JP2007291036A - Method for producing microsphere preparation and microsphere preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a microsphere preparation exhibiting nearly constant sustained releasing performance and a method for producing the microsphere preparation. <P>SOLUTION: The method for producing a microsphere preparation having a structure containing a drug in a capsule skin made of a polymer and exhibiting nearly constant sustained release performance comprises the dissolution of the polymer constituting the capsule skin in a solvent, the dispersion of the drug in the solvent, the addition of a nonsolvent of the polymer to the dispersion to obtain a first solution, the addition of the first solution to a second solution containing an oily liquid immiscible with the first solution, the emulsification of the mixture to obtain an emulsion liquid composed of a disperse phase containing an inner layer containing the solvent and the nonsolvent in the outer layer composed of the polymer in the first solution and a continuous phase composed of the second solution, the slow heating of the emulsion liquid to evaporate the solvent in the inner layer while controlling the evaporation rate of the solvent and the separation of the disperse phase from the emulsion liquid. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for producing a microsphere preparation and a microsphere preparation.

  When a drug is to be administered over a long period of time, a microsphere formulation that is a capsule body having a core-shell structure (core-shell structure) in which a core drug is wrapped inside a capsule film that forms a shell is used. Attempts have been focused on controlling the property of the drug being gradually released from the inside of the capsule body to the outside of the capsule film after the administration, that is, the sustained release, so that the drug efficacy can be maintained for a long time.

  As a method for producing such a microsphere preparation, a solution in which the film constituent material constituting the capsule film is dissolved and the core material is dispersed is dispersed in an aqueous or oily medium immiscible with the solution, A method of forming an emulsion having a solution as a dispersed phase, and further evaporating a solvent of a film constituent material in the dispersed phase to form a capsule film and forming a capsule body in which a core substance is taken into the capsule film ( Various methods such as in-liquid drying method have been proposed.

  In addition, as a method for producing a microsphere preparation, not only a method for producing a safe microsphere preparation is required, but also the elapsed time after administration of the drug is not affected, so that a valuable and expensive drug can be used efficiently. Therefore, there is a demand for a method for producing a microsphere preparation that can ensure a certain sustained release property. Such a request is very large when the microsphere preparation is used in the medical field and administered to a living body.

  In response to such a demand, a method for producing a microsphere preparation using a safe material has been proposed, and further, a non-solvent of a film constituent material is added to the dispersed phase, and the amount of drug contained in the capsule film is excellent. A method for producing a microsphere preparation has been proposed (for example, Non-Patent Document 1).

C.-Y.Yang and two others, J. MICROENCAPSULATION, 2001, Vol. 18, No. 2, pp. 223-236

  However, in the method for producing a microsphere preparation according to Non-Patent Document 1, the microsphere preparation obtained by adding a non-solvent can improve the drug content. In this case, the drug is suddenly released from the inside of the capsule film to the outside, and a microsphere preparation excellent in sustained release could not be obtained.

  The present invention relates to a microsphere preparation which exhibits excellent drug content and exhibits almost constant sustained release without being affected by the elapsed time after administration even immediately after the start of administration, and a method for producing such a microsphere preparation The purpose is to provide.

  The present invention relates to (1) a method for producing a microsphere preparation having a structure in which a drug is contained inside a capsule film made of a polymer, wherein the polymer constituting the capsule film is dissolved in a solvent and the drug is contained in the solvent. And adding a non-solvent for the polymer to the second solution containing an oily liquid that is immiscible with the first solution and emulsifying the first solution in the first solution. An emulsified liquid in which an inner layer including a drug, a solvent, and a non-solvent is formed inside an outer layer made of a polymer and a continuous phase composed of the second solution is formed. (2) emulsification, characterized in that the solvent in the inner layer of the dispersion layer is evaporated while the temperature of the solvent is increased to control the evaporation rate of the solvent, and the dispersed phase is separated from the emulsion. Insoluble from the inner layer of the dispersed phase separated from the liquid (3) The method for producing a microsphere preparation according to (1) or (2) above, wherein the non-solvent is water, and (4) a polymer, The method for producing a microsphere preparation according to any one of (1) to (3) above, which is a hydrophobic dextran derivative, (5) The dispersion according to any one of (1) to (4) above, wherein the dispersion is acetone. The gist is a method for producing a microsphere formulation, and (6) a microsphere formulation obtained by the method for producing a microsphere formulation according to any one of (1) to (5) above.

  According to the present invention, it is possible to produce a microsphere preparation that can maintain a substantially constant sustained release property regardless of the time lapse after administration even at the stage immediately after the start of administration.

  According to the present invention, after the emulsion is prepared, the temperature is raised to evaporate the solvent contained in the first solvent. Therefore, the solvent is evaporated more than the case where the solvent is evaporated at a constant temperature without raising the temperature of the emulsion. The transpiration rate can be increased, and the microsphere preparation can be produced quickly and in a short time.

  According to the present invention, after separating the dispersed phase from the emulsion, the step of evaporating the non-solvent in the dispersed phase is performed so that the non-solvent is evaporated after the solvent is more reliably evaporated. And the residual solvent can be further suppressed.

  In the present invention, water can be used as a non-solvent, a hydrophobic dextran derivative can be used as a polymer, and acetone can be used as a dispersion. Therefore, according to the present invention, a microsphere preparation can be produced using a substance that can ensure safety for a living body as a raw material constituting a capsule film. Furthermore, since it is possible to manufacture a microsphere formulation based on readily available raw materials, it is possible to suppress the manufacturing cost as much as possible.

  In the present invention, a first solution in which a drug is dispersed and a polymer is dissolved and a non-solvent is added, and a second solution containing an oily liquid that is immiscible with the first solution are prepared. The first solution is added to this second solution and suspended to create an emulsion. At this time, the emulsified liquid uses the first solution as the dispersed phase and the second solution as the continuous phase. In the dispersed phase, an outer layer made of a polymer is formed, and an inner layer containing a drug and a non-solvent in addition to a solvent that dissolves the polymer in the first solution is formed inside the outer layer. Further, the solvent for dissolving the polymer is vaporized and distilled from the dispersed phase, and the outer layer of the dispersed phase is formed into a capsule film to form a capsule body. And the capsule body which is a dispersed phase is isolate | separated from an emulsion, and the microsphere formulation provided with the structure of the capsule body which contains a chemical | medical agent inside the capsule membrane | film | coat which consists of a polymer in this way is manufactured.

  In the first solution used in the present invention, the kind of the drug is not particularly limited, and any kind of water-soluble or fat-soluble can be used. For example, antibiotics, antitumor agents, anti-tumor agents, Ulcer agent, antiepileptic agent, antidepressant agent, antiallergic agent, analgesic agent, antipyretic agent, anti-inflammatory agent, beta blocker, antitussive agent, sedative agent, muscle relaxant, vasodilator, hyperlipidemic agent, bronchodilator , H2 receptor antagonists, proton pump inhibitors, sex hormones, vitamins, urinary incontinence drugs, and the like. More specifically, as drugs, penicillin antibiotics such as amoxicillin, benzylpenicillin, piperacillin, mesilinum, macrolide antibiotics such as erythromycin, clarithromycin, roxromycin, azithromycin, tetracycline antibiotics such as tetracycline, minocycline, etc. Aminoglycoside antibiotics such as gentamicin, amikacin and streptomycin, imidazole compounds such as metronidazole, tinidazole and miconazole, quinolone compounds such as ofloxacin and cyproxacin, hydroxamic acid, hydroxamic acid derivatives, salicylic acid, diclofenac, ketoprofen, nadolol, pindolol, Clinofibrate, theophylline, cimetidine, ranitidine, omeprazole, lanso Razoru, estradiol, thiamine disulfide, riboflavin, 5FU (5-fluorouracil), leuprolide, can be specifically presented oxybutynin like.

The drug is not particularly limited in particle size, but preferably has a particle size of 1/3 or less with respect to the average particle size of the microsphere preparation to be obtained.
When the particle size of the drug is 1/3 or less of the average particle size of the microsphere preparation, the drug particles protrude from the capsule film and the shell structure of the microsphere preparation is partially destroyed. It becomes easy to obtain a microsphere preparation in which a drug is well encapsulated in a capsule film.

  The drug whose particle size is 1/3 or less with respect to the average particle diameter of the microsphere preparation to be obtained seems to have an opening of 1/3 or less with respect to the value of the average particle diameter of the microsphere preparation. It can be specifically obtained by collecting the particles of the drug that has passed through the standard sieve using a standard sieve (standard sieve specified in Japanese Pharmacopoeia (14th edition) (Japanese Pharmacopoeia)).

  In addition, the average particle diameter of a microsphere formulation is calculated | required according to Japanese Pharmacopoeia (14th edition) powder particle size measuring method 2nd method (sieving method).

  The polymer is not particularly limited as long as it can be solidified in a certain shape, and can be appropriately selected according to the solvent or the non-solvent. Specifically, as a polymer, polyvinyl acetal diethylaminoacetate (external code), dimethylaminoethyl methacrylate / methyl methacrylate copolymer (external code), cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate (JP 14) ), Hydroxypropyl methylcellulose succinate (external code), ethyl methacrylate acrylic acid copolymer (external code), carboxymethylethylcellulose (external code), ethyl cellulose (external code), cellulose acetate, methacrylic acid methacrylate Acid methyl copolymers (external regulations), polylactic acid, polyglycolic acid, polyacrylic acid, polyεcaprolactam, polystyrene, dextran, zein, etc., and one or a mixture of two or more of these Mixture may be used which is formed by.

  As the polymer, for example, when water is selected as the non-solvent in the first solution, hydrophobic derivatives of each substance such as dextran specifically mentioned above may be used as an example of the polymer. it can. Examples of such a hydrophobic polymer include a hydrophobic dextran derivative, and specific examples include PDME (Propyl Dextran Mixture Ester) and IDME (Isobutyryl Dextran Mixture Ester).

  The solvent for dissolving the polymer can be appropriately selected according to the properties of the selected polymer, but is selected from those that sufficiently disperse the drug in the first solution. Specific examples of the solvent for dissolving the polymer include alcohols such as methyl alcohol and ethyl alcohol, ketones such as acetone, acetonitrile, chloroform, dichloromethane, dichloroethane, and ethyl acetate.

  A non-solvent that does not become a polymer solvent is used. Here, what does not serve as a solvent means at least the solubility of the polymer constituting the capsule film is lower than that of the solvent that dissolves the polymer, and preferably does not dissolve the polymer.

  Moreover, it is preferable that a non-solvent is a thing with a larger boiling point than the solvent in a 1st solution. When such a non-solvent is used, the solvent capable of dissolving the polymer can be sufficiently evaporated and distilled off.

  Accordingly, the non-solvent is appropriately selected according to the types of both the polymer and the solvent selected. Specifically, examples of the non-solvent include water, methyl alcohol, ethyl alcohol, hexane, octane, decane, xylene, dioxane and the like. The non-solvent is preferably water from the viewpoint of safety. Moreover, it is preferable that the non-solvent is water from the point that the boiling point is moderate. If the boiling point of the non-solvent is too low, the number of types of solvents that can be selected as the solvent for dissolving the polymer is reduced. If the boiling point is too high, it is difficult to remove the non-solvent when it is removed from the capsule by evaporation. There is a fear.

  In addition, you may use the conventional additive used for manufacture of a solid pharmaceutical formulation as needed for the 1st solution. Examples of the additive include a glaze that reinforces the structure containing the drug inside the capsule film. Examples of the excipient include corn starch, shellac, talc, crystalline cellulose, magnesium stearate, mannitol, light anhydrous silicic acid, magnesium carbonate, calcium carbonate and the like. Moreover, the 1st solution may mix | blend the stabilizer used for the additive of various pharmaceuticals other than a glaze agent, a corrigent, a coloring agent, antiseptic | preservative, etc. as an additive. The amount of these additives to be added is appropriately selected within a range that does not impair the sustained release of the drug from the microsphere preparation.

  The oily liquid in the second solution is not a solvent for both the drug and polymer constituting the first solution, and is not miscible with any of the solvent or non-solvent constituting the first solution. An oily liquid is selected. Here, the oily liquid that does not serve as a solvent for either the drug or the polymer has a lower solubility for the drug or polymer than the solvent in the first solution and does not dissolve the drug or polymer. It is preferable that

  Specific examples of the oily liquid include oils and fats such as castor oil, cottonseed oil, soybean oil and olive oil, hydrocarbons such as paraffin, liquid paraffin, and microcrystalline wax, and silicon oil.

  An emulsifier is preferably added to the second solution. When an emulsifier is added, the emulsified state of the first solution in the second solution can be stably maintained. Moreover, the particle size distribution which is the average particle diameter of a microsphere formulation and a particle size distribution can be controlled by changing the addition amount of an emulsifier variously.

  Examples of the emulsifier include monoglycerin fatty acid ester, polyglycerin fatty acid ester, propylene glycol fatty acid ester, polyoxyethylene hydrogenated castor oil, sorbitan fatty acid ester, plant lecithin, and sucrose fatty acid ester (sugar ester). Examples of fatty acids used in emulsifiers such as fatty acids used in sucrose fatty acid esters include lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, erucic acid, and behenic acid.

  Next, the method for producing the microsphere preparation of the present invention will be described in detail.

  First, a solution in which a polymer is dissolved and a drug is dispersed is prepared. A first solvent is prepared by adding a non-solvent for the polymer to this solution.

  The addition amount of the non-solvent can be selected as appropriate, but is preferably 1% to 30%, more preferably 5% to 20%, and still more preferably 10% by volume with respect to the total amount of the first solution. % To 15%. If the addition amount of the non-solvent is too small, the addition of the non-solvent may not contribute to the improvement of the sustained release of the microsphere. If the addition amount of the non-solvent is too large, the polymer is not uniform in the first solution. There is a risk of becoming.

Next, the 2nd solution containing an oily liquid is created.
The blending amount of the oily liquid in the second solution is not particularly limited as long as the amount is such that the oily liquid is a main component, that is, an amount exceeding 50% by weight. The second solution may be composed only of an oily liquid, or an emulsifier or the like may be added as appropriate.

  The first solution is added to the second solution and suspended to emulsify to form an emulsion. The suspension of the liquid obtained by adding the first solution to the second solution can be carried out by stirring the liquid with a stirring device. Specifically, the emulsion can be realized by stirring using a stirring device such as a propeller stirrer, a turbine stirrer, a homogenizer, or an ultrasonic homogenizer.

  The amount of the second solution and the first solution should be larger in the second solution than in the first solution, but the first solution and the second solution are effective in forming an emulsion. The ratio of the volume of the solution is preferably about 1: 4 to 1:30 in volume ratio.

  The temperature at which the emulsion is formed is appropriately selected depending on the polymer and solvent constituting the first solution and the oily liquid constituting the second solution, but is a temperature at which the drug is not denatured and below the boiling point of the solvent. I just need it.

  In addition, the stirring speed in stirring when forming the emulsion can be appropriately selected depending on the total amount of the first solution and the second solution and the particle size of the microsphere preparation to be obtained. From the point of making the emulsion more uniformly emulsified, it is preferably 10 rpm to 10000 rpm, more preferably 100 rpm to 5000 rpm, and further preferably 200 rpm to 1000 rpm. If the stirring speed is too slow, the dispersibility of the first solution in the second solution will deteriorate, causing agglomeration of polymers and the like contained in the first solution, and the recovery rate of a good microsphere preparation will decrease. There is a risk of it. If the stirring speed is too high, excessive mechanical force is applied to the dispersed phase, and the shape of the microsphere preparation may become distorted.

  In the emulsion thus obtained, a dispersed phase and a continuous layer are formed. At this time, the dispersed phase is composed of an outer layer composed of a polymer in the first solution and an inner layer containing a solvent and a non-solvent in addition to the drug inside the outer layer, and the continuous phase is the second solution. Composed.

  When the emulsion is prepared, the solvent is evaporated from the inner layer of the dispersed phase to the outside while controlling the evaporation rate of the solvent. At this time, from the viewpoint of preventing the solvent from remaining in the microsphere preparation, the solvent is preferably evaporated until the solvent is almost completely distilled off from the dispersed phase.

  The evaporation of the solvent to the outside of the dispersed phase can be performed by stirring the emulsion using a stirring device such as the above-described propeller type stirrer and heating the emulsion to gradually raise the temperature. The solvent transpiration rate is controlled by controlling the temperature rising rate of the emulsion.

  The emulsified liquid can be heated specifically by immersing a container containing the emulsified liquid in a water bath filled with water to raise the temperature of the water in the water bath.

  In gradually raising the temperature of the emulsion, the rate of temperature rise can be appropriately selected according to the amount of the emulsion or the solvent, but is preferably controlled so that the temperature is raised at a substantially constant rate. . Specifically, the rate of temperature increase is controlled so that the temperature increase rate of the emulsion rises from a predetermined rate within 10% or less (within a range of 10% before and after). It is preferable that the rate of temperature increase be controlled so that the magnitude of the deviation is 5% or less.

  Further, the temperature of the emulsion before and after the temperature rise is not particularly limited. The temperature of the emulsion before the temperature rise is generally room temperature and preferably 0 ° C. to 30 ° C. The temperature of the emulsion after the temperature rise generally exceeds the temperature near the boiling point of the solvent. The temperature, specifically, the temperature exceeding the “temperature below the boiling point of the solvent by about 5 ° C.”. In the case where the drug is denatured at a temperature exceeding the boiling point of the solvent, while maintaining the temperature at which the temperature of the emulsion after the temperature rise does not exceed the temperature near the boiling point of the solvent and the drug is not denatured, Gently evaporate the solvent.

  In the series of processes of adding the first solution to the second solution to form an emulsified state and evaporating the solvent from the inner layer of the dispersed phase to the outside from the emulsion, The polymer constituting the outer layer is solidified to form a capsule film, and the dispersed phase forms a capsule body.

After evaporating the solvent from the inner layer of the dispersed phase to the outside, the capsule body which is the dispersed phase is separated from the emulsion.
This sorting can be performed, for example, as follows. The emulsion is allowed to stand to precipitate the capsule body, and the emulsion is separated into a precipitate and a supernatant. At this time, the supernatant is roughly composed of the second solution. And the supernatant liquid of this emulsion liquid is removed by moving to another container, and the capsule body which is a deposit is obtained.

  In addition to the above, methods for separating the capsule body from the emulsion include a method of separating using a centrifuge, a method of filtering the emulsion, and the like.

  In order to separate the capsule body from the emulsion, it is preferable that the temperature of the emulsion is lowered to about room temperature.

The second solution adheres to the outer surface of the capsule film of the capsule body as the dispersed phase thus obtained, and this second solution is washed away.
The second solution can be removed by washing by immersing the capsule body in the cleaning liquid or pouring the cleaning liquid into the capsule body. The cleaning liquid used for the cleaning is not particularly limited as long as it does not easily dissolve the capsule body. Specifically, isopropanol, n-hexane, heptane, or the like can be used.

  In this way, a microsphere preparation in which a drug is encapsulated inside a polymer capsule can be obtained.

Note that the microsphere preparation may be further dried after washing the second solution.
This drying can be performed by leaving the microsphere preparation at room temperature. By doing so, the non-solvent inside the capsule of the microsphere preparation can be more reliably removed, and the cleaning liquid can be sufficiently removed. In addition, by drying such a microsphere preparation, even if a slight amount of solvent remains in the microsphere preparation, the slight solvent can be more reliably removed.

  In addition to the above, the microsphere preparation may be dried by placing the microsphere preparation in a reduced-pressure atmosphere. The reduced pressure atmosphere can be formed using a vacuum pump or the like.

  Next, the method for producing the microsphere preparation of the present invention will be described more specifically with reference to examples. In the examples, theophylline (TH) was used as the drug in the first solution, the hydrophobic dextran derivative was used as the polymer, acetone was used as the solvent, water was used as the non-solvent, and liquid paraffin was used as the oily liquid in the second solution. The case will be described.

Example 1
First, a mixed solution of acetone and water was prepared with a blending amount as shown in Table 1. In this mixed solution, 6.75 g of a hydrophobic dextran derivative (manufactured by Meito Sangyo Co., Ltd., PDME (Propyl Dextran Mixture Ester), molecular weight (Mw) 40000) is dissolved, and TH (Theophylline anhydrous) as shown in Table 1 is further dissolved. 2.25 g (manufactured by Sigma Aldrich Co., Ltd.) was added and dispersed in the mixed solution to prepare a first solution.

(Table 1)

  * 1; TH having a particle size of less than 75 μm is obtained by recovering TH that has passed through a standard sieve having a mesh opening of 75 μm (standard sieving with JP 14 and sieve number 200) out of the raw material TH. Further, TH having a particle size of 75 μm or more and less than 150 μm passes through a standard sieve having a mesh opening of 150 μm (THA 14 standard sieve having a sieve number of 100) among TH as a raw material, and passes through a standard sieve having a mesh opening of 75 μm. It is obtained by recovering the missing TH.

  A second solution is prepared by adding 0.75 g of sucrose ester (Daiichi Kogyo Seiyaku Co., Ltd., DFK-10) as an emulsifier to 150 mL of liquid paraffin (JP 14). 1 solution was added, and a propeller type stirring device (manufactured by Shinto Chemical Co., Ltd., Three One Motor 1200G type) (stirring speed 300 rpm, number of installed propellers) was used at room temperature (in this example, 20 ° C.). The mixture was suspended for 30 minutes and emulsified to prepare an emulsion.

  The emulsion was heated at a heating rate of 30 ° C./hour while stirring at a stirring rate of 300 rpm, and the temperature was gradually raised to 60 ° C. The temperature rise of the emulsion was performed by gradually heating the container containing the emulsion through the water in the water bath by immersing the container containing the emulsion in the water bath.

  Furthermore, after the temperature of the emulsion was 60 ° C., the emulsion was maintained at a temperature of 60 ° C. for 30 minutes while stirring the emulsion at a stirring speed of 300 rpm. Here, acetone evaporated from the inner layer of the dispersed phase of the emulsion to the outside.

  In the course of a series of processes from preparation of emulsion to evaporation of acetone, a hydrophobic dextran derivative constituting the outer layer of the dispersed phase is solidified to form a capsule film, and capsules containing TH inside the capsule film The body is formed.

  After the emulsion was stirred at 60 ° C. for 30 minutes, the emulsion was allowed to stand in a room temperature atmosphere to precipitate the capsule body as a dispersed phase, and the precipitate and the supernatant were separated. This standing was performed until the temperature of the emulsion was lowered from 60 ° C. to almost room temperature. It should be noted that the supernatant obtained after this standing is almost composed of the second solution.

  The supernatant was poured out (discharged) to obtain a precipitate, whereby a capsule body as a dispersed phase was separated from the emulsion.

  The obtained capsule body was washed three times with a washing liquid consisting of n-hexane. After washing, the capsule body was left to stand for a whole day under a reduced-pressure atmosphere and dried. Note that the reduced-pressure atmosphere was formed using a vacuum pump. Then, by drying the capsule body, the washing liquid and water evaporated from the capsule body, and a microsphere preparation was obtained.

  The obtained microsphere preparation was measured for the drug recovery rate, encapsulation rate, encapsulation efficiency, average particle size, and sustained release as follows.

"Drug recovery rate"
The obtained microsphere preparation is passed through a standard sieve having an opening of 1700 μm (National Bureau of Japan, sieve number 10 standard sieve), and further applied to a standard sieve having an opening of 300 μm (National Bureau of Japan, sieve number 50 standard sieve). The microsphere preparation that passed through the 1700 μm standard sieve and did not pass through the 300 μm standard sieve was collected. Thus, a microsphere preparation having a pore size in the range of 300 to 1700 μm was selected as an effective microsphere preparation.
The weight (assumed as W) of the selected microsphere preparation was measured, and the ratio of W to the total amount of the hydrophobic dextran derivative amount (6.75 g) and the TH amount (2.25 g) used in this example was determined. This value was calculated as the drug recovery rate. The results are shown in Table 2.

"Encapsulation rate and encapsulation efficiency"
40 mg is weighed from a microsphere preparation having a pore size of 300 to 1700 μm, dissolved in 50 mL of dichloromethane to prepare a solution, the absorbance at 274 nm is measured for the solution, and the concentration of TH in the solution is derived. Calculate the mass. Based on this calculated value, the proportion (inclusion rate) (wt%) of TH in 40 mg of the microsphere preparation is calculated.

  On the other hand, the theoretical value (% by weight) of the ratio of TH derived from the amount of the hydrophobic dextran derivative used in producing the microsphere preparation and the total amount of TH is calculated. In this example, the ratio of TH (2.25 g) to 9 g of the total amount of the hydrophobic dextran derivative and TH is 25% by weight.

  The encapsulation efficiency was determined as a value obtained by dividing the TH ratio in the obtained microsphere preparation by the theoretical value of the TH ratio. The results are shown in Table 2.

"Average particle size"
The average particle size of the microsphere preparation was determined according to the Japanese Pharmacopoeia (14th edition) powder particle size measurement method Method 2 (sieving method). At that time, the obtained microsphere preparation is screened. The microsphere preparation is screened using standard sieves having openings of 1700, 1400, 1180, 1000, 850, 710, 600, 500, 425, 355, and 300 μm. Continuing the microsphere formulation in descending order of the size of the mesh for (Nippon bureau 14, standard sieves of sieve numbers 10, 12, 14, 16, 18, 22, 26, 30, 36, 42, 50) It was carried out by passing through.
The results are shown in Table 2.

(Table 2)

"Slow release"
The test for evaluating the sustained release property of the obtained microsphere preparation was performed according to the Japanese Pharmacopoeia (14th edition) dissolution test method method 2 (paddle method). This test was used as an aqueous solution (volume 900 mL, pH 1.2) (referred to as a basic solution) containing HCl (concentration 0.07 M), NaCl (concentration 0.0342 M), and 0.02 wt% Tween 20 and called micro. This was carried out using a dispersion in which 100 mg of the sphere formulation was dispersed in the base solution as a test solution, and was carried out under conditions of a temperature of 37 ± 0.5 ° C. and a paddle rotation speed of 100 rpm.

  At each time point (t) when 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours have elapsed from the start point of the dissolution test, 5 mL of the test solution is taken. The solution taken was filtered through a filtration membrane having a pore diameter of 0.45 μm, and the absorbance at 274 nm was measured for the filtrate obtained by filtration. Then, based on the measured absorbance value, the TH concentration (Mt) was calculated. Based on the amount of microsphere preparation to be dissolved in the test solution and the value of TH inclusion, the concentration of TH (Mterminal) when all TH was eluted from the microsphere preparation into the basic solution was calculated. The release rate (Mt / Mterminal) was derived using the value of. The (Mt / Mterminal) value was derived for each time point based on the absorbance value at each time point.

Furthermore, on the coordinate plane with the logarithmic value of elapsed time (t) on the horizontal axis and the logarithmic value of (Mt / Mterminal) on the vertical axis, it corresponds to each value of (Mt / Mterminal) at each elapsed time (t). The approximate straight line indicating the relationship between the logarithmic value of elapsed time (t) and the logarithmic value of (Mt / Mterminal) is obtained using the least square method. Based on the obtained approximate straight line, the value of the proportionality constant k in the mathematical formula shown below (Equation 1), the value of the constant n related to the sustained release of the drug, and the value of the correlation coefficient r were obtained.
The results are shown in Table 3.

(Equation 1)
(Mt / Mterminal) = k × t ⁿ
However,
t: Time (unit: hour) elapsed from the start of the sustained release test
Mt; concentration of the drug eluted in the basic solution from the microsphere preparation at the time when t time has passed (unit: M),
Mterminal: concentration of drug when all drugs are eluted from the microsphere preparation into the basic solution (unit: M)
, Indicate.

(Table 3)

Examples 2 and 3 and Comparative Example 1
A microsphere preparation was obtained in the same manner as in Example 1 except that a mixed solution of acetone and water was prepared at the blending amounts shown in Table 1 and TH as shown in Table 1 was used. In the same manner as in Example 1, the obtained microsphere preparation was measured for the drug recovery rate, encapsulation rate, encapsulation efficiency, average particle size, and sustained release property.
The results are as shown in Table 2 and Table 3, respectively.

  As shown in Table 3, the microsphere preparation obtained in Example 1 has a value of n close to 1 as compared with the microsphere preparation in Comparative Example 1, so that the TH release rate from the inside of the capsule film to the outside Even in the stage immediately after the start of administration, the change is almost constant without being affected by the elapsed time. Therefore, the microsphere preparation obtained by the present invention is excellent in sustained release in that it has a certain sustained release even immediately after the start of administration.

Claims (6)

A method for producing a microsphere preparation having a structure in which a drug is contained inside a capsule film made of a polymer,
A first solution obtained by dissolving a polymer constituting a capsule film in a solvent and dispersing a drug in the solvent and adding a non-solvent to the polymer includes an oily liquid that is immiscible with the first solution. In addition to the second solution, emulsification, a dispersed phase composed of an outer layer composed of a polymer in the first solution, and an inner layer containing a drug, a solvent, and a non-solvent inside the outer layer, No emulsion formed with a continuous phase composed of a solution,
A process for producing a microsphere preparation, characterized by gradually elevating the temperature of an emulsion and controlling the evaporation rate of the solvent to evaporate the solvent in the inner layer of the dispersed phase and fractionating the dispersed phase from the emulsion.
The method for producing a microsphere preparation according to claim 1, wherein the non-solvent is evaporated from the inner layer of the dispersed phase separated from the emulsion.
The method for producing a microsphere preparation according to claim 1 or 2, wherein the non-solvent is water.
The method for producing a microsphere preparation according to any one of claims 1 to 3, wherein the polymer is a hydrophobic dextran derivative.
The method for producing a microsphere preparation according to any one of claims 1 to 4, wherein the dispersion is acetone.
The microsphere formulation obtained by the manufacturing method of the microsphere formulation in any one of Claim 1 to 5.