (1H) -Quinolinone monomethanesulfonate, 4- (N-methyl-2-phenylethylamino) -1- (3,5-dimethyl-4-propionylaminobenzoyl) piperidi Hydrochloride monohydrate, (±) -5-dimethylamino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine hydrochloride, 6- [2 -(3,4-diethoxyphenyl) thiazol-4-yl] pyridine-2-carboxylic acid and the like.
[0017]
Specific examples of more preferred pharmacologically active substances include, for example, theophylline, cilostazol, grepafloxacin, carteolol, procaterol, rebamipide, aripiprazole, 5-fluorouracil, diclofenac, cyclosporine, nifedipine, phenol red and the like.
[0018]
These pharmacologically active substances are used singly or in combination of two or more.
[0019]
Among the drug absorption accelerators, certain compounds have an action of assisting the dissolution of the pharmacologically active substance, so that a hardly soluble pharmacologically active substance can be used as the pharmacologically active substance. A compound which is a drug absorption accelerator and has an action of assisting dissolution of a pharmacologically active substance is referred to as “dissolution aid” in the present specification.
[0020]
Here, the poorly soluble pharmacologically active substance means a pharmacologically active substance having a solubility in water of 10 mg / ml or less. For example, a drug whose solubility specified in the 13th revised Japanese Pharmacopoeia is “extremely insoluble” and “almost insoluble” corresponds to a hardly soluble pharmacologically active substance.
[0021]
Among the pharmacologically active substances, the hardly soluble pharmacologically active substances are cilostazol, rebamipide, aripiprazole, cyclosporine and nifedipine. Of these poorly soluble pharmacologically active substances, those having poor absorbability are rebamipide, cyclosporine and nifedipine. Here, the pharmacologically active substance having poor absorbability means a pharmacologically active substance having an absorption rate of less than 40%. The absorption rate and the measuring method thereof are described in, for example, Walter E., Janich S., Roessler B. J., Hilfinger J.H., Amidon G., 1996; J. Pharm. Sci. 85, 1070-1076.
[0022]
The drug absorption promoter is a compound that promotes the absorption of the pharmacologically active substance, and is not particularly limited. A wide variety of known drugs can be used. Specific examples include bile salts, medium chain fatty acid salts, long chain fatty acid salts, surfactants, cyclodextrins, alkyl saccharides, chelating agents, alkyl carbamates, sorbitan fatty acid esters, and the like.
[0023]
Examples of bile salts include alkali metal salts of bile acids such as cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, chenodeoxycholic acid, taurodeoxycholic acid, specifically sodium cholate, glycochol. Sodium acid, sodium taurocholate, sodium deoxycholate, sodium chenodeoxycholate, sodium taurodeoxycholate and the like are included.
[0024]
Examples of the medium chain fatty acid salt include salts of fatty acids having 6 to 13 carbon atoms (particularly alkali metal salts). Specifically, alkali metal salts (sodium salts) such as caproic acid, caprylic acid, lauric acid, lauryl sulfuric acid, etc. , Potassium salts, etc.).
[0025]
Examples of the long-chain fatty acid salt include salts of fatty acids having 14 to 20 carbon atoms (particularly alkali metal salts). Specifically, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, Alkali metal salts such as arachidonic acid (sodium salt, potassium salt, etc.) are included.
[0026]
Examples of the surfactant include an anionic surfactant and a nonionic surfactant. Nonionic surfactants include, for example, monostearic glyceride, tricapric glyceride, trilauric glyceride, glyceryl monoundecylenate, tetraglyceryl pentastearate, polysorbate 80, polyoxyethylene cured Castor oil, polyoxyethylene castor oil, polyoxyethylene lanolin, polyoxyethylene lanolin alcohol, polyoxyethylene lauryl ether, polyoxyethylene cetyl ether and the like can be mentioned.
[0027]
Examples of the cyclodextrin include dimethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin and the like.
[0028]
Examples of the alkyl saccharide include carboxyfluorescein and lauryl maltoside.
[0029]
Examples of the chelating agent include polyaminocarboxylic acids such as EDTA, oxycarboxylic acids such as citric acid, and oximes such as dimethylglyoxime.
[0030]
Examples of the alkyl carbamate include C₁-C_FourExamples of the alkyl carbamate include methyl carbamate, ethyl carbamate, and butyl carbamate.
[0031]
Examples of the sorbitan fatty acid ester include sorbitan monolaurate, sorbitan monopalmitate, sorbitan sesquistearate, sorbitan sesquioleate, and the like.
[0032]
Among these, compounds that have an action of assisting dissolution of a pharmacologically active substance and can be used as a solubilizer include, for example, bile salts, medium chain fatty acid salts, long chain fatty acid salts, surfactants, cyclodextrins, etc. It is.
[0033]
Preferred drug absorption enhancers are, for example, bile salts, medium chain fatty acid salts, long chain fatty acid salts and the like.
[0034]
More preferred drug absorption promoters are, for example, bile salts, medium chain fatty acid salts and the like.
[0035]
These drug absorption accelerators are used singly or in combination of two or more.
[0036]
In the present invention, it is essential to add a polyamine in a composition containing the pharmacologically active substance and a drug absorption accelerator (dissolution aid).
[0037]
The polyamine is not particularly limited, and known ones can be widely used. Specific examples of polyamines include spermine, spermidine, putrescine, cadaverine, 1,3-diaminopropane, cardine, homospermidine, aminopropyl cadaverine, theremin, thermospermine, canabalmin, aminopertyl norspermine, N, N′-bis ( Aminopropyl) cadaverine, cardopentamine, homocardopentamine, cardohexamine and the like can be exemplified.
[0038]
Preferred polyamines are spermine, spermidine, putrescine, cadaverine, theremin, thermospermine, canabalmin, aminopertyl norspermine, N, N′-bis (aminopropyl) cadaverine, cardopentamine, homocardopentamine, cardohexamine and the like. .
[0039]
More preferred polyamines are spermine, spermidine, putrescine, cadaverine and the like.
[0040]
These polyamines are used singly or in combination of two or more.
[0041]
The compounding amount of the polyamine is not particularly limited, but considering the absorption promotion enhancing effect, economy and the like, it is usually 0.001 to 5000% by weight, preferably 0.005 to the drug absorption promoter. It is good to set it as 1000 weight%, More preferably, it is 0.05-1000 weight%, More preferably, it is 0.1-500 weight%.
[0042]
The compounding amount of the pharmacologically active substance and the drug absorption promoter in the pharmaceutical composition of the present invention is not particularly limited and may be a normal compounding amount. However, the effect of increasing the absorption of the pharmacologically active substance from the intestinal tract or the drug absorption promotion Since it has the effect | action which strengthens the absorption effect of the pharmacologically active substance by an agent, the compounding quantity of a drug absorption promoter can be decreased. For example, an effective amount of a pharmacologically active substance is used, and the drug absorption accelerator is usually 0.01 to 1000% by weight, preferably 0.05 to 500% by weight, more preferably 0.1 to 500%, based on the pharmacologically active substance. It is good to mix | blend weight%, especially 0.1-100 weight%.
[0043]
The pharmaceutical composition of the present invention is usually formulated by combining with the above pharmacologically active substance, drug absorption accelerator and polyamine together with various carriers such as excipients, binders and disintegrants.
[0044]
As the excipient, known ones can be widely used, for example, various sugars such as lactose, sucrose and glucose, various starches such as potato starch, wheat starch and corn starch, various celluloses such as crystalline cellulose, Examples include various inorganic salts such as anhydrous calcium hydrogen phosphate and calcium carbonate.
[0045]
As the binder, known ones can be widely used, and examples thereof include crystalline cellulose, pullulan, gum arabic, sodium alginate, polyvinyl pyrrolidone, macrogol and the like.
[0046]
As the disintegrant, known ones can be widely used, and examples thereof include carboxymethyl cellulose, carboxymethyl cellulose calcium, hydroxypropyl cellulose, hydroxypropyl starch, starch, sodium alginate and the like.
[0047]
The preparation form of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include various preparation forms such as tablets, capsules, granules, solutions, and suppositories. The pharmaceutical composition of the present invention is usually administered orally. Since the pharmacologically active substance contained in the pharmaceutical composition of the present invention has the property of being absorbed from the intestinal mucosa, the pharmaceutical preparation of the present invention is preferably an enteric disintegrating preparation such as the small intestine, large intestine, and rectum.
[0048]
The dose of polyamine is usually 0.0001 to 100 mg, preferably 0.005 to 20 mg, more preferably 0.05 to 20 mg, still more preferably 0.5 to 20 mg per kg body weight per day. .
[0049]
The present invention provides a method for improving the absorption of a pharmacologically active substance by blending a polyamine with a pharmaceutical composition containing a pharmacologically active substance and a drug absorption accelerator.
[0050]
The present invention provides a method for inhibiting or preventing intestinal mucosa damage by blending a polyamine with a pharmaceutical composition containing a pharmacologically active substance and a drug absorption promoter.
[0051]
Polyamines have the effect of improving the absorption of pharmacologically active substances. Therefore, the content of the drug absorption accelerator in the pharmaceutical composition can be reduced. Therefore, damage to the intestinal mucosa caused by the drug absorption promoter can be suppressed or prevented.
[0052]
Polyamine-containing drug absorption enhancer
The polyamine has the effect of enhancing the absorption of the pharmacologically active substance possessed by the drug absorption promoter as described above. Accordingly, the present invention provides a drug absorption enhancer containing a polyamine.
[0053]
The polyamine is not particularly limited, and known ones can be widely used. Specific examples of polyamines include spermine, spermidine, putrescine, cadaverine, 1,3-diaminopropane, cardine, homospermidine, aminopropyl cadaverine, theremin, thermospermine, canabalmin, aminopertyl norspermine, N, N′-bis ( Aminopropyl) cadaverine, cardopentamine, homocardopentamine, cardohexamine and the like can be exemplified.
[0054]
Preferred polyamines are spermine, spermidine, putrescine, cadaverine, theremin, thermospermine, canabalmin, aminopertyl norspermine, N, N′-bis (aminopropyl) cadaverine, cardopentamine, homocardopentamine, cardohexamine and the like. .
[0055]
More preferred polyamines are spermine, spermidine, putrescine, cadaverine and the like.
[0056]
These polyamines are used singly or in combination of two or more.
[0057]
The content of the polyamine is not particularly limited and is appropriately selected from a wide range. For example, polyamine is usually contained in the preparation in a proportion of 0.01 to 80% by weight, preferably 0.1 to 50% by weight, more preferably 1 to 20% by weight.
[0058]
The drug absorption enhancer of the present invention is usually formulated by blending with various carriers such as excipients, binders and disintegrants together with polyamines.
[0059]
As the excipient, known ones can be widely used, for example, various sugars such as lactose, sucrose and glucose, various starches such as potato starch, wheat starch and corn starch, various celluloses such as crystalline cellulose, Examples include various inorganic salts such as anhydrous calcium hydrogen phosphate and calcium carbonate.
[0060]
As the binder, known ones can be widely used, and examples thereof include crystalline cellulose, pullulan, gum arabic, sodium alginate, polyvinyl pyrrolidone, macrogol and the like.
[0061]
As the disintegrant, known ones can be widely used, and examples thereof include carboxymethyl cellulose, carboxymethyl cellulose calcium, hydroxypropyl cellulose, hydroxypropyl starch, starch, sodium alginate and the like.
[0062]
The preparation form of the drug absorption enhancer of the present invention is not particularly limited, and examples thereof include various preparation forms such as tablets, capsules, granules, solutions, and suppositories. The pharmaceutical composition of the present invention is usually administered orally. Since polyamine has an action of suppressing or preventing intestinal mucosal damage caused by a drug absorption accelerator, the drug absorption enhancer of the present invention is preferably an intestinal disintegrating preparation such as the small intestine, large intestine, and rectum.
[0063]
In using the drug absorption enhancer of the present invention, it is used in combination with a pharmaceutical composition containing a pharmacologically active substance and a drug absorption accelerator.
[0064]
When the drug absorption enhancer and the pharmaceutical composition are used in combination, both can be administered simultaneously. Alternatively, the drug absorption enhancer can be administered at intervals and then in the order of the pharmaceutical composition, or in the order of the pharmaceutical composition and then the drug absorption enhancer.
[0065]
The dose of polyamine is usually 0.0001 to 100 mg, preferably 0.005 to 20 mg, more preferably 0.05 to 20 mg, still more preferably 0.5 to 20 mg per kg body weight per day. .
[0066]
Polyamine-containing intestinal mucosa protective agent
Since the polyamine has the effect of enhancing the absorption of the pharmacologically active substance possessed by the drug absorption promoter as described above, the amount of the drug absorption promoter used can be reduced, and as a result, the drug absorption promoter Injury to the intestinal mucosa due to the side effects can be suppressed or prevented. Therefore, this invention provides the intestinal mucosa protective agent containing a polyamine.
[0067]
The polyamine is not particularly limited, and known ones can be widely used. Specific examples of polyamines include spermine, spermidine, putrescine, cadaverine, 1,3-diaminopropane, cardine, homospermidine, aminopropyl cadaverine, theremin, thermospermine, canabalmin, aminopertyl norspermine, N, N′-bis ( Aminopropyl) cadaverine, cardopentamine, homocardopentamine, cardohexamine and the like can be exemplified.
[0068]
Preferred polyamines are spermine, spermidine, putrescine, cadaverine, theremin, thermospermine, canabalmin, aminopertyl norspermine, N, N′-bis (aminopropyl) cadaverine, cardopentamine, homocardopentamine, cardohexamine and the like. .
[0069]
More preferred polyamines are spermine, spermidine, putrescine, cadaverine and the like.
[0070]
These polyamines are used singly or in combination of two or more.
[0071]
The content of the polyamine is not particularly limited and is appropriately selected from a wide range. For example, polyamine is usually contained in the preparation in a proportion of 0.01 to 80% by weight, preferably 0.1 to 50% by weight, more preferably 1 to 20% by weight.
[0072]
The intestinal mucosa protective agent of the present invention is usually formulated with various carriers such as excipients, binders and disintegrants together with polyamines.
[0073]
As the excipient, known ones can be widely used, for example, various sugars such as lactose, sucrose and glucose, various starches such as potato starch, wheat starch and corn starch, various celluloses such as crystalline cellulose, Examples include various inorganic salts such as anhydrous calcium hydrogen phosphate and calcium carbonate.
[0074]
As the binder, known ones can be widely used, and examples thereof include crystalline cellulose, pullulan, gum arabic, sodium alginate, polyvinyl pyrrolidone, macrogol and the like.
[0075]
As the disintegrant, known ones can be widely used, and examples thereof include carboxymethyl cellulose, carboxymethyl cellulose calcium, hydroxypropyl cellulose, hydroxypropyl starch, starch, sodium alginate and the like.
[0076]
The preparation form of the intestinal mucosa protective agent of the present invention is not particularly limited, and examples thereof include various preparation forms such as tablets, capsules, granules, solutions, and suppositories. The pharmaceutical composition of the present invention is usually administered orally. Since polyamine has an action of suppressing or preventing intestinal mucosal damage caused by a drug absorption accelerator, the intestinal mucosa protective agent of the present invention is preferably an enteric disintegrating preparation such as the small intestine, large intestine, and rectum.
[0077]
When the intestinal mucosa protective agent of the present invention is used, it is used in combination with a pharmaceutical composition containing a pharmacologically active substance and a drug absorption accelerator.
[0078]
When the intestinal mucosa protective agent and the pharmaceutical composition are used in combination, both can be administered simultaneously. Alternatively, the intestinal mucosa protective agent can be administered at an interval and then in the order of the pharmaceutical composition, or the pharmaceutical composition and then the intestinal mucosa protective agent.
[0079]
The dose of polyamine is usually 0.0001 to 100 mg, preferably 0.005 to 20 mg, more preferably 0.05 to 20 mg, still more preferably 0.5 to 20 mg per kg body weight per day. .
[0080]
Since the polyamine has an action of improving the absorption of the pharmacologically active substance, the content of the drug absorption promoter in the pharmaceutical composition can be reduced. Therefore, damage to the intestinal mucosa caused by the drug absorption promoter can be suppressed or prevented.
[0081]
Polyamine-containing pharmaceutical composition B
The pharmaceutical composition containing a polyamine will be described below.
[0082]
The polyamine has an effect of increasing absorption of a pharmacologically active substance. Therefore, the present invention provides a pharmaceutical composition containing a poorly soluble pharmacologically active substance and a polyamine and not containing a drug absorption accelerator (dissolution aid).
[0083]
The poorly soluble pharmacologically active substance means a pharmacologically active substance having a solubility in water of 10 mg / ml or less. For example, a drug whose solubility specified in the 13th revised Japanese Pharmacopoeia is “extremely insoluble” and “almost insoluble” corresponds to a hardly soluble pharmacologically active substance.
[0084]
The poorly soluble pharmacologically active substance is not particularly limited as long as it is a pharmacologically active substance absorbed from the intestinal mucosa, and widely known substances can be used. Examples of such pharmacologically active substances include respiratory preparations, digestive organ preparations, circulatory organ preparations, central nervous system preparations, peripheral nerve preparations, antibiotic preparations, chemotherapeutic agents, antitumor agents, and platelet aggregation. Examples include normal pharmacologically active substances that are blended in various preparations such as inhibitors, antiallergic agents, vitamins, and diagnostic agents.
[0085]
Specific examples of such poorly soluble pharmacologically active substances include cilostazol, rebamipide, aripiprazole, cyclosporine, nifedipine and the like. Among these poorly soluble pharmacologically active substances, those having poor absorbability are rebamipide, cyclosporine and nifedipine. Here, the pharmacologically active substance having poor absorbability means a pharmacologically active substance having an absorption rate of less than 40%. The absorption rate and the measuring method thereof are described in, for example, Walter E., Janich S., Roessler B. J., Hilfinger J.H., Amidon G., 1996; J. Pharm. Sci. 85, 1070-1076.
[0086]
These poorly soluble pharmacologically active substances are used singly or in combination of two or more.
[0087]
The polyamine is not particularly limited, and known ones can be widely used. Specific examples of polyamines include spermine, spermidine, putrescine, cadaverine, 1,3-diaminopropane, cardine, homospermidine, aminopropyl cadaverine, theremin, thermospermine, canabalmin, aminopertyl norspermine, N, N′-bis ( Aminopropyl) cadaverine, cardopentamine, homocardopentamine, cardohexamine and the like can be exemplified.
[0088]
Preferred polyamines are spermine, spermidine, putrescine, cadaverine, theremin, thermospermine, canabalmin, aminopertyl norspermine, N, N′-bis (aminopropyl) cadaverine, cardopentamine, homocardopentamine, cardohexamine and the like. .
[0089]
More preferred polyamines are spermine, spermidine, putrescine, cadaverine and the like.
[0090]
These polyamines are used singly or in combination of two or more.
[0091]
The compounding amount of the polyamine is not particularly limited, but considering the absorption promotion enhancing effect, economy and the like, it is usually 0.01 to 10000% by weight, preferably 0.05 to 1000% with respect to the pharmacologically active substance. % By weight, more preferably 0.1 to 500% by weight, still more preferably 1 to 100% by weight.
[0092]
The compounding amount of the pharmacologically active substance in the pharmaceutical composition of the present invention is not particularly limited and may be a normal compounding amount, for example, usually 0.01 to 80% by weight, preferably 0.1 to 50% by weight, more preferably It is good to set it as 1 to 20 weight%.
[0093]
The pharmaceutical composition of the present invention is usually formulated with various carriers such as excipients, binders and disintegrants together with the pharmacologically active substance and polyamine.
[0094]
As the excipient, known ones can be widely used, for example, various sugars such as lactose, sucrose and glucose, various starches such as potato starch, wheat starch and corn starch, various celluloses such as crystalline cellulose, Examples include various inorganic salts such as anhydrous calcium hydrogen phosphate and calcium carbonate.
[0095]
As the binder, known ones can be widely used, and examples thereof include crystalline cellulose, pullulan, gum arabic, sodium alginate, polyvinyl pyrrolidone, macrogol and the like.
[0096]
As the disintegrant, known ones can be widely used, and examples thereof include carboxymethyl cellulose, carboxymethyl cellulose calcium, hydroxypropyl cellulose, hydroxypropyl starch, starch, sodium alginate and the like.
[0097]
The preparation form of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include various preparation forms such as tablets, capsules, granules, solutions, and suppositories. The pharmaceutical composition of the present invention is usually administered orally. Since the pharmacologically active substance contained in the pharmaceutical composition of the present invention has the property of being absorbed from the intestinal mucosa, the pharmaceutical preparation of the present invention is preferably an enteric disintegrating preparation such as the small intestine, large intestine, and rectum.
[0098]
The dose of polyamine is usually 0.0001 to 100 mg, preferably 0.005 to 20 mg, more preferably 0.05 to 20 mg, still more preferably 0.5 to 20 mg per kg body weight per day. .
[0099]
Drug absorption improver containing polyamine
The polyamine has an effect of improving absorption of a pharmacologically active substance as described above. Accordingly, the present invention provides a drug absorption improving agent containing a polyamine.
[0100]
The polyamine is not particularly limited, and known ones can be widely used. Specific examples of polyamines include spermine, spermidine, putrescine, cadaverine, 1,3-diaminopropane, cardine, homospermidine, aminopropyl cadaverine, theremin, thermospermine, canabalmin, aminopertyl norspermine, N, N′-bis ( Aminopropyl) cadaverine, cardopentamine, homocardopentamine, cardohexamine and the like can be exemplified.
[0101]
Preferred polyamines are spermine, spermidine, putrescine, cadaverine, theremin, thermospermine, canabalmin, aminopertyl norspermine, N, N′-bis (aminopropyl) cadaverine, cardopentamine, homocardopentamine, cardohexamine and the like. .
[0102]
More preferred polyamines are spermine, spermidine, putrescine, cadaverine and the like.
[0103]
These polyamines are used singly or in combination of two or more.
[0104]
The content of the polyamine is not particularly limited and is appropriately selected from a wide range. For example, polyamine is usually contained in the preparation in a proportion of 0.01 to 80% by weight, preferably 0.1 to 50% by weight, more preferably 1 to 20% by weight.
[0105]
The drug absorption improving agent of the present invention is usually formulated by blending with various carriers such as excipients, binders and disintegrants together with polyamines.
[0106]
As the excipient, known ones can be widely used, for example, various sugars such as lactose, sucrose and glucose, various starches such as potato starch, wheat starch and corn starch, various celluloses such as crystalline cellulose, Examples include various inorganic salts such as anhydrous calcium hydrogen phosphate and calcium carbonate.
[0107]
As the binder, known ones can be widely used, and examples thereof include crystalline cellulose, pullulan, gum arabic, sodium alginate, polyvinyl pyrrolidone, macrogol and the like.
[0108]
As the disintegrant, known ones can be widely used, and examples thereof include carboxymethyl cellulose, carboxymethyl cellulose calcium, hydroxypropyl cellulose, hydroxypropyl starch, starch, sodium alginate and the like.
[0109]
The preparation form of the drug absorption improving agent of the present invention is not particularly limited, and examples thereof include various preparation forms such as tablets, capsules, granules, solutions, and suppositories. The pharmaceutical composition of the present invention is usually administered orally. Since absorption of the pharmacologically active substance is carried out in the intestine, the drug containing polyamine is preferably an enteric disintegrating preparation such as the small intestine, large intestine, and rectum.
[0110]
In using the drug absorption improving agent of the present invention, it is used in combination with a pharmaceutical composition containing a hardly soluble pharmacologically active substance.
[0111]
The poorly soluble pharmacologically active substance is the same as the hardly soluble pharmacologically active substance described above.
[0112]
When the drug absorption improving agent and the pharmaceutical composition are used in combination, both can be administered simultaneously. Alternatively, the drug absorption improver can be administered at intervals and then in the order of the pharmaceutical composition or in the order of the pharmaceutical composition and then the drug absorption improver.
[0113]
The dose of polyamine is usually 0.0001 to 100 mg, preferably 0.005 to 20 mg, more preferably 0.05 to 20 mg, still more preferably 0.5 to 20 mg per kg body weight per day. .
[0114]
【The invention's effect】
The pharmaceutical composition containing the polyamine of the present invention has an excellent performance of suppressing damage to the intestinal mucosa and remarkably improving the drug absorption promoting effect.
[0115]
By using a pharmaceutical composition containing a pharmacologically active substance and a drug absorption accelerator together with a drug absorption enhancer containing a polyamine, the effect of the drug absorption accelerator can be remarkably enhanced.
[0116]
The combined use of a pharmaceutical composition containing a pharmacologically active substance and a drug absorption enhancer and a drug absorption enhancer containing a polyamine can reduce the amount of the drug absorption enhancer used, resulting in damage to the intestinal mucosa. Can be suppressed or prevented.
[0117]
Since polyamine has an action of enhancing absorption of a pharmacologically active substance from the intestinal tract, the amount of the drug absorption accelerator used can be reduced, and as a result, damage to the intestinal mucosa can be suppressed.
[0118]
【Example】
Hereinafter, the present invention will be further clarified by providing formulation examples and test examples. The formulation examples shown below are only examples, and the present invention is not limited thereto.
[0119]
Formulation Example 1
800 g of cilostazol jet mill raw powder having an average particle size of about 2 μm, 800 g of hydroxypropylmethylcellulose, 224 g of D-mannitol, 60 g of sodium lauryl sulfate (drug absorption promoter) and 60 g of spermine (manufactured by Sigma-Aldrich) are mixed and purified water Wet granulation was performed while adding 900 g, followed by drying and sizing. Next, 16 g of magnesium stearate (lubricant) was added to and mixed with this sized product, and the mixture was tableted using a tool with a diameter of 6.5 mm so that one tablet would be 98 mg, and 40 mg / tablet was contained as cilostazol. Tablets were obtained.
[0120]
The obtained tablets were filled into 5 capsules per capsule to obtain multiple unit capsules containing 200 mg / capsule as cilostazol.
[0121]
Formulation Example 2
3.3 g of polyvinyl alcohol, 10 g of mannitol, 2 g of sodium lauryl sulfate and 3 g of spermine (manufactured by Sigma-Aldrich) were dissolved in 106 g of water. In this solution, 20 g of cilostazol jet mill pulverized bulk powder having an average particle size of about 3 μm was dispersed and dissolved, and then the resulting solution was spray-dried to obtain a cilostazol powder formulation.
[0122]
Formulation Example 3 (tablet)
20 g of rebamipide, 10 g of sodium taurocholate (manufactured by Tokyo Chemical Industry Co., Ltd.), 5 g of spermine (manufactured by Sigma-Aldrich), 100 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.) and 100 g of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd.) are further mixed. 0.5 g of magnesium (manufactured by Taihei Chemical Co., Ltd.) was added. This mixture was tableted with a mortar having a diameter of 8.0 mm to obtain a tablet having a weight of 235.5 mg.
[0123]
Formulation Example 4 (tablet)
20 g of rebamipide, 10 g of sodium taurocholate (manufactured by Tokyo Chemical Industry Co., Ltd.), 10 g of spermine (manufactured by Sigma Aldrich), 100 g of corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.) and 100 g of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd.) are further mixed. 0.5 g of magnesium (manufactured by Taihei Chemical Co., Ltd.) was added. This mixture was tableted with a mortar having a diameter of 8.0 mm to obtain a tablet having a weight of 240.5 mg.
[0124]
Formulation Example 5 (granule)
Rebamipide 20 g, sodium taurocholate (manufactured by Tokyo Chemical Industry Co., Ltd.) 10 g, spermine (manufactured by Sigma Aldrich Co.) 10 g, corn starch (manufactured by Nippon Shokuhin Kako Co., Ltd.) 100 g and crystal cellulose (manufactured by Asahi Kasei Co., Ltd.) 100 kneader (Okada Seiko Co., Ltd.) Manufactured and trade name: NSK-150), and after mixing, 200 g of water was added to obtain a kneaded product. This kneaded product is extruded and granulated using an extrusion granulator equipped with a 0.8 mm hole dome die (trade name: Dome Gran DG-L1 manufactured by Fuji Paudal Co., Ltd.). The particles were sized in a spherical shape using a granulator (Fuji Paudal, trade name: Malmerizer QJ-400). The obtained sized product was dried to obtain granules.
[0125]
Formulation Example 6 (granule)
The granules obtained in Formulation Example 5 were sprayed with a coating liquid containing 6% hydroxypropylmethylcellulose, 2% polyethylene glycol, 1% talc and 1% titanium oxide to obtain coated granules.
[0126]
Formulation Example 7 (Liquid)
A mixture of 20 g of rebamipide, 10 g of sodium taurocholate (manufactured by Tokyo Chemical Industry Co., Ltd.), 10 g of spermine (manufactured by Sigma Aldrich) and 100 g of hydroxypropylmethylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), 100 g of water and 0.5 ml of 2N sodium hydroxide aqueous solution Was heated to 37 ° C. and mixed until uniform to obtain a solution.
[0127]
Formulation Example 8 (Liquid)
A mixture of 20 g of rebamipide, 10 g of sodium taurocholate (manufactured by Tokyo Chemical Industry Co., Ltd.), 10 g of spermine (manufactured by Sigma Aldrich) and 100 g of hydroxypropylmethylcellulose (manufactured by Shin-Etsu Chemical Co., Ltd.), 100 g of water and 0.5 ml of 2N sodium hydroxide aqueous solution Was heated to 37 ° C. and mixed until uniform to obtain a solution.
[0128]
Formulation Example 9 (suppository)
A mixture of 20 g of rebamipide, 150 g of Witepsol W-35 (manufactured by SASOL Germany GmbH), 10 g of sodium taurocholate (manufactured by Tokyo Chemical Industry Co., Ltd.) and 10 g of spermine (manufactured by Sigma-Aldrich) is heated to 37 ° C. to be uniform. To obtain a solution. This solution was poured into a mold to obtain a suppository.
[0129]
Formulation Example 10 (suppository)
A mixture of 20 g of rebamipide, 150 g of Witepsol H-15 (manufactured by SASOL Germany GmbH), 10 g of sodium taurocholate (manufactured by Tokyo Chemical Industry Co., Ltd.) and 10 g of spermine (manufactured by Sigma-Aldrich) is heated to 37 ° C. to be uniform. To obtain a solution. This solution was poured into a mold to obtain a suppository.
[0130]
Formulation Example 11 (suppository)
Rebamipide 20 g, polyethylene glycol 1000 (manufactured by Sigma-Aldrich) 150 g, polyethylene glycol 4000 (manufactured by Sigma-Aldrich) 200 g, water 100 g, sodium taurocholate (manufactured by Tokyo Chemical Industry) 10 g and spermine (manufactured by Sigma-Aldrich) 10 g of the mixture was heated to 37 ° C. and mixed until uniform to obtain a solution. This solution was poured into a mold to obtain a suppository.
[0131]
Formulation Example 12 (suppository)
Rebamipide 20 g, polyethylene glycol 1000 (manufactured by Sigma-Aldrich) 150 g, polyethylene glycol 8000 (manufactured by Sigma-Aldrich) 200 g, water 100 g, sodium taurocholate (manufactured by Tokyo Chemical Industry) 10 g and spermine (manufactured by Sigma-Aldrich) 10 g of the mixture was heated to 37 ° C. and mixed until uniform to obtain a solution. This solution was poured into a mold to obtain a suppository.
[0132]
Formulation Example 13 (tablet)
5 g of spermine (manufactured by Sigma Aldrich), 100 g of corn starch (manufactured by Nippon Shokuhin Kako) and 100 g of crystalline cellulose (manufactured by Asahi Kasei) were mixed, and 0.5 g of magnesium stearate (manufactured by Taihei Chemical Co., Ltd.) was further added. This mixture was tableted with a mortar having a diameter of 8.0 mm to obtain a tablet having a weight of 225.5 mg.
[0133]
Formulation Example 14 (Granule)
10 g of spermine (manufactured by Sigma Aldrich), 100 g of corn starch (manufactured by Nippon Shokuhin Kako) and 100 g of crystalline cellulose (manufactured by Asahi Kasei) are added to a kneader (manufactured by Okada Seiko Co., Ltd., trade name: NSK-150) and mixed. 200 g of water was added to obtain a kneaded product. This kneaded product is extruded and granulated using an extrusion granulator equipped with a 0.8 mm hole dome die (trade name: Dome Gran DG-L1 manufactured by Fuji Paudal Co., Ltd.). The particles were sized in a spherical shape using a granulator (Fuji Paudal, trade name: Malmerizer QJ-400). The obtained sized product was dried to obtain granules.
[0134]
Formulation Example 15 (Liquid)
A mixture of 10 g of spermine (manufactured by Sigma Aldrich), 100 g of hydroxypropylmethylcellulose (manufactured by Shin-Etsu Chemical), 100 g of water and 0.5 ml of 2N sodium hydroxide aqueous solution was heated to 37 ° C. and mixed until uniform. A liquid was obtained.
[0135]
Formulation Example 16 (suppository)
A mixture of 150 g of Witepsol W-35 (manufactured by SASOL Germany GmbH) and 10 g of spermine (manufactured by Sigma-Aldrich) was heated to 37 ° C. and mixed until uniform to obtain a solution. This solution was poured into a mold to obtain a suppository.
[0136]
Formulation Example 17 (suppository)
A mixture of 150 g of polyethylene glycol 1000 (manufactured by Sigma-Aldrich), 200 g of polyethylene glycol 4000 (manufactured by Sigma-Aldrich), 100 g of water and 10 g of spermine (manufactured by Sigma-Aldrich) is heated to 37 ° C. until uniform. Mix to give a solution. This solution was poured into a mold to obtain a suppository.
[0137]
Formulation Example 18 (suppository)
A mixture of 150 g of polyethylene glycol 1000 (manufactured by Sigma-Aldrich), 200 g of polyethylene glycol 8000 (manufactured by Sigma-Aldrich), 100 g of water and 10 g of spermine (manufactured by Sigma-Aldrich) is heated to 37 ° C. until uniform. Mix to give a solution. This solution was poured into a mold to obtain a suppository.
[0138]
Test example 1
Phenol red (PR) was used as a model compound for absorption, and the following seven types of solutions were prepared.
Solution PA (Control 1):
A solution PA was prepared by adding PR to Tris-HCl buffer (pH 7.4) so that the PR would be 100 μM.
Solution PB (Control 2):
Solution PB was prepared by adding PR and spermine to Tris-HCl buffer (pH 7.4) so that PR was 100 μM and spermine (polyamine) was 10 mM.
Solution PC (Comparative Example 1):
Solution PC was prepared by adding PR and sodium taurodeoxycholate to Tris-HCl buffer (pH 7.4) so that PR was 100 μM and sodium taurodeoxycholate (dissolution aid) was 5 mM.
Solution PD (Comparative Example 2):
Solution PD was prepared by adding PR and sodium taurodeoxycholate to Tris-HCl buffer (pH 7.4) so that PR was 100 μM and sodium taurodeoxycholate (dissolution aid) was 0.5 mM. .
Solution PE (Example 1):
PR, sodium taurodeoxycholate and spermine in Tris-HCl buffer (pH 7.4) so that PR is 100 μM, sodium taurodeoxycholate (dissolution aid) is 0.5 mM and spermine (polyamine) is 10 mM. Was added to prepare solution PE.
Solution PF (Control 3):
A solution PF was prepared by adding PR and sodium laurate to Tris-HCl buffer (pH 7.4) so that PR was 100 μM and sodium laurate (dissolution aid) was 2 mM.
Solution PG (Example 2):
Add PR, sodium laurate, and spermine to Tris-HCl buffer (pH 7.4) so that PR is 100 μM, sodium laurate (dissolution aid) is 2 mM, and spermine (polyamine) is 10 mM. Was prepared.
[0139]
(1) Test using sodium taurodeoxycholate as a solubilizer
SD male rats (body weight about 250 g) were used as test animals. A 5 cm loop was prepared in the upper part of the large intestine of the rat, and 2.5 ml of each of the solutions prepared above (solution PA, solution PB, solution PC, solution PD or solution PE) was administered into the loop. 1.5 hours after administration, the solution remaining in the loop was collected.
[0140]
The residual amount of PR in the collected solution was determined, and the absorption rate (%) of PR absorbed from the large intestine of rats was determined.
[0141]
In addition, the amount (mg) of protein leaked (eluted) from the rat large intestine was measured. This amount of protein leakage is a measure of colonic damage.
[0142]
The results are shown in Table 1.
[0143]
[Table 1]

[0144]
Each numerical value in Table 1 is a mean ± S.E. Value using 4 to 11 rats.
[0145]
Table 1 shows the following.
[0146]
The solution PB (control 2) containing spermine (polyamine) has almost no change in the absorption rate of PR and the amount of protein leakage is the same level as the solution PA (control 1) containing no spermine (polyamine). there were. From this, it can be seen that spermine itself has no effect on absorption of pharmacologically active substances and rat large intestine mucosa.
[0147]
A solution PD (Comparative Example 2) containing sodium taurodeoxycholate (dissolution aid) at a low concentration was prepared by adding solution PA (control 1) and spermine (polyamine) not containing sodium taurodeoxycholate (dissolution aid). Although the absorption rate of PR was lower than that of the contained solution PB (control 2), the amount of protein leakage was hardly changed. The cause of the decrease in the absorption rate of PR may be that PR was not absorbed from the intestinal tract because PR was taken into micelles formed by sodium taurodeoxycholate (dissolution aid).
[0148]
The solution PC (Comparative Example 1) containing sodium taurodeoxycholate (dissolution aid) at a high concentration is compared to the solution PD (Comparative Example 2) containing sodium taurodeoxycholate (dissolution aid) at a low concentration. Although the absorption rate of PR was improved, the amount of protein leakage was remarkably increased and the large intestine of the rat was damaged.
[0149]
The solution PE (Example 1) containing spermine (polyamine) together with low-concentration sodium taurodeoxycholate (dissolution aid) greatly improves the absorption rate of PR and has almost no effect on the amount of protein leakage. The rat colon was not damaged.
[0150]
(2) Test using sodium laurate as a solubilizer
SD male rats (body weight about 250 g) were used as test animals. A 5 cm loop was prepared in the upper part of the large intestine of a rat, and 2.5 ml of the various solutions (solution PA, solution PF, or solution PG) prepared above was administered into the loop. 1.5 hours after administration, the solution remaining in the loop was collected.
[0151]
The residual amount of PR in the collected solution was determined, and the absorption rate (%) of PR absorbed from the large intestine of rats was determined.
[0152]
In addition, the amount (mg) of protein leaked (eluted) from the rat large intestine was measured. This amount of protein leakage is a measure of colonic damage.
[0153]
The results are shown in Table 2.
[0154]
[Table 2]

[0155]
Each numerical value in Table 2 is a mean ± S.E. Value using 4 to 11 rats.
[0156]
Table 2 shows the following.
[0157]
The solution PF containing sodium laurate (dissolution aid) (Control 3) has improved PR absorption compared to the solution PA (Control 1) not containing sodium laurate (dissolution aid). The amount of protein leakage was significantly increased and the rat colon was damaged.
[0158]
Solution PG (Example 2) containing spermine (polyamine) together with sodium laurate (dissolution aid) absorbs PR compared to solution PF (control 3) containing only sodium laurate (dissolution aid). The rate was greatly improved, and the amount of protein leakage was hardly affected, and the rat colon was not damaged.
[0159]
From the results of Tables 1 and 2 above, by adding a solubilizing agent and polyamine to the pharmaceutical composition, a high-concentration dissolution causing intestinal mucosal damage with a low concentration of solubilizing agent that does not cause intestinal mucosal damage. It can be seen that the drug absorption enhancing effect equivalent to or more than the amount of the adjuvant can be exhibited, and the safety is improved.
[0160]
Test example 2
Rebamipide (trade name: Mucosta, manufactured by Otsuka Pharmaceutical Co., Ltd.) was used as a model compound for absorption, and the following four types of solutions were prepared.
Solution PH (Control 4):
Rebamipide and hydroxypropyl in Tris-HCl buffer (pH 7.4) so that rebamipide is 2.0 mg / ml and hydroxypropylmethylcellulose (trade name: TC-5E, manufactured by Shin-Etsu Chemical Co., Ltd.) is 1% by weight. Methylcellulose was added, and 2N-NaOH was added dropwise so as to obtain a solution state, thereby preparing a solution PH. Solution PI (Control 5):
Rebamipide, hydroxypropylmethylcellulose and taurocholic acid in Tris-HCl buffer (pH 7.4) so that rebamipide is 2.0 mg / ml, hydroxypropylmethylcellulose is 1% by weight and sodium taurocholate (dissolution aid) is 5 mM. Sodium was added, and 2N-NaOH was added dropwise so as to obtain a solution state to prepare a solution PI.
Solution PJ (Example 3):
Rebamipide in Tris-HCl buffer (pH 7.4) so that rebamipide is 2.0 mg / ml, hydroxypropylmethylcellulose is 1% by weight, sodium taurocholate (dissolution aid) is 5 mM and spermine (polyamine) is 10 mM. Hydroxypropylmethylcellulose, sodium taurocholate and spermine (polyamine) were added, and 2N-NaOH was added dropwise so as to be in a solution state to prepare a solution PJ.
Solution PK (Example 4):
Add rebamipide, hydroxypropylmethylcellulose and spermine (polyamine) to Tris-HCl buffer (pH 7.4) so that rebamipide is 2.0 mg / ml, hydroxypropylmethylcellulose is 1% by weight and spermine (polyamine) is 10 mM. A solution PK was prepared.
[0161]
SD male rats (body weight about 250 g) were used as test animals. A 5 cm loop was prepared in the upper part of the large intestine of a rat, and 2.5 ml of the various solutions prepared above (solution PH, solution PI, solution PJ or solution PK) was administered into the loop. Blood was collected from the rat jugular vein 5 minutes, 15 minutes, 30 minutes, 45 minutes, 60 minutes and 90 minutes after the administration. In addition, 90 minutes after administration, the solution remaining in the loop was collected.
[0162]
The total amount of rebamipide absorbed (ng.hr/ml) within 90 minutes after administration was determined, and AUC_1.5hrAs shown in Table 3. Also, the maximum blood concentration (ng / ml) of rebamipide 5 to 90 minutes after administration was determined, and C_maxAs shown in Table 3. Further, the amount of phospholipid leaked (eluted) from the rat large intestine was measured and shown in Table 3.
[0163]
[Table 3]

[0164]
Each numerical value in Table 3 is a mean ± S.E. Value using 4 rats.
[0165]
Table 3 shows the following.
[0166]
The solution PI (control 5) containing a low concentration of sodium taurocholate (dissolution aid) has a lower rebamipide absorption rate than the solution PH (control 4) not containing sodium taurocholate (dissolution aid). Despite this, the amount of phospholipid leakage hardly changed. The reason for the decrease in rebamipide absorption may be that rebamipide was not absorbed from the intestinal tract because it was taken into micelles formed by sodium taurocholate (dissolution aid).
[0167]
The solution PJ (Example 3) containing spermine (polyamine) together with a low concentration of sodium taurocholate (dissolution aid) greatly improved the absorption rate of rebamipide, and almost affected the amount of phospholipid leakage. The rat colon was not damaged.
[0168]
Solution PK containing spermine (polyamine) (Example 4) increased rebamipide absorption. When spermine (polyamine) was used for PR in Test Example 1 above, no effect of increasing PR absorption was observed, so spermine (polyamine) acts specifically on poorly soluble pharmacologically active substances, It was found that the effect of increasing absorption was exhibited.
[0169]
In the solution PK of Example 4, when cilostazol was used instead of rebamipide, the same result as above was obtained.
[0170]
Further, in the solution PK of Example 4, the same result as above was obtained when a polyamine other than spermine was used.

Claims (4)

A pharmaceutical composition comprising a pharmacologically active substance, at least one drug absorption promoter selected from the group consisting of alkali metal salts of bile acids and alkali metal salts of C _6-13 fatty acids, and spermine .   The pharmaceutical composition according to claim 1, wherein the alkali metal salt of bile acid is an alkali metal salt of glycocholic acid, an alkali metal salt of taurocholic acid, or an alkali metal salt of taurodeoxycholic acid. 2. The pharmaceutical composition according to claim 1, wherein the alkali metal salt of _C6-13 fatty acid is an alkali metal salt of caproic acid, an alkali metal salt of caprylic acid, an alkali metal salt of lauric acid or an alkali metal salt of lauryl sulfate.   Pharmacologically active substances are theophylline, cilostazol, grepafloxacin, carteolol, procaterol, rebamipide, aripiprazole, 5-fluorouracil, diclofenac, cyclosporine, nifedipine, phenol red, tolpabutane, interferon α, interferon β, vesnarinone, nadifloxacin, tobonone Pranidipine, cefazoline, buprenorphine, probucol, γ-oryzanol, 1- [3- [4- (3-chlorophenyl) -1-piperazinyl] propyl] -5-methoxy-3,4-dihydro-2 (1H) -quinolinone mono Methanesulfonate, 4- (N-methyl-2-phenylethylamino) -1- (3,5-dimethyl-4-propionylaminobenzoyl) piperidine Hydrochlora Id monohydrate, (±) -5-dimethylamino-1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine hydrochloride, 6- [2- (3,4-diethoxyphenyl) thiazol-4-yl] pyridine-2-carboxylic acid, pravastatin, loxoprofen, candesartan, voglibose, lansoprazole, cefothiam, cerivastatin, manidipine, amlodipine, atorvastatin, doxazosin, sildenafil, levofloxacin, ticlopidine, Famotidine, tamsulosin, nicardipine, teprenone, menatetrenone, donepezil, simvastatin, losartan, enalapril, cefcapene, flomoxef, cefaclor, ketotifen, terbi Fins, epoetin beta, cefdinir, pharmaceutical composition according to claim 1 is at least one selected from the group consisting of cromoglycate, and nilvadipine.