KR100268038B1 - Microsphere composition and microsphere prepared therefrom capable of controlling the content of residual organic solvent and release rate of drug - Google Patents

Abstract

The present invention relates to a microsphere composition capable of controlling the amount of residual organic solvent and the drug release rate of the microspheres prepared by the solvent evaporation drying method, and to a uniform spherical microspheres prepared therefrom, the glass of the biocompatible biodegradable polymer In the case of using the microsphere composition of the present invention to which a substance for lowering the transition temperature is added, the amount of organic solvent can be reduced by gradually diffusing and exiting the organic solvent into the trauma during the preparation of the microsphere, thereby reducing the drug release rate. I can regulate it.

Description

Microsphere Compositions and Microspheres Prepared Therefrom That Can Control the Amount of Residual Organic Solvents and Drug Release Rates

The present invention relates to a microsphere composition capable of controlling the amount of residual organic solvent and the drug release rate of the microspheres prepared by the solvent evaporation drying method, and the microspheres prepared therefrom, specifically, the glass transition of the biocompatible biodegradable polymer A microsphere composition to which a material capable of lowering the temperature is added and a homogeneous spherical microsphere prepared therefrom.

In the case of drugs requiring continuous drug administration, drugs with a short half-life in the body, drugs requiring frequent drug administration, or drugs requiring local drug concentration at specific sites, a drug carrier using a biocompatible biodegradable polymer may be inserted or implanted in the body. Alternatively, many agents have been used to slowly release a drug by decomposing the biodegradable polymer by administration to exhibit physiological activity.

There are a variety of methods for preparing microspheres or microcapsules by incorporating drugs into biodegradable polymers, and in particular, representative methods are solvent evaporation drying. It is a solution prepared by mixing a drug in a solution in which a polymer is dissolved in a volatile, organic solvent, and then added to a solvent containing one or more surfactants, and then an emulsion is formed, followed by evaporation of the organic solvent and drying in water to form a microsphere or As a method of preparing a microcapsule, the organic solvent used at this time should be capable of dissolving the hydrophobic biodegradable polymer, and should be harmless to the human body when used as a drug carrier for implantation or administration into the body. However, since most organic solvents that are harmless to the human body are water soluble, emulsions are not produced in the aqueous solution, which is a dispersion medium, and thus are not suitable for preparing microspheres.

There are few organic solvents that can be produced by microspheres and are harmless to humans at present, and organic solvents of halogenated alkanes are mainly used for solvent evaporation drying. Representative solvents of halogenated alkanes are dichloromethane, which is classified as class II solvent (ICH guideline), and the residual amount of halogenated alkanes is regulated to 300 ppm or less (ICH guideline) in medicine. In addition, the regulation of residual organic solvents is expected to be stricter in the future to ensure the safety of medicines. Therefore, removal of organic solvents during or after microsphere preparation is an essential condition for pharmaceuticals.

Generally, microcapsules or microspheres prepared by the solvent evaporation drying method are known to contain about 1 to 6% of dichloromethane, depending on the preparation method thereof. This is impossible to use because it is not secured when applied to the human body in the amount far exceeding the allowable dichloromethane 300ppm. Drying under reduced pressure to remove dichloromethane below the regulatory level after manufacture may reduce the amount of dichloromethane to ppm, but the long-term drying time and the rapid release of the drug increases as the drying time increases, resulting in long-term drug release. It is not suitable for formulations designed to be.

In addition to halogenated alkanes, ethyl acetate is a solvent that can be used in the solvent evaporation drying method with a low degree of harmfulness to the human body. Since the solubility in water is high, the organic solvent, which is a dispersion medium, diffuses quickly into an aqueous solution. The disadvantage is that it is difficult to obtain microspheres (Journal of Controlled Release, 47, 233-245 (1997)).

Blowing gas such as nitrogen into the emulsion (European Patent No. 0 779 072 A1) as a method of removing the residual organic solvent, volatilization of the organic solvent by controlling the manufacturing temperature (Journal of Controlled Release, 29, 374 -384 (1994)), and the method of lowering the pressure of the system, but the method of increasing the manufacturing temperature has the disadvantage that the release of the drug is rapid by forming a hollow core-shaped microsphere, The method of lowering the pressure of the system has a disadvantage in that a uniform spherical microsphere cannot be obtained.

In addition, there is a method of increasing the volume and time of the diluent so that the organic solvent is well evaporated, but when using a water-soluble drug, there is a disadvantage in that the encapsulation efficiency is low and manufacturing is not easy.

In US Patent No. 5,609,886, a microsphere is prepared by dissolving a polypeptide, which is a physiologically active substance, using a secondary solvent that can be mixed with both an organic solvent and a traumatic aqueous solution, and then mixing the polymer with an organic solvent in which a polymer is dissolved, thereby without initial release. A method of reducing residual organic solvent to 1.5% or less is proposed. However, this could reduce the residual amount and toxicity of the primary solvent by using the secondary solvent, but the safety and residual amount of the secondary solvent used in the preparation must also be considered separately, so its use is limited.

In addition, since the microspheres prepared using cellulose are generally hollow-centered types having thin walls, the drug is not well incorporated and the drug cannot be released for a long time. Attempts have been made to improve this. For example, U.S. Patent No. 5,725,869 proposes a method for producing a sponge-like microsphere consisting of pores with irregular inside and surface of the microsphere by adding a plasticizer to an oil phase composed of a polymer, a drug, and an organic solvent. Porous sponge-shaped microspheres have some advantages in drug incorporation and drug release compared to hollow-centered microspheres, but the drug is excessively released at first and the drug release period is not long. Zero has the disadvantage of not being suitable.

Accordingly, the present inventors have continued to study the production of uniform spherical microspheres that can control the amount of residual organic solvent and the rate of drug release, and as a result, a material capable of lowering the glass transition temperature of a biodegradable polymer is incorporated into the microsphere composition. By reducing the glass transition temperature of the polymer during the manufacturing process to allow the organic solvent to gradually diffuse into the trauma to escape, to reduce the amount of residual organic solvent, to control the initial rapid release according to the type and amount of the additive, the release of the drug The present invention was completed by discovering that the speed can be adjusted.

It is an object of the present invention to provide a microsphere composition capable of controlling the amount of residual organic solvent and the rate of drug release and a uniform spherical microsphere prepared therefrom.

1 is a graph showing the change in the amount of residual organic solvent in the microspheres according to the change in the amount of acetyl citric acid tributyl ester (ATBC), which is a substance for lowering the glass transition temperature of the biodegradable polymer according to the present invention,

2 is a graph showing the amount of drug released over time for each of the addition amount of the acetyl citric acid tributyl ester as an additive according to the present invention.

In order to achieve the above object, in the present invention, 50 to 99% by weight of biocompatible biodegradable polyester, 1 to 50% by weight of drug and 0.1 to 15% by weight of alkyl ester of organic acid based on the weight of the biodegradable polyester, It provides a microsphere composition comprising triacetin, glycerin or polyethylene glycol.

In addition, the present invention provides a uniform spherical microsphere having a residual organic solvent content of 0.5% or less prepared by the solvent evaporation drying method from the microsphere composition.

The microspheres prepared using the microsphere composition of the present invention have a uniform spherical inside of the matrix form, and the drug is evenly distributed in the matrix, thereby allowing controlled release of the drug for a long time without initial rapid release.

The biodegradable polymers used in the microsphere composition of the present invention are fatty acid polyesters that can be decomposed into water and carbon dioxide, which are harmless to the human body when hydrolyzed, for example, glycolic acid polymers, lactic acid polymers or copolymers of lactic acid and glycolic acid or Mixtures of these are preferred. The molecular weight of these polymers is an important factor in the drug release period and degradation of the microsphere. As the molecular weight increases, the release and degradation of the drug takes a long time and takes longer to degrade the lactic acid polymer than the glycolic acid polymer. Therefore, in the case of the copolymer of lactic acid and glycolic acid, the larger the ratio of lactic acid is, the longer it takes to release and decompose the drug.

The duration of drug release can be controlled depending on the molecular weight of the polymer used as well as the solubility of the drug used. Accordingly, it is possible to prepare a formulation having an independent release pattern that slowly releases the drug for a desired period in consideration of the type and molecular weight of the polymer used or the solubility of the drug.

Drugs that can be used in the present invention are not specified and can be used in both water-soluble or fat-soluble, for example, polypeptides having antibiotic activity, antibiotics, anticancer agents, analgesics, anti-inflammatory agents, antitussives and expectorants, sedatives, muscle relaxants, therapeutic agents for epilepsy Applicable to all drugs requiring long-term medications, such as ulcers, antidepressants, antiallergic agents, cardiovascular drugs, antiarrhythmic drugs, ulcer dilatants, diuretics, antidiabetics, anticoagulants, hemostatics, anti-nodule, hormones, anesthetic antagonists .

The amount of the drug can be selected in consideration of the type of drug, the desired pharmaceutical effect and the duration of the drug, and the content of the drug in the microsphere is generally 1 to 70% (weight / weight), in particular 1 to 50% (weight / weight) is more preferable.

In microspheres produced by solvent evaporation drying, the rate at which the organic solvent diffuses into the trauma affects the physicochemical properties of the microspheres. In other words, if the diffusion speed is rapid, the surface of the microsphere is cured relatively quickly, so that a hollow-centered microsphere having a thin wall is formed, and thus the drug cannot be uniformly distributed in the matrix, and the polymer is removed from the surface. By hardening quickly to form a hard skin, the organic solvent inside does not escape to the trauma, which results in a large amount of organic solvent remaining inside.

In the present invention, by lowering the glass transition temperature of the biodegradable polymer to delay the curing of the polymer and to gradually diffuse the organic solvent into the external phase, a material capable of reducing the residual amount of the organic solvent without significantly increasing the porosity of the microspheres micro By adding during spear preparation, the drug can be continuously controlled and released without excessive release of the drug initially. As a material for lowering the glass transition temperature of the biodegradable polymer, alkyl citrate, phthalic acid alkyl ester, sebacic acid alkyl ester, benzoic acid alkyl ester, succinic acid alkyl ester, malonic acid alkyl ester, adipic acid alkyl ester, lactic acid alkyl There are alkyl esters of organic acids such as esters and glycolic acid alkyl ester derivatives, triacetin, glycerin and polyethylene glycol, and the amount of residual organic solvent is adjusted according to their type and amount. Especially preferred are citric acid alkyl esters, sebacic acid alkyl esters and benzoic acid alkyl esters.

As the amount of the material increases, the organic solvent diffuses well into the outer phase to reduce the amount of the residual organic solvent. As the flexibility of the polymer increases during the manufacturing process and the curing is delayed, the porosity inside the matrix increases. At this time, the pores generated inside the matrix have small and uniform characteristics and can control drug release according to the degree of porosity. However, if the amount of the material that lowers the glass transition temperature of the polymer is too high, it has an excessively low glass transition temperature, so the strength is weak and sensitive to temperature, resulting in poor workability.

The material for lowering the glass transition temperature of the biodegradable polymer is preferably added 0.1 to 15% by weight based on the weight of the polymer.

According to the present invention, microspheres can be prepared as follows. A solution or suspension prepared by dissolving the biodegradable polymer in an organic solvent such as dichloromethane and then lowering the glass transition temperature of the drug and the biodegradable polymer is added to a solvent containing one or more surfactants to form an emulsion. After evaporation, the organic solvent is evaporated to dryness in water to prepare a microsphere.

The microspheres of the invention, in particular, comprise 70 to 95% by weight of biodegradable polyester, 5 to 30% by weight of drug and 1 to 10% by weight of citric acid alkyl ester or benzoic acid alkyl ester, based on the weight of the polyester. It is preferable that it is prepared by.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1

Ofloxacin was ground to a particle size of 5 μm or less by jet mill. 14.0 g of a lactic acid polymer having a molecular weight of 8,000, 6.0 g of the pulverized ofloxacin and 0.7 g of acetyl citrate tributyl ester were added to 14 ml of dichloromethane and stirred to prepare a well-dispersed suspension. This suspension was added to a 5% aqueous polyvinylalkoxy solution to form an emulsion, followed by well stirring to allow the dichloromethane to slowly evaporate. Subsequently, distilled water was added to the reaction mixture to dilute it, followed by washing with polyvinyl alcohol and freeze-drying to obtain microspheres containing opoxacin.

[Examples 2 to 11]

Drug-containing microspheres having the composition shown in Table 1 below were prepared in the same manner as in Example 1.

[Comparative Examples 1 to 3]

Except for the addition of acetyl citric acid tributyl ester, which is a substance that lowers the glass transition temperature of the biodegradable polyester (Comparative Example 1), or using 4.0g (Comparative Example 2) and 5.0g (Comparative Example 3) Drug-containing microspheres were prepared in the same manner as in Example 1.

The drug content, encapsulation efficiency and particle size of the microspheres prepared in Examples 1 to 11 and Comparative Examples 1 to 3 were measured and shown in Table 2. Drug content was analyzed by HPLC and particle size was measured by particle size analyzer (Mastersizer X., Malvern Instruments Ltd) using water as a dispersion medium.

[Test Example 1: Residual Organic Solvent Determination]

0.3 g of the microspheres prepared in Examples 1 to 11 and Comparative Examples 1 to 3 were added to 0.03N methanolic acid hydrochloric acid solution, and the remaining dichloromethane was extracted and analyzed by gas chromatography using helium as a carrier gas. The results are shown in Table 3 below.

1 is a graph showing the change in the amount of residual organic solvent in the microspheres according to the addition amount of the acetyl citric acid tributyl ester which is a substance for lowering the glass transition temperature of the biodegradable polymer according to the present invention, as shown here acetyl citrate tributyl ester As the amount of was increased, the amount of residual dichloromethane decreased. It can be seen from this that the additive of the present invention helps the organic solvent to slowly diffuse into the trauma during microsphere preparation.

Test Example 2: Drug Release Experiment

15.0 mg of the microspheres prepared in Examples 1 to 11 and Comparative Examples 1 to 3 were added to a phosphate buffer solution (pH 7.4, 0.02% polysorbate) and the stirring speed was maintained at 50 rpm while maintaining the temperature in a constant temperature bath at 37 ° C. The amount of drug released over time was analyzed by UV absorbance. The results are shown in Table 4 below.

On the other hand, Figure 2 is a graph showing the amount of drug released over time with respect to each of the addition amount of the acetyl citric acid tributyl ester as an additive according to the present invention, as shown here, as the addition amount of acetyl citric acid tributyl ester increases Drug release tends to be faster and drug release periods tend to be shorter.

[Test Example 3: Coagulation phenomenon and particle size of the microsphere]

The aggregation of the microspheres prepared in Examples 1 to 3 and Comparative Examples 1 to 3, after storage for 1 month at 4 ° C. and room temperature, and storage for 1 month at 40 ° C. was visually observed and particles were observed. The size was measured. The results are shown in Table 5 below.

According to the present invention, by using a microsphere composition in which an appropriate amount of a substance which lowers the glass transition temperature of the biodegradable polymer is added, the organic solvent is diffused into the dispersion medium during the microsphere manufacturing process to reduce the amount of the organic solvent remaining in the microsphere. Reduce and release the drug continuously for an extended period of time without initial immediate release.

Claims (6)

50 to 99% by weight biocompatible biodegradable polyester, 1 to 50% by weight drug and 0.1 to 15% by weight of alkyl ester of organic acid, triacetin, glycerin or polyethylene glycol based on the weight of the biodegradable polyester Microsphere Composition. The composition of claim 1 wherein the biodegradable polyester is a lactic acid polymer, a glycleic acid polymer, a copolymer of lactic acid and glycolic acid, or a mixture thereof. The alkyl ester of the organic acid according to claim 1, wherein the alkyl ester of the organic acid is citric acid alkyl ester, phthalic acid alkyl ester, sebacic acid alkyl ester, benzoic acid alkyl ester, succinic acid alkyl ester, malonic acid alkyl ester, adipic acid alkyl ester, lactic acid alkyl ester or glycolic acid A composition comprising an alkyl ester derivative. A solution or suspension prepared by mixing the microsphere composition according to claim 1 to an organic solvent is added to a solvent containing a surfactant to form an emulsion, followed by evaporation of the organic solvent and drying in water. Uniform spherical microspheres of less than or equal to%. The method according to claim 4, wherein the composition is 70 to 95% by weight biodegradable polyester, 5 to 30% by weight drug selected from the group consisting of lactic acid polymer, glycolic acid polymer, copolymers of lactic acid and glycolic acid and mixtures thereof Microspheres comprising from 1 to 10% by weight citric acid alkyl esters, based on the weight of the polyester. The method according to claim 4, wherein the composition is 70 to 95% by weight biodegradable polyester, 5 to 30% by weight drug selected from the group consisting of lactic acid polymer, glycolic acid polymer, copolymers of lactic acid and glycolic acid and mixtures thereof Microspheres comprising from 1 to 10% by weight of benzoic acid alkyl esters, based on the weight of the polyester.