JP2001199879A - Medicine-releasing preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an endodwelling preparation with a novel constitution that can control the release rate of the active ingredients. SOLUTION: The objective endodwelling preparation comprises the particles including at least the combinations given in the following (a), (b) and (c) in the carriers made of hydrophobic macromolecule: (a) the particles including the active ingredients, the particles including a carbonate salt, and the particles including the substance evolving carbon dioxide by reaction with the carbonate salt in an aqueous solution; (b) the particles including the active ingredients and carbonate salt, and the substance evolving carbon dioxide by the reaction with the carbonate salt in the aqueous solution and (c) the particles including carbonate salt, the substance evolving carbon dioxide by the reaction with the carbonate salt in the aqueous solution and the active ingredients.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a sustained-release preparation for maintaining the efficacy of drugs and veterinary drugs.

[0002]

2. Description of the Related Art Research has been conducted on sustained release of active ingredients, reduction of side effects, and reduction in the number of administrations by using a hydrophobic polymer as a pharmaceutical carrier to sustainably release an active ingredient. Controlling the release rate of the active ingredient is one of the important issues in these studies, and attempts have been made to devise the form and structure of the formulation and to use additives (US 3,279,996, Contraception, 27
(5), 483-495, 1983, Published Patent Gazette No. 45694, No. 45694,
Published Patent Publication No. 174007, 1987, WO95 / 1788
No. 1).

[0003] In particular, in the case of an implantable body in which an active ingredient that is hardly soluble in water is dispersed in a hydrophobic polymer,
Due to low solubility in surrounding body fluids, the amount released per unit time is small, and sufficient drug efficacy may not be exhibited. In the case of a formulation in which the release rate was extremely reduced by dispersing it in a polymer, mineral oil, glycerol,
A method of controlling the release rate by using an alcohol or the like as an additive has been reported (Proceed. Inter.
n. Symp. Control. Rel. Bioact. Mater., 14, 223-224
(1987), Proceed. Intern. Symp. Control. Rel. Bioac
t. Mater., 12, 145-146 (1985), published patent publication No. 100315, 1980). These methods use poorly soluble substances in mineral oil,
By dispersing in a hydrophobic polymer together with an amphipathic solvent such as glycerol and alcohol or an organic solvent, the solubility of a poorly soluble substance is increased, and the amount of release is increased. However, in the preparations according to such conventional techniques, the effects are various depending on the combination of the hardly soluble substance, the additive and the hydrophobic polymer, and the applicable range is limited.

[0004] On the other hand, it has not been known whether an active ingredient which does not dissolve in an organic solvent or water, such as a live vaccine or an inactivated vaccine, can be released from a hydrophobic polymer.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide an in-vivo implant having a novel structure capable of controlling the release rate of an active ingredient.

[0006]

Means for Solving the Problems The present inventors consider that there is a limit in the applicable range in the conventional release enhancement by increasing the solubility, and physically generate a force to push out the active ingredient from the inside of the preparation. As a result of diligent research, we have completed a completely new release control technology applicable to the case of sustained release of active ingredients from hydrophobic polymers. That is, this is a method in which particles containing a carbonate and a substance containing a substance that reacts with the carbonate in an aqueous solution to generate carbon dioxide are contained in a hydrophobic polymer together with an active ingredient. The present technology is applicable regardless of the type of active ingredient, but is particularly useful for hardly soluble or insoluble substances. The present invention relates to the following formulations. [1] An implantable preparation in which at least particles of the following combination (a), (b) or (c) are dispersed in a carrier made of a hydrophobic polymer; (a) containing an active ingredient Particles, particles containing carbonate, particles containing a substance that reacts with the carbonate in an aqueous solution to generate carbon dioxide, (b) particles containing an active ingredient and a carbonate, and the carbonate and an aqueous solution Particles containing a substance that reacts in and generates carbon dioxide,
(C) Particles containing a carbonate, and particles containing a substance capable of reacting with the carbonate in an aqueous solution to generate carbon dioxide and an active ingredient. [2] The preparation according to [1], wherein the active ingredient is a poorly soluble substance or an insoluble substance. [3] The preparation of [2], wherein the insoluble substance is a live vaccine or an inactivated vaccine. [4] The preparation according to any one of [1] to [3], wherein the hydrophobic polymer is a non-degradable polymer in vivo. [5] The preparation according to [4], wherein the hydrophobic polymer is silicone.

In the preparation of the present invention, after administration into a living body, at least one of particles containing a carbonate and a substance containing a substance capable of generating carbon dioxide by reacting with the carbonate in an aqueous solution by infiltration of body fluid. By dissolving and reacting, carbon dioxide gas is generated inside the preparation. The pressure at which the gas escapes outside the formulation facilitates the release of the active ingredient present in the formulation. Therefore, in the present invention, since the release rate can be promoted irrespective of the solubility of the active ingredient in body fluid, the present invention can be applied to insoluble substances.

More specifically, (1) a substance capable of reacting with a carbonate-containing particle in a preparation and the carbonate in an aqueous solution to generate carbon dioxide when the preparation is administered into a living body and a body fluid is infiltrated. At least one of the particles containing is dissolved in the body fluid,
Both react to produce carbon dioxide gas, and
(2) by the pressure of carbon dioxide gas, the active ingredient dispersed in the formulation is pushed out of the formulation, characterized in that,
This facilitates the release of the active ingredient. In addition, the formation of minute cracks in the preparation carrier by the pressure of the gas accelerates the rate of infiltration of water into the preparation, thereby promoting the release of the active ingredient. Therefore, it is particularly useful for promoting the release of a hardly soluble substance or an insoluble substance having a slow release rate. In the present invention, the amount and rate of generation of gas are changed by selecting a combination and content of a carbonate and a substance that reacts with the carbonate in an aqueous solution to generate carbon dioxide, thereby extruding the active ingredient out of the preparation. Because the pressure and crack formation can be adjusted, the rate of release of the active ingredient can be controlled.

[0009] As will be described later, a typical substance used in combination with a carbonate to react with the carbonate in an aqueous solution to generate carbon dioxide is an acid. Abbreviated as "substance such as acid".

Therefore, the active ingredient in the preparation of the present invention,
Substances such as carbonates and acids may be present in the carrier consisting of the hydrophobic polymer in any of the following combinations (a), (b) or (c): (a) Effective Particles containing a component, particles containing a carbonate, and particles containing a substance such as an acid, (b) particles containing a substance such as an active ingredient and a carbonate, and particles containing a substance such as an acid, and (c) carbonic acid. Particles containing salts, and particles containing substances such as acids and active ingredients. Usually, carbonates are alkaline, and substances such as acids are acidic.
These combinations can be selected in consideration of pH stability.

Particles containing an active ingredient, particles containing a carbonate, particles containing a substance such as an acid, particles containing an active ingredient and a carbonate, and particles containing a substance such as an acid and an active ingredient (general name) Hereinafter, if necessary, abbreviated as "particles containing an active ingredient, etc.")
It may consist solely of substances such as carbonates and acids, active ingredients and carbonates, and substances such as acids and active ingredients, or may contain one or more physiologically acceptable excipients, stabilizing agents It may contain additives such as agents, solubilizers, preservatives, and soothing agents.

The particles containing the respective active ingredients are not particularly limited as long as they can be formed into a solid powder.
In addition, any solid particles in the preparation at the body temperature of the animal (preferably mammal) or human to be administered may be used,
Specific examples include those which are solid particles at a temperature at least about 1 ° C. higher than the normal body temperature of animals or humans. However, when the disease to be treated particularly involves high fever, the temperature is higher than the normal body temperature. And must be solid particles.

Illustrative examples of a temperature at least about 1 ° C. higher than the normal body temperature of animals or humans are 38 ° C. for preparations administered to humans and 43 ° C. for preparations used for diseases involving high fever. ℃ is an animal (eg dog, cat, pig,
40 ° C. for preparations to be administered to cattle and the like, and 45 ° C. for preparations used for diseases accompanied by high fever. The body temperature of animals is described in, for example, Clinical Veterinary Internal Medicine Diagnostics (Ryoichi Nakamura, Yokendo, 3rd revised edition, revised 2nd edition, 1982). The minimum temperature to be determined can be determined. Considering the above body temperature, the particles containing the active ingredient etc. are at 50 ° C.
It can be seen that solid particles are often applicable to animals or humans.

The hydrophobic polymer is not particularly limited as long as it is biocompatible, and one of them may be used alone or in combination of two or more. Hydrophobic polymers are roughly classified into those that are non-degradable in vivo and those that are degradable in vivo. Examples are shown below, but the invention is not limited thereto. Examples of the in vivo non-degradable hydrophobic polymer include silicone, ethylene vinyl acetate copolymer, polyethylene, polypropylene, polytetrafluoroethylene, polyurethane, polyacrylate, polymethacrylate, and the like. Preferably silicone, more preferably SILASTIC®
Medical grade ETR elastomer Q7-47
50 or Dow Corning® MDX
-4-4210 Medical grade elastomer or the like is used. Examples of the biodegradable hydrophobic polymer include polyesters such as polylactic acid-co-glycolic acid (PLPG) and polylactic acid, polyamino acids, and polyanhydrides.

The carbonate is not particularly limited as long as it is physiologically acceptable and generates carbon dioxide by reacting with a substance such as an acid in an aqueous solution. Those that generate carbon dioxide can be mentioned. Specific examples include, but are not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate, lithium carbonate and the like. Preferably, sodium carbonate and sodium hydrogen carbonate are used. Also, only one of them alone,
Alternatively, two or more kinds may be used in combination.

The substance (a substance such as an acid) which reacts with the carbonate in an aqueous solution to generate carbon dioxide is particularly physiologically acceptable and can react with the carbonate to generate carbon dioxide. Not limited. Specific examples include acids,
More specifically, organic acids such as citric acid, tartaric acid, malic acid, gluconic acid, fumaric acid, itaconic acid, phthalic acid, lactic acid, and ascorbic acid; and inorganic acids such as sodium dihydrogen phosphate and potassium dihydrogen phosphate. Examples include, but are not limited to, salts and inorganic acids such as boric acid. Preferably citric acid and tartaric acid are used. Further, only one of them may be used alone, or two or more thereof may be used in combination.

It is necessary that at least one of the substances such as carbonate and acid is water-soluble.

The active ingredient is not particularly limited as long as it is physiologically acceptable. Preferably, a sparingly soluble substance or an insoluble substance is used. One of the hardly soluble or insoluble substances may be used alone, or two or more of them may be used as a mixture. Also, a combination of a sparingly soluble substance and a water-soluble substance, an insoluble substance and a water-soluble substance, or a combination of a sparingly soluble, insoluble, and a water-soluble substance may be used.

The term "poorly soluble" as used herein means that the solubility in water is low. Specifically, for example, the solubility in water as expressed in the 13th revised Japanese Pharmacopoeia (1996) is almost zero. Does not dissolve (the amount of solvent required to dissolve 1 g or 1 mL of solute is 10,000 mL or more), or is extremely insoluble (the amount of solvent required to dissolve 1 g or 1 mL of solute is 1,000 mL or more and less than 10,000 mL), or is hardly soluble ( (The amount of solvent required to dissolve 1 g or 1 mL of the solute is 100 mL or more and less than 1,000 mL).

Examples of poorly soluble substances include avermectin,
Antibiotics such as ivermectin and spiramycin; antibacterials such as amoxicillin, erythromycin, oxytetracycline and lincomycin; anti-inflammatory agents such as dexamethasone and phenylbutazone; hormones such as levothyroxine; dexamethasone palmitate, triamcinolone acetonide and acetic acid corticosteroids such as halopredone, indomethacin, nonsteroidal anti-inflammatory drugs such as aspirin, artery occlusion therapeutic agents, such as prostaglandin E _1, anticancer, such as actinomycin and daunomycin, antidiabetic agents such as acetohexamide, such as estradiol Bone disease drugs and the like. It may be substances such as assisting or inducing substance or bioactive showing a bioactive not only those with more direct therapeutic effect, and for example, vitamin D _3, in a vaccine typified by hydrophobic muramyl dipeptide Adjuvants and the like.

The term "water-soluble" refers to, for example, that the solubility in water as expressed in the 13th Revised Japanese Pharmacopoeia (1996) is slightly soluble (the amount of solvent required to dissolve 1 g or 1 mL of a solute is 30 mL or more). Less than 100 mL),
Alternatively, it is slightly soluble (the amount of solvent required to dissolve solute 1 g or 1 mL is 10 mL or more and less than 30 mL), or easily soluble (the amount of solvent required to dissolve 1 g of solute or 1 mL is 1 mL or more and less than 10 mL), or extremely soluble (1 g of solute). Or the amount of solvent required to dissolve 1 mL is less than 1 mL).

Examples of water-soluble substances include cytokines such as interferon and interleukin, hematopoietic factors such as colony stimulating factor and erythropoietin, growth hormone, growth hormone releasing factor, calcitonin, luteinizing hormone, luteinizing hormone releasing hormone, Hormones such as insulin, somatomedin, nerve growth factor,
Growth factors such as neurotrophic factor, fibroblast growth factor, hepatocyte growth factor, cell adhesion factor, immunosuppressant, asparaginase, superoxide dismutase, tissue plasminogen activator, urokinase, prourokinase and other enzymes Blood coagulation factors such as blood coagulation factor 8, blood metabolism-related proteins such as BMP (Bone Morphogenetic Protein), antigens that can be used as vaccines for humans and / or animals, adjuvants, cancer antigens, nucleic acids, Antibodies, adriamycin, bleomycin, mitomycin, fluorouracil, peplomycin sulfate, daunorubicin hydrochloride, hydroxyurea, neocarzinostatin, schizophyllan, estramustine phosphate sodium salt, carboplatin, fosfomycin,
Examples include anticancer agents such as ceftiofur sodium salt and ceftiofur hydrochloride, antibiotics, anti-inflammatory agents, alkylating agents and the like. The term “interferon” here means
Any of interferons such as α, β, γ, and the like, or a combination thereof may be used. Similarly, the interleukin may be any of IL-1, IL-2, IL-3 and others, and the colony stimulating factors are muluti-CSF (pluripotent CSF), GM-CSF (granulocyte-monocyte macrophage CSF), G -CSF (granulocyte CSF), M-CSF
(Monocyte macrophage CSF) Others may be used.

The term "insoluble" means a property that is insoluble in water.

Examples of the insoluble substance include vaccines (live vaccine and inactivated vaccine) containing viruses and bacteria. Further, it may be not only a substance having a direct therapeutic effect but also a substance showing a biological activity or a substance which assists or induces a biological activity, and examples thereof include an adjuvant in a vaccine typified by aluminum hydroxide.

Further, additives such as a physiologically acceptable stabilizer, solubilizer, preservative, and soothing agent may be added to the preparation. Further, an additive for controlling release may be added. These additives can be contained in a carrier or the like regardless of whether the additive is contained in the particles containing the active ingredient or the like or not.

As a method for producing particles containing an active ingredient and a carbonate, for example, a homogeneous solution containing the active ingredient and a carbonate (optionally, an additive) is formed, followed by drying to obtain a solid. Perform crushing and sieving. The drying here may be any method as long as it is a commonly used method, but typical examples include drying by airflow using nitrogen, helium, and air, drying under reduced pressure, freeze drying, natural drying, granulation, and spraying with a spray drier. Drying and the like and combinations thereof are mentioned. Particles containing a substance such as an active ingredient and an acid can be prepared in the same manner. The same method can be used when particles containing an active ingredient, particles containing a carbonate, and particles containing a substance such as an acid are prepared as separate particles.

The release rate of the active ingredient of the preparation of the present invention can be controlled by the following factors. That is, 1) physicochemical properties of substances such as carbonates and acids, 2) quantitative ratio of substances such as carbonates and acids, 3) in the preparation of particles containing active ingredients and other additives. The total content, 4) the size of particles containing the active ingredient and the like and the particles of other additives. Substances such as carbonates and acids generate strong carbon dioxide gas in a short time as they are strongly basic and strongly acidic, respectively. Regarding the quantitative ratio of the substance such as carbonate and acid, carbon dioxide gas can be generated most efficiently when the equivalents of the substance such as base and acid are equal. The total amount of particles and additives containing the active ingredient and the like in the preparation is not particularly limited as long as it can be substantially dispersed and molded in the carrier, and varies depending on the hydrophobic polymer material used. 70% by weight or less, preferably 50% by weight or less, more preferably 3% by weight or less, based on the total amount of the particles and additives containing
It can be contained at 0% by weight or less. Note that the content of the active ingredient can naturally vary depending on the type, the disease to be treated, and the degree thereof. Furthermore, the particle diameter of the particles containing the active ingredient and the like is not particularly limited as long as these particles can be substantially dispersed and molded in the carrier, and varies depending on the hydrophobic polymer material used. 1,
700 μm or less, preferably 500 μm or less, more preferably 300 μm or less. When the active ingredient is an insoluble substance, it depends on the particle size of the particles containing the active ingredient, etc., although it depends on the physicochemical properties of the hydrophobic polymer used.
The particle size of the insoluble substance itself is 50 μm or less, preferably 20 μm or less, more preferably 1 μm or less.

The shape of the preparation of the present invention may be any as long as it can be safely administered to a living body, and specific examples include a column, a prism, an elliptic column, a flat plate, and a sphere. When administration by an injection needle is considered, a columnar shape is preferable. In the case of a columnar or flat plate, the side surface of the preparation may be covered with an outer layer composed of only a hydrophobic polymer. In that case, the inner layer may be a single layer or a plurality of layers. When it has a plurality of inner layers, it may have a single-centered form that draws concentric circles, or may have a multi-centered form in which several inner layers are scattered in a cross section. Also,
In the case of a preparation having a plurality of inner layers, each inner layer may contain the same active ingredient or different active ingredients. Specific examples include the form described in Published Patent Application No. 1995-187994.

To prepare the preparation of the present invention, (a) particles containing an active ingredient, particles containing a carbonate, and particles containing a substance such as an acid, and (b) particles containing an active ingredient and a carbonate. Particles, as well as particles containing substances such as acids,
Or (c) mixing powder containing any combination of particles containing carbonate, and particles containing a substance such as an acid and an active ingredient with a hydrophobic polymer before curing, and extruding using a nozzle. And a method of molding a mold. Examples of the curing method include a method using a polymerization reaction such as silicone, a method of dissolving in an organic solvent such as an ethylene vinyl acetic acid copolymer and drying. When forming the outer layer, the inner layer and the outer layer may be formed separately, or the inner layer and the outer layer may be formed simultaneously. For example, in the case of manufacturing a single-centered dosage form having a columnar shape, a rod-shaped inner layer is prepared and then coated with a solution in which an outer layer material is dissolved and dried, or a tube made of an outer layer material. A method of inserting an inner layer component separately prepared, a method of forming an inner layer in a tube made of an outer layer material, a method of simultaneously extruding an inner layer and an outer layer using a nozzle, and the like, but are not limited thereto. is not.

[0030]

The present invention will now be described in detail with reference to examples and test examples, but the scope of the present invention is not limited to these examples.

Example 1 Fluorescently labeled latex beads (Polyscience, 1 μm in diameter), which is a model of an insoluble drug, were washed with water, and 0.22 μm in diameter.
And dried under reduced pressure. Citric acid 10
3.63 g of a 0 mg / ml aqueous solution and 60 mg of fluorescent-labeled latex beads were mixed and freeze-dried. Freeze-dried cake opening 300μm
To prepare Powder 1. On the other hand, powder 2 was prepared by passing sodium bicarbonate powder through a sieve having openings of 300 μm. Silastic (registered trademark) Medical grade ETR elastomer Q7-4750 A component 0.70 g and B component 0.70 g
g. After mixing, 282.25m of powder 1 immediately
g, 317.75 mg of powder 2 were kneaded. The kneaded product was filled in a syringe. It was extruded under pressure from a nozzle having a diameter of 1.6 mm, and was allowed to stand at 37 ° C. for 1 day to cure. Cut this into a columnar preparation 1 (preparation length 10 mm, preparation diameter 1.7 m
m).

Example 2 Fluorescent labeled latex beads (Polyscience, diameter 20
μm) was washed with water, filtered through a 0.22 μm filter, and dried under reduced pressure. 3.63 g of a 100 mg / ml aqueous solution of citric acid and 60 mg of fluorescent-labeled latex beads were mixed and freeze-dried. The freeze-dried cake was passed through a sieve having an opening of 300 μm to prepare Powder 3. Silastic (registered trademark) Medical Grade ETR Elastomer Q7-4750 A component 0.70 g and B component 0.
70 g were mixed. Immediately after mixing, 282.25 m of powder 3 above
g, 317.75 mg of powder 2 of Example 1 were kneaded. The kneaded product was filled in a syringe. It was extruded under pressure from a nozzle having a diameter of 1.6 mm, and was allowed to stand at 37 ° C. for 1 day to cure. This was cut to obtain a columnar preparation 2 (preparation length 10 mm, preparation diameter 1.7 mm).

Example 3 In the same manner as in Example 1, a kneaded product of silastic containing fluorescent labeled latex beads was prepared and filled in a syringe. Separately, 50 g of Silastic (registered trademark) Medical Grade ETR elastomer Q7-4750A component and 50 g of the same B component were mixed and filled into another syringe. The concentrically arranged 1.6 mm diameter and 1.9 mm diameter nozzles are extruded with the fluorescent-labeled latex bead-containing silastic stick inside and only the silastic stick outside, and are allowed to stand at 37 ° C for 1 day. And cured. Cut this into a columnar preparation 3 (preparation length 10 mm, preparation diameter 2 m
m, inner layer diameter 1.6 mm).

Reference Example 1 Silastic (registered trademark) Medical Grade ET
0.98 g of the R elastomer Q7-4750A component and 0.98 g of the B component were mixed. After mixing, 40 mg of fluorescent-labeled latex beads (Polyscience, 1 μm in diameter) were promptly kneaded. The kneaded product was filled in a syringe. It was extruded under pressure from a nozzle having a diameter of 1.6 mm, and was allowed to stand at 37 ° C. for 1 day to cure. This is cut into a columnar reference preparation 1 (preparation length 10
mm, 1.7 mm diameter of the formulation).

Reference Example 2 Fluorescently labeled latex beads (Polyscience, 1 μm in diameter)
m) was washed with water, filtered through a 0.22 μm filter and dried under reduced pressure. 8.4 g of an aqueous solution of glycine 100 mg / ml and 60 mg of fluorescent labeled latex beads were mixed and freeze-dried. The freeze-dried cake was passed through a sieve having a mesh size of 300 μm to produce Powder 4. Silastic (registered trademark) Medical grade ETR elastomer Q7-4750 A component 0.70 g and B component 0.70 g
g. After mixing, 600 mg of the above powder 4 was kneaded immediately. The kneaded product was filled in a syringe. 1.6mm diameter
And then extruded under pressure from the nozzle and allowed to stand at 37 ° C. for 1 day to cure. This was cut to obtain a columnar reference preparation 2 (preparation length 10 mm, preparation diameter 1.7 mm).

Test Example 1 Preparations 1 and 2 prepared in Examples 1 and 2, Reference Example 1
0.1% each of reference preparations 1 and 2 prepared in
Polyoxyethylene polyoxypropylene copolymer (trade name: Adeka Pluronic, Asahi Denka Kogyo Co., Ltd.),
Phosphate buffer containing 0.01% sodium azide (pH 7.
4) Put into 2 ml, shake slowly at 37 ° C., measure the amount of latex beads released using a fluorescence intensity measuring device (excitation wavelength 485 nm, measurement wavelength 538 nm) to determine the cumulative release rate. Table 1 shows the results. As is evident from Table 1, Reference Formulations 1 and 2 showed no release of latex beads, which was a model of insoluble substance, whereas Formulation 1 did not.
And 2 promoted the release of latex beads, demonstrating the effect of the present invention.

[0037]

[Table 1] Table 1 ━━━━━━━━━━━━━━━━━━━ Formulation Amount released in 15 days (μg / ml) ────────────── ───── Formulation 1 32.4 ± 0.8 Formulation 2 36.7 ± 3.2 Reference formulation 1 0.0 ± 0.0 Reference formulation 2 0.1 ± 0.0 ━━━━━━━━━━━━━━━━━━━

Example 4 110 mg of ivermectin obtained by crushing and sieving with a sieve having a mesh size of 212 μm, 275 mg of sodium hydrogen carbonate
mg and 275 mg of citric acid were mixed vigorously. A portion (600 mg) of the obtained mixed powder and SILASTIC (registered trademark) Medical Grade E
TR Elastomer Q7-4750 700 mg A component and SILASTIC® Medical Grade ETR Elastomer Q7-4750
700 mg of the B component was mixed to obtain an inner layer component. On the other hand, SILASTIC (registered trademark) medical grade ETR elastomer Q7-4750 A component 5
0g and SILASTIC® Medical Grade ETR Elastomer Q7-475
50 g of 0B component was mixed to obtain an outer layer component. The thus obtained inner layer component and outer layer component are extruded by a double extruder (inner diameter of the outer nozzle of 1.9 mm, inner diameter of the inner nozzle of 1.6 mm) capable of extruding the inner layer so that the inner layer is concentrically covered with the outer layer. And allowed to stand at 37 ° C. to cure. This was cut to obtain a columnar preparation 4 (preparation length 5 mm, preparation diameter 1.9 mm, inner layer diameter 1.5 mm).

Reference Example 3 Powders of 150 mg of ivermectin and 750 mg of sucrose obtained by crushing and sieving with a sieve having an opening of 212 μm were mixed vigorously. Part 60 of the obtained mixed powder
0mg and SILASTIC (registered trademark) Medical Grade ETR Elastomer Q7-475
0 A component 700mg and SILASTIC
C, (registered trademark) Medical Grade ETR Elastomer Q7-4750 700 mg of the B component was mixed to obtain an inner layer component. On the other hand, SILASTIC (registered trademark) medical grade ETR elastomer Q7
-4750 A component 50g and silastic (SI
LASTIC (registered trademark) Medical Grade ETR Elastomer Q7-4750 B component (50 g) was mixed to prepare an outer layer component. The thus obtained inner layer component and outer layer component are extruded by a double extruder (inner diameter of the outer nozzle 1.9 mm, inner diameter of the inner nozzle 1.6 mm) capable of extruding the inner layer so that the inner layer is concentrically covered with the outer layer. The mixture was allowed to stand at room temperature and cured. This was cut to obtain a columnar reference preparation 3 (preparation length 5 mm, preparation diameter 2.0 mm, inner layer diameter 1.5 mm).

Test Example 2 Preparation 4 prepared in Example 4 and Reference Preparation 3 prepared in Reference Example 3 were subcutaneously administered to mice, respectively. The test preparation was euthanized under ether anesthesia on the measurement day, and the administered preparation was recovered, eluted with methanol, and quantified by high performance liquid chromatography to determine the ivermectin residual ratio in the preparation after subcutaneous administration to mice. The release rate was determined from the residual rate, and the results are shown in FIG. As is clear from FIG. 1, the ratio of ivermectin remaining in the preparation is sharply reduced in the preparation 4 as compared to the case of the reference preparation 3, and the release of ivermectin from the preparation 4 is promoted as compared with the reference preparation 3. You can see that. This shows the effect of the present invention.

[0041]

According to the present invention, the release rate of the active ingredient can be controlled by physically generating a force for pushing out the active ingredient from the inside of the preparation. The formulation of the present invention can be applied regardless of the type of the active ingredient, but is particularly useful for hardly soluble substances and insoluble substances.

[0042]

[Brief description of the drawings]

FIG. 1 is a graph showing the reduction of the ivermectin residual ratio in a preparation in Test Example 2 when the preparation 4 prepared in Example 4 and the reference preparation 3 prepared in Reference Example 3 were each administered subcutaneously to mice. .

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) A61K 47/34 A61K 47/34 (72) Inventor Hiroo Maeda 1-3-45 Kuragakiuchi, Ibaraki City, Osaka Sumitomo Pharmaceutical Co., Ltd. F term (reference) 4C076 AA41 BB32 CC31 DD25 DD43 EE27A FF02 FF04 FF05 FF31 GG14 4C084 AA17 MA35 MA67 NA12 4C085 AA03 FF13 GG05

Claims (5)

[Claims] 1. A bioimplant preparation comprising at least particles of the following combination (a), (b) or (c) dispersed in a carrier comprising a hydrophobic polymer: (a) an active ingredient Containing particles, particles containing a carbonate, particles containing a substance that reacts with the carbonate in an aqueous solution to generate carbon dioxide, (b) particles containing an active ingredient and a carbonate, and the carbonate Particles containing a substance that reacts with an aqueous solution to generate carbon dioxide,
(C) Particles containing a carbonate, and particles containing a substance capable of reacting with the carbonate in an aqueous solution to generate carbon dioxide and an active ingredient. 2. The preparation according to claim 1, wherein the active ingredient is a poorly soluble substance or an insoluble substance. 3. The preparation according to claim 2, wherein the insoluble substance is a live vaccine or an inactivated vaccine. 4. The preparation according to claim 1, wherein the hydrophobic polymer is a non-degradable polymer in vivo. 5. The preparation according to claim 4, wherein the hydrophobic polymer is silicone.