JPS62142111A - Tissue-target type drug preparation composition - Google Patents

Abstract

PURPOSE:To obtain the titled composition having improved tissue-target property to specific organ especially lung and liver by the enzymatic activity in the organ of living body, by adding a drug to a small sphere of a mixture of a hydrogenated phospholipid and a polyhydric alcohol fatty acid ester. CONSTITUTION:For example, a hydrogenated phospholipid and a polyhydric alcohol fatty acid ester are dissolved in a solution produced by dissolving a drug in an organic solvent. The solvent is distilled off to form coarse granular substance, which is dispersed in hot water. The dispersion is cooled, centrifuged and freeze-dried to obtain the titled composition. It has excellent biocompatibility and drug absorptivity. When the small sphere reaches an organ having high enzymatic activity of internal organ of living body, especially lipase activity, rapid decomposition of the polyhydric alcohol fatty acid ester takes place to release the contained drug (e.g. antitumor agent, agent for hepatopathy, etc.) at the site. It has remarkable target effect especially for lung and liver.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a pharmaceutical composition containing a drug in a mixed matrix of hydrogenated phospholipid and polyhydric alcohol fatty acid ester. is dissolved in a mixture of hydrogenated phospholipid and polyhydric alcohol fatty acid ester and then dried to form spherules,
The present invention relates to a tissue-targeting pharmaceutical composition that has improved tissue targeting to specific organs through the enzyme activity of in-vivo organs.

[Conventional technology]

In recent years, various administration agents have been developed for the purpose of adjusting the in vivo metabolism, absorption, and excretion of drugs, selectively localizing drugs to specific organs, or slowing and sustaining drug release. A model has been proposed.

In order to improve the tissue targeting of drugs, administration of prodrugs, micronized emulsions, complex emulsion preparations, polymeric microcapsules such as methylcellulose, ethylcellulose, carboxymethylcellulose, polycarboxylic acid, and polylactic acid, antibodies, etc. Conjugated liposomes have been proposed.

[Problem that the invention seeks to solve]

However, when administered as a prodrug, side effects may occur that are not due to the parent compound. Methods using polymeric substances have many disadvantages in terms of formulation, such as compatibility with the body and absorption into the body, and the amount of polymeric substance used in relation to the drug is too large. In addition, liposomes have many problems, such as a low drug trapping rate and poor stability of the liposomes themselves.

In addition, in the case of emulsions and composite emulsion preparations, tissue targeting is affected by the emulsion particle size, so there are many problems that need to be solved, such as uniformity of the emulsion particle size and emulsion stability.

Therefore, it is desired to develop a pharmaceutical composition that is compatible with living organisms, has a high drug trapping rate, and has excellent targeting properties to specific organs.

[Means for solving problems]

In order to meet these demands, the present inventors have completed the present invention as a result of intensive studies to develop a formulation that can contain a large amount of drug, has excellent targetability to specific organs, and is easy to manufacture. .

Specifically, we focused on the fact that hydrogenated phospholipids have excellent biocompatibility and swell with water but are hardly soluble, and polyhydric alcohol fatty acid esters are rapidly degraded when they come into contact with lipases in internal organs. By incorporating the drug into a mixed liquid crystal structure of hydrogenated phospholipid and polyhydric alcohol fatty acid ester to form a matrix, and then dispersing it in an aqueous layer, it utilizes the enzymatic activity of in-vivo organs, especially lipase activity. The inventors have discovered that a novel pharmaceutical composition can be obtained, and have arrived at the present invention.

The pharmaceutical composition of the present invention is a tissue-targeted pharmaceutical composition that utilizes the enzymatic activity of in-vivo organs and contains a drug in mixed spherules containing hydrogenated phospholipid and polyhydric alcohol fatty acid ester as essential components. be.

In the pharmaceutical composition of the present invention, the drug is transparently dissolved in an organic solvent such as hexane, heptane, or chloroform, and the required amount of a hydrogenated product of phospholipid derived from egg yolk or a plant and a polyhydric alcohol fatty acid ester are dissolved therein. After that, the solvent is completely distilled off to form a coarse granular material, which is dispersed in a warm aqueous layer, cooled, and then centrifuged, freeze-dried, or filtered.

In the hydrogenated phospholipid-polyhydric alcohol fatty acid ester microspheres according to the present invention, the drug does not need to be dissolved in an organic solvent as long as the microspheres are from several tens of micrometers to several millimeters in size, and the drug fine powder can be suspended. There is no problem.

The concentration of the hydrogenated phospholipid in the solution may be any percentage as long as matrix formation is possible. Moreover, it is preferable that the drug is blended in the pharmaceutical composition in an amount of 1 to 20% by weight.

Phospholipids are substances widely distributed in the animal and plant world, and the hydrogenated phospholipids of the present invention use phospholipids extracted from egg yolks, soybeans, etc., or phospholipids containing neutral lipids as raw materials, It is hydrogenated by the method. In the present invention, the iodine value of the hydrogenated phospholipid is 0 to 60.
It is preferable to use one type or a combination of two or more types.

Polyhydric alcohol fatty acid esters that can be used in the present invention include glycerin fatty acid esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, sucrose fatty acid esters, polyglycerin fatty acid esters, and glycerin fatty acid esters that have 8 to 2 carbon atoms.
Glycerin mono-, di-, or triesters of 2 saturated straight chain, saturated branched fatty acids or unsaturated fatty acids or 2 of them
Propylene glycol fatty acid esters include propylene glycol mono- and diesters of saturated straight chain fatty acids, saturated branched fatty acids, or unsaturated fatty acids having 8 to 22 carbon atoms, or mixtures thereof; sorbitan fatty acid esters include 8 to 22 carbon atoms; Sorbitan or sorbitol mono-, sesqui-, di-, or triesters of saturated straight-chain, saturated branched fatty acids or unsaturated fatty acids, or mixtures of two or more thereof; sucrose fatty acid esters include saturated straight-chain, saturated branched fatty acids having 8 to 22 carbon atoms; Sucrose mono-, di-, or tri-esters of fatty acids or unsaturated fatty acids, or mixtures of two or more thereof; polyglycerin fatty acid esters include polyglycerols of saturated straight chain, saturated branched fatty acids or unsaturated fatty acids with 8 to 22 carbon atoms; Examples include mono- and deca-esters of diglycerin to decaglycerin, or mixtures of two or more thereof.

In practicing the present invention, the oil component may be incorporated into the organic solvent solution. Such oily components include liquid paraffin, squalane, α-olefin oligomers, liquid polyisobutylene, petrolatum, hydrocarbons such as paraffin wax, cetyl isooctanoate, isopropyl myristate,
Higher fatty acid esters such as isostearyl isostearate and wax are preferred. In addition, any oily ingredients commonly used in pharmaceuticals, cosmetics, foods, etc., such as animal and vegetable oils, higher alcohols, and higher fatty acids, can be used.

Drugs used in the present invention include antitumor agents such as actinomycin D1, aclarubicin hydrochloride, pleomycin sulfate, chromomycin A3, mitomycin C1, nimustine hydrochloride, carbocon, Kalsefur, tegaflu, and fluorouracil, orotic acid, and liver hydrolysis. agents for liver diseases such as thioctic acid, thioctic acid amide, protoporphyrin sodium, diisopropylamine dichloroacetate, chlorbrenalin hydrochloride, tulobuterol hydrochloride, methylephedrine hydrochloride, methoxyphenamine hydrochloride, dextromethorphan hydrobromide, salbutamol sulfate, etc. Examples include agents for lung diseases.

Furthermore, bases or additives commonly used in pharmaceuticals can be used in the pharmaceutical composition of the present invention.

〔Effect of the invention〕

The pharmaceutical composition of the present invention uses a hydrogenated product of phospholipid, which is a type of biological component, and a polyhydric alcohol fatty acid ester, so it has excellent compatibility with living organisms and excellent drug absorption. ing.

Furthermore, when the microspheres of the present invention circulating in the body reach an organ with high lipase activity, the polyhydric alcohol fatty acid ester contained therein is rapidly decomposed and the drug contained therein is released, providing extremely excellent targeting. Represents the effect.

In particular, targeting to the lungs and liver is remarkable.

Further, by adjusting the iodine value of the hydrogenated phospholipid and the melting point of the polyhydric alcohol fatty acid ester, the melting point and elasticity of the microspheres can be adjusted.

Furthermore, the particle size of the small spheres can be adjusted as desired by changing the stirring method in the water dispersion step during the production of the small spheres. For example, when ultrasonicated, the diameter is 0.5~
3- microsphere is generated, 200-300rp
When stirring at m, relatively large small spheres of several mm in size are obtained.

In addition, the composition of the hydrogenated phospholipids, the blending ratio of the drug to the hydrogenated phospholipids and polyhydric alcohol fatty acid esters, the water temperature during water dispersion, the addition of water-soluble components such as glycerin and carboxymethyl cellulose, etc. Uniformity, particle size distribution, drug release properties, drug stability, etc. can be controlled.

Additionally, a wide range of drugs is available to choose from;
It can be used in a wide range of formulations such as oral preparations, injections, and suppositories.

〔Example〕

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples.

Example 1 After dissolving 0.5 g of fluorouracil and 5 g of trilaurin in chloroform 20n+1 at 65"C, hydrogenated soybean lecithin (iodine number 7, Resinol S5-1o)
5 was added and uniformly dissolved and mixed. Next, chloroform was completely removed under reduced pressure and the mixture was powdered. This powder was dispersed in 100 ml of warm water at about 80° C. and subjected to ultrasonic treatment for 10 minutes.

After cooling, the small spheres were precipitated by centrifugation, filtered and dried to obtain a small sphere powder of about Log. The average particle size of the spherules was approximately 300 nm.

Example 2 0.2 g of Sudan III, 5 g of hydrogenated coconut oil, and 5 g of hydrogenated soybean lecithin were mixed in 5 g of chloroform.
The mixture was dissolved and mixed in 0ml at 60°C. Thereafter, the same procedure as in Example 1 was carried out to obtain small spheres. The particle size of these small spheres is 1~
There were five voices. Wister male rat (weight 200
~300g) was used to examine the retention of the above-mentioned spherules in organs. As a control, Sudan ■ was dissolved in a fat emulsion for intravenous injection.

The results are shown in Table 1.

Table 1: Storage of Sudan ■ in rat organs 1 hour after administration (% of dose) As is clear from Table 1, in the case of this microsphere, storage in the liver is more pronounced than in the case of fat emulsion. It is expected that it will have an excellent effect on targeting for liver diseases.

Claims (1)

[Claims] A tissue-targeted pharmaceutical composition that utilizes the enzyme activity of in-vivo organs and contains a drug in mixed small spheres containing hydrogenated phospholipids and polyhydric alcohol fatty acid ester as essential components.