JP2539789B2 - Process for producing sustained-release drug complex composed of polylactone - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention is a method in which a lactone containing an ester functional group (-Coo-) in the ring is subjected to ring opening using a catalytic method, a photo- or ionizing radiation method, The present invention relates to a sustained-release complex comprising a polylactone as a carrier and a drug, and a method for producing the same, and more particularly to a method for producing a sandwich-type needle-like sustained-release drug complex.

(Prior Art) Catalytic polymerization of lactones is described in, for example, HK Hall, Jr., J. Am. Che.
n, Soc., 80 6409 ( 1958) of the report, and radiation polymerization, for example Okamura Makotosan like Japan radiation polymer Research Association Annual Report 2 12
There are 9 (1960) reports.

On the other hand, studies using polylactone as a material for sustained-release drug conjugates are described in, for example, CGPitt et al., J. Pharm. Sci., 68 1534.
(1979). It is a well-known fact that when this material is embedded in a living tissue, it is decomposed by an enzyme present in the living body and completely disappears. However, when the drug is impregnated (included) in polylanktone, in the conventional method, a solvent is dissolved and mixed using an organic solvent or the like to form a film when the solvent is removed.

Also, US Pat. No. 4,148,871 discloses that a mixture of one or more kinds of polylactone and a drug is molded under heating and pressurization to produce a drug-containing complex having a sustained release function. And a method of increasing the biological stability of polylactones by irradiating them with radiation.

(Problems to be Solved by the Invention) However, in the method using an organic solvent, the organic solvent may remain in the final complex, and when embedded in a living tissue, the influence of the residual solvent on the living body Can no longer be ignored and remains a problem that must be resolved.

Further, the method of U.S. Pat.No. 4,148,871 also uses an organic solvent in the same manner, and the organic solvent may remain in the final composite, and does not indicate specific pressure treatment conditions or the like. In particular, it is unclear how much pressure should be applied in the case of no solvent.

Furthermore, although it suggests using radiation,
Especially, there is no description of radiation dose, and the purpose is to increase biological stability, and it is difficult to control the sustained release of the drug.

(Means for Solving the Problems) As a result of earnest research, the present invention shows that when a drug is included in a polylactone material, one or more polylactones are added in an amount of 100 to 5000 Kg / cm ² , 60 After forming a concave cylindrical carrier under the condition of heating and pressurizing at 200 ° C, the inner groove portion of the cylindrical carrier is filled with a drug, and one or more other drugs are added from above the drug. Add polylactone, 100-5
The present invention has been completed by finding that a sandwich type needle-like sustained release drug complex can be produced by melt-processing under pressure-heating conditions of 000 Kg / cm ² and 60 to 200 ° C.

The drug-containing coal obtained by this method is provided with high-density and high-rigidity properties due to the pressure-heat melting process.

Another object of the present invention is to provide a polylactone useful as a material for biodegradable sustained release complexes. In this case, the biodegradation rate of the polylactone can be adjusted by the ionizing radiation irradiation treatment in some cases, and it is to provide such a polylactone.

In the present invention, any means for polymerizing a polymer composed of one or more lactones that can be used does not matter. That is, those polymerized by any method such as catalyst, light, ionizing radiation and heat can be used in the present invention.

(Operation) In the present invention, one or two or more polylactones are prepared in the absence of a solvent to form a concave cylindrical carrier under heating-pressurization conditions of 100 to 5000 Kg / cm ² and 60 to 200 ° C. The inner groove portion of the cylindrical carrier is filled with a drug, and further one or more polylactones are added from above the drug to obtain 100-500.
A drug-containing complex having a sustained release function is produced by producing a sandwich type needle-shaped sustained release drug complex by melt processing under pressure-heating conditions of 0 Kg / cm ² and 60 to 200 ° C. The copoly (lactone) can also be used as the carrier.

Further, by performing irradiation with ionizing radiation after the pressure-heat melting treatment, the in vivo decomposition rate of polylactone can be adjusted.

That is, the sustained-release composite of the present invention controls the molecular weight of the carrier by irradiating with ionizing radiation during its molding to control the biodegradation rate of the composite, and further to release the physiologically active substance. Controlling and simultaneous radiation sterilization of the complex can be performed. Irradiation with this ionizing radiation is carried out by using a raw material polylactone carrier,
It can be carried out for both the pre-molded mixture of the polylactone carrier and the drug and the molded product of the polylactone drug.
The radiation source that can be adopted may be any of X-rays, gamma rays, beta rays, alpha rays, and electron rays. It is desirable to keep the irradiation dose as low as possible because the drug is inactivated during the treatment process when the irradiation dose is large, but it is generally 1 × 10 ⁴ to 1 × 10 ⁸
A dose of rad is required. A preferable irradiation dose is 1 × 10 ⁵ to 1 × 10 ⁷ rad for molecular weight control and 5 × 10 ^{5 to} 5 × 10 ⁶ rad for sterilization.

Since the present invention relates to a sustained-release complex obtained by entrapping and immobilizing a drug on a carrier polylactone and a method for producing the sustained-release complex, the drug is not particularly limited. Specific examples are given in.

(1) Anti-neoplastic agent: It is classified as follows depending on its mechanism of action.

(1) -1; Alkylating agents such as chlormethine, nitrodiene mustard-N-oxide, cyclophosphamide, chlorambucil, thiotepa and the like.

(1) -2; antimetabolite; for example, cytosine arabinoside, 6-mercaptopurine, 5-fluorouracil and the like.

(1) -3; a plant mitotic poison, such as vinblastine sulfate and demecorcin.

(1) -4; antibiotics; for example, sarcomycin, actinomycin, mitomycin C, chromomycin A _{3 and the} like.

(1) -5; Hormonal agents; for example, corticosteroid hormones, sex hormones and the like.

(1) -6; other antineoplastic agents; 864T, guanylhydrazone, L-asparaginase, PC-B-45, mitodein and the like.

(2) Hormonal agents (2) -1; Steroid hormones; Steroid-metabolizing enzymes such as hydroxylase, isomerase and hydrogenase; Sex hormone drugs such as androgens and estrogens; Adrenal cortex hormones such as glucocorticoids and mineralocorticoids medicine.

(2) -2; peptide hormones; hypothalamic hormones such as thyroid-stimulating hormone-releasing hormone, luteinizing phorphone-releasing hormone, somatostatin; adrenocorticotropic hormone, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, growth Anterior pituitary hormones such as hormones; Phosphorus-stimulating hormones; Posterior pituitary hormones, thyroid hormones; Parathyroid hormones, calcitonin; Insulin, glucagon; Gastrin; Cholecystokinin, Pancreosyzin, Secretin, Motilin tubes hormone; LH-RH, and LH-RH analogs, e.g. ^{[D-Ala 6, des-} Gly-NH 2 10] -LH-RH- _{ethylamide, [D-Leu 6, des} -Gly-NH 2 10] - LH-RH-
Ethylamide, and ^{[D-Ser (TBU) 6} , des-Gly-NH 2
¹⁰ ] -LH-RH-ethylamide; TRH, ADH and the like.

(2) -3; Catecholamine (2) -4; Insect hormone including ecdysone, juvenile hormone, and brain hormone (2) -5; Plant hormone (3) Other general medicines and sedatives exemplified below
Hypnotics; cranial nerve spasmolytics and sedatives; neuropsychiatric stabilizing agents; neuropsychiatric stimulants; autonomic central regulators, antihistamines; sedatives;
Antiemetics, analgesics; Autonomic nerve blockers; Muscle relaxants; Muscle tonics; Neuralgia / rheumatic disease therapeutics; Uric acid metabolism improvers;
Anti-inflammatory agent; antipyretic agent; cardiotonic agent; cell activating agent; vasodilator / circulatory enhancer; pressor agent; diuretic agent; antihypertensive agent; anticoagulant agent; antitussive agent; stomachic agent; therapeutic agent for peptic ulcer; antiparasitic agent; Agents; diuretics; liver stimulants; altering agents; hypoglycemic agents; anti-aging agents; vitamin agents; general agents; chemotherapeutic agents; biologics; antibiotics; eye disease agents; otolaryngology agents; skin diseases Agents; tooth disease agents; diagnostic agents; public health agents; various heromones; narcotics, etc.

In the present invention, the drug as exemplified above is one kind or two kinds.
It goes without saying that more than one species can be included in the complex.

(Example) Next, the present invention will be specifically described with reference to examples.

Reference Example 1 100 mg of γ-butyrolactone polymer obtained by thermal polymerization (80 ° C., 5 hr, nitrogen atmosphere, 760 mm Hg) and 20 mg of testosterone were mechanically well mixed and filled in a glass ampoule having an inner diameter of 100 mmφ. When this was heat-treated at a pressure of 200 Kg / cm ² at 80 ° C for 10 seconds, the mixture of γ-butyrolactnoe polymer and testosterone apparently contracted in volume, resulting in high density and high rigidity. The testosterone-containing flat bottom plate composite (inner diameter 10 mmφ, height 3 mm) was obtained. The obtained complex was embedded in the subcutaneous part of the back of male Wistar rats, and the degradation rate of γ-butyrolactone polymer and the in vivo release of testosterone from the complex were examined, and the results are shown in FIG.

Reference Example 2) β-propiolactone polymer 15 mg and des-Gly ^10- [D obtained by irradiating γ-ray from Co-60 for 1 Hrad at −78 ° C. in vacuum
-Leu ^6] were mixed mechanically well -LH-RH ethylamide 5mg, were charged into a glass ampoule having an inner diameter of 1.6 mm. After that, heat treatment at 70 ° C for 5 seconds under a pressure of 300 Kg / cm ² results in high density and high rigidity des-Gly ^10- [D-Leu ⁶ ]-
An acicular composite containing LH-RH ethylamide (inner diameter 1.6 mmφ, length 7 mm) was obtained. Digestibility of β-propiolactone polymer and des-Gly ^10- [D-Leu ⁶ ] -LH-RH ethy from the complex when the obtained needle-like complex was implanted in the back of the rabbit.
The in vivo release of lamide was investigated and the results are shown in FIG.

Example 1) 10 mg of the β-propiolactone polymer obtained in Reference Example 2) was filled in a glass ampoule having an inner diameter of 1.6 mmφ, and heat-treated at 70 ° C. for 5 seconds under a pressure of 200 Kg / cm ² to form a concave cylindrical carrier. It was
Next, des is applied to the groove portion (concave portion) of the concave cylindrical carrier.
-Gly ^10- [D-Ser (TBU) ⁶ ] -LH-RH ethylamide
5 mg of β-propiolactone polymer was added from the top, and heat-treated at 70 ° C for 5 seconds at a pressure of 200 Kg / cm ² , resulting in high density and high rigidity with the drug filled in the center of the carrier. Sandwich type needle-shaped composite with various properties (inner diameter 1.6m
mφ, length 8 mm) was prepared. The resulting sandwich acicular composite male rats back subcutaneously portion implanted with polymer des-Gly ¹⁰ from the time - [D-Ser (TBU) ^6] -LH-RH et
The in vivo release of hylamide was examined and the results are shown in FIG.

Reference Example 3) Equimolar amount of glycolide and β-propiolactone was used as Fecl ₃
Then, bulk polymerization was performed at 60 ° C. for 20 minutes to obtain a copolymer. 50 mg of the copolymer and 5 mg of calcitonin were mechanically mixed and filled in a glass tube having an inner diameter of 5 mmφ. Then, it is heat-treated at a pressure of 100 Kg / cm ² at 60 ° C. for 10 seconds, and has a high-density and high-rigidity property, a flat bottom disc-shaped composite containing calcitonin (inner diameter 5 mm
φ, thickness 3 mm) was prepared. The obtained complex was embedded in the subcutaneous part of the back of a hypercalcemic rat (male Wistar), and the in vivo degradation rate of the copolymer and the in vivo release of calcitonin from the complex were examined. It is shown in FIG.

(Effects of the Invention) The present invention provides a polylactone carrier containing a drug,
Since a polylactone carrier is pressure-heated and melt-molded under appropriate pressure and temperature without using any organic solvent to produce a sandwich-type needle-shaped drug-containing sustained-release complex, The obtained molded composite has high density and high rigidity, and when it is embedded in a living body, it is effective if the influence of the solvent or the like on the living body can be ignored.

Further, as shown in FIG. 3, it is possible to provide a sandwich-type needle-like drug-containing sustained release complex in which the drug release amount is extremely stable over the implantation period.

[Brief description of drawings]

FIG. 1 and FIG. 2 are graphs showing the relationship between the polylactone decomposition rate and the drug release amount with respect to the implantation period of the sustained-release complex of Reference Example of the present invention. FIG. 3 is a graph showing the relationship between the rate of polylactone decomposition and the amount of drug released with respect to the implantation period of the sustained-release complex of the present invention. FIG. 4 is a graph showing the relationship between the rate of polylactone decomposition and the amount of drug released with respect to the implantation period of the sustained-release complex of Reference Example of the present invention.

Claims (3)

(57) [Claims] 1. A concave-shaped cylindrical carrier is prepared from one or more polylactones in the absence of a solvent under heating and pressurizing conditions of 100 to 5000 Kg / cm ² and 60 to 200 ° C., and then the cylinder. 100-500 by filling the inner groove portion of the carrier with a drug, and then adding another one or more polylactone from above the drug.
A method for producing a sandwich-type needle-like sustained-release drug complex, which comprises melt-processing under a pressure-heating condition of 0 Kg / cm ² and 60 to 200 ° C. 2. Under the above-mentioned pressurization-heating conditions, another 1 type or 2 or more types of polylactone are melt-treated, and then ionizing radiation is irradiated at 1 × 10 ⁴ to 1 × 10 ⁸ rad. The method for producing a sandwich-type needle-shaped sustained-release drug complex according to claim 1. 3. The ionizing radiation is 5 × 10 ^{5 to} 5 × 10 ⁶ ra.
The method for producing a sandwich-type needle-shaped sustained-release drug complex according to claim 2, wherein d-irradiation is performed.