JPH04218528A - In vivo degradable type high-molecular polymer - Google Patents

Abstract

PURPOSE:To develop an in vivo degradable type high-molecular polymer capable of suppressing initial release of a medicine and approaching the release rate of the medicine to a prescribed value over the whole period. CONSTITUTION:An in vivo degradable aliphatic polyester is obtained by dissolving an in vivo degradable type aliphatic polyester containing a low-molecular substance in a readily water-soluble organic solvent, adding water to the resultant solution and removing the aforementioned low-molecular substance. The resultant in vivo degradable type aliphatic polyester has <3.0% content of the low-molecular substance having <=1000 molecular weight. Furthermore, a medicine-containing pharmaceutical is prepared by using the aforementioned polyester as a release controlling substance. A sustained release type pharmaceutical produced by using the in vivo degradable type aliphatic polyester of this invention has a high incorporation ratio of the medicine with suppressed initial release and is capable of stably releasing the medicine.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a biodegradable polymer useful as a base in pharmaceutical preparations, a method for producing the same, and uses thereof.

0002

BACKGROUND OF THE INVENTION Biodegradable polymers can be used as bases for preparations such as microcapsules. Such biodegradable polymers include:
For example, JP-A-61-28521 describes that polymers or copolymers of these can be obtained by polycondensing lactic acid and/or glycolic acid in the presence or absence of a catalyst. ing. Special fair 1-
Publication No. 57098 discloses a method for producing sustained release microcapsules using such a biodegradable polymer. Furthermore, JP-A No. 62-54760 discloses that the initial release of drugs from microcapsules can be improved by washing a biodegradable polymer solution with water to remove easily water-soluble low-molecular compounds. Are listed.

0003

Problems to be Solved by the Invention In sustained release preparations in which a drug is dispersed in a biodegradable polymer, it is desirable to be able to arbitrarily control the release rate of the drug. Generally, in sustained release preparations, the drug release period is controlled by the molecular weight of the biodegradable polymer that is the base thereof. However, the initial release of the drug is often too large, although the degree varies depending on the type and amount of drug. The initial release can be improved by removing easily water-soluble low-molecular compounds by the method disclosed in JP-A No. 62-54760, but the degree of improvement is limited to the extent that the drug release rate approaches a constant value over the entire period. Even if it is possible to control the rate of release in the later stages by suppressing the early stage release, it is not possible.

0004

[Means for solving the problem] As a result of intensive research to solve the above problems, it was discovered that the relatively low molecular weight portion of the biodegradable polymer is deeply involved in the initial release. Ta.

That is, high molecular polymers produced by polymerization reactions (JP-A-61-28521 and JP-A-62-
54760) was found to contain a large amount of oligomers with a molecular weight of 1,000 or less in addition to the raw material monomers, and when these relatively low molecular weight parts were used as a formulation with a high molecular weight polymer as a wall material. It was revealed that this is the cause of excessive initial release.

[0006] The above-mentioned relatively low molecular weight portion could not be removed by applying ordinary purification methods such as washing to the polymer, but the present inventors have conducted extensive research and have made it possible. They discovered a method and completed the present invention.

[0007] The present invention involves dissolving a biodegradable aliphatic polyester containing a low molecular weight substance in an easily water-soluble organic solvent,
A method for purifying a biodegradable aliphatic polyester characterized by adding water thereto to precipitate a polymer substance and removing a low-molecular substance; The present invention provides a biodegradable aliphatic polyester having a content of less than 3.0 (%), and a drug-containing preparation using the biodegradable polyester as a release-controlled substance.

[0008] In this specification, the molecular weight refers to a polystyrene equivalent molecular weight measured by gel permeation chromatography (GPC) using polystyrene as a reference material.

The biodegradable aliphatic polyester used in the method of the present invention is preferably one with excellent biocompatibility, such as polycondensation polyesters such as polyglycolic acid, polylactic acid, polyhydroxybutyric acid, polyhydroxypivalic acid, and polymalic acid. These include ring-opening polymerized polyesters such as polyesters, polyglycosides, polylactides, poly-β-propiolactone, poly-γ-butyrolactone, and poly-ε-caprolactone. In particular, it can be advantageously applied to the purification of polycondensed polyesters of hydroxy aliphatic carboxylic acids.

[0010] The polyesters are not limited to the homopolymers exemplified above, but also include copolymers consisting of two or more components. The form of copolymerization may be random, block, or graft.

[0011] These high molecular polymers (polyesters)
In this case, it is preferable to use one that decomposes relatively quickly in the living body.

Preferred examples of the biodegradable aliphatic polyesters of the present invention include polylactic acid and copolymers of lactic acid and glycolic acid. Examples of copolymers of lactic acid and glycolic acid include those having a composition ratio of 100 to 50 mol % of lactic acid and the remainder of glycolic acid.

Furthermore, a copolymer of lactic acid and glycolic acid has a peak molecular weight value of 3,000 to 3,000 by GPC.
50,000, especially 5,000 to 30,000.

Examples of the easily water-soluble organic solvent used in the present invention include acetone, tetrahydrofuran, dioxane, dimethylformamide, and dimethyl sulfoxide, with acetone being particularly advantageous.

The ratio of the amount of water to the biodegradable polymer solution used in the present invention is not particularly limited, but if the amount of water is too large, the removal of low molecular weight polymers will be insufficient. However, if it is too small, the recovery rate of the biodegradable polymer will be poor. Usually, 50 to 100 parts of water is added to 100 parts of the easily water-soluble organic solvent.
150 (volume ratio) If water is gradually added to the biodegradable polymer solution to be used while stirring using an appropriate method, the desired biodegradable polymer will precipitate or separate, so add an appropriate amount of water to the biodegradable polymer solution. The precipitate or oil layer is separated using a method, thoroughly washed with water, and then dried.

[0016] If the removal of low molecular weight polymers is insufficient in one dissolution and precipitation step, the dissolution and precipitation steps may be repeated several times.

The biodegradable polymer obtained by the method of the present invention can be used, for example, as a base material for microcapsules. For example, an aqueous solution of water-soluble polypeptides such as luteinizing hormone-releasing hormone, its analogs, thyroid hormone-releasing hormone, its salts, and derivatives thereof may be used as the inner water layer, and if necessary, gelatin, albumin, pectin, agar, etc. may be added to the inner water layer. A W/O type emulsion is prepared by adding a drug-retaining substance and using the solution containing the biodegradable polymer obtained in the present invention as an oil layer, and the emulsion is dispersed in the water layer to form a W/O type emulsion. By making an emulsion and drying it in water, sustained release microcapsules of water-soluble drugs can be produced.

The microcapsules thus obtained can be administered as sustained-release injections. The dosage depends on the type and content of the main water-soluble drug, the dosage form,
Although it varies depending on the duration of drug release, the animal to be administered (eg, warm-blooded mammals such as mice, rats, horses, cows, and humans), and the purpose of administration, it may be an effective amount of the main drug. For example, the amount per dose can be appropriately selected from a range in which the weight of microcapsules is about 0.02 to 200 mg/kg, preferably about 0.2 to 40 mg/kg. The volume of the suspension when administered as the above-mentioned injection can be appropriately selected from the range of about 0.1 to 5 ml, preferably about 0.5 to 3 ml.

In addition to microcapsules, the biodegradable polymer of the present invention in which the drug is dispersed is melted and shaped into spheres, rods, needles, etc. to produce sustained-release preparations. You can also do that.

[0020]

[Function and Examples] The present invention will be explained in more detail below with reference to Comparative Examples and Examples. In the comparative examples and examples, leuprorelin acetate (TAP-144) was used as a luteinizing hormone-releasing hormone derivative. Comparative Example 1 375.3 g of 90% lactic acid aqueous solution and 95.1 g of glycolic acid were charged into a 1000 ml four-necked flask equipped with a nitrogen introduction tube and a cooling tube, and heated at 90° C. and 400 mmH under nitrogen flow.
Distilled water was removed by heating under reduced pressure from g to 150° C. and 30 mmHg over 5 hours. Further 5-7mmHg
After heating under reduced pressure at 150 to 175° C. for 24 hours, the mixture was cooled to obtain an amber-colored lactic acid/glycolic acid copolymer. The obtained copolymer was dissolved in 1000 ml of dichloromethane and poured into warm water at 60°C under stirring. The separated rice cake-like polymer was collected and vacuum-dried at 30°C. The obtained lactic acid/glycolic acid copolymer had a peak molecular weight of 10,000 by GPC, and the content of low molecular weight polymers having a molecular weight of 1,000 or less was 6.8%.

Comparative Example 2 350 mg of TRH (thyroid hormone releasing hormone) was dissolved in 0.625 ml of distilled water, and 5 g of the lactic acid/glycolic acid copolymer (PLGA) obtained in Comparative Example 1 was dissolved in 6.25 ml of dichloromethane. The mixture was added to the liquid and mixed for 60 seconds using a small homogenizer to obtain a W/O emulsion. After cooling this emulsion to 18°C, it was poured into 12 50ml of a 0.25% polyvinyl alcohol (PVA) aqueous solution previously adjusted to 18°C, and a W/O/W emulsion was created using a turbine homomixer. And so. Thereafter, while stirring the W/O/W emulsion at room temperature, dichloromethane was volatilized to solidify the W/O emulsion inside and collected using a centrifuge. This was dispersed again in distilled water and further centrifuged to wash free drugs and the like. The collected microcapsules were obtained as a powder by freeze-drying. Table 1 shows the drug trapping rate of the microcapsules obtained and the results of an in vitro dissolution test conducted at 37° C. and in a phosphate buffer of pH 7.0.

Comparative Example 3 375.3 g of a 90% lactic acid aqueous solution and 95.1 g of glycolic acid were charged into a 1000 ml four-necked flask equipped with a nitrogen introduction tube and a cooling tube, and heated at 90° C. and 400 mmH under nitrogen flow.
Distilled water was removed by heating under reduced pressure from g to 150° C. and 30 mmHg over 5 hours. Further 5-7mmHg
After heating under reduced pressure at 150 to 175° C. for 36 hours, the mixture was cooled to obtain an amber-colored lactic acid/glycolic acid copolymer. The obtained copolymer was dissolved in 1000 ml of dichloromethane and poured into warm water at 60°C under stirring. The separated rice cake-like polymer was collected and vacuum-dried at 30°C. The obtained lactic acid/glycolic acid copolymer had a peak molecular weight of 13,000 by GPC, and the content of low molecular weight polymers having a molecular weight of 1,000 or less was 5.5%.

Comparative Example 4 TAP-144 (450 mg) and 40 mg of gelatin were dissolved in 0.8 ml of distilled water, and the lactic acid obtained in Comparative Example 3 was dissolved.
A solution of 3.5 g of glycolic acid copolymer (PLGA) dissolved in 5 ml of dichloromethane was added and mixed for 60 seconds using a small homogenizer to obtain a W/O emulsion. After cooling this emulsion to 18°C,
0.5% polyvinyl alcohol (
PVA) was injected into 200 ml of aqueous solution, and a W/O/W emulsion was prepared using a turbine homomixer. Thereafter, while stirring the W/O/W emulsion at room temperature, dichloromethane was volatilized to solidify the W/O emulsion inside and collected using a centrifuge. This was dispersed again in distilled water and further centrifuged to wash free drugs and the like. The collected microcapsules were obtained as a powder by freeze-drying. [
Table 2].

Comparative Example 5 190.2 g of glycolic acid and 260.2 g of D,L-2-hydroxybutyric acid were charged into a 1000 ml four-necked flask equipped with a nitrogen introduction tube and a cooling tube, and heated at 90° C. under a nitrogen stream.
Distilled water was removed by heating under reduced pressure from 400 mmHg to 150° C. and 30 mmHg over 5 hours. 5 more
After heating under reduced pressure at 7 mmHg and 150 to 185° C. for 72 hours, the mixture was cooled to obtain an amber-colored glycolic acid/2-hydroxybutyric acid copolymer. The obtained polymer was dissolved in 1000 ml of dichloromethane and poured into 60°C warm water with stirring. Collect the flaky polymer that separates and heat it at 30°C.
It was vacuum dried. The resulting glycolic acid/2-hydroxybutyric acid copolymer had a peak molecular weight of 12,000 by GPC, and a content of low molecular weight polymers with a molecular weight of 1,000 or less at 5.2%.

Comparative Example 6 350 mg of TRH (thyroid hormone releasing hormone) was dissolved in 0.3 ml of distilled water, and 4.65 g of the glycolic acid/2-hydroxybutyric acid copolymer obtained in Comparative Example 5 was dissolved in 5 ml of dichloromethane. The mixture was added to the liquid and mixed for 60 seconds using a small homogenizer to obtain a W/O emulsion. After cooling this emulsion to 18°C,
0.1% polyvinyl alcohol (
PVA) was injected into 1000 ml of aqueous solution, and a W/O/W emulsion was prepared using a turbine homomixer. Thereafter, while stirring the W/O/W emulsion at room temperature, dichloromethane was volatilized to solidify the W/O emulsion inside and collected using a centrifuge. This was dispersed again in distilled water and further centrifuged to wash free drugs and the like. The collected microcapsules were obtained as a powder by freeze-drying. Table 3 shows the drug trapping rate of the obtained microcapsules and the results of an in vitro dissolution test conducted at 37°C and in a phosphate buffer solution of pH 7.0.

Comparative Example 7 450 g of D,L-lactic acid was charged into a 1000 ml four-necked flask equipped with a nitrogen introduction tube and a cooling tube, and the mixture was heated for 9 hours under a nitrogen stream.
Distilled water was removed by heating under reduced pressure from 0° C. and 400 mmHg to 150° C. and 30 mmHg over 5 hours. Further, the mixture was heated under reduced pressure at 5 to 7 mmHg and 150 to 185°C for 23 hours, and then cooled to obtain slightly yellow polylactic acid. The obtained polylactic acid was dissolved in 1000 ml of dichloromethane,
The mixture was poured into warm water at 60°C under stirring. The separated flaky polymer was collected and vacuum-dried at 30°C. The obtained polylactic acid had a peak molecular weight of 8,000 by GPC, and the content of low molecular weight polymers with a molecular weight of 1,000 or less was 5.6%.

Comparative Example 8 TAP-144 (400 mg) was dissolved in 0.4 ml of distilled water, added to a solution in which 4.0 g of polylactic acid obtained in Comparative Example 7 was dissolved in 5 ml of dichloromethane, and mixed for 60 seconds using a small homogenizer. A W/O emulsion was obtained. After cooling this emulsion to 18°C,
The mixture was poured into 1000 ml of a 0.1% polyvinyl alcohol (PVA) aqueous solution adjusted to 8°C, and a W/O/W emulsion was prepared using a turbine homomixer. Thereafter, while stirring the W/O/W emulsion at room temperature, dichloromethane was volatilized to solidify the W/O emulsion inside and collected using a centrifuge. This was dispersed again in distilled water and further centrifuged to wash free drugs and the like. The collected microcapsules were obtained as a powder by freeze-drying. Table 4 shows the drug trapping rate of the microcapsules obtained and the results of an in vitro dissolution test conducted at 37°C and in a phosphate buffer solution of pH 7.0.

Example 1 20 g of lactic acid/glycolic acid copolymer obtained in Comparative Example 1
was dissolved in 100 ml of acetone. 60 ml of distilled water was added dropwise to this solution while stirring. The separated oil layer was collected and washed twice with 500 ml of distilled water, and the oil layer became cake-like. This was vacuum dried at 30°C. Yield is 17.4
It was g. G of the obtained lactic acid/glycolic acid copolymer
Peak value of molecular weight by PC 10000, molecular weight 100
The content of low molecular weight polymers of 0 or less was 2.0%.

Example 2 Using the lactic acid/glycolic acid copolymer obtained in Example 1, microcapsules were prepared in the same manner as in Comparative Example 2. Drug trapping rate of the obtained microcapsules and 37
Inv carried out in phosphate buffer at pH 7.0 at °C.
The results of the itro dissolution test are shown in [Table 1].

[Table 1] ────────────────────────
─── Trap
Release rate (%) b)
──────────────────
Rate (%) a) 1 day
1 week 2 weeks ──────────
──────────────── Comparative example 2
93.0 8.8 47.8
95.2 Example 2 93.6
5.7 27.8 77
．． 6 ──────────────────────
─────a) Actual amount of TRH taken in relative to the amount of TRH charged b) pH 7.0, 1/30M phosphate buffer, 37°C

Example 3 20 g of lactic acid/glycolic acid copolymer obtained in Comparative Example 3
was dissolved in 100 ml of acetone. 60 ml of distilled water was added dropwise to this solution while stirring. The separated oil layer was collected and washed twice with 500 ml of distilled water, and the oil layer became cake-like. This was vacuum dried at 30°C. Yield is 17.4
It was g. G of the obtained lactic acid/glycolic acid copolymer
Peak value of molecular weight by PC 13000, molecular weight 100
The content of low molecular weight polymers of 0 or less was 2.2%.

Example 4 Using the lactic acid/glycolic acid copolymer obtained in Example 3, microcapsules were prepared in the same manner as in Comparative Example 4. Drug trapping rate of the obtained microcapsules and 37
Inv carried out in phosphate buffer at pH 7.0 at °C.
The results of the itro dissolution test are shown in [Table 2].

[Table 2] ────────────────────────
───── Trap
Release rate (%) b)
──────────────
────── Rate (%)a)
1 day 1 week 2 weeks 3 weeks 4 weeks ─
──────────────────────────
── Comparative example 4 95.0 10.4
30.7 41.3 59.5 65
．． 2 Example 4 97.2 4.8
9.7 24.5 41.2 55
．． 7 ──────────────────────
────────a) Actual amount taken in with respect to the amount of TAP-144 charged b) pH 7.0, 1/30M phosphate buffer, 37°C

Example 5 20 g of the glycolic acid/2-hydroxybutyric acid copolymer obtained in Comparative Example 5 was dissolved in 100 ml of acetone. 80 ml of distilled water was added dropwise to this solution while stirring. The separated oil layer was collected and washed twice with 500 ml of distilled water, resulting in a lumpy oil layer. This was vacuum dried at 30°C. The yield was 18.1g. Obtained glycolic acid 2
The peak value of the molecular weight of the -hydroxybutyric acid copolymer by GPC was 13,000, and the content of low molecular weight polymers with a molecular weight of 1,000 or less was 2.5%.

Example 6 Using the glycolic acid/2-hydroxybutyric acid copolymer obtained in Example 5, microcapsules were prepared in the same manner as in Comparative Example 6. Table 3 shows the drug trapping rate of the microcapsules obtained and the results of an in vitro dissolution test conducted at 37° C. and in a phosphate buffer of pH 7.0.

[Table 3] ──────────────────────────
───── Trap
Release rate (%) b)
────────────
──────── Rate (%) a)
1 day 1 week 2 weeks
3 weeks──────────────────────
────────── Comparative example 6 85.6
17.3 50.1 89
．． 7 99.8 Example 6 95.
6 9.0 40.5
85.1 99.9──────────
──────────────────────a) T
Amount actually taken in relative to the amount of RH charged b) pH
7.0, 1/30M phosphate buffer, 37°C

[0034]
Example 7 20 g of polylactic acid obtained in Comparative Example 7 was dissolved in 100 ml of acetone. While stirring this solution, add 80ml of distilled water.
1 was added dropwise. The separated oil layer was collected and washed twice with 500 ml of distilled water, resulting in a lumpy oil layer. 30 of this
Vacuum dried at ℃. Yield was 18.5g. The peak value of the molecular weight of the obtained polylactic acid by GPC was 8,000, and the content of low molecular weight polymers with a molecular weight of 1,000 or less was 2.3%.

Example 8 Using the polylactic acid obtained in Example 7, microcapsules were prepared in the same manner as in Comparative Example 8. Table 4 shows the drug trapping rate of the obtained microcapsules and the results of an in vitro elution test conducted at 37° C. in a phosphate buffer solution of pH 7.0.

[Table 4] ──────────────────────────
───── Trap
Release rate (%) b)
────────────
──────── Rate (%)a)
1 day 1 week 2 weeks
3 weeks──────────────────────
────────── Comparative example 8 92.5
22.4 36.8 44
．． 1 56.8 Example 8 98.
6 8.4 18.2
28.5 48.2──────────
──────────────────────a) T
Actual amount taken in relative to the amount of AP-144 charged b) pH 7.0, 1/30M phosphate buffer, 37°C

[0036]

Effects of the Invention The sustained-release preparation produced using the biodegradable polymer of the present invention has a high drug uptake rate, little initial excessive release, and stably releases the drug.

Claims (3)

[Claims] Claim 1: A biodegradable aliphatic polyester containing a low-molecular substance is dissolved in a readily water-soluble organic solvent, water is added thereto to precipitate the high-molecular substance, and the low-molecular substance is removed. A method for purifying biodegradable aliphatic polyester. 2. A biodegradable aliphatic polyester obtained by the method according to claim (1), in which the content of low-molecular substances with a molecular weight of 1,000 or less is less than 3.0 (%). 3. A drug-containing preparation comprising the biodegradable polyester according to claim 2 as a release-controlled substance.