JP2003171264A - Microcapsule and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing a sustained release microcapsule exhibiting sufficient sustained release property without using a thickening material, preventing the complication of the production of the raw materials and the process for the drug preparation and keeping high content of the main drug in the capsule. <P>SOLUTION: A W/O-type emulsion is produced by using a solution containing a water-soluble drug as the inner water phase and a solution containing a polymer as the oil phase. The emulsion is dispersed in an outer water phase to obtain a W/O/W-type emulsion and the product is dried in liquid to obtain the sustained release microcapsule of the water-soluble drug. A water-soluble metal salt compound is added to the water phase to be used at or after the preparation of the W/O/W-type emulsion. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing microcapsules of a water-soluble drug, and more particularly to a method for producing sustained-release microcapsules useful as a sustained-release preparation of a water-soluble drug.

[0002]

2. Description of the Related Art A pharmaceutically active substance exerts a medicinal effect within a certain blood concentration range, but beyond the concentration range, it begins to show toxicity and the risk of adverse effects increases. Therefore, it is necessary to administer the drug so that the pharmaceutically active substance does not exceed the above-mentioned blood concentration, and in particular, when the drug is administered for a long period of time, the drug concentration should be controlled so that no adverse effect is expressed. Is important.

In particular, various vitamins, hormones, antidiabetic agents, hypertensive diuretics, uric acid excretion promoting agents and other agents for maintaining biological homeostasis often require long-term administration. Due to the mechanism of manifestation of pharmacological effects, these pharmaceuticals that require long-term administration include: a) the pharmacological effects are not so dependent on the effective concentration in the body fluid, and the excessive pharmacological effects are not harmful to the living body; There are pharmacological effects that appear depending on the medium effective concentration, and there is a drug that requires a regular adjustment of the dosage because rapid pharmacological effects and excessive pharmacological effects are harmful to the living body. . In particular, in the latter type of medicine, it is extremely important to maintain the blood concentration within a constant effective concentration range continuously, and therefore, it is highly necessary to prepare a continuous preparation.

In the field of pharmaceuticals, several means for obtaining a sustained-release preparation are known, and one of them is the use of controlled-release microcapsules. For example, JP-A-57-118512 discloses that
Microencapsulation by a phase separation method using a coacervation agent such as mineral oil and vegetable oil is disclosed.

Further, in JP-A-60-100516 and JP-A-62-201816, a drug retention rate is improved by adding a thickening substance such as gelatin to the inner aqueous phase to increase the viscosity. An improved method of preparing microcapsules by an in-water drying method is disclosed. Furthermore, JP-A-8-
No. 217691 discloses a method for preparing microcapsules using a water-insoluble or sparingly water-soluble polyvalent metal salt of a water-soluble peptide-based physiologically active substance, and JP-A-8-3055 discloses a method for preparing a water-soluble aliphatic carboxylic acid metal salt and a raw material. Create a biodegradable matrix in advance with biodegradable polymer,
A method of preparing a microcapsule in which a water-soluble polypeptide is allowed to penetrate into a biodegradable matrix in water is disclosed in Japanese Patent Laid-Open No. 10-7583, in which a microcapsule utilizing a biodegradable polymer polymer which is a metal salt in advance is used. According to the method of preparation, in JP-A-10-231252, a microcapsule is prepared by dispersing a physiologically active substance in a solid state in a lactic acid-glycolic acid copolymer (hereinafter, may be abbreviated as PLGA) which is a zinc oxide body in advance. The law is disclosed.

Furthermore, in JP-A-8-169818, PLG using lactic acid and glycolic acid as raw materials is disclosed.
A microcapsule characterized by removing the monomer as a raw material in A and making it below a certain value and using the PLGA uses PLGA manufactured without using a catalyst in JP-A No. 11-1443. A microcapsule characterized by the above is disclosed.

However, the above-mentioned method has not been said to be sufficiently satisfactory. For example, the content of the main drug trapped in the microcapsules is about 10% with respect to the charged amount (JP-A-62-201816, Example), and it is necessary to process the drug or the microcapsule coating itself. In addition, the raw material procurement is limited, such as the manufacturing method of the microcapsule coating raw material is limited, and the process and operation are complicated. Further, it has not been desirable clinically to use an additive having a problem of antigenicity such as gelatin as a thickening substance.

[0008]

Therefore, without using a thickening substance, the process of preparing raw materials and the process of formulation are not complicated, the encapsulation rate of the active ingredient is high, and sufficient sustained release is achieved. It has been desired to provide a method for producing the sustained-release microcapsules shown below.

[0009]

Means for Solving the Problems As a result of studies to solve the above-mentioned problems, the present inventors have found that a W / O / W type emulsion is subjected to an in-liquid drying method to obtain a sustained-release microbe of a water-soluble drug. In the method of producing capsules, if a water-soluble metal salt compound is added to the aqueous phase used after the step of making the W / O / W type emulsion, addition of a thickening substance and preparation of special raw materials are required. It was found that a sustained-release microcapsule with sufficient drug uptake and a small initial burst can be obtained. Further, they have found that this method improves the sustained-release property of the drug, and completed the present invention.

That is, according to the present invention, a solution containing a water-soluble drug is used as an internal water phase, and a solution containing a polymer is used as an oil phase for W / O.
Type emulsion is prepared, and the emulsion is dispersed in an outer aqueous phase to form W /
A method for producing a sustained-release microcapsule of a water-soluble drug by preparing an O / W-type emulsion and then subjecting this to an in-liquid drying method, which is used after the preparation of the W / O / W-type emulsion. The method for producing microcapsules is characterized in that a water-soluble metal salt compound is added to the aqueous phase.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION To carry out the present invention, first, a W / O emulsion is prepared in which a solution containing a water-soluble drug is used as an inner aqueous phase and a solution containing a polymer is used as an outer oil phase. Is required (primary emulsification).

As the water-soluble drug used in the present invention,
It is not particularly limited as long as it is water-soluble, and examples thereof include polypeptides having physiological activity, various vitamins, hormones, antidiabetic agents, uric acid excretion enhancers, antibiotics, antitumor agents, antipyretics, analgesics, anti-inflammatory agents, Antitussive expectorant, muscle relaxant, antiepileptic agent, antiulcer agent, antidepressant, antiallergic agent, cardiotonic agent, arrhythmic agent, vasodilator, antihypertensive diuretic, antidiabetic agent, anticoagulant, hemostatic agent, Antituberculosis agents, hormonal agents, narcotic antagonists and the like can be mentioned.

Of the hormonal agents, a gonadotropin-releasing hormone (GnHR) -enhancing drug is particularly preferable as the drug used in the present invention because of its pharmacological effect. These include luteinizing hormone-releasing hormone or a derivative having an action similar to that of luteinizing hormone-releasing hormone, and leuprorelin acetate is one of its specific examples.

On the other hand, the high molecular weight polymer contained in the outer oil phase is
A substance that acts as a controlled-release substance, has biocompatibility, and can continuously release a water-soluble drug can be mentioned. In addition, it is an emulsifiable substance with a hydrophilic group and a lipophilic group,
Even in the case of a polymer or a substance having a low molecular weight, a substance capable of forming a film structure with a substance that is polymerized in the production process is desirable. Examples of these include polylactic acid, or lactic acid /
A lactic acid-glycolic acid copolymer having a glycolic acid ratio of 100/0 to 10/90, mucopolysaccharides such as hyaluronic acid or a salt thereof, chondroitin sulfate or a salt thereof, an interfacially polymerizable amino acid, and a polyamino acid such as polyaspartic acid. Is mentioned. In the present invention, one or more selected from these can be used.

In order to prepare a W / O emulsion using these water-soluble drug and polymer, the release controlling substance is dissolved in an appropriate solvent, and then the water-soluble drug is dissolved in an aqueous solvent. The solution may be added and stirred / dispersed.

The solvent for dissolving the high molecular polymer is
Depending on the release controlling substance used, for example,
Solvents such as dichloromethane, chloroform and tetrahydrofuran are used. Of these, a more preferable solvent is 0.01 to 0.01% of the release controlling substance per 1 ml of the solvent.
A solvent capable of dissolving about 10 g may be mentioned.

The aqueous solvent for dissolving the water-soluble drug is not particularly limited as long as it is an aqueous solvent, but water such as purified water, ion-exchanged water and water for injection, glycerin, polyethylene glycol, propylene glycol. Alcohols such as the above are used, and one of these may be used alone, or two or more thereof may be mixed and used. Of these, a mixed solution of water and a polyhydric alcohol is preferable, and a combination of water and polyethylene glycol is particularly preferable. The mixing ratio of water and polyhydric alcohol needs to be appropriately adjusted depending on the polyhydric alcohol used, but is preferably 0.1 to 200 parts by weight, more preferably 1 to 150 parts by weight, and more preferably 10 parts by weight to 100 parts by weight of water. -100 parts by weight is more preferable. The degree of polymerization of polyethylene glycol used in the present invention is not particularly limited, but those having an average molecular weight of less than 6,000 are preferable, and those of less than 600 are more preferable.

The stirring and dispersion of this W / O emulsion is
The degree can be adjusted according to the drug used and the release controlling substance to obtain a W / O emulsion having a desired particle size. The stirring / dispersing conditions are not particularly limited, but, for example, when a shaker is used, shaking 1,000 to
It may be carried out at 3,000 times / minute for about 10 to 30 minutes, and in the case of a high speed stirrer, 1,500 to 30,000 rpm
It may be performed for about 10 to 1,200 seconds. In the case of a gonadotropin-releasing hormone-enhancing drug, it is necessary to prepare a sufficiently fine W / O emulsion due to its mode of action, and it is preferable to stir / disperse the primary emulsion until it becomes transparent. Further, the liquid temperature at the time of primary emulsification is appropriately adjusted depending on the drug used and the release controlling substance,
5 for gonadotropin-releasing hormone enhancing drugs
-25 degreeC is preferable.

The W / O emulsion thus obtained is then added dropwise to the outer aqueous phase to prepare a W / O / W emulsion (secondary emulsification).

To obtain sustained-release microcapsules from this W / O / W emulsion, the solvent may be volatilized from the oil phase of the emulsion and solidified. Volatilization of the solvent from the oil phase can be carried out by a so-called in-liquid drying method, and an aqueous solvent may be added to the W / O / W emulsion solution to carry out stirring under an air stream, stirring under reduced pressure and the like. (Drying in liquid).

In the present invention, it is important to add the water-soluble metal salt compound to either one or both of the aqueous phases used for secondary emulsification or drying in liquid.
As the metal component in the water-soluble metal salt compound to be added, alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), transition metals (eg, iron, copper, zinc, etc.) Is mentioned. Among them, polyvalent metal salts are preferable, alkaline earth metals or transition metals are particularly preferable, and zinc is more preferable.

Examples of the anion component of the water-soluble metal salt compound include acetate anion, chloride anion and sulfate anion.

The amount of the water-soluble metal salt compound added to the aqueous phase used after the preparation of the W / O / W emulsion is such that the water-soluble pharmaceutically active ingredient to be microencapsulated, the type of the microcapsule coating and It is necessary to appropriately adjust the amount, but 0.01 to 30 W / V% is preferable, and 0.05 to 1
0 W / V% is more preferable, and 0.1 to 5 W / V% is further preferable.

When the water-soluble metal salt compound is added to the aqueous phase at the time of secondary emulsification, an emulsion stabilizer or a dispersion aid can be added alone or in combination, if necessary. Among them, as the emulsion stabilizer, a surfactant such as polysorbate, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin,
Examples thereof include gelatin, and among these, one kind or a combination of two or more kinds may be used. Examples of the dispersion aid include sugar alcohols such as D-sorbitol and mannitol, water-soluble polysaccharides, amino acids and the like, and one or more of these may be used in combination.

The amount of these emulsifiers or dispersion aids to be added to the aqueous phase at the time of secondary emulsification is not particularly limited, but is preferably about 0.01 to 5 W / V%.

The emulsification and stirring during the secondary emulsification is 1,500 to
It may be carried out at 30,000 rpm for 10 to 6,000 seconds, more preferably 3,000 to 20,000 rpm.
Then, it is 30 to 3,000 seconds.

When the water-soluble metal salt compound is added to the aqueous phase during in-liquid drying, one of polyhydric alcohols such as ethylene glycol, propylene glycol, glycerin and polyvinyl alcohol for promoting in-liquid drying or Two or more kinds can be added in combination. In addition, as the environment and operating conditions for drying in liquid, stirring under reduced pressure or under a nitrogen stream can be mentioned.

After solidification by drying in liquid, if necessary,
The microcapsules of the present invention can be obtained by washing and drying. This washing is performed by dispersing the sustained-release type microcapsules solidified by centrifugation or the like, and then dispersing this in the aqueous phase. If necessary, a sugar alcohol or sugar such as D-mannitol, which also serves as an excipient, may be added to the aqueous phase used here. Also,
The washed sustained-release microcapsules can be obtained as solid sustained-release microcapsules by drying by means such as freeze-drying.

The sustained-release type microcapsules obtained as described above contain a high molecular weight polymer as a release controlling substance in the outer layer and a water-soluble drug in the inner layer, so that the water-soluble drug is released in a sustained manner. The effect of sustained release is expected.

The sustained-release microcapsules may be nasal drops, eye drops, suppositories, if they are liquids dispersed in a liquid.
It may be an injection solution, a liquid oral administration agent, or the like. In particular, when used as an injection solution, it is preferable to use a prefilled syringe dosage form.

The dried and solidified product can be used as it is, for example, as fine granules, injectable preparations, etc., but further various preparations such as granules, capsules, tablets, and injection preparations can be used. It can be used as a raw material when manufacturing a preparation or the like. In particular, when used as an injection preparation, it is preferable that a solid preparation for injection and a solution for dissolution are stored in the same syringe in an isolated state, and a double-chamber syringe type dosage form that can be adjusted as an injection solution at the time of use .

[0032]

INDUSTRIAL APPLICABILITY The sustained-release microcapsules thus obtained have an improved drug encapsulation rate, a small initial burst, and an excellent sustained-release property, which is economically and clinically excellent. It is a capsule.

[0033]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Lactic acid / glycolic acid copolymer (3: 1 average molecular weight 15,
000 / PLGA) 870 mg to dichloromethane 1.0
A solution dissolved in ml was prepared. To this solution was added leuprorelin acetate 98.8 mg, and polyethylene glycol 102 mg with an average molecular weight of 400 was dissolved in 85 mg of water for injection, and an aqueous solution of leuprorelin acetate was added, and the mixture was stirred and mixed using a vortex mixer until it became transparent ( Shaking was performed 2,000 times / minute for 10 minutes) to obtain a W / O emulsion.

This W / O emulsion was stirred and mixed with 3 ml of a 1 W / V% aqueous polyvinyl alcohol solution (10,000 rpm; 60 seconds) to obtain a W / O / W emulsion.

Separately, 2.1 g of zinc acetate and 3.0 g of polyvinyl alcohol were dissolved in 300 ml of water for injection, W / O / W emulsion was added to this aqueous solution, and the mixture was stirred with a propeller stirrer and dried in the liquid. Yes (3 hours).

The microcapsules thus obtained were sieved with 200 mesh, and the microcapsules were separated, added with 86 mg of D-mannitol, stirred, mixed, lyophilized, and sustained-release microcapsules. Was obtained as a powder.

The yield of microcapsules with respect to the amount of PLGA charged was 78.7%, and the encapsulation rate of leuprorelin acetate in the microcapsules was 102.5%.

Example 2 Lactic acid / glycolic acid copolymer (3: 1 average molecular weight 15,
000 / PLGA) 870 mg to dichloromethane 1.0
A solution dissolved in ml was prepared. To this solution was added leuprorelin acetate 98.8 mg, and polyethylene glycol 102 mg with an average molecular weight of 400 was dissolved in 85 mg of water for injection, and an aqueous solution of leuprorelin acetate was added, and the mixture was stirred and mixed using a vortex mixer until it became transparent ( Shaking was performed 2,000 times / minute, 10 minutes) to obtain a W / O emulsion.

Separately, 0.9 g of zinc acetate and 3.0 g of polyvinyl alcohol were dissolved in 300 ml of water for injection to prepare an aqueous solution containing zinc acetate. 3 ml of this zinc acetate-containing aqueous solution and a W / O emulsion are stirred and mixed together (10,000 rpm; 60 seconds), and W / O / W
An emulsion was obtained.

A W / O / W emulsion was added to the remaining aqueous zinc acetate solution, and the mixture was stirred with a propeller stirrer and dried in the liquid (3 hours).

The thus-obtained microcapsules were sieved with 200 mesh, and the microcapsules were separated, added with 86 mg of D-mannitol, stirred, mixed, lyophilized, and sustained-release microcapsules. Was obtained as a powder.

The yield of microcapsules with respect to the amount of PLGA charged was 70.7%, and the encapsulation rate of leuprorelin acetate in the microcapsules was 99.7%.

Comparative Example Lactic acid / glycolic acid copolymer (3: 1 average molecular weight 15,
000 / PLGA) 870 mg to dichloromethane 1.0
A solution dissolved in ml was prepared. To this solution, 98.8 mg of leuprorelin acetate and 102 mg of polyethylene glycol having an average molecular weight of 400 were dissolved in 85 mg of water for injection, and an aqueous solution of leuprorelin acetate was added, and the mixture was stirred and mixed using a vortex mixer until it became transparent (shaking. (2,000 times / minute, 10 minutes) to obtain a W / O emulsion.

Apart from this, polyvinyl alcohol 3.
0 g was dissolved in 300 ml of water for injection to prepare an aqueous solution containing polyvinyl alcohol. 3 ml of this polyvinyl alcohol-containing aqueous solution and a W / O emulsion were stirred and mixed together (10,000 rpm; 60 seconds), and W / O was added.
A / W emulsion was obtained.

The remaining polyvinyl alcohol aqueous solution contains W /
An O / W emulsion was added, and the mixture was stirred with a propeller stirrer and dried in the liquid (3 hours).

The microcapsules thus obtained were sieved through 200 mesh, the microcapsules were separated, 86 mg of D-mannitol was added, and the mixture was stirred, mixed and freeze-dried. Got as.

The yield of microcapsules was 58.6% based on the amount of PLGA charged, and the encapsulation rate of leuprorelin acetate in the microcapsules was 58.2%.

Test Example Leuprorelin acetate microcapsules obtained in Example 2 (as 3.75 m of leuprorelin acetate)
g) and a commercially available leuprorelin acetate microcapsule injection preparation (3.75 mg of leuprin) were suspended in 1 ml of a suspension for the following composition, and 0.9 mg of leuprorelin acetate was subcutaneously administered to 10 rats. Then 2
Changes in serum concentration for 8 days (blood sampling points: 3 hours, 6 hours, 1, 2, 3, 7, 14, 21, 28 days after administration)
Was measured.

Suspension liquid in 1 ml D-mannitol 50mg Carmellose sodium 5mg Polysorbate 80 1mg Water for injection

As a result of measurement of serum concentration in rat, Example 2
The formulation has an average serum concentration of 4.35 ng / 3 hours after administration.
The average serum concentration of the commercial preparation 3 hours after administration was 9.13 ng / ml. The mean serum concentrations on day 21 and day 28 of administration were 0.86 ng / ml and 0.49 ng / ml for the preparation of Example 2, respectively,
0.10 ng / ml and 0.24 n for commercial formulations
It was g / ml.

Therefore, the microcapsules of the present invention had a suppressed initial burst and were superior in sustainability to the commercial products.

Example 3 3.75 mg amount of leuprorelin acetate microcapsules obtained in Example 2 as leuprorelin acetate and 1 ml of the suspension for the test example were added to a double syringe equipped with a midist topper. Each of the chamber syringes was filled in an isolated state to obtain a prefilled syringe type pharmaceutical preparation.

Practical Example 4 Pyridoxine hydrochloride microcapsules were obtained in the same manner as in Example 1 except that leuprorelin acetate was replaced with pyridoxine hydrochloride. The yield of the microcapsules and the encapsulation rate of the active ingredient in the microcapsules were the same as in Example 1. that's all

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Keisuke Takeyama             3-26-5 Shimonuma Town, Ichinomiya City, Aichi Prefecture F term (reference) 4C076 AA67 BB11 CC24 CC30 EE24H                       FF32 GG30                 4C084 AA03 BA44 DB09 MA38 MA66                       NA12 ZC032 ZC242                 4G005 AA01 AB15 AB25 BA12 BB01                       DB22X DD27Y EA03

Claims (11)

[Claims] 1. A W / O type emulsion is prepared using a solution containing a water-soluble drug as an inner aqueous phase and a solution containing a high molecular weight polymer as an oil phase, and the W / O type emulsion is dispersed in an outer aqueous phase to prepare W / O emulsion. After preparing an O / W type emulsion and subjecting this to an in-liquid drying method to produce sustained-release microcapsules of a water-soluble drug,
A method for producing microcapsules, which comprises adding a water-soluble metal salt compound to an aqueous phase used after the preparation of the O / W emulsion. 2. The aqueous phase to which the water-soluble metal salt compound is added,
The method for producing microcapsules according to claim 1, wherein the microcapsule is an external water phase when a W / O / W emulsion is prepared. 3. The aqueous phase to which the water-soluble metal salt compound is added,
The method for producing microcapsules according to claim 1, wherein the microcapsules are in an aqueous phase when dried in liquid. 4. The water-soluble drug is a gonadotrophin-releasing hormone (GnHR) -enhancing drug.
The method for producing a microcapsule according to any one of 1. 5. The method for producing microcapsules according to claim 4, wherein the water-soluble drug is luteinizing hormone-releasing hormone or a derivative having an action similar to that of luteinizing hormone-releasing hormone. 6. The water-soluble metal salt compound is an alkaline earth metal or transition metal salt compound.
The method for producing a microcapsule according to any one of 1. 7. The method of producing a microcapsule according to claim 1, wherein the water-soluble metal salt compound is a zinc salt compound. 8. The method for producing microcapsules according to claim 1, wherein the high molecular weight polymer is polylactic acid or a copolymer of lactic acid and glycolic acid. 9. A W / O type emulsion is prepared by using a solution containing a water-soluble drug as an inner aqueous phase and a solution containing a high molecular weight polymer as an oil phase, and the emulsion is prepared by containing a water-soluble metal salt compound. A sustained-release microcapsule of a water-soluble drug obtained by dispersing in a water phase to prepare a W / O / W type emulsion and then subjecting this to an in-liquid drying method. 10. A W / O emulsion is prepared by using a solution containing a water-soluble drug as an inner aqueous phase and a solution containing a polymer as an oil phase, and the W / O type emulsion is dispersed in an outer aqueous phase to prepare a W / O emulsion. A sustained-release microcapsule of a water-soluble drug obtained by preparing an O / W emulsion and then subjecting this to an in-liquid drying method using an aqueous phase containing a water-soluble metal salt compound. 11. A pharmaceutical product containing sustained-release microcapsules of the water-soluble drug according to claim 9.