JP2000128805A - Trans-mucosal absorption promoter comprising polyvalent unsaturated fatty acid and polymer gel and pharmaceutical preparation containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a trans-mucosal absorption promoter being a safe substance having a promoting effect on the trans-mucosal absorption, capable of making a medicine having a problem about absorption property in a digestive tract absorb from mucosa and having a sufficient absorption property and a low damage to the mucosa. SOLUTION: This trans-mucosal absorption promoter comprises a polyvalent unsaturated fatty acid and a polymer gel. The polyvalent unsaturated fatty acid and a medicine are mixed with or included in the polymer gel. The polyvalent unsaturated fatty acid is eicosapentaenoic acid and/or docosahexaenoic acid. A medicine such as insulin having a low absorption property from a digestive tract, i.e., the medicine not capable of being formulated as an oral preparation due to the low absorption property when the medicine will be used as an oral preparation, can be used as a medicine.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a transmucosal absorption promoter comprising a polyunsaturated fatty acid and a polymer gel and a drug containing the same.

[0002]

2. Description of the Related Art Orally administered insulin passes through the same portal vein as secretion from the pancreas, so that excess insulin can be metabolized in the liver to avoid hyperinsulinemia, and it is easy to apply in daily life. It is considered to be the optimal administration method because it has certain advantages. However, since insulin has poor membrane permeability and stability in the digestive tract, there are many problems to be solved when administered orally. As an oral dosage form that avoids these obstacles and enhances absorption in the gastrointestinal tract, we have used special carriers, combined use of protease inhibitors and absorption enhancers, and chemically modified the molecular structure of insulin. Although many attempts have been made, sufficient bioavailability has not yet been obtained. Also,
The possibility of nasal mucosal absorption and skin absorption as alternatives to oral administration is also being investigated, but sufficient methods have not yet been developed.

[0003]

An object of the present invention is to provide a safe substance having an effect of promoting transmucosal absorption. An object of the present invention is to provide a transmucosal absorption enhancer which absorbs a drug having a problem of absorption in the gastrointestinal tract, such as insulin, from the mucous membrane and has sufficient absorbability and little damage to the mucosa.

[0004]

Means for Solving the Problems The present inventors have already clarified that the absorption of insulin is increased by making a polyunsaturated fatty acid and insulin into a W / O / W emulsion. Further research has led to the use of a polymer gel as a medium for polyunsaturated fatty acids and drugs, which eliminates complicated steps in its manufacture, and provides a high degree of freedom in setting drug concentrations and polyunsaturated fatty acid concentrations. The present invention has been found to exhibit sufficient absorption promoting action, and has completed the present invention.

The gist of the present invention is a transmucosal absorption enhancer comprising a polyunsaturated fatty acid and a polymer gel. The polyunsaturated fatty acid only needs to be mixed or included in the polymer gel. Therefore, the present invention is a transmucosal absorption enhancer in which the polyunsaturated fatty acid is mixed or included in the polymer gel. The polyunsaturated fatty acid is eicosapentaenoic acid and / or docosahexaenoic acid. Therefore, the present invention is a transmucosal absorption enhancer comprising eicosapentaenoic acid and / or docosahexaenoic acid and a polymer gel.

The gist of the present invention is to provide a drug in which a polyunsaturated fatty acid is mixed or included in a polymer gel together with a drug as a transmucosal absorption promoter. The polyunsaturated fatty acid is eicosapentaenoic acid and / or docosahexaenoic acid. Therefore, the present invention relates to a drug in which eicosapentaenoic acid and / or docosahexaenoic acid is mixed or included in a polymer gel together with a drug as a transmucosal absorption enhancer. is there. As the drug of the present invention, insulin having low absorption by the digestive tract and the like are used. Drugs with low absorption from the gastrointestinal tract are drugs that cannot be formulated as an orally administered drug when they are used as medicaments because of poor absorption from the gastrointestinal tract.
Antibiotics, peptide derivatives and the like, and specific examples include insulin, calcitonin, griseofulvin, cyclosporine, vasopressin, vancomycin and the like.

[0007] The polymer gel of the present invention has a function of retaining a drug and a polyunsaturated fatty acid in the vicinity thereof and protecting the drug and the polyunsaturated fatty acid from those that degrade or hinder the action. Anything, PLURONIC (R) F127 (B
ASF). Therefore, the gist of the present invention is a transmucosal absorption enhancer comprising polyunsaturated fatty acid and PLURONIC (R) F127 gel, and a drug containing the transmucosal absorption enhancer together with a drug.

[0008]

Next, the present invention will be described in more detail with reference to preferred embodiments. In the present invention, the rectum is used as an administration site, and polyunsaturated fatty acids eicosapentaenoic acid, docosahexaenoic acid and polymer gel PLURON
The effect of the absorption enhancer consisting of IC (R) F127 was studied. PLURONIC (R) F-127 is a non-toxic nonionic surfactant composed of a block copolymer of polyoxyethylene and polyoxypropylene. This polymer has a sol-like property at low temperatures, but has a gel-like property at body temperature.

In the present invention, the applicability to drugs having low absorption from the gastrointestinal tract was evaluated using insulin, which is a peptide drug hardly absorbed from the gastrointestinal tract, as a model drug, ie, PLURONIC with polyunsaturated fatty acids. (R) F
The effect of insulin on the intestinal mucosal absorption of 127 gel was investigated. The results suggested that this dosage form could increase the absorption of poorly absorbable drugs from the intestinal mucosa. And it was clarified that the addition of eicosapentaenoic acid or docosahexaenoic acid to the polymer gel PLURONIC (R) F127 promotes the rectal mucosal absorption of insulin.

[0010]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in detail with reference to embodiments. The present invention is not limited by these examples.

Example << PLURONIC (R) F-127 (PF127) Solution Preparation Method >> (Reference: IR Schmolka, J. Biomed. Mater. Res., 6, 57)
1-582 (1972)) The weighed PF127 was slowly added to the aqueous solution at 5-10 ° C, and the mixture was stirred gently until the polymer was completely dissolved. About pH with 0.1N hydrochloric acid and 0.1N sodium hydroxide solution
Insulin was dissolved in the solution prepared in step 4 and refrigerated overnight
It was added to the PF127 solution with gentle stirring. The polyunsaturated fatty acid was added later and gently stirred for 20 minutes. The final concentration of PF127 was adjusted to 20%, and the final concentration of polyunsaturated fatty acid was adjusted to 5%. The final concentration of insulin was adjusted to be 5 units (5 U / ml) per 1 ml of gel. Approximately 2 ml of this solution was used for rectal administration to rats.

<< Evaluation of Rectal Mucosal Absorption of Insulin by In Vivo Rectal Absorption Test >> After the specimen prepared by the above method was administered to the rectum of rats, the blood glucose concentration and insulin concentration were measured over time to evaluate. went. As a control, the effects of a gel containing only insulin, an insulin solution containing no gel, and eicosapentaenoic acid alone were compared.

In these control experiments, neither the blood glucose level nor the insulin level caused a significant change in the initial level (FIG. 1). However, when the gel using polyunsaturated fatty acid as the absorption enhancer was administered, it was remarkable. There was a significant increase in insulin levels and a decrease in blood glucose levels (FIG. 2,
3). The pharmacological utilization was about 25%. From these results, it was found that a simple method of uniformly mixing a polymer gel, a polyunsaturated fatty acid, and insulin can effectively administer insulin having low biomembrane permeability by transmucosal administration. .

[0014]

According to the present invention, it is possible to provide a safe substance having an effect of promoting transmucosal absorption, which is one of the administration routes of drugs instead of oral administration. By using it in combination with a drug having a problem of absorption in the gastrointestinal tract, it has become possible to provide a drug that can be expected to have sufficient drug efficacy.

[Brief description of the drawings]

FIG. 1. Changes in blood glucose concentration and insulin concentration in an in vivo rectal administration test (control)

FIG. 2: Changes in blood glucose concentration and insulin concentration in an in vivo rectal administration test (eicosapentaenoic acid)

[FIG. 3] Changes in blood glucose concentration and insulin concentration in an in vivo rectal administration test (docosahexaenoic acid)

Continued on the front page (72) Inventor Mariko Morishita F-term (reference) 4C076 AA09 BB21 CC21 DD09 DD42 EE23 EE49 FF34 FF67 FF68

Claims (6)

[Claims] 1. A transmucosal absorption enhancer comprising a polyunsaturated fatty acid and a polymer gel. 2. The transmucosal absorption enhancer according to claim 1, wherein the polyunsaturated fatty acid is mixed or included in a polymer gel. 3. The transmucosal absorption enhancer according to claim 1, wherein the polyunsaturated fatty acid is eicosapentaenoic acid and / or docosahexaenoic acid. 4. A drug in which a polyunsaturated fatty acid is mixed or included in a polymer gel together with a drug as a transmucosal absorption enhancer. 5. The drug according to claim 4, wherein the polyunsaturated fatty acid is eicosapentaenoic acid and / or docosahexaenoic acid. 6. The drug according to claim 4, wherein the drug is insulin.