KR20130070353A - Composition of biodegradable polymer microparticles with high dispersibility and method for preparing the same - Google Patents

Abstract

PURPOSE: A solid composition containing a biodegradable polymer particle is provided to suspend using distilled water or other mainly used water without the use of dilution water including carboxymethylcellulose or mannitol etc. CONSTITUTION: A solid composition contains a biodegradable polymer particle and 'the salt of polylactic acid which have at least one terminal of carboxy group or derivatives thereof'. The weight average molecular weight of the salt of polylactic acid and or derivatives thereof is ranged 500-7,000. A production method of the solid composition containing the biodegradable polymer particle comprises a step that mixes the biodegradable polymer particle into 'the aqueous solution composed of the salt of polylactic acid which have at least one terminal of carboxy group or the derivative of the polylactic acid'; and a step that freezes and dries the resulted mixture.

Description

Composition of biodegradable polymer microparticles with high dispersibility and method for preparing the same

The present invention relates to a composition of biodegradable polymer microparticles with improved dispersibility and a method for preparing the same, and more particularly, to a biodegradable polymer microparticles in sustained release formulation and a salt of polylactic acid as a dispersing agent. The present invention relates to a solid composition of biodegradable polymer microparticles which can be suspended using only distilled water or other water for injection, can shorten the suspension time, and can increase the ease of suspension, and a method for producing the same.

Proteins and peptides, when administered orally, are readily denatured or degraded by enzymes in the digestive tract, resulting in very low bioavailability. Due to these problems, most protein and peptide drugs are sold in the form of injectables, and sustained-release preparations that have sustained long-term efficacy with a single dose have been developed and marketed. At the same time various methods have been tried to develop more improved formulations. (Khaled Al-Tahami et. Al., “Smart Polymer Based Delivery Systems for Peptides and Proteins”, Recent Patents on Drug Delivery & Formulation 2007, vol. 1, No. 1, pp. 65-71, 2007; Fei Wu et al.)

Among these various methods, microsphere formulations prepared using polylactic acid or poly (lactic acid-glycolic acid) copolymers, which are biodegradable polymers, have been applied as an effective technique to date. Leuprolide acetate (Lupron ^® Depot) and Octreotide (Sandostatin ^® ), Goserelin acetate (Zoladex ^® ) and Triptorelin Pamoate (Trelatar ^® Depot) were developed and commercialized as carriers for peptide drugs.

Polymer microparticles prepared using biodegradable polymers are mixed with water for injection or other solvents for administration.The polylactic acid or poly (lactic acid-glycolic acid) copolymers, which are the main components of the polymer microparticles, are very hydrophobic and do not dissolve in the solvent. They do not mix and are suspended and agglomerate with each other to form a lump of particulate or settle to the bottom of the container. Due to this coagulation phenomenon, there is a difficulty in administration. To solve this problem, polysorbate 80, a surfactant, and carboxymethyl cellulose, a thickener, are added to the administration solvent (diluent).

Commonly used diluents include 0.1% Polysorbate 80 and 0.5% Carboxymethylcellulose. These diluents are supplied simultaneously with the polymer microparticles containing the drug. The fine particles are mixed with a diluent and suspended to administer. However, when the diluent is mixed with the polymer microparticles, there is a problem in that it is not uniformly suspended in a short time and shakes or impacts for a long time.

In order to improve this, lyophilization is carried out by adding mannitol (Korean Patent No. 10-0994658) during the manufacturing process of polymer fine particles, or lyophilization by mixing carboxymethylcellulose or mannitol, which is a diluent component, with polymer microspheres to reduce the suspension time. There was an attempt (US Patent Publication No. 2010-0086597).

The present invention is to solve the problems of the prior art, can be suspended using only distilled water or other water for injection as a solid composition containing drug-containing polymer microparticles, shorten the suspension time, improve the ease of suspension It is a technical object of the present invention to provide a composition of biodegradable polymer microparticles and a method for producing the same.

To solve the above technical problem, the present invention provides a solid composition comprising a biodegradable polymer microparticles, and a salt of polylactic acid having at least one terminal carboxyl group or derivatives thereof as a separate dispersant.

According to another aspect of the present invention, there is provided a method for producing a biodegradable polymer microparticle, comprising: injecting and mixing biodegradable polymer microparticles into an aqueous solution of a salt of polylactic acid having at least one terminal carboxyl group or a derivative thereof; And lyophilizing the resultant mixture, a method for producing a biodegradable polymer microparticle-containing solid composition is provided.

According to another aspect of the invention there is provided an injectable reconstitution composition in which the solid composition is suspended in an injectable liquid medium.

The biodegradable polymer microparticle-containing solid composition according to the present invention can be suspended using distilled water or other water for injection only without the use of diluents including carboxymethylcellulose or mannitol, and can greatly reduce the time required for suspension and ease of suspension. It can also be used very well for injection administration of drugs, especially protein or peptide drugs.

Hereinafter, the present invention will be described in detail.

The solid composition of the present invention contains a salt of polylactic acid or a derivative thereof having at least one terminal carboxyl group as a dispersant.

According to a preferred embodiment of the present invention, as the salt of the polylactic acid or derivatives thereof, the compound of formula 1 disclosed in Korea Patent Publication No. 2011-0076783 may be used.

[Formula 1]

In Formula 1,

X and X 'are independently hydrogen, alkyl or aryl,

Y and Z are not independently present or are alkali metals,

m and n are independently an integer from 0 to 95, 5 <m + n <100,

a and b are independently an integer of 1 to 6,

R is substituted or unsubstituted-(CH ₂ ) _k- , divalent alkenyl having 2 to 10 carbon atoms, divalent aryl having 6 to 20 carbon atoms or a combination thereof, wherein k is an integer of 0-10.

In the above description, "does not independently exist" means that oxygen independently connected to Ｙ and 음 is negatively charged, that is, ^_ O-.

According to an embodiment of the present invention, in formula 1, X and X 'is independently aryl of 6 carbon atoms unsubstituted or substituted with hydrogen, alkyl of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms, more specifically Hydrogen, methyl or phenyl, and more specifically methyl. Alkali metals are specifically independently sodium, potassium or lithium.

In Formula 1, when R is divalent alkenyl having 2 to 10 carbon atoms or divalent aryl having 6 to 20 carbon atoms, each of them may be independently substituted with a hydroxyl group or C 1 -C 5 alkyl. In addition, in Chemical Formula 1, m and n preferably satisfy 10 <m + n <70.

The salt of polylactic acid of Formula 1 or a derivative thereof and a method of preparing the same are disclosed in detail in Korean Patent Application Laid-Open No. 2011-0076783, the entire contents of which are incorporated herein by reference.

According to another preferred embodiment of the present invention, as the salt of the polylactic acid or derivatives thereof, the branched compound of the formula (2) as disclosed in Korean Patent No. 10-0724719 can be used.

[Formula 2]

I - (- R'-X) _n

In Formula 2,

R 'is-[R ₁ ] _k- [R ₂ ] _m- , where R ₁ is -C (= 0) -CHZ-O-, R ₂ is -C (= 0) -CHY-O-, —C (═O) —CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ —O— or —C (═O) —CH ₂ —O—CH ₂ CH ₂ —O—, where Z and Y are each hydrogen, Methyl or phenyl, k is an integer from 1-30, m is an integer from 0-30;

X is -C (= 0)-(CH ₂ ) _a -C (= 0) -OM, where a is an integer from 0-10 and M is hydrogen, sodium, potassium or lithium;

I is diol, such as ethylene glycol, propandiol, propandiol, butandiol, pentandiol, hexanediol, or glycerol, erythritol, or thritol (threitol), pentaerythritol, xylitol, adonitol, sorbitol, mannitol, or palatinose, maltose monohydrate, Polyols having 2-12 hydroxyl groups, such as disaccharides such as maltitol or trisaccharides such as D-raffinose pentahydrate, n is an integer of 2-12, where It is equal to the number of records.

When expressed by expressing the coupling of n OH and n (R'-X) of the polyol in the above, it can be represented as I '(O-R'-X) _n , the polyol before bonding is I' (OH) _n Corresponds to

The salt of polylactic acid of Formula 2 or a derivative thereof and a preparation method thereof are disclosed in detail in Korean Patent No. 10-0724719, the entire contents of which are incorporated herein by reference.

As the salt of the polylactic acid or a derivative thereof used as the dispersant in the present invention, a single or random copolymer of 2-hydroxy carboxylic acid or a derivative thereof, or a copolymer of lactic acid and caprolactone is preferable. Preferably D, L-polylactic acid; Copolymers of D, L-lactic acid and mandelic acid; Copolymers of D, L-lactic acid and glycolic acid; Copolymers of D, L-lactic acid and caprolactone; Or a copolymer of D, L-lactic acid and 1,4-dioxane-2one.

The salt of the polylactic acid or derivative thereof used as the dispersant in the present invention is at least one, preferably one or two, more preferably two terminal carboxyl groups such as carboxylic acid groups (-COOH) or alkali metals and ions. Bound carboxylate groups (-COOM, where M is an alkali metal). The alkali metal is for example sodium, potassium or lithium (preferably sodium) and the monovalent ions and terminal carboxyl groups of these alkali metals combine to form salt forms of polylactic acid or derivatives thereof, which salt compounds are solid at room temperature. It exists in the state and is very stable since pH is neutral even if it exposes to moisture in air. Synthesis and properties of such polymer compounds are described in detail in Korean Patent Nos. 10-0517253 and 10-0724719.

The weight average molecular weight of the salt of polylactic acid or derivatives thereof used as the dispersant in the present invention is preferably 500 to 7,000, more preferably 700 to 5,000, still more preferably 1,000 to 4,000. If the weight average molecular weight of the salt of polylactic acid or its derivative is less than 500, the hydrophobicity of the salt of polylactic acid or the derivative thereof is reduced, and the dispersibility becomes weak. On the contrary, if the weight average molecular weight exceeds 7,000, the hydrophobicity becomes too strong. Salts of lactic acid or derivatives thereof cannot be prepared in aqueous solution.

In the solid composition of the present invention, the salt of the polylactic acid as described above or a derivative thereof is contained in an amount of preferably 1 to 300 parts by weight, more preferably 100 to 300 parts by weight per 100 parts by weight of the biodegradable polymer fine particles described below. . When the content of the salt of the polylactic acid or derivative thereof in the solid composition of the present invention is less than 1 part by weight per 100 parts by weight of the biodegradable polymer microparticles, the polymer microparticles may be dispersed even if the dispersion time is long and the dispersion time is long when the solid composition is rebuilt. Rapid precipitation may occur, and if it exceeds 300 parts by weight, the freeze-drying time may be long, and the viscosity of the polymer microparticles may be high after reconstruction, causing difficulty in administration.

The solid composition of the present invention also includes biodegradable polymer microparticles.

As the biodegradable polymer constituting the fine particles, for example, those selected from polylactic acid, polyglycolic acid, copolymers of glycolic acid and lactic acid, polycaprolactone acid, and mixtures thereof can be used.

In view of its usefulness as a sustained release injectable preparation, the particle size of the fine particles is preferably 10 nm to 1 mm, more preferably 0.1 to 200 μm.

There is no particular limitation on the method for producing the biodegradable polymer microparticles included in the solid composition of the present invention, it can be prepared according to the conventional polymer microparticles manufacturing method that can produce the particles of the above-described level using the biodegradable polymer. For example, water / oil / water (W / O / W) type, solid / oil / water (S / O / W) type, oil / oil / water (O / O / W) type, water / oil / oil ( Emulsion method such as W / O / O) method (coacervation), solid / oil / oil (S / O / O) method, spray dry method, spray dry and freezing after spray drying method dry, ultrasonic atomization method, electrospray, pore-closing method, thermoeversible-gel method, microfluidic method, micromachining Method (mircofabrication method), a polymer composite method using a metal ion can be used.

Preferably, the biodegradable polymer microparticles may contain a material exhibiting pharmacological activity, more preferably may contain a protein, polypeptide or peptide drug. Examples of such drugs include growth hormone, erythropoietin, monoclonal antibody, granulocyte colony stimulator, macrophage colony stimulator, granulocyte-macrophage colony stimulator, thrombopoietin, insulin-like growth factor, epidermal growth factor, platelet Derived growth factor, fibroblast growth factor, metastasis growth factor, interferon, interleukin, tumor necrosis factor, streptokinase, urokinase, staphylokinase, dieases (DNAs), glucocerebrosidase, alpha galactosidase, exena Tide, Octreotide, Insulin, Glucagon, Progesterone Hormone, Goserelin, Leuprorelin, Follicle Stimulating Hormone, Thyroid Stimulating Hormone, Fertirelin, Calcitonin, Calcitonin Corticotropin Releasing Factor, Brain Natriuretic Peptide, Timopentin, Corticotropin, Elcatonin, Beta Amyloid, Triptorelin, Busserelin, Thymosin, Somatostatin, Aralelin ), Angiotensin, Argipressin, Atosiban, Vivalirudin, Cetrorelix, Deslorelin, Desmopressin, Elcatonin, Enfuvirtide, Eptifibatide, GLP-1, Gonandorelin, Lyspressin, Nafarelin, Necitride Nesiritide, Oxytocin, Pramlintide, Secretin, Terparaparatide, Terlipressin, Tetracosactide, Vapreotide or these A mixture of the above, but is not necessarily limited to the above, the polymer fine particles If it may be encapsulated protein, polypeptide or peptide drug, which can all be applied to this invention. That is, a feature of the present invention is not to provide a specific formulation suitable for a particular drug, but to provide a drug delivery system that is applicable to various proteins, polypeptides, or peptide drugs. According to a preferred embodiment of the present invention, the protein, polypeptide or peptide drug may include goserelin, exenatide, tryptorelin, buserelin, urolorlin, somatostatin, calcitonin, octreotide, GLP-1 or these And mixtures thereof. Such bad substances are preferably contained in the biodegradable polymer microparticles in an amount of 0.1 to 10 wt% with respect to 100 wt% of the microparticles.

According to embodiments of the present invention, the polymer fine particles may be prepared by the following method.

First, pharmacologically active substances and biodegradable polymers are dissolved in methylene chloride or chloroform, poured into a polyvinyl alcohol solution (O / W method), dispersed, and the organic solvent is evaporated to prepare microspheres. In this process, the solvent may be stirred with a propeller stirrer, a magnetic stirrer, or the like to evaporate the solvent, and may be evaporated under reduced pressure or a rotary evaporator may be used.

If the pharmacologically active substance is a peptide or protein, a step is added. Peptides or proteins are dissolved in an aqueous solution together with a carrier such as gelatin, albumin, citric acid, salicylic acid, or dextrin, and then mixed and dispersed in an organic solvent in which biodegradable polymers are dissolved to form an O (oil phase) / W (aqueous phase) emulsion. Form. The formed emulsion is poured into an aqueous solution in which polyvinyl alcohol is dissolved, and the organic solvent is evaporated while dispersing using a stirrer to prepare microspheres (W / O / W method).

In the case of the W / O / W method, the peptide-containing microspheres undergo freeze-drying at the final stage and may be less active. Therefore, the microspheres may be prepared by dissolving the peptide in methanol or the like and mixing it with a polymer solution dissolved in an organic solvent (S / O / W method).

In order to facilitate the preparation of microspheres, pharmacologically active substances such as peptides and compounds are mixed in an organic solvent in which a polymer is dissolved, sprayed using hot air, and the organic solvent is evaporated when contacted with hot air. Spray drying method of the type can also be used. The microspheres prepared by the spray drying method generate a large initial release upon administration.In order to reduce the initial release, the microspheres prepared by the spray drying method are placed in a polyvinyl alcohol aqueous solution to remove peptides or pharmacologically active substances remaining on the surface of the microspheres. You can also add a wash step.

Sustained release particulate formulations in the form of particles that are not spherical, such as microspheres, can be prepared as follows. First, an aqueous solution containing a protein or polypeptide and a biodegradable polymer (eg, polylactic acid) is prepared, and the aqueous solution is slowly dropwise precipitated into an aqueous solution of a polyvalent metal salt, and then the precipitate is centrifuged and washed with water. Lyophilization can produce polymer microparticles containing polypeptides or proteins.

Most of the method for preparing polymer microparticles including the microspheres described above may include washing the peptide or the pharmacologically active substance on the surface of the microparticles using an aqueous solution.

The solid composition of the present invention essentially comprises a salt of a polylactic acid having a at least one terminal carboxyl group or a derivative thereof as the biodegradable polymer microparticles described above, and a dispersant separate from these, and contains only the components thereof to a desired level of powder. Acidity can be achieved. However, this does not exclude the possibility of containing other optional ingredients, and additive components such as polysorbate, which are usually included in the lyophilized composition of the polymer microparticles for injection, as necessary within the scope of achieving the object of the present invention. 80, polysorbate 20, sodium carboxymethylcellulose, and the like may be further included.

According to another aspect of the present invention, there is provided a method for producing a biodegradable polymer microparticle, comprising: injecting and mixing biodegradable polymer microparticles into an aqueous solution of a salt of polylactic acid having at least one terminal carboxyl group or a derivative thereof; And lyophilizing the resultant mixture, a method for producing a biodegradable polymer microparticle-containing solid composition is provided.

In the method for preparing a solid composition of the present invention, as described above, salts or derivatives of polylactic acid having biodegradable polymer microparticles and at least one terminal carboxyl group can be used. There are no particular restrictions on the mixing method and conditions thereof. For example, the pharmacologically active substance-containing polymer microparticles prepared by the various methods described above may be added to an aqueous solution of a salt of polylactic acid or a derivative thereof, and then mixed at 4 to 30 ° C. with conventional stirring means for 5 to 30 minutes. . According to one embodiment of the present invention, 100 mg of the polymer fine particles are added to 1 milliliter of an aqueous sodium polylactic acid solution previously dissolved in distilled water at a rate of 1 mg to 500 mg, more preferably 1 mg to 300 mg, and then at about 25 ° C. Stir and mix.

The solid composition of the present invention can be obtained by lyophilizing an aqueous solution of a mixture of the polymer fine particles and a salt of polylactic acid or a derivative thereof obtained as described above. There is no particular limitation on the method of lyophilization, and conventional lyophilization methods and equipment can be used.

According to another aspect of the invention there is provided an injectable reconstitution composition in which the solid composition is suspended in an injectable liquid medium.

As the liquid medium for injection, for example, distilled water, saline solution, sodium chloride / dextrose aqueous solution, dextrose aqueous solution, Ringer's solution, etc. may be used, but is not particularly limited thereto. Suspension of the solid composition of the present invention in such an injectable liquid medium can significantly shorten the suspension time and significantly reduce the difficulties encountered in diluent fractionation in conventional methods.

Hereinafter, the present invention will be described in more detail with reference to Examples, which are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.

[ Example  One]

Manufactured by S / O / W method Microparticle  Preparation of Containing Lyophilized Compositions: Sodium D, L-Polylactate (D, L-) PLA - COONa ) use

20 mg goserelin (BCN peptides) completely dissolved in 0.1 g of methanol, 0.2 g of methylene chloride was mixed with a solution of 0.4 g of a poly (lactide-glycolide) copolymer (Evonik, RG502H). The mixture was slowly poured into 200 ml of 1% polyvinyl alcohol aqueous solution, and the organic solvent methanol and methylene chloride were removed by evaporation while stirring at 500 rpm for 1 hour 30 minutes using a stirrer. After removal of the organic solvent, the resultant was added to 1000 ml of distilled water and stirred for 10 minutes to repeat the washing twice. The washed microsphere solution was centrifuged to recover only the microspheres.

To prepare a solution in which the weight average molecular weight (Mw) and weight (mg) of sodium polylactic acid (DL-sodium polylactic acid, corresponding to Formula 1) shown in Table 1 was dissolved in 1 g of distilled water, and 100 mg of the microspheres obtained above were prepared. After adding and mixing, lyophilization for 24 hours to obtain a polymer microspheres-containing solid composition.

1 ml of distilled water was added to the obtained lyophilized solid composition, and then lightly beated 2-3 times with a palm, and then to an apparatus (LAB-LINE, thermal rocker, USA) set to be shaken from side to side at 10 speeds (4 cm shaking) per 10 seconds. The required time was determined until positioning and uniform suspension. The measurement results are shown in Table 1 below.

In Comparative Composition 1, 100 mg of the microspheres prepared by the S / O / W method were placed in an injection vial (5 ml volume), and the diluent (Lupron depot ^® diluent, composition: 5 mg of carboxymethyl cellulose, 1 mg of polysorbate 80, 50 mg of mannitol, and 50 ml of distilled water) were added, and the required time was measured until the suspension was uniformly suspended in the same manner as described above. The measurement results are shown in Table 1 below.

[Table 1]

[ Example  2]

Manufactured by S / O / W method Microparticle  Preparation of Containing Lyophilized Compositions: Bi-branched D, L-polylactic acid salt (D, L- PLA - COONa ) use

Goserelin-containing polymer microspheres were prepared in the same manner as in Example 1.

To prepare a solution in which the weight average molecular weight (Mw) and weight (mg) of bi-branched sodium polylactic acid (DL-sodium polylactic acid, corresponding to Formula 2) shown in Table 2 in 1 g of distilled water, 100 mg of microspheres were added and mixed, followed by lyophilization for 24 hours to obtain a polymer microsphere-containing solid composition.

1 ml of distilled water was added to the obtained lyophilized solid composition, suspended in the same manner as in Example 1, and the required time until uniform suspension was measured. The measurement results are shown in Table 2 below.

As Comparative Composition 2, 100 mg of the prepared microspheres was placed in an injection vial (5 ml volume), and 1 ml of the diluent used in the Comparative Composition of Example 1 was added thereto, and when suspended in the same manner as above, the suspension was uniformly suspended. The time required was measured. The measurement results are shown in Table 2 below.

[Table 2]

[ Example  3]

By spray drying method  Manufactured Microparticle  Preparation of Containing Lyophilized Compositions: Bi-branched D, L-polylactic acid salt (D, L- PLA - COONa ) use

20 mg goserelin (BCN peptides) completely dissolved in 0.1 g of methanol, 0.2 g of methylene chloride was mixed with a solution of 0.4 g of a poly (lactide-glycolide) copolymer (Evonik, RG502H). The mixed solution was supplied to a spray dryer (BUCHI, B-191) equipped with a spray nozzle (0.7 mm) at a flow rate of 1.5 ml / min to supply dry air at 60 ° C. to obtain microspheres. Some of the prepared microspheres were left for comparative composition, and the remainder was mixed in 1000 ml of distilled water and mixed for 10 minutes, followed by washing twice. Microspheres-containing liquid was washed by centrifugation to recover only the microspheres.

To prepare a solution in which the weight average molecular weight (Mw) and weight (mg) of the bi-branched sodium polylactic acid (DL-sodium polylactic acid, corresponding to the formula (2)) shown in Table 3 was dissolved in 1 g of distilled water, 100 mg of microspheres were added and mixed, followed by lyophilization for 24 hours to obtain a polymer microsphere-containing solid composition.

1 ml of distilled water was added to the obtained lyophilized solid composition, suspended in the same manner as in Example 1, and the required time until uniform suspension was measured. The measurement results are shown in Table 3 below.

As Comparative Composition 3, 100 mg of the microspheres prepared by the spray drying method were placed in an injection vial (5 ml volume), and 1 ml of the diluent used in the Comparative Composition of Example 1 was added thereto, and then suspended in the same manner as above. The time required until the suspension was measured. The measurement results are shown in Table 3 below.

[Table 3]

[ Example  4]

Polyvalent metal salts  Manufactured using Microparticle  Preparation of Containing Lyophilized Compositions: Bi-branched D, L-polylactic acid salt (D, L- PLA - COONa ) use

4.9 g of 2-branched D, L-polylactic acid salt (2-arm D, L-PLA-COONa) and 100 mg of exenatide were prepared in 45 ml of water, which was then filtered through a 0.45 μm filter to remove impurities. Removed. 500 ml (25 mg / ml) of zinc chloride (ZnCl ₂ ) aqueous solution was prepared as a polyvalent metal salt, and the exenatide-polymer aqueous solution was added dropwise at a rate of 3 mL / min and stirred at a speed of 120 rpm to obtain an exenatide-containing composition. A precipitate was obtained. The precipitate was filtered off, washed twice with 500 ml of distilled water, and vacuum dried at room temperature for 1 day. After the vacuum-dried composition was pulverized by a pulverizer, exenatide-containing polymer microparticles of 50-150 μm were obtained using a 100-400 mesh sieve. Some of the fine particles thus prepared were left for comparative composition, and the remainder was mixed in 1000 ml of distilled water and mixed for 10 minutes, followed by washing twice. The fine particles containing the washed solution was centrifuged to recover only the fine particles.

To prepare a solution in which the weight average molecular weight (Mw) and weight (mg) of bi-branched sodium polylactic acid (DL-sodium polylactic acid, corresponding to Formula 2) shown in Table 4 was dissolved in 1 g of distilled water, 100 mg of the fine particles were added and mixed, followed by lyophilization for 24 hours to obtain a solid composition containing the polymer fine particles.

1 ml of distilled water was added to the obtained lyophilized solid composition, suspended in the same manner as in Example 1, and the required time until uniform suspension was measured. The measurement results are shown in Table 4 below.

As Comparative Composition 4, 100 mg of the microparticles prepared by using the polyvalent metal salt were stored in an injection vial (5 ml volume), and 1 ml of the diluent used in the Comparative Composition of Example 1 was added thereto and suspended in the same manner as described above. The time required until the suspension was uniformly measured. The measurement results are shown in Table 4 below.

[Table 4]

Claims (13)

A solid composition comprising a biodegradable polymer microparticle and a salt of polylactic acid having at least one terminal carboxyl group or a derivative thereof as a dispersant. The solid composition of claim 1, wherein the salt of polylactic acid or derivative thereof is a compound of formula (I):
[Formula 1]

In Chemical Formula 1,
X and X 'are independently hydrogen, alkyl or aryl,
Y and Z are not independently present or are alkali metals,
m and n are independently an integer from 0 to 95, 5 <m + n <100,
a and b are independently an integer of 1 to 6,
R is substituted or unsubstituted-(CH ₂ ) _k- , divalent alkenyl having 2 to 10 carbon atoms, divalent aryl having 6 to 20 carbon atoms, or a combination thereof k is an integer of 0-10. The solid composition according to claim 1, wherein the salt of polylactic acid or a derivative thereof is a compound of formula (II):
(2)
I - (- R'-X) _n
In Formula 2,
R 'is-[R ₁ ] _k- [R ₂ ] _m- , where R ₁ is -C (= 0) -CHZ-O-, R ₂ is -C (= 0) -CHY-O-, —C (═O) —CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ —O— or —C (═O) —CH ₂ —O—CH ₂ CH ₂ —O—, where Z and Y are each hydrogen, Methyl or phenyl, k is an integer from 1-30, m is an integer from 0-30;
X is -C (= 0)-(CH ₂ ) _a -C (= 0) -OM, where a is an integer from 0-10 and M is hydrogen, sodium, potassium or lithium;
I is a polyol having 2-12 hydroxy groups, n is an integer of 2-12, which is equal to the number of hydroxyl groups of the polyol. The solid composition of claim 1, wherein the salt of polylactic acid or derivative thereof has two terminal carboxyl groups. The solid composition according to claim 1, wherein the weight average molecular weight of the salt of polylactic acid or a derivative thereof is 500 to 7,000. The solid composition according to claim 1, comprising 1 to 300 parts by weight of a polylactic acid salt or derivative thereof per 100 parts by weight of biodegradable polymer microparticles. The solid composition according to claim 1, wherein the biodegradable polymer constituting the biodegradable polymer fine particles is selected from polylactic acid, polyglycolic acid, copolymers of glycolic acid and lactic acid, polycaprolactone acid, and mixtures thereof. The method of claim 1, wherein the biodegradable polymer microparticles are emulsion method, solid / oil / oil (S / O / O) method, spray drying method, lyophilization method after spray drying, ultrasonic atomization method, electrospray method, pore closure A solid composition, characterized in that produced by a method, a phase transition gel method, a microfluidic method, a microfabrication method or a polymer complexation method using a metal ion. The solid composition of claim 1, wherein the biodegradable polymeric microparticles contain a protein, polypeptide or peptide drug. The method of claim 1, wherein the biodegradable polymer microparticles are growth hormone, erythropoietin, monoclonal antibody, granulocyte colony stimulator, macrophage colony stimulator, granulocyte-macrophage colony stimulator, thrombopoietin, insulin-like growth factor, Epidermal growth factor, platelet-derived growth factor, fibroblast growth factor, metastatic growth factor, interferon, interleukin, tumor necrosis factor, streptokinase, urokinase, staphylokinase, dieases (DNAs), glucocerebrosidase, alpha galacto Sidase, exenatide, octreotide, insulin, glucagon, luteinizing hormone secretion hormone, goserelin, leuproline, follicle stimulating hormone, thyroid stimulating hormone, puttyreline, calcitonin, corticotropin releasing factor, brain natrieu Retic Peptide, Timofentin, Corticotropin, Elkatonin, Beta Amyloid, Tryptorelin, Buserelin, Tee Mosin, Somatostatin, Arellalin, Angiotensin, Argipressin, Atosivan, Vivalidrudine, Setlorrelic, Deslorerlin, Desmopressin, Elkatonin, Enfuvirtid, Eptibartid, GLP-1 , Gondolinin, rispressin, naparerlin, necitrides, oxytocin, pramlinted, secretin, teriparatide, tarypressin, tetracosactide, vapreotide or mixtures thereof Solid composition. Injecting and mixing the biodegradable polymer microparticles into an aqueous solution of a salt of polylactic acid or a derivative thereof having at least one terminal carboxyl group; And lyophilizing the resultant mixture, wherein the biodegradable polymer microparticle-containing solid composition according to any one of claims 1 to 10 is prepared. An injectable reconstructive composition in which the solid composition according to any one of claims 1 to 10 is suspended in an injectable liquid medium. 13. The injectable reconstitution composition according to claim 12, wherein the liquid medium for injection is distilled water, saline solution, sodium chloride / dextrose aqueous solution, dextrose aqueous solution, Ringer's solution or mixtures thereof.