JPS61197529A - Slow-releasing drug preparation - Google Patents

Abstract

PURPOSE:To provide a slow-releasing drug preparation containing a porous powder of deacetylated chitin as a carrier of a drug component, and having mitigated side effects and improved durability of the drug action. CONSTITUTION:The objective slow-releasing agent is produced by using a porous granule of deacetylated chitin as a carrier, and impregnating a physiologically active substance (e.g. carcinostatic agent, hormonic agent, etc.) therein. The deacetylated chitin is obtained by deacetylating a chitin having a chemical structure of poly-N-acetylglucosamine to amino group, and its deacetylation degree (DA) is 0<DA<100%. The product is suitable as an adsorption carrier for medicinal drug. The deacetylated chitin is infested by the macrophage activated by the intracutaneous injection or embedding of the preparation and the circumference of the remaining aminoacetyl group is hydrolyzed by lysozyme to effect the slow release of the drug component.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention relates to medical drugs, which reduce the toxicity and side effects of conventional drugs, maintain their pharmacological effects for a long time, and prevent diseases. It concerns sustained release formulations that provide therapeutic benefits.

[Conventional technology]

Recently, research on chemotherapeutic agents and immunochemotherapeutic agents has been widely conducted. Anticancer drugs are commercially available for the purpose of curing cancer, but many of them have strong toxicity and side effects. There are drawbacks such as.

In the usual administration method, the blood concentration of the drug increases and side effects such as 8 toxicity occur, so this is dealt with by keeping the concentration to the minimum necessary and repeating the administration in short periods. is the current situation.

Furthermore, it is desired to similarly prevent side effects caused by administration of high concentrations of endocrine drugs such as hormone drugs.

Chitin, a polysaccharide with N-acetyl-D-glucosamine β-1,4-glufuside bonds, which is widely distributed and present in nature and is found in crustaceans such as crabs and shrimp, and insects such as grasshoppers and captomillas. A:2 Regarding the use of chitosan, a deacetylated chitin obtained by heat treatment with caustic alkali to hydrolyze acetyl groups, for sustained release of drugs,
At the 102nd Annual Meeting of the Pharmaceutical Society of Japan (1982), Mr. Hiroichi Sawayanagi et al. talked about ``increasing the dissolution of poorly soluble drugs by mixing and grinding with chitin and chitosan'', and at the 103rd Annual Meeting of the Pharmaceutical Society of Japan (1983). ), Mr. Fukuji Higashide et al. presented on ``Study of mixed pulverization method for sustained release of drugs using chitin and chitosan,'' and discussed the difficulties when mixing and pulverizing chitin, chitosan, or crystalline cellulose with drugs to form tablets. We investigated the dissolution properties of soluble drugs. Furthermore, at the 103rd Annual Meeting of the Pharmaceutical Society of Japan (1983), Mr. Hideo Takenaka et al.
The application of chitosan to aspirin sustained release formulations utilizes the property of chitosan to gel in a dilute acid aqueous solution.
This was mixed with aspirin, molded into granules and tablets using a wet method, and the dissolution performance of aspirin was investigated and published.

Furthermore, at the 104th Annual Meeting of the Pharmaceutical Society of Japan (1984), Mr. Fukuji Higashide et al. mixed and pulverized chitin or chitosan and drugs in their article ``Study of chitin and chitosan as additives for enzyme-fixed tablets - Regarding α-amylase.'' After that, granule molding is carried out.
We are reporting on the relationship between drug elution and crushing methods.

[Problem that the invention seeks to solve]

As mentioned above, the possibility of using chitin and chitosan in sustained release preparations has been suggested, but in order to mix chitin or chitosan with a drug and mold it into 9 tablets, gelatin, etc. It is necessary to add a third component, and the selection range of the third component is narrow due to the weight and alkali resistance properties of chitin and chitosan, which poses a danger to life, especially when used as a sustained-release preparation buried in the body. In order to solve the conventional drawbacks, the present inventors created porous granules of deacetylated chitin and used them as carriers for drugs such as anticancer drugs and hormones. It has been found that by incorporating this into a sustained-release preparation, this preparation can be implanted in the body for the treatment of diseases.

[Means for solving problems]

The carrier used in the present invention is a porous granular body of deacetylated chitin, which is produced by the method previously disclosed by the present inventors in Japanese Patent Application No. 161192/1982, or by the method previously disclosed by the present inventors in Japanese Patent Application No. 161192/1983. The degree of deacytylation was adjusted again.

The chemical structure of chitin is N-a7tylglucosamine, but chitin is generally deacylated by about 5 to 10%, according to Pergamon Press.
"CHITIN" published by PI'1LESS
) and Po1Jv-Jana A/ (PolymerJo
urnal) 15, No. 597 (1983).

Deacetylated chitin is obtained by further deacetylating chitin, and more specifically, the aminoa7tyl group of chitin is converted into an amino group by deacetylating, and the degree of deacetylation (hereinafter abbreviated as DA) is 0 (
◎Any deacetylated chitin with DA<100% is
It can be obtained by performing IRm deacylation treatment on chitin. The deacetylated chitin carrier used in the present invention can be molded into porous granules after the desired DA&:[knot], or porous granules with a DA in a range that is easy to mold, and then re-molded after molding. It is also possible to adjust the DA.

The deacetylated chitin of the porous granules in the present invention is
As described in the previously filed specification, low molecular weight chitosan, preferably with an average molecular weight of 10,000 to 230,00
It is obtained by dissolving 2 to 20% by weight of low molecular weight chitosan such as 0% in an acidic aqueous solution and dropping the solution into a basic solution to coagulate and precipitate granular porous chitosan.

The deacetylated chitin thus obtained is a porous granule with uniform fine open cells throughout the interior.
The particle size, pore size, and specific surface area are obtained by selecting optimal conditions by the method disclosed above, taking into consideration the potency and sustained release rate of the drug contained. The obtained porous granules can be used in any desired state, such as in a wet state after thorough washing with ethyl alcohol or the like, or in a wet state, or after being dried and swollen, especially for medical purposes.

As described above, the present invention uses deacetylated chitin of any DA, and contains pharmacologically active substances such as anticancer drugs and hormones in a porous granular carrier whose particle size, pore size, and specific surface area are selected. This relates to sustained-release preparations. Pharmacologically active substances include anticancer agents, hormones, antiepileptic agents, and antidepressants.

Psychotropic agents, sedatives 1 Cardiotropes, antiarrhythmia agents, vasoconstrictors, vasodilators, sulfa drugs, etc. can be used.

[For production]

Regarding the use of deacetylated chitin as a drug carrier, in addition to the above publication, the present inventors, et al.
+ NJ (VACCINB) Vol, 2.
As published in JLL (1984), a mixture of mouse cancer cells (Meth-A fibrosarcoma cells) and deacetylated chitin was administered subcutaneously, and the survival rate after 4 weeks and repeated administration of the same mixture were determined. As a result of examining the survival rate after two weeks, it was found that antibodies against deacetylated chitin were not produced in the bodies of anti-tumor mice. That is, O<DA<
Deacetylated chitin in the 100% range not only does not produce antibodies but also has the effect of increasing immune activity, so it can be said to be a suitable material as an adsorption carrier for drugs.

The sustained release property of the preparation using the porous granules of deacetylated chitin of the present invention as a carrier is that when the preparation is administered into the body by subcutaneous administration, implantation, or other appropriate method, activated macrophages and macrophages are activated. The deacetylated chitin is gradually depleted, and the area around the remaining amino-7tyl group is hydrolyzed by lysozyme, which together with the gradual release of the drug, produces a sustained release effect.

〔Example〕

Next, the present invention will be explained with reference to Examples. The degree of deacetylation (DA) was measured using an infrared spectrophotometer at 165°C.
The ratio of the absorption wavelengths of 5cm-' and 2867cIfL-1 was determined and obtained from the calibration curve.

Example 1 Deacetylated chitin with an average molecular weight of 46,000 and a DA of 80% was made into a deacetylated chitin solution using dichloroacetic acid and water to a concentration of 6%, and the solution was heated at a nitrogen gas pressure of 2 kg/cT. ! ! The particles were dropped into a mixed basic aqueous solution of 5% caustic soda, 50% methanol and water through a nozzle diameter of 0.15111 to obtain porous granules, which were thoroughly washed with water.

DA80%0 particle size 42-80 obtained as above
Mesh, pore diameter 0.4μm, specific surface area 30.9mF/!
The porous granules of desorbed heptatylated chitin 5ssy (dry) of I were suspended in 50+j of deionized water, and the anticancer agent Atriazine (Seiroku trademark, manufactured by Kyowa Hakko Co., Ltd. ◎hereinafter A) was suspended in 50+j of deionized water.
Define as DM hydrochloride. ) was added thereto, and the mixture was stirred at room temperature under reduced pressure for 4 hours. After heating to 30℃ and drying, heat again at 50℃.
Add 20 mg of water, filter, wash twice with 20 mj of water, wash with 20 ypl of ethyl alcohol, air dry, and
The product was vacuum dried at ℃ to obtain a preparation containing ADMjj salt in porous granules of deacetylated chitin. This was packed into a small column, and the eluent containing 20 plAl of egg white lysozyme in physiological saline was heated to 0.3 mV at 37°C.
The sustained release elution of ADM hydrochloride was carried out at a flow rate of 45 min.
The absorbance of 877721 was quantified over time, and the results shown in FIG. 1 were obtained.

Example 2 Deacetylated chitin powder was stone-hardened with onion stone and was obtained in the same manner as described in Example 1, except that the basic aqueous solution was a mixed aqueous solution of 2% caustic soda, 60% methanol, and water. DA80%9 particle size 20-40 mesh, pore size 0.3μ
Deacetylated chitin porous granules 401 (wet state) with a specific surface III of 49.7 rr7 g were suspended in 150 ml of methyl alcohol, allowed to stand for 30 minutes, filtered, and then poured into 150 ml of ethyl alcohol again. Suspended. Repeat this operation 3 times and after dehydration, ethyl alcohol 15
Test 7, which is a male hormone suspended in 0d, fa>
(Made by FLUKAA, G) Add 5d of 20W/xtl zf alcohol, shake at room temperature under reduced pressure, 2 hours later concentrate to dryness at 30°C, wash again with 150ml of ethyl alcohol, concentrate and dry under reduced pressure, A preparation containing male hormones in porous granules of deacetylated chitin was obtained. This was packed into a small column and 20μ97m thick in physiological saline.
0.2 m// of eluent containing 1 l of egg white lysozyme
The sustained release elution of testosterone was performed at a flow rate of 238 min.
It was quantified over time using absorbance at pm, and the results shown in FIG. 2 were obtained.

Example 3 Porous granules of deacetylated chitin used in Example 2=
SOG (wet state) was suspended in 5Qm/methyl alcohol, left to stand for 30 minutes, and then filtered to remove the methyl alcohol content. Repeat this operation 3 times and then 100 mj? The suspension was suspended in ethyl alcohol, 5 ml of acetic anhydride was added, and the mixture was shaken at room temperature. After 1 hour, the reaction solution was removed by filtration, washed 10 times with 3 Q ml of ethyl alcohol, and dried to obtain porous granules. In this porous granule, DA progressed from 5% near the surface to 72% inside the granule, the particle size was 40 to 80 mesh, the pore diameter was 0.2 μm, and the specific surface area was 20.13 Mg.

A preparation containing the male hormone testosterone was obtained in the same manner as in Example 2. The sustained release properties of this product were tested in the same manner as in Example 2, and the results are shown in FIG.

(Effect of the invention) As is clear from FIG. 1 showing the results of Example 1 above,
It can be seen that the drug is gradually released from the carrier surface through the porous pores over time. Therefore, it can be fully used as an anticancer drug.
Comparing FIG. 2 showing the results of Example 3 with FIG. 3 showing the results of Example 3, both show sustained release properties, but FIG.
It can be seen that the sustained release elution of the drug progresses quickly compared to the figure.

This is because the surface of the porous particles is acetylated, so that hydrolysis by lysozyme progresses quickly. This shows that it is possible to achieve rapid local effects by changing the state of the carrier.

Therefore, in the present invention, when porous granules of deacetylated chitin are used as a carrier to contain drugs such as anticancer agents, hormones, etc., and implanted as a preparation in the body for curing diseases,
When buried, the drug is contained in the porous granules of cleaved heptatylated chitin, so the drug is released at a constant concentration over a long period of time to the local site where the disease is located, causing toxicity. The number of side effects is extremely reduced, and the treatment can be effective.

Conventionally, when administering drugs alone, there is a shortcoming that the blood concentration temporarily increases, which poses a high risk to life, and the titer cannot be increased.As a result, the drug is rapidly metabolized and becomes inactive in a short period of time. Therefore, the next dose must be given early.

Adriamycin, an anticancer drug, has a LD50 (mouse)
9. BIt9Ag is highly toxic and has conventionally been administered only to terminally ill patients.1 It has also been reported that physical medication may be required for 7 to 18 days to suppress side effects.

When a drug is contained in a porous granular deacetylated chitin carrier to form a sustained release preparation as in the present invention, the drug is released locally at a constant concentration due to its sustained release effect, and is active for a long period of time. Because it lasts for a long time, the interval between doses can be extended, which has the advantage of reducing the psychological and physical pain caused to patients.

[Brief explanation of the drawing]

FIG. 1 shows ADM*a! from the formulation of the present invention! Salt elution (I bow 7- when the ice cap of 1 is said to be irre) 笈tsu M flute 1 quality 1-+-
7. Graphs showing changes over time in the amount of testosterone eluted from the formulations of other examples of the formulations of the present invention. a,. '□Patent Applicant: Fujibo Co., Ltd. Representative Patent Attorney Katsu Ohno Reiko Ohno
Ryunosuke Ohno No. 1 Figure n flit (min,) Figure 2 Time (hr,)

Claims (1)

[Scope of Claims] 1. A sustained release preparation characterized by using porous granules of deacetylated chitin as a carrier and containing a pharmacologically active substance therein. 2. The sustained release preparation according to claim 1, wherein the porous granules of deacetylated chitin are obtained by adjusting the degree of deacetylation of porous granules obtained from deacetylated chitin. . 3. The sustained release preparation according to claim 1, wherein the pharmacologically active substance is an anticancer agent or a hormonal agent.