JPS60181029A - Preparation of sustained release preparation - Google Patents

Abstract

PURPOSE:To prepare a sustained release preparation, by adding a drug to a specific lactic acid polymer or copolymer in the absence of a solvent at <=80 deg.C. CONSTITUTION:99.99-30pts.wt. lactic acid polymer or copolymer (e.g., L-lactic acid polymer, DL-lactic acid polymer, copolymer of L-lactic acid and glycolic acid, etc.) having 2,000-20,000mol.wt., softening at <=80 deg.C is blended with 0.01- 70pts.wt. drug (e.g., antibacterial agent, antitumor agent, etc.) in the absence of a solvent, molded, to give a sustained release preparation. The temperature in the preparation is <=80 deg.C, preferably 20-80 deg.C. The preparation causes no deterioration of the object drug, has improved sustained release effect, and can be prepared simply.

Description

[Detailed description of the invention] The present invention relates to a method for producing sustained release preparations.

Conventionally, lactic acid polymers and glycolic acid polymers have been used as biodegradable polymers and as materials that are bioabsorbable and hardly cause foreign body reactions, and have been used as retention materials for sustained-release drugs (IJ wax materials). It has become known.

In addition, the conventional method for preparing a complex of a lactic acid polymer or a copolymer of lactic acid and glycolic acid with a drug is a method using an organic solvent in which the polymer is soluble such as chloroform (for example, Pharmaceutical Factory Vol. 13, N1110, 1983,
P2S5-553: JP 55-44727: JP 56-46822) and (b) a method of melting at a high temperature of about 200°C (JP 58-216117) have been adopted.

Therefore, when using a high-boiling organic solvent in conventional sustained-release drug preparations, removal of the organic solvent requires unsuitable methods that involve high-temperature heating conditions, and other methods that are unstable to organic solvents. It has the disadvantage that it cannot be used even with drugs and there is a risk that solvent may remain.

Furthermore, the conventional melting method requires heating to nearly 200°C, so it cannot be used for drugs that are unstable to heat.

Furthermore, formulations made by microencapsulation have the disadvantage that they can only be used for hydrophobic drugs.

The present inventors conducted intensive research into a good and simple sustained release preparation for drugs, and unexpectedly found that a copolymer of lactic acid polymer and a copolymer of lactic acid and glycolic acid with polycolic acid
The present invention was achieved based on the discovery that a polymer having a softening temperature of 0° C. or lower and a molecular weight of 20,000 or higher not only has a high softening temperature but also exhibits viscoelasticity, making it impossible to mix drugs uniformly.

In the method of the present invention, drugs can be uniformly mixed into lactic acid polymers or copolymers without a solvent at a temperature of 80°C or lower, so drugs with poor thermal stability that could not be used in the past can also be used, and even drugs with poor thermal stability can be used. Various configurations are possible.

Conventional methods have used organic solvents for drugs with poor thermal stability, but these organic solvents may remain and cannot be used for unstable drugs. The invention has the advantage that these drugs can also be used.

The present invention was completed based on the above findings, and involves adding a drug without a solvent at a temperature of 80°C or lower to a lactic acid polymer or copolymer having a molecular weight of 2.000 to 20.000 and softening at 80°C or lower. The present invention relates to a method for producing a sustained release preparation, which is characterized by mixing and molding.

The lactic acid polymer or copolymer used in the present invention is L-
It is selected from the group consisting of lactic acid main 4 polymer, DL-lactic acid removed polymer, L-lactic acid and glycolic acid copolymer, and DL=lactic acid and glycolic acid copolymer, and has a molecular weight of 2,000 to 20,000. It has a softening temperature of 80°C or less.

When producing a complex of a lactic acid polymer and a drug by the method of the present invention, the temperature at which the drug is mixed with the lactic acid polymer or copolymer B in a cage solvent and molded is determined in consideration of the thermal stability and moldability of the drug. 80
℃ or less, preferably from 20°C to 80°C.

In the present invention, lactic acid polymers and copolymers that are compatible with the above-mentioned mixing and molding a degree can be obtained. The softening point of the same polymer with a molecular weight of about 4,000 is about 30°C, the softening point of the DL-lactic acid polymer with a molecular weight of about 16,000 is about 70°C, the softening point of the same polymer with a molecular weight of about 8,000 is about 40°C, and the softening point of the same polymer with a molecular weight of about 4,000. The point is about 25°C, and the molecular weight is about 16,000 L-lactic acid-glycolic acid copolymer or DL-lactic acid-glycolic acid copolymer (copolymer molar ratio = 75 to 50
: 25-50) has a softening point of about 65°C, and the softening point of Kudo copolymer (25Nia 5) is about 70°C, and the molecular weight of the same copolymer is about 8,000-4,000 (mole ratio of copolymer = 75-25). :25-75) has a softening point of about 40
~20°C. The molecular weight range of lactic acid polymers and copolymers is 2.000 to 20.000.

If the molecular weight is less than 2,000, the softening point of the lactic acid polymer or copolymer will be low (20°C), making storage adjustment difficult.
On the other hand, when the molecular weight is 20,000 or more, ' is 80℃J:
#) The above molecular weight range was determined because the drug softens at high temperatures, which may cause deterioration of the drug used, and the viscoelasticity after softening is high, making it difficult to mix the drug into a polymer or copolymer.

In the lactic acid copolymer, the blending ratio of lactic acid and glycolic acid is 99 to 20 moles of L-lactic acid or DL-lactic acid to 80 moles of glycolic acid, taking into consideration the molecular weight and softening temperature (point) from the above description.

There is no particular restriction on the blending ratio of the lactic acid polymer or copolymer and the drug as long as a composite preparation can be produced, but the ratio of the drug to 0.01
9 to 70 parts by weight of the silactic acid polymer or copolymer 9
9.99 to 30 parts by weight. Preferably 0.5:
99.5 to 50:50 (weight ratio).

The present invention relates to sustained release pharmaceutical compositions containing antibacterial drugs, antitumor active drugs, peptide or protein drugs, steroid hormones, heat-labile anti-inflammatory enzymes, fibrinolytic enzymes, etc. It can be suitably used in the production of sustained-release preparations containing enzymes, and sustained-release preparations containing heat-labile polypeptide or protein drugs. Examples of preferred drugs for use in the formulations of the invention include urokinase, hyaluronidase, other enzymes, calcitonin, insulin, somatostatin, polypeptides such as endorphins, various lymphokines, mitomycin C1 adriamycin, ampicillin, amoky y47 Phosphorus, cloxacillin, dicloxacillin, cephalexin, mizoribine, vitamin 1, vitamin Km % active vitamin D
, other vitamins, and estrogen enanthate.

More specifically, examples of antibiotics that are antibacterial drugs include chlortetracycline, oxytetracycline,
Tetracyclines such as doxycycline and tetracycline, seed penicillins, cephalosporins and also streptomycin, horn biocin,
neomycin, sulfonamides, erythromycin,
゛Colistin, lincomycin, nalidixic acid, abramycin, salinomycin, nigericin, kanamycin, chitosamycin, tylosin, furaltadone, noguncomycin, thiostrepton, gentamicin, dov2mycin, spiramycin, listeptin, soimycin and so on. Examples include erythromycin, spiramycin, tylosin, 5-0-mikaminosi IV tylonolide, neomycin, lymphokine y, and the like.

The preparations according to the invention can contain, in addition to the polymeric and copolymer matrix and the active ingredient, other substances commonly used in pharmaceutical preparations, such as solid diluents, carriers, binders, excipients and auxiliaries. for example,
Gum tragacanth, gum arabic, corn starch, gelatin, alginic acid, magnesium stearate, aluminum monostearate, beeswax, sucrose, lactose, methylparaben, probylnocrapene, mannitol, propylene glycol/L, fine quality cellulose, silicic acid. These include calcium, silica, polyvinylpyrrolidone, cetostearyl alcohol, cocoa butter, polyoxyethylene sorbitan monolaurate, ethyl lactate, nrubitan trioleate, calcium stearate, and talc.

Next, to show an example of manufacturing the sustained release preparation of the present invention, for example, a lactic acid polymer or copolymer having a molecular weight of 2,000 to 20,000 and softening at 80°C or less is appropriately selected, and a certain amount of this is placed in a container, preferably made of stainless steel. Add to a container and soften by heating directly or in a water bath or thermostatic bath. Then, after softening, a certain amount of the target drug is added thereto, and the mixture is thoroughly mixed in the softened state. Thereafter, this mixture may be directly molded and processed into a desired shape under the softening conditions, or it may be extruded, solidified, and further heated to form the desired shape, such as a spherical shape, under the softening conditions. You can also make it grainy.

The preparation thus obtained does not cause any deterioration of the target drug, exhibits a good sustained release effect, and can be manufactured easily.

Next, the present invention will be explained with reference to examples, but the present invention is not limited thereto.

Example 1 50I of L-lactic acid polymer (molecular weight about 16,000) was placed in a stainless steel container, heated to 80°C in a constant temperature bath to soften it, and then heated to 600.000°C under the same temperature conditions.
Unit (manufactured by Toyo Jojo Co., Ltd.) was added and kneaded until uniformly mixed, and then extruded into a rod-shaped body having a diameter of 3+ m. After cutting the obtained molded product into a length of approximately 3 m, coating/
After placing the mixture in a 4-inch container, it was heated at about 70°C to form a ball and cooled to room temperature. Enzyme activity was measured by the ficiling rate method, and no decrease in enzyme activity was observed.

The elution test was carried out by immersing the spherical molded product in physiological saline using a constant temperature bath with a shaker at 37°C, and quantifying the urokinase concentration in the external fluid using ultraviolet absorption spectroscopy (UV method) at 280 nm. Ta. As a result of quantitative analysis, the drug elutes approximately 10 times per day, and then the elution amount gradually decreases to approximately 1.
The entire amount was eluted within a few months.

Similarly, using an L-lactic acid polymer with a molecular weight of about 7,800 instead of an L-lactic acid polymer with a molecular weight of about 16,000,
When the mouth part was softened at 50°C, approximately 20 units of urokinase were leached out in a day, and the entire amount was eluted in two weeks. When an L-lactic acid polymer with a molecular weight of about 3,200 was used and softened by heating at 25°C, about 30 pieces were leached out in a day, and the entire amount was eluted in about a week.

Example 2 50g of DL-lactic acid polymer (molecular weight: approximately IB, ooo) was placed in a stainless steel container, heated to 80°C on a water bath to soften it, and then 1g of Adriamycin (manufactured by Kyowa Hakko Co., Ltd.) was added and mixed uniformly. The mixture was kneaded and extruded into a rod-shaped body with a diameter of 3 m. This molded product was cut into a length of about 3 m, placed in a coating pan, heated to about 60° C., shaped into a sphere, and cooled to room temperature to obtain a product.

The dissolution test was conducted in physiological saline in the same manner as in Example 1. Adriamycin concentration in the external fluid was measured by UV absorption at 290 nm.

The quantitative results showed that about 10% of adriamycin was eluted in 1 day, and then the elution amount gradually decreased, and in about 1 month, the entire amount of 1% was eluted.

Example 3 Copolymer of DL-lactic acid and glycolic acid (75:25
) (molecular weight approximately 6.900) 50.9 was placed in a stainless steel container, heated to 40℃ on a water bath to soften it, then added 2 (Toyo Jojo #) 100■ to the vitamins and kneaded until uniformly mixed. It was molded into a rod-shaped body with a diameter of 3. This molded product was cut into a length of about 3 m, placed in a coating machine, heated to about 40° C. to form a spherical product, and cooled to room temperature to obtain a product. As a result of measuring the presence or absence of decomposition of vitamins using high performance liquid chromatography (HPLC) (254 nm), no decomposition was observed during the manufacturing process. The elution test was carried out in Example 1 in a phosphate buffer (pf[7,0) under the protection of light.
It is carried out under the same conditions as the vitamins in the external fluid! Concentrations were determined by UV absorption at 261 nm.

In addition, a copolymer of DL-lactic acid and glycolic acid (50
: 50 N (molecular weight 7,200) and a copolymer of DL-lactic acid and glycolic acid (25 N 5) (molecular weight 6,50
0), both were softened at 40° C. and then products were obtained in the same manner as in Example 1.

Elution test results DL-lactic acid-glycolic acid copolymer (
In the case of 75:25), about 20 pieces of 3 were eluted in pita bread in 1 day, and the entire amount of 3 was eluted in about 3 weeks.

DL-lactic acid-gelcholic acid copo IJmer (50:50)
In the case of , about 25 units of vitamin 2 are eluted at the 18th point, and about 2
The entire amount was eluted within a week. Similarly, DL-, lactic acid-glycolic acid copolymer (25:75) No'yA
Approximately 30% of Tamin K2 was eluted, and the entire amount was eluted in about one week.

Example 4 DL-lactic acid polymer (molecular weight approximately 4.800) 50.9
Place in a stainless steel container, soften on a water bath at 30°C, add 10g of ena/testosterone tolate, knead until uniformly mixed, and extrude into a rod with a diameter of 3m.
Molded. This molded product was cut into a length of about 3+ m, placed in a coating pan, and heated to about 30° C. to form a sphere to obtain a product.

UV to determine whether or not testosterone enanthate is decomposed.
As a result of absorption measurements, no decomposition was observed during the manufacturing process.

The dissolution test was conducted in physiological saline under the same conditions as in Example 1, and the concentration of testosterone enanthate in the external solution was 241n.
Quantitated by UV absorption at rnK.

As a result of quantitative determination, the amount of testosterone enanthate was approximately 2 at 18 eyes.
After that, the elution amount gradually decreased, and after about 2 weeks, the entire amount of testosterone enanthate was eluted.

Example 5 Copolymer of L-lactic acid and glycolic acid (75:25)
(Molecular weight approximately 7.600) 509 was placed in a stainless steel container and heated to 40°C on a water bath to soften it, and then 10,000 elcatonin (@ synthetic calcitonin derivative, manufactured by Toyo Jozo)
The units were added, kneaded until uniformly mixed, and extruded into a rod-shaped body with a diameter of 3 m. This molded product was cut into a length of about 3 cm, placed in a coach tube pan, and heated to about 50° C. to form a sphere to obtain a product. The calcitonin activity of elcatonin was measured by its serum calcium lowering effect, and no decrease in activity was observed.

The dissolution test was conducted in physiological saline under the same conditions as in Example 1, and the concentration of ercatonin in the external fluid was determined by EIA method.

As a result of quantitative analysis, approximately 7 elcatonin were eluted at 18 points.
Thereafter, the elution amount gradually decreased, and the entire amount was eluted in about 2 months.

Example 6 50g of L-lactic acid polymer (molecules [16,000) was placed in a stainless steel container and heated to 80°C in a constant temperature bath to soften it. Mizoribine (manufactured by Toyo Jojo) under the subsequent temperature conditions 10
．． 9 and kneaded until uniformly mixed, and then extruded into a rod-shaped body with a diameter of 3 mm. After cutting this molded product into approximately 3-fold lengths, place it in a coating pan at approximately 70°C.
A product was obtained by shaping the product into spheres under heating. As a result of quantifying the mizoribine content in the drug by UV absorption, no decomposition was observed during the manufacturing process.

The dissolution test was conducted in physiological saline under the same conditions as in Example 1.

Mizorpine concentration in the external fluid was measured by UV absorption at 279 nm. As a result of the quantitative determination, about 25#) of misorpine was released at the 18th mark, and the amount eluted gradually decreased thereafter, and the entire amount was eluted in about 2 weeks.

Example 7゜DL-lactic acid and glycolic acid copolymer (75:25
) (molecular weight approximately 6,900) was placed in a stainless steel container, heated on a water bath to 40°C to soften it, then added 10 g of ampicillin trihydrate (manufactured by Toyo Jozo) and kneaded until uniformly mixed. It was extrusion molded into a rod-shaped body with three sizes of diameter.

This molded product was cut into a length of about 3vR, placed in a coating pan, and heated to about 40'CK to form a sphere to obtain a product.

As a result of quantifying the ampicillin content in this product by UV absorption, no decomposition was observed during the manufacturing process7.

The dissolution test was conducted in the same manner as in Example 1 in physiological saline.

Ampicillin concentration in external fluid is U at 258 nm
Measured by V absorption. As a result of quantitative determination, the elution of ampicillin was about 20 hours per day, and then gradually decreased, and in about 3 weeks, the entire amount of ampicillin was eluted.

Attorney Kazuo Tamana and 1 other procedural amendment (voluntary) March 26, 1980 Commissioner of the Japan Patent Office Kazuo Wakasugi 1 Indication of the case 1981 Patent Application WG No. 6127 2 Name of the invention Sustained-release preparation Manufacturing process 3, relationship with the case of the person making the amendment Patent applicant Address Name (Meibune Toyo Jozo Co., Ltd. (1 other person) 4, Agent 100 Name (5930) Patent attorney Tamana Kousei (1 other person) )5
, Date of amendment order (-1 Voluntary 6, Number of inventions increased by amendment 07, Subject of amendment 8 Contents of amendment (1) The power of attorney shall be supplemented as shown in the attached sheet.

(2) The scope of claims in the 8A specification shall be amended as shown in the attached sheet.

(3) On page 5, line 17 of the same page, ``[selected from the group consisting of]'' should be corrected to ``may also be used as a mixture of one or more selected from the group consisting of''.

□ (5) “Lactic acid polymers and drugs” on page 5, line 1 from the bottom
should be corrected to "Lactic acid primer or copolymer and drug."

(6) Correct "microcrystal" in line 10 of the same text to "crystal". 1 (Claims) 1) Adding, mixing, and molding a drug to lactic acid/limer or copolymer having a molecular weight of 2,000 to 20,000 and softening at 80°C or lower without a solvent at a temperature of 80°C or lower. A method for producing a sustained-release preparation characterized by:

2) The method according to claim 11, wherein the lactic acid primer or copolymer is an L-lactic acid polymer, a DL-lactic acid polymer, a copolymer of L-lactic acid or DL-lactic acid and glycolic acid, or a mixture thereof.

3) Copolymer of L-lactic acid and glycolic acid or D
3. The process according to claim 1, wherein the copolymer of L-lactic acid and glycolic acid contains 1 to 80 moles of glycolic acid per 99 to 20 moles of L-lactic acid or DL-lactic acid.

4) The method according to claim 1, wherein the ratio of the drug to the lactic acid polymer or copolymer is 0.01 to 70 parts by weight of the drug to 99.99 to 30 parts by weight of the lactic acid 4-limer or copolymer.

5) The method according to claim 1, wherein the drug is a pegtide, a protein drug, an antibacterial drug, or a drug with anticancer activity.

(6) The production method according to claim 5, wherein the hegtide drug is a pegtide hormone or lymphokine.

(7) The manufacturing method according to claim 5, wherein the protein drug is an enzyme.

(8) The manufacturing method according to claim 5, wherein [% is a sufOoid hormone.

(9) The manufacturing method according to claim 1, wherein the temperature of 80°C or less is 20°C to 80°C.

Claims (9)

[Claims] (1) Molecular weight 2,000 to 20,000 and 8
A method for producing a sustained-release preparation, which comprises adding a drug to a lactic acid polymer or copolymer that softens at 0°C or lower without a solvent, mixing and molding at a temperature of 80°C or lower. (2) The lactic acid polymer or copolymer is an L-fil polymer, 1) an L-lactic acid polymer, a copolymer of L-lactic acid and glycolic acid, or a copolymer of DL-lactic acid and 1,1-cholic acid. Manufacturing method described in section. (3) Copolymer of L-lactic acid and glycolic acid or D
3. The method according to claim 1, wherein the copolymer of L-lactic acid and glycolic acid contains 1 to 80 moles of 9-gelcolic acid per 99 to 20 moles of L-lactic acid or DL-lactic acid. (4) The method according to claim 1, wherein the ratio of the drug to the lactic acid polymer or copolymer is 0.01 to 70 parts by weight of the drug to 99.99 to 30 parts by weight of the lactic acid polymer or copolymer. (5) The method according to claim 1, wherein the drug is a peptide or protein drug, an antibacterial drug, or a drug with antitumor activity. (6) The production method according to claim 5, wherein the -2 peptide compound is a peptide hormone or lymphokine. (7) The manufacturing method according to claim 5, wherein the protein drug is an enzyme. (8) The manufacturing method according to claim 5, wherein the drug is a steroid hormone. (9) The manufacturing method according to claim 1, wherein the temperature below 80°C is 20°C to 80°C.