JPH05331074A - Drug carrier - Google Patents

Abstract

PURPOSE:To provide a drug carrier having organ directiveness, esp. digestive organ directiveness, having its selective residence possibility inside the upper digestive organs carrying a drug thereon, consisting of a polymeric compound having both carboxyl group and cyclodextrin residue at the side chain. CONSTITUTION:The carrier consisting of a polymeric compound pref. 1000-10000000 in the molecular weight of the main chain, having at the side chain 5-65wt.%, based on the polymeric compound, of carboxyl group and 1-90wt.%, based on the polymeric compound, of cyclodextrin residue (e.g. prepared by ester-linking of a cyclodextrin to an unsaturated carboxylic acid homopolymer or copolymer). This carrier can be obtained by activating the carboxylic acid segment of a polymer bearing carboxyl group at the side chain with a carbonyldiimidazole followed by reaction with a cyclodextrin.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a digestive tract-directed drug carrier and a therapeutic agent for digestive tract diseases carrying the drug.

[0002]

2. Description of the Related Art Conventionally, drug administration to patients with gastrointestinal diseases such as gastric ulcer, gastric cancer, enteritis, and colon cancer is generally performed by oral administration such as capsules, tablets, and granules except for some patients who cannot be orally administered. The method of administering in various forms is performed. Further, a sustained-release preparation using a superabsorbent polymer is known as a drug for gastric diseases using a polymer (JP-A-3-1).
No. 01615).

[0003]

However, the conventional oral administration method has a low affinity for the drug to the stomach, duodenum, large intestine, etc., and it is excreted and administered before it directly acts on the affected area and exerts its drug effect. Only part of the dose acts on the affected area. Therefore, there is a strong tendency that a large amount of drug is administered, and there are drawbacks such that the drug migrates to a site that should not be treated and which should not be reached, or that side effects are likely to occur. There were also problems such as the large number of administrations. In addition, a sustained-release preparation using a superabsorbent polymer is not yet satisfactory in terms of affinity and retention for the stomach, duodenum, and large intestine.

The object of the present invention is to solve the above-mentioned problems and to enhance the affinity and retention to the digestive organs of the stomach, duodenum, large intestine, etc., and to exert a long-term action with a small amount of drug. A drug dosage form is provided.

[0005]

Means for Solving the Problems The present inventors have found that a polymer compound having a carboxyl group and a cyclodextrin residue in its side chain specifically retains in the digestive tract or the like, and at the same time, the coexisting drug also retains. They found that they could obtain it, and as a result of further research, they completed the present invention.

That is, the present invention provides a gastrointestinal drug carrier comprising a polymer compound having a carboxyl group and a cyclodextrin residue in the side chain, and supporting the drug in the gastrointestinal drug carrier. The present invention relates to a characteristic therapeutic agent for digestive diseases.

Examples of the polymer compound having a carboxyl group and a cyclodextrin residue in the side chain in the drug carrier in the present invention include, for example, a homopolymer of unsaturated carboxylic acid or a copolymer thereof with an ester bond of cyclodextrin. Examples of the polymer compound include a polymer compound obtained by homopolymerizing a cyclodextrin ester of an unsaturated carboxylic acid or a copolymer compound with an unsaturated carboxylic acid, and a polymer compound obtained by esterifying cyclodextrin to a carboxylic acid-containing polysaccharide. Be done.

Examples of the unsaturated carboxylic acid include acrylic acid, methacrylic acid, maleic acid, fumaric acid, itaconic acid, mesaconic acid and the like.

Examples of the carboxylic acid-containing polysaccharides include hyaluronic acid, pectin, alginic acid and carboxymethyl cellulose.

The number average molecular weight of the main chain portion of the polymer compound having a carboxyl group and a cyclodextrin residue in the side chain in the present invention is not particularly specified,
1,000 to 10,000,000 is preferable.

In the present invention, the carboxyl group content of the polymer compound having a carboxyl group and a cyclodextrin residue in the side chain is about 5 based on the weight of the polymer compound.
To about 65% by weight.

The cyclodextrin content of the polymer compound in the present invention is about 1 to about 90% by weight based on the weight of the polymer compound.

For example, the amount of cyclodextrin bound in a polymer compound obtained by esterifying a cyclodextrin group to the homopolymer or copolymer of the unsaturated carboxylic acid depends on the number of moles of cyclodextrin used in the esterification reaction. The maximum theoretical amount that can bind to the equivalent amount of the side chain carboxylic acid is possible.

When the cyclodextrin ester of unsaturated carboxylic acid and the unsaturated carboxylic acid are copolymerized, for example, the amount of cyclodextrin bound can be freely changed by controlling the number of moles of the compound to be polymerized. it can.

As the type of the cyclodextrin, one or a mixture of two or more types of α, β and γ types can be used according to the size of the drug molecule to be added.

In the present invention, a polymer compound containing a carboxyl group and a cyclodextrin residue in its side chain is prepared by activating the carboxylic acid moiety of a polymer having a carboxyl group in its side chain with carbonyldiimidazole and then cyclodextrin. It is also produced by reacting with, but can also be synthesized by a method known per se [Polymer Letters, Vol . 13.357 (1975)].

As the drug used in the therapeutic agent for digestive tract diseases of the present invention, a drug for treating diseases in the digestive tract is selected. For example, a therapeutic agent for peptic ulcer, a therapeutic agent for gastritis, and improvement of abnormal digestive function. Known drugs such as agents and anticancer agents can be mentioned.

Examples of the above-mentioned therapeutic agent for peptic ulcer, therapeutic agent for gastritis, and agent for improving gastrointestinal function include allantoin, aldioxa, alcloxa, pirenzepine hydrochloride, secretin, urogastrone, cetraxate, cimetidine, ranitidine, famotidine, metoclopramide, tributine maleate, Examples of the above anticancer agents such as domperidone include 5-FU derivatives such as tegafur and carmofur, cytarabine, cyclophosphamide, and mitomycin.

The therapeutic agent for digestive organ diseases of the present invention can be easily obtained by contacting and mixing the above-mentioned digestive organ-directed drug carrier and the above-mentioned drug in a solution state.

The therapeutic agent for digestive tract diseases comprising the digestive tract-directed drug carrier and the drug is formed into various dosage forms such as tablets, granules, powders, capsules and aqueous solutions according to the known physical properties of the drug. It can be processed. The therapeutic agent for digestive system diseases of the present invention can be orally administered to mammals such as humans, and the dose at that time is appropriately determined depending on the kind and content of the drug, the kind and degree of the disease, etc. You can

[0021]

INDUSTRIAL APPLICABILITY The drug carrier of the present invention has an organ-directed property, particularly a digestive-directed property, and since the therapeutic agent used can be retained selectively in the digestive tract, particularly in the upper digestive tract, A therapeutic agent for gastric ulcer, upper gastrointestinal cancer, etc. can be efficiently given to the affected area, aiming to maintain the medicinal effect and
The occurrence of side effects in other organs can be reduced. The present invention is also useful as a drug directed to organs (especially digestive organs and upper digestive tract).

[0022]

EXAMPLES Next, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

[0023]

Example 1 100 mg of polyacrylic acid (manufactured by Aldrich, number average molecular weight = 250,000) was dissolved in 3 ml of dry DMF, 30 mg of carbonyldiimidazole was added, and the mixture was stirred at room temperature for 30 minutes. Β-cyclodextrin 10
0 mg and 4-pyrrolidinopyridine 3 as a reaction accelerator
A solution prepared by dissolving 1 mg in 2 ml of dry DMF was added, and the mixture was allowed to stand at room temperature for 3 days for reaction. After the reaction, the generated polymer was precipitated with ether, centrifuged and washed with ether three times and dried under reduced pressure to obtain 239 mg of a crude polyacrylic acid partial cyclodextrin complex. This was extracted with methanol, and the dissolved portion was dried under reduced pressure to obtain 131 mg of a methanol-soluble portion. The methanol-soluble part was subjected to gel filtration with Sephadex G-50, and the target polymer part was lyophilized to form a sponge-like partial cyclodextrin complex 80 of polyacrylic acid as a drug carrier directed to digestive organs.
mg was obtained.

The cyclodextrin residue was quantified from the calibration curve prepared by using β-cyclodextrin by the sulfuric acid-phenol method. The cyclodextrin content was 75 w relative to the partial cyclodextrin complex of polyacrylic acid.
It was t%.

[0025]

Example 2 270 μg of the digestive organ-directed drug carrier obtained in Example 1 (200 μm as β-cyclodextrin
g) and [ ³ H] cholesterol / ethanol solution ([ ³ H]
[H] Cholesterol (4 × 10 ⁻³ μg) was dissolved in 0.2 ml of phosphate buffer and left for 1 hour to obtain a digestive organ-directed drug carrier-cholesterol solution. Next, 0.2 ml of this digestive organ-directed drug carrier-cholesterol solution was orally administered by a sonde to 9 6-week-old male mice that had been fasted for 1 day. After 30 minutes, 1 hour, and 5 hours, three mice were sacrificed, and the stomach and duodenum were taken out together with the contents, and their ³ H radioactivity was measured. The results are shown in Table 1.

[0026]

Comparative Example 1 Mixture of polyacrylic acid and β-cyclodextrin (polyacrylic acid / cyclodextrin = 2
5/75 weight ratio) to 270 μg of [ ³ H] cholesterol / ethanol solution (4 × as [ ³ H] cholesterol
10 ⁻³ μg) was added and the solution was dissolved in 0.2 ml of phosphate buffer and left for 1 hour. Then, 0.2 ml of this mixture-cholesterol solution was orally administered by a sonde to each of 6-week-old male mice fasted for 1 day. 30 minutes later, 1
After three hours, three mice were sacrificed and the stomach and duodenum were taken out together with the contents, and their ³ H radioactivity was measured. The results are shown in Table 2.

[0027]

[Comparative Example 2] To 200 μg of β-cyclodextrin [ ³
H] cholesterol ethanol solution (4 × 10 ⁻³ μg as [ ³ H] cholesterol) was added, dissolved in 0.2 ml of phosphate buffer, and left for 1 hour. Next, this solution was orally administered to three 6-week-old male mice by a sonde. After 5 hours, the mice were sacrificed, and the stomach and duodenum were taken out together with the contents, and their ³ H radioactivity was measured. Further, the same test was carried out for a solution prepared by dissolving only [ ³ H] cholesterol ethanol solution (4 × 10 ⁻³ μg as [ ³ H] cholesterol) in 0.2 ml of phosphate buffer. The results are shown in Table 2.

From the results of Example 2 and Comparative Example 1, it was revealed that the partial cyclodextrin complex of polyacrylic acid of the present invention is effective as a drug carrier directed to digestive organs.

[0029]

[Table 1]

[0030]

[Table 2]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Masako Chino 1155-14 Miyawada, Fujishiro-cho, Kitasoma-gun, Ibaraki Prefecture (72) Inventor Toshio Kasama 4-35-11 Mejiro, Toshima-ku, Tokyo (72) Inventor Yasuhisa Noguchi 531-1-101 Miyawada, Fujishiro-cho, Kitasoma-gun, Ibaraki Prefecture (72) Inventor Hideo Honda 3-13-5-704 Takaban, Meguro-ku, Tokyo (72) Inventor Katsuyuki Uchida 2-2-1 Ichinomiya, Samukawa-cho, Takaza-gun, Kanagawa Prefecture 7-19

Claims (2)

[Claims] 1. A digestive organ-directed drug carrier comprising a polymer compound having a carboxyl group and a cyclodextrin residue in its side chain. 2. A therapeutic agent for digestive tract diseases, which comprises supporting a drug on the digestive tract-directed drug carrier according to claim 1.