JPH05155784A - Sustained release pharmaceutical - Google Patents

Abstract

PURPOSE:To obtain a sustained release pharmaceutical, containing a DNA as a sustained release base, excellent in control of the sustained release properties and usable for oral and intracorporeal embedding, etc. CONSTITUTION:The objective sustained release pharmaceutical is obtained by subjecting a DNA solution containing an optional medicine to insolubilizing or sparingly solubilizing treatment, gelatinizing the solution and providing a hydrogel or drying the hydrogel, affording a dry gel. Otherwise, an extender is added to a mixture of the optional medicine with the DNA to provide a pasty form and a water insolubilizing agent or a sparingly water solubilizing agent is added thereto. Dry forming is then carried out to afford the objective matrix-like sustained release pharmaceutical.

Description

Detailed Description of the Invention

[0001]

INDUSTRIAL APPLICABILITY The sustained-release preparation of the present invention uses DNA as a sustained-release base material which is free from toxicity to the living body, is excellent in controlling the sustained-release of a drug, and can be used for oral or internal implantation. It can be used as a release preparation.

[0002]

2. Description of the Related Art Deoxyribonucleic acid DNA is attempted to be commercialized in the fields of cosmetics and health foods by utilizing the physiological action of this substance itself. However, no attempt has been made to produce a sustained-release preparation using DNA.

[0003]

With respect to conventional pharmaceuticals and the like, various attempts have been made to achieve sustained release, and many sustained release preparations have been produced. However, since the sustained-release performance and the like required for each drug are different, new sustained-release technology is always required. The present inventors have completed the present invention as a result of various studies to obtain a new sustained-release preparation using DNA that does not cause toxicity to the living body.

[0004]

Means for Solving the Problems The present inventors have paid attention to the property of DNA as a strongly acidic polyelectrolyte, and found that it can be used in a sustained-release preparation by making it insoluble or sparingly soluble in water. completed. That is, the present invention relates to a sustained-release preparation characterized in that it contains water-insolubilized or sparingly-solubilized DNA or a salt thereof, or is coated with a film of the DNA or a salt thereof.

The DNA used in the present invention is not particularly limited, but is mainly industrially extracted from testes of fish (salmon, herring, cod, etc.) or other cells. Generally D
NA exists in the cell nuclei of animals and plants and microorganisms, and can be obtained from the thymus of E.coli or Escherichia coli, but it is an extract obtained by removing impurities such as lipids and proteins from algae and usually has a molecular weight of 1 million or more. However, the value is not particularly limited. In general, the molecular weight is 100,000 or more, usually about 800,000 or more, and preferably 1 million or more from the viewpoint of use in sustained-release preparations. This DNA can be used in any state of an acid type and a water-soluble salt with a strong base, for example, an alkali metal salt type, but an alkali metal salt type is usually used.

The water-insolubilized or sparingly water-soluble DNA or a salt thereof (hereinafter, simply referred to as DNA includes the salt) in the present invention has a solubility in water of not more than half of that of DNA, preferably not more than a fraction thereof. Means DNA treated in such a manner that, for example, DNA is treated with acid or alkali to render it insoluble or sparingly soluble in water, or coexist with polyvalent metal ions, cationic polymers, polypeptides or aldehydes. DNA
Examples thereof include those insoluble in water or insoluble in water.

The sustained-release preparation of the present invention is manufactured, for example, as follows. (1) Arbitrary granules, tablets, etc. containing a drug are treated with an aqueous DNA solution (usually a concentration of about 0.1 w / w% to 85 w / w% DN
After coating with (A aqueous solution), water insolubilization or water insolubilization treatment is performed by spraying a water insolubilization or water insolubilization treatment liquid.

(2) A DNA solution containing a drug is dripped into a water-insolubilized or sparingly water-solubilized treatment liquid to cause gelation. This hydrogel can be directly used as a sustained release preparation, or this gel can be dehydrated and dried to give a dry gel to give a sustained release preparation. This dry gel gradually releases the drug while hydrogelling in water.

The above-mentioned water-insolubilizing agent or water-insolubilizing agent (acid, alkali, polyvalent metal ion, cationic polymer, in the water-insolubilizing or water-insolubilizing treatment liquid used in the above (1) or (2),
The concentration of (polypeptides or aldehydes) cannot be unconditionally determined because it varies depending on its type, purpose, etc., but is usually 0.001 w / w% to 50 w / w, preferably 0.05 w / w% to 40 w / It is about w%.

(3) Drugs and bulking agents such as lactose and starch, and D
It is possible to obtain a matrix-form sustained release preparation by adding water to a mixture of NA to form a paste, and adding a water-insolubilizing agent or water-insolubilizing agent to the mixture, and drying and molding.

The various water-insolubilizing agents or water-insolubilizing agents will be specifically described below. As the acid or alkaline acid (a), either an inorganic acid or an organic acid can be used, but preferred examples include hydrochloric acid, phosphoric acid, lactic acid, tartaric acid, malic acid, succinic acid and fumaric acid. The alkali is usually an alkali metal hydroxide such as NaO.
Examples thereof include inorganic alkalis such as H and organic alkalis.

(B) Polyvalent metal ion Examples of the polyvalent metal ion include salt solutions of calcium, barium, strontium, aluminum, titanium and ferric iron. (c) Cationic Polymer Examples of the cationic polymers include histone, polylysine, protamine, chitosan, polyethyleneimide, polyvinylbenzyl, trimethylammonium chloride and the like.

(D) Polypeptides Polypeptides include polypeptides such as albumin, globulin, fibrin, gelatin, collagen, various polyamine acids, and casein. In the case of insolubilization with polypeptides, it is preferable to adjust the pH and to add an alkali metal chloride, for example,
The pH is adjusted to 1.2 to 7.5, preferably about 2.0 to 6.5, and sodium chloride is used as the alkali metal chloride.
1-20 w / potassium chloride for polypeptides
It is preferably used in the proportion of w%.

(E) Aldehydes Examples of the aldehydes include aldehydes such as glutaraldehyde, formaldehyde, acetaldehyde, benzaldehyde, and dialdecit starch. The above water-insolubilizing agent or water-hardening agent may be used in an appropriate combination depending on the case.

The amount of the DNA used in the present invention added to the whole preparation is in the form of hydrogel, dried hydrogel,
Although it cannot be determined unconditionally because it varies depending on the coating film, the matrix, and the like, it is 0.01 to 90 w / w%, and more preferably 0.05 to 80 w / w% in the case of hydrogel and dry hydrogel. In the case of a coating film, it is 0.1 to 99%, more preferably 0.5 to 95%, based on the whole film material. In the case of a matrix, it is 0.5 to 95 w / w%, more preferably 1 to 90 w / w.
%. Further, the acid to be coexistent may have a molar equivalent to the alkali metal ion bound to DNA. The polyvalent metal ion may be added in a molar equivalent to the phosphate group of DNA. The addition amount of the cationic polymer, the polypeptides and the aldehydes may be arbitrarily set depending on each chemical species. Hereinafter, the present invention will be specifically described with reference to experimental examples and examples.

[0016]

【Example】

Example 1. Sodium salt of DNA extracted and purified from alga of herring (nitrogen content about 14.5%, phosphate content about 8.4)
%) 0.75 g and indomethacin 0.1 g are dissolved in water to prepare 5 cc of homogeneous solution. Then, this solution 0.5
g is added dropwise to a 10 w / w% DL-tartaric acid solution and left for several hours to obtain a spherical hydrogel preparation. (Invention Experimental Sample No. 1) Next, this hydrogel is dried by ventilation at 40 ° C. to obtain a dry gel preparation. (Inventive Experimental Sample No. 2)

Embodiment 2. D extracted and purified from the salmon roe
NA potassium salt (nitrogen content about 14%, phosphoric acid content about 8.0%) 1 g and isosorbite dinitrate 0.
Dissolve 05 g in water to prepare 5 cc of homogeneous solution. 0.5 g of this solution was added dropwise to a 15 w / w% calcium chloride solution and left for 4 hours to obtain a spherical hydrogel preparation.
(Invention Experimental Sample No. 3) Next, the hydrogel is dried by ventilation at 40 ° C. to obtain a gel preparation. (Inventive Experimental Sample No. 4)

Example 3. Lactose 5 parts by weight (hereinafter, parts by weight is simply referred to as “parts”), Avicel 3 parts, polyvinylpyrrolidone 0.5 parts, magnesium stearate 0.5 parts and metropropramide 1 part. Then, a tablet of 200 mg is prepared. This tablet was sprayed with a 1 w / w% aqueous solution of a sodium salt of DNA extracted and purified from cod roe (nitrogen content: about 14.5%, phosphoric acid content: 8.4%), and a film having a thickness of 100 μm was applied to the tablet. A coating film is formed. Furthermore, the surface of this film coating tablet is sprayed with a 1 w / w% aluminum chloride solution, kept in a wet state for about 1 hour, and then air-dried at 40 ° C. to obtain a product. (Invention Experimental Sample No. 5) 0.5 w / w% chitosan acetate salt solution was sprayed on the surface of the film coating tablet of DNA sodium described above, kept wet for about 30 minutes, and then dried by ventilation at 40 ° C., The product. (Inventive Experimental Sample No. 6)

Example 4. D extracted and purified from cod roe
40 parts of sodium salt of NA (nitrogen content of about 14.3%, phosphoric acid content of about 8%), fibrin of 24 parts, human serum albumin of 24 parts, glutaraldehyde of 2 parts and ibuprofen of 10 parts, 100 parts in total, are uniformly mixed. Then, add 20 parts of water thereto, knead for 30 minutes, and granulate with a speed mill.
Dry at 0 ° C. for 2 hours to obtain 20-40 mesh granules. (Experimental sample No. 7 of the present invention)

Example 5. D extracted and purified from cod roe
NA sodium salt (nitrogen content 14%, phosphoric acid content 8
%) 44 parts, atelocollagen 44 parts, sodium chloride 2 parts, and bleomycin hydrochloride 10 parts to a total of 100 parts, and 15 parts of water are added and kneaded sufficiently uniformly to obtain a kneaded product of 0.1%.
25 g is molded into a rod shape, immersed in 10% calcium chloride for 1 hour, and dried at 40 ° C. to obtain a product. (Inventive Experimental Sample No. 8)

[0021]

[Action]

Experimental Example The dissolution rate of the sustained-release preparations No. 1 to No. 8 of the present invention was measured. Each sample was placed in a USP dissolution tester rotating basket (50 rpm) and immersed in Ringer's solution, 37
The dissolution rate was measured by measuring the dissolution rate of the drug under the condition of each hour. The results are shown in Fig. 1. As shown in FIG. 1, it is clear that all of the products of the present invention gradually release the contained drug in 37 ° C. Ringer's solution.

INDUSTRIAL APPLICABILITY The sustained-release preparation of the present invention is excellent in controlling the sustained-release property of a drug and is useful as a sustained-release preparation such as oral and implantable bodies.

[Brief description of drawings]

FIG. 1 shows the dissolution rates of drugs in the sustained-release preparations No. 1 to No. 8 of the present invention.

Claims (1)

[Claims] 1. A sustained-release preparation comprising a water-insoluble or water-insoluble deoxyribonucleic acid (DNA) or a salt thereof, or being coated with a film of the DNA or a salt thereof.