JP5258224B2 - Solid formulation of solid dispersion and method for producing the same - Google Patents

Description

  The present invention relates to a solid preparation of a solid dispersion produced for the purpose of improving dissolution of a poorly soluble drug and a method for producing the same. In particular, the present invention relates to a solid preparation of a solid dispersion containing a solid dispersion characterized by rapid disintegration and drug dissolution and a method for producing the same.

  Since poorly soluble drugs have high crystallinity and extremely low solubility in water, when they are formulated, there is a problem that their bioavailability or absorbability in the body is low and their drug efficacy is insufficient. As a technique for solving this problem, a solid dispersion in which a poorly soluble drug is molecularly dispersed in an amorphous state on a polymer carrier such as a cellulose derivative has been developed.

  Conventional solid dispersions are prepared by spray-drying a product in which a poorly soluble drug and carrier are dissolved in a co-solvent and filling the capsule into a capsule, or by directly formulating it into fine granules or granules. However, tableting, which is a general-purpose dosage form of a solid preparation, is most preferable from the viewpoints of quantitative prescription and quantitative dosage, actual patient handling and ease of administration.

  However, from previous findings, tableting the solid dispersion powder not only reduces the specific surface area, but also causes amorphous drug molecules to undergo plastic deformation during the compression molding process and strong binding of the carrier polymer. As a result, the porosity of the tablet often becomes low, and as a result, the penetration of water molecules into the tablet during administration is delayed, the disintegration of the tablet is delayed, and the original dissolution improvement property of the solid dispersion cannot be obtained. It was happening. In addition, the water-soluble or enteric polymer used as a carrier increases in viscosity upon hydration / dissolution, so that a kind of hydrogel layer is formed on the tablet surface at the time of dissolution and water infiltration is further prevented. It was happening.

  As a means for solving these problems, in Patent Document 1, a tablet containing a solid dispersion powder obtained by spray drying, a disintegrant and an excipient of porosigen is disclosed in Patent Document 2, which is soluble in a poorly soluble drug. A powder having a polymer base, an excipient and a disintegrating agent added as necessary has been proposed. However, since the concentration-enhancing polymer or water-soluble polymer base as a carrier is added in a large amount, the drug release from the preparation is weak and the dissolution rate tends to be delayed. Further, the solid dispersion powder obtained by spray drying as in Patent Document 1 must be mixed with other components and then once compressed and crushed to form a granulated powder for tableting. Thus, since the solid dispersion powder prepared by spray drying has a small particle size, segregation occurs when it is simply mixed with other excipients, and a tableting powder with non-uniform ingredients can be obtained. Furthermore, if such a process is performed, the operation becomes complicated, and there is a concern that the solid dispersion by recompression once recrystallizes. In addition, the disintegrant is added after preparing the solid dispersion, and when the solid dispersions are aggregated and bonded by the strong binding force of the carrier in the tablet, It causes a decrease in drug dissolution.

  On the other hand, in Patent Document 3, a tablet using fine granules obtained by spraying, granulating and drying a solution of itraconazole, a water-soluble polymer and an enteric polymer, in a mixed powder of an excipient and a disintegrant. Has been proposed. However, since it is inferior in disintegration, it took 360 minutes until the drug was eluted from the tablet, and the disintegration of the tablet was not improved.

Hirasawa et al. (Non-Patent Document 1) put nilvadipine and crospovidone, which are poorly soluble drugs, and an ethanol dispersion of methylcellulose into a mixed powder of lactose, methylcellulose, low-substituted hydroxypropylcellulose, etc., and granulated with stirring. You get tablets from things. However, in ethanol solution of nilvadipine and carrier crospovidone and methylcellulose, they do not dissolve, and therefore, it does not go through a co-dissolved state and is considered to function merely as a dispersion diluent for amorphous nilvadipine. In order to disperse an amorphous drug molecule in a polymer as a carrier, it is necessary to go through a co-solvent state with a co-solvent that dissolves both, so that the amorphous nilvadipine obtained by Non-Patent Document 1 is used. This solid dispersion is considered not to have sufficient solubility. In addition, disintegration is suppressed due to the influence of the water-soluble polymer, and it is considered difficult to obtain an immediate-eluting preparation.
JP 2005-517690 JP-A-5-262642 JP 2004-67606 A Pharmaceutical Journal, 124 (1), 19-23 (2004)

  The present invention has been made in view of the above circumstances, and provides a solid preparation of a solid dispersion capable of rapidly eluting the drug in the preparation without impairing the dissolution property of the solid dispersion and a method for producing the same. It is.

As a result of diligent research to solve the above problems, the present inventors have used a special low-substituted hydroxypropyl cellulose as a disintegrant, thereby reducing the disintegration in a tablet in which a solid dispersion is compression-molded. The present inventors have found that a solid preparation has rapid disintegration and drug dissolution without causing the present invention.
Specifically, the present invention is a solid preparation of a solid dispersion containing a poorly soluble drug, a water-soluble polymer and a disintegrant, the disintegrant having an average particle size of 10 to 100 μm, and a BET method. Provided is a solid preparation of a solid dispersion which is a low-substituted hydroxypropylcellulose having a measured specific surface area of 1.0 m ² / g or more. The solid formulation of the solid dispersion may preferably contain excipients. Further, as a disintegrant, a poorly soluble drug is dispersed or dispersed in a powder in which a low-substituted hydroxypropyl cellulose having an average particle size of 10 to 100 μm and a specific surface area measured by the BET method of 1.0 m ² / g or more is mixed. There is provided a method for producing a solid preparation of a solid dispersion comprising spraying, granulating and drying a dissolved water-soluble polymer solution.

  According to the present invention, a high dissolution property is recognized in the case of a granulated product, and in the case of a tablet, it disintegrates within 10 minutes after introduction into a dissolution medium, and releases at least 70% by mass of a poorly soluble drug. A solid preparation with excellent solubility can be obtained.

Hereinafter, the present invention will be described in more detail.
The poorly soluble drug used in the present invention has a very low solubility in water and is generally a poorly absorbed drug when administered orally. For example, it refers to a drug that is “almost insoluble” or “extremely insoluble” as defined in the 15th revision of the Japanese Pharmacopoeia. “Solubility” of a drug in the 15th revision of the Japanese Pharmacopoeia is 30 minutes when it is powdered when the drug is solid, then placed in a solvent and shaken every 20 minutes at 20 ± 5 ° C. for 30 minutes The amount of solvent required to dissolve 1 g or 1 ml of drug (in this case water) is 10,000 ml or more, and “extremely insoluble” means 1 g or 1 ml of drug. The property that the amount of solvent required for dissolution is 1,000 ml or more and less than 10,000 ml.

  Specific examples of the poorly soluble drug used in the present invention include nifedipine, phenacetin, phenytoin, digitoxin, nilvadipine, diazepam, griseofulvin, chloramphenicol, but are not particularly limited thereto.

  In the present invention, a water-soluble polymer is used as a carrier in order to molecularly disperse a poorly soluble drug in an amorphous state. For water-soluble polymers, add the polymer to half of the amount required for dissolution to the total amount of hot water (70 ° C or higher), stir and disperse, and if the total amount of hot water is not used, use the remaining amount of cold water or ice water. When added with stirring, it is stipulated in the 15th revision of the Japanese Pharmacopoeia “Easily soluble (the amount of water required to dissolve 1 g or 1 ml of drug is less than 1 ml)”, “Easily soluble (1 g or 1 ml of drug) The amount of water required for 1 mg or more and less than 10 ml) ”or“ Slightly soluble (the amount of water required for dissolving 1 g or 1 ml of drug is 10 ml or more and less than 30 ml) ”. Specific examples include alkylcelluloses such as methylcellulose, hydroxyalkylcelluloses such as hydroxyethylcellulose and hydroxypropylcellulose, hydroxyalkylalkylcelluloses such as hydroxyethylmethylcellulose and hydroxypropylmethylcellulose, polyvinyl alcohol, and polyvinylpyrrolidone. Methyl cellulose is preferred.

  The content of the water-soluble polymer is 1 to 75% by mass, preferably 1 to 50% by mass, more preferably 1 to 35% by mass, and particularly preferably 1 to 20% by mass in the whole solid preparation. If the content of the water-soluble polymer is less than 1% by mass, it may be difficult to make the sparingly soluble drug in the solid dispersion completely amorphous. If the content is more than 75% by mass, the water-soluble polymer is contained in the preparation. When the ratio is increased, the dose and the formulation size are increased, and the disintegration property is lowered.

  The addition ratio of the water-soluble polymer to the hardly soluble drug is preferably 1 to 5 mass of the water-soluble polymer with respect to 1 mass of the hardly soluble drug. If the ratio of the water-soluble polymer is smaller than 1, the poorly soluble drug in the solid dispersion may not be completely amorphous. If it is larger than 5, the ratio of the water-soluble polymer in the preparation increases. Therefore, as a result, the preparation size is increased and the dissolution rate is decreased, which may not be suitable as a general preparation.

The solvent for preparing a solid dispersion of a poorly soluble drug comprising a water-soluble polymer is preferably a solvent that dissolves poorly soluble drugs well and dissolves water-soluble polymers. For example, in addition to methanol, ethanol, methylene chloride, acetone, or a mixed solvent thereof, and a mixed solvent of these with water, the solvent can be appropriately selected depending on the solubility of the poorly soluble drug and the water-soluble polymer in the solvent.
The amount of the solvent added is such that the solid concentration is preferably 3 to 18% by mass, particularly preferably 3.5 to 12% by mass.

Examples of the excipient used in the present invention include lactose, corn starch, sucrose, mannitol, anhydrous calcium phosphate, crystalline cellulose, a mixture thereof, and the like. Particularly, a mixed powder of lactose: corn starch = 7: 3 (mass ratio) is used. preferable.
The content of the excipient is preferably an amount (remainder) excluding the poorly soluble drug, the water-soluble polymer and the disintegrant described later.

The disintegrant of the present invention provides a high fluidity to the granulated product and guarantees a high dissolution property from the compression-molded preparation, and has an average particle diameter of 10 to 100 μm and a specific surface area measured by the BET method. Is a low-substituted hydroxypropylcellulose having a viscosity of 1.0 m ² / g or more.
The average particle size of the low-substituted hydroxypropylcellulose of the present invention is about 10 to 100 μm, preferably about 20 to 60 μm. If it is less than 10 μm, the agglomeration may increase due to micronization and the fluidity of the powder may be reduced, and if it exceeds 100 μm, the mixing property with the drug may be reduced and non-uniform. The average particle diameter can be measured using HELOS & RODOS (manufactured by Sinpack), which is a laser diffraction particle size distribution measurement.
Furthermore, the specific surface area of the low-substituted hydroxypropylcellulose of the present invention is 1.0 m ² / g or more. This is because if it is less than this, high binding properties may not be obtained.
In general, it is known that the higher the specific surface area of the powder, the higher the binding property of the powder. Specific surface area analysis is a method of adsorbing molecules with a known adsorption area on the surface of powder particles at the temperature of liquid nitrogen, and obtaining the specific surface area of the sample from the amount. BET method based on low-temperature low-humidity physical adsorption of inert gas Can be used. For example, it can be measured using MICROMERITICS GEMINI 2375 (manufactured by Shimadzu Corporation).
In general, the specific surface area can be increased by reducing the average particle size, but if the average particle size becomes too small as described above, the cohesiveness of the powder increases and the fluidity of the powder decreases. There is a fear. In the present invention, a powder having a high specific surface area can be obtained by compaction grinding, although it has an average particle diameter that provides fluidity of the powder.

The low-substituted hydroxypropylcellulose preferably has a loose bulk density of 0.30 g / ml or more.
Here, “loose bulk density” refers to the bulk density in a loosely packed state, and a sample is placed in a cylindrical container (material: stainless steel) having a diameter of 5.03 cm and a height of 5.03 cm (volume: 100 ml) according to JIS 24 mesh. It is measured by feeding uniformly from above (23 cm) through a sieve and grinding the top surface. These operations can be measured by using a powder tester (PT-D) manufactured by Hosokawa Micron.

As the low-substituted hydroxypropylcellulose of the present invention, it is preferable to use one having an elastic recovery rate of 7% or less when compression-molded at a compression pressure of 50 MPa. Thereby, a dense molded body can be formed during compression.
The elastic recovery rate is an index indicating the compression moldability of the powder. Tablet when the powder is compressed and molded at a tablet weight of 480 mg and a compression pressure of 50 MPa using a flat plate (tablet tester (manufactured by Sankyo Powtech)) with a tablet diameter of 11.3 mm and a flat contact surface From thickness, it can obtain | require from following Formula.
Elastic recovery rate = {(Tablet thickness after 30 seconds−Minimum tablet thickness) / (Minimum tablet thickness)} × 100
Here, "minimum tablet thickness" refers to the lowest point when the powder is compressed with an upper punch using a flat punch with a fixed lower punch, that is, the thickness when the tablet is most compressed, “Tablet thickness after 30 seconds” refers to the tablet thickness 30 seconds after the upper eyelid is opened upward.

As a method for measuring the swelling property of low-substituted hydroxypropyl cellulose, for example, low-substituted hydroxypropyl cellulose is molded into a tablet having a flat surface with a diameter of 15 mm at a tableting pressure of 1 t, and water is added dropwise to the tablet. It can be evaluated by the swelling volume increase rate and the swelling volume increase rate when swelling. When using alkali cellulose having a mass ratio of caustic soda to anhydrous cellulose of 0.1 to 0.3, the swelling volume increase rate is preferably 300% or more, and the swelling volume increase rate is preferably 100% / min or more. .
The swelling volume increase rate is obtained by forming a powder into a tablet having a flat surface with a diameter of 15 mm at a tableting pressure of 1 t, and then attaching a ridge with a conduit instead of the upper ridge, through which water is applied to the tablet in a state where it enters the mortar. Is added as a swelling volume increase rate when the tablet absorbs water for 10 minutes. Water is added dropwise at a rate of 1 ml / min for 10 minutes. The increase in volume can be determined by the following equation from the change in tablet thickness.
Swelling volume increase rate = (difference in tablet thickness before and after water addition / tablet thickness before water addition) × 100
In the above formula, “the difference in tablet thickness before and after water addition” is obtained by subtracting the tablet thickness before water addition from the tablet thickness after water addition for 10 minutes.
Further, the swelling volume increase rate of the low-substituted hydroxypropylcellulose powder is preferably 300% or more from the viewpoint of swelling characteristics which are important characteristics as a disintegrant. When the swelling volume increase rate is less than 300%, the disintegration time may be extended when the preparation is formulated.
The swelling volume increase rate means the initial swelling rate 30 seconds after the start of water addition when the swelling volume increase rate is measured under the same conditions as in the above method, and can be determined from the following equation.
Swelling volume increase rate = (difference in tablet thickness before and after initial water addition / tablet thickness before water addition) × 100 / 0.5
In the above formula, “the difference in tablet thickness before and after initial water addition” is obtained by subtracting the tablet thickness before water addition from the tablet thickness 30 seconds after the start of water addition.
The swelling volume increase rate of the low-substituted hydroxypropylcellulose powder of the present invention is preferably 100% / min or more from the viewpoint of swelling characteristics which are important characteristics as a disintegrant. When the swelling volume increase rate is less than 100% / min, the disintegration time may be extended when the preparation is formulated.

The low-substituted hydroxypropylcellulose of the present invention has a high fluidity and is a powder having an angle of repose, which is one of the indexes of the fluidity of the powder, preferably 42 ^° or less. The angle of repose refers to an angle formed between a generatrix of a cone deposited by dropping a sample on a plane and a horizontal plane. For example, by using a powder tester PT-D type (manufactured by Hosokawa Micron Corporation), a sample is allowed to flow out on a metal disk-shaped table having a diameter of 80 mm until a certain angle is reached from a height of 75 mm. It can be calculated by measuring the angle with the table. It can be said that the smaller the angle, the better the powder.

  As shown in Japanese Patent Application No. 2006-215401, the low-substituted hydroxypropyl cellulose of the present invention is obtained by adding and mixing a caustic soda aqueous solution to powdered pulp, and the mass ratio of caustic soda to anhydrous cellulose is 0.1 to 0.3. It is obtained by producing a certain alkali cellulose and then conducting an etherification reaction, neutralizing caustic soda with or without a dissolving step, washing and drying, and then compacting and grinding in a pulverizing step.

  More specifically, (1) a step of producing alkali cellulose by adding and mixing an aqueous caustic soda solution in an amount such that the mass ratio of caustic soda to anhydrous cellulose is 0.1 to 0.3 to powdered pulp; ) A step of obtaining a crude reaction product by performing an etherification reaction of the obtained alkali cellulose; (3) a step of neutralizing caustic soda contained in the obtained crude reaction product; and (4) a subsequent washing / A low-substituted hydroxypropylcellulose powder can be obtained using a production method comprising a dehydration step, (5) a drying step, and (6) a pulverization step for compaction grinding. A method for producing a low-substituted hydroxypropylcellulose powder having a water-insoluble and water-absorbing swellability in which the number of substituted moles per anhydroglucose unit is 0.05 to 1.0, comprising: (1) A step of adding and mixing an aqueous solution of caustic soda in an amount such that the mass ratio of caustic soda to anhydrous cellulose is 0.1 to 0.3, and (2) conducting an etherification reaction of the resulting alkali cellulose to rough A step of obtaining a reaction product, (3) a step of neutralizing caustic soda contained in the obtained crude reaction product without undergoing a dissolution step of dissolving a part or all of the crude reaction product, and (4) Obtaining a low-substituted hydroxypropylcellulose powder using a production method comprising a subsequent washing / dehydrating step, (5) a drying step, and (6) a pulverizing step for compaction grinding. It can be. The washing / dehydrating step is preferably a step of performing dehydration with washing and a moisture content of 65% by mass or less.

First, any pulverization method may be used for powdered pulp used as a raw material. The average particle diameter is preferably 60 to 300 μm. It is industrially inefficient to prepare a powdered pulp of less than 60 μm, and if it exceeds 300 μm, the miscibility with aqueous caustic soda solution may be poor.
The step of producing alkali cellulose is preferably performed by dropping or spraying a caustic soda aqueous solution into the powdered pulp and mixing. At this time, caustic soda acts as a catalyst for the etherification reaction. In the production of alkali cellulose, preferably, mixing is performed in an internal stirring type reactor, followed by etherification reaction, or alkali cellulose prepared in another mixer is charged into the reactor for etherification reaction. Any method may be used.
In addition, it was found that the amount of caustic soda in the alkali cellulose affects not only the reaction efficiency but also the swelling property and binding property of the final product. The optimum amount of caustic soda in the alkali cellulose is 0.1 to 0.3 in terms of a mass ratio of caustic soda to anhydrous cellulose (referred to excluding moisture in the pulp). If it is less than 0.1, the volume increase rate at the time of swelling characteristic, especially water absorption swelling becomes low, the disintegration property is lowered, and the binding property may be lowered. Moreover, when it exceeds 0.3, the swelling volume increase rate at the time of water absorption mentioned later and the swelling volume increase rate also become low, and binding property may also fall.
Caustic soda is preferably added as a 20 to 40% by weight aqueous solution.

In the next step of performing the etherification reaction, alkali cellulose is charged into the reactor, and after purging with nitrogen, propylene oxide is charged into the reactor as an etherifying agent to perform the reaction. The charging ratio of propylene oxide is preferably about 0.1 to 1.0 mol with respect to 1 mol of anhydroglucose unit. The reaction temperature is about 40 to 80 ° C., and the reaction time is about 1 to 5 hours.
In addition, a dissolution process can be performed as needed after the process of performing an etherification reaction. The dissolution step is performed by dissolving a part or all of the crude reaction product after the etherification reaction in water or hot water. The amount of water or hot water used varies depending on the amount of dissolution of the crude reaction product, but the amount of water used to dissolve all of the crude reaction product is usually based on the low-substituted hydroxypropyl cellulose in the crude reaction product. The mass ratio is 0.5 to 10.
In consideration of the load in the washing / dehydration process described later and the further improvement of the low-substituted cellulose ether bondability, it is more preferable not to perform this dissolution process.

In the next neutralization step, the caustic soda used as a catalyst remains in the reaction product. Therefore, it is preferable to add the crude reaction product to water or hot water containing an equivalent amount of acid to the caustic soda. Do the sum. Further, the reaction product may be neutralized by adding water containing an equivalent amount of acid or hot water.
Examples of the acid to be used include mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, and organic acids such as formic acid and acetic acid.

In the next washing / dehydrating step, the obtained neutralized product is preferably dehydrated by a method selected from centrifugal separation, vacuum filtration, pressure filtration and the like while washing with water or hot water. The low-substituted hydroxypropylcellulose in the obtained dehydrated cake becomes a fibrous material in the same manner as the raw material pulp. Depending on the number of moles substituted in the dehydrated product that has undergone the dissolution step, the dehydration rate is generally 70 to 90% by mass, and the dehydration rate that does not pass through the dissolution step is usually 65% by mass or less. It can be reduced and productivity is improved. Furthermore, since there is no dissolution process, there is an advantage that the process can be simplified.
In addition, from the viewpoint of product binding, a product obtained by pulverization using a fiber-shaped product has a high specific surface area and a high binding property.
The drying step for drying the dehydrate obtained above can be preferably performed at 60 to 120 ° C. using a dryer such as a fluid dryer or a drum dryer.

The pulverization step is carried out by compacting and grinding the dried product obtained by the above method.
For the compaction grinding, a pulverizer such as a roller mill, a ball mill, a bead mill, or a stone mill pulverizer can be used. A roller mill is a crusher in which a roller or ball rolls while compressing and shearing the material to be crushed by the centrifugal force and gravity load associated with its rotational movement. IS Mill manufactured by Ishikawajima-Harima Heavy Industries, Ltd. VX mill manufactured by MS, MS roller mill manufactured by Masuno Seisakusho Co., Ltd. can be used. The ball mill is a pulverizer using steel balls, magnetic balls, cobblestones and the like as pulverization media, and a ball mill manufactured by Kurimoto Tekko Co., Ltd., a tube mill manufactured by Otsuka Tekko Co., Ltd., a planetary ball mill manufactured by FRITSCH, etc. can be used. The bead mill is similar to the ball mill. However, the bead mill manufactured by Ashizawa Seisakusho Co., Ltd. can be used. For example, a bead mill manufactured by Ashizawa Seisakusho can be used. The stone mill type crusher is a machine that can grind powder by rotating the stone mill at a high speed with a narrow clearance. For example, a serendipeater manufactured by Masuko Sangyo Co., Ltd. can be used.
In particular, a roller mill with less metal foreign matter, a small installation area, and high productivity is preferable.
The particles in the fibrous form, which is the pulverized raw material, can reduce the primary particles by repeating the compaction and grinding, and the primary tubular particles can be made smaller by eliminating the fibrous and hollow tubular form derived from the raw material pulp. Increase. Moreover, the fibrous form derived from raw material pulp disappears, and a powder having a uniform particle shape is obtained.
In addition, it has been said that the low-substituted hydroxypropyl cellulose produced by conventional impact pulverization is expressed by the entanglement of the fibrous form. For this reason, if the amount of fibrous particles is increased in order to enhance the bonding property, the fluidity is lowered. However, the low-substituted hydroxypropylcellulose powder produced by compaction milling surprisingly exhibits high binding properties even though the fibrous form has disappeared due to compaction milling. It was.

Next, preferably, the desired low-substituted hydroxypropylcellulose powder can be obtained by sieving the pulverized product according to a conventional method. A sieve having an opening of about 38 to 180 μm can be used.
The low-substituted hydroxypropylcellulose powder thus obtained has high fluidity, excellent binding properties and excellent swelling characteristics despite the fibrous form derived from the raw material pulp. In addition, since it has excellent binding and disintegration properties, not only can the amount of addition in the tablet be reduced, the size of the tablet can be reduced, but the compression molding pressure at the time of tablet production can be lowered, so that a solid dispersion can be produced during the process. There is also an advantage that physical influences such as recrystallization can be reduced.

  In the present invention, in addition to low-substituted hydroxypropyl cellulose, for example, carmellose, carmellose sodium, carmellose calcium, croscarmellose sodium, hydroxypropyl starch, carboxymethyl starch sodium, crospovidone, and the like, or a mixture thereof may be used. it can.

  The content of the disintegrant is preferably 1 to 98% by mass, more preferably 1 to 60% by mass in the whole solid preparation. If the content of the disintegrant is less than 1% by mass, the solid preparation may be difficult to disintegrate due to the small amount of disintegrant, and if it is more than 98% by mass, an effective amount of drug may not be contained.

Among the solid preparations of the present invention, the granulated product refers to powders and granules defined in the Japanese Pharmacopoeia 15th revision.
When the solid preparation is a tablet, a lubricant can be added as necessary. Examples of the lubricant include magnesium stearate, sucrose fatty acid ester, polyethylene glycol, talc, stearic acid and the like.

  When a lubricant is added, the amount of lubricant added is preferably 0.5 to 2% by mass with respect to the whole preparation excluding the lubricant. If the addition amount of the lubricant is less than 0.5% by mass, sufficient lubricity may not be obtained. Adhesion to the mortar may be observed at the time of tableting. Decay in disintegration may be observed.

Next, the manufacturing method of the solid formulation of the solid dispersion in this invention is demonstrated.
When the solid preparation of the solid dispersion of the present invention is a granulated product, preferably after spraying and granulating a water-soluble polymer solution in which a poorly soluble drug is dispersed or dissolved in a mixed powder of an excipient and a disintegrant, Obtained by drying. Specifically, the mixed powder of the excipient and the disintegrant is flowed in a granulating apparatus, and a water-soluble polymer solution in which a poorly soluble drug previously prepared is dispersed or dissolved is sprayed, granulated, and dried. Sizing.
Examples of the granulating apparatus include a fluidized bed granulating apparatus, a high speed stirring granulating apparatus, a rolling granulating apparatus, a dry granulating apparatus, etc., but a fluidized bed in that no mechanical share is applied to the granulated product. A granulator is particularly preferred.
The method for producing a solid preparation of a solid dispersion according to the present invention comprises disintegrating a low-substituted hydroxypropyl cellulose having an average particle diameter of 10 to 100 μm and a specific surface area measured by the BET method of 1.0 m ² / g or more. There is no particular limitation except that it is used as, for example, it can be carried out by the following method.
After the water-soluble polymer is completely dissolved in the above-mentioned solvent such as ethanol / water, a poorly soluble drug is added to obtain a solid dispersion solution. The components that make up the solid dispersion solution may be added to the solvent at once, but if the water-soluble polymer is dissolved first, the stability and poor solubility of the drug in the final solid preparation This is more preferable from the viewpoint of shortening the dissolution time of the drug. The concentration of the solid dispersion solution is not particularly limited, but is 400 mPa · s or less, particularly 100 mPa · s or less in consideration of spraying.
Then, while the mixture of various components including the disintegrant is fluidized in, for example, a fluidized bed granulator, the solid dispersion solution is sprayed, granulated, and dried to obtain a granulated product. In consideration of the case where an organic solvent is used, the air supply temperature in the spraying / granulating process is preferably 150 ° C. or less, particularly preferably 100 ° C. or less.
The exhaust temperature is preferably 30 ° C. or more, particularly 40 ° C. or more, the spray rate is 50 g / min or less, particularly 30 g / min or less, and the spray air pressure is 250 kPa or less, particularly 200 kPa or less. Moreover, the air supply temperature of the drying process performed so that a solvent does not remain in the obtained granulated material after spraying is preferably 150 ° C. or lower, particularly 100 ° C. or lower, and the drying time is preferably 10 to 60 minutes.
The obtained granulated product may be used as it is, but it is also possible to obtain a solid preparation having a more uniform particle size distribution by sieving, pulverizing and the like. For example, the particles can be sized through a sieve having an opening of 500 μm.

On the other hand, when the solid preparation of the solid dispersion is a tablet, the granulated product obtained by the above method is used as a tableting powder, and if necessary, a lubricant is added and compression molded with a tableting machine. Is obtained.
As a device used for tableting, for example, a rotary tableting machine, a single-shot tableting machine, or the like is used. However, the invention is not limited to this, and a tableting machine with a special specification can also be used. The molding pressure at the time of tableting is 1 to 130 kg / cm ² , particularly 10 to 100 kg / cm ² .

The granulated product of the solid dispersion thus obtained has a drug elution concentration of 70% of the dose within 5 minutes after administration, when evaluated by the “dissolution test method 2” described in the 15th revision of the Japanese Pharmacopoeia. % Or more and high elution can be shown.
The obtained solid dispersion tablets disintegrate within 10 minutes after administration when evaluated by the “disintegration test” described in the 15th revision of the Japanese Pharmacopoeia, and are described in the 15th revision of the Japanese Pharmacopoeia. In addition, when evaluated by the “dissolution test second method”, the drug dissolution concentration within 10 minutes after administration is 70% or more of the dose, and high disintegration and dissolution properties can be exhibited.

  The solid preparation obtained in the present invention may be coated by a method known per se for the purpose of masking of taste / odor, enteric dissolution or sustained release. In this case, as the coating agent, for example, enteric polymer cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxy In addition to methyl ethyl cellulose and the like, gastric soluble polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, and the above-mentioned water-soluble polymers can be mentioned.

EXAMPLES The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to these examples.
Synthesis Examples 1 to 3
Example of synthesis of low-substituted hydroxypropylcellulose powder 806 g of powdered pulp (750 g of anhydrous conversion) was charged into a 10 L internal stirring reactor, and 303 g of 26% caustic soda was charged into the reactor, and mixed at 45 ° C. for 30 minutes. Alkaline cellulose having a mass ratio of caustic soda to 0.105 was obtained. Next, nitrogen substitution was performed, 123 g of propylene oxide (0.164 parts by mass with respect to cellulose) was added thereto, and the reaction was performed at a jacket temperature of 60 ° C. for 1.5 hours, and hydroxypropoxyl per anhydroglucose unit. As a result, 1232 g of a crude reaction product of hydroxypropylcellulose having a group substitution mole number of 0.28 was obtained. The etherification efficiency was 61.4%.
Next, neutralization was performed by adding 236 g of 50% by mass of acetic acid to a 10 L internal stirring reactor. This neutralized product was washed and dehydrated with hot water at 90 ° C. using a batch centrifuge at 3000 rpm. The water content of the dehydrated product was 58.2% by mass. This dehydrated product was dried at 80 ° C. for a whole day and night with a shelf dryer.
The dried product was pulverized for 60 minutes at 255 rpm using a batch planetary ball mill FRITSH P-5. The obtained pulverized product was sieved with a sieve having openings of 38, 75 and 180 μm to obtain low-substituted hydroxypropylcellulose powders (samples 1 to 3, respectively) having a hydroxypropoxyl group content of 10.9% by mass. It was. The average particle diameter, specific surface area, loose bulk density, angle of repose, elastic recovery rate, bondability, swelling volume increase rate, and swelling volume increase rate of this powder were evaluated by the above methods. The evaluation results are shown in Table 1.

Examples 1-3
Predetermined amounts of nifedipine and hydroxypropylmethylcellulose (HPMC) shown in Table 2 (hydroxypropoxyl group 8.7% by mass, methoxyl group 28.8% by mass, 6 mPa · s) ethanol: water = 8: 2 (mass ratio) Were dissolved in a mixed solvent to prepare a solid dispersion solution. Then, a mixture of a predetermined amount of low-substituted hydroxypropylcellulose (L-HPC) shown in Table 2, lactose (Pharmatose manufactured by DMV) and corn starch (Corn Starch W manufactured by Nippon Food Processing Co., Ltd.) is fluidized bed granulator (POWREX). The solid dispersion solution was sprayed, granulated, and dried by flowing in Multiplex MP-01, and then granulated with a 30 mesh (aperture 500 μm) sieve to obtain a granulated product. The spray / granulation and drying conditions at this time are as follows.
Supply temperature: 60 ° C, exhaust temperature: 40 ° C,
Spray speed: 10 g / min, spray air pressure: 200 kPa,
Supply temperature of the drying process: 75 ° C., drying time: 15 minutes.

Comparative Example 1
A granulated product was produced in the same manner as in Example 1 except that various powders excluding the low-substituted hydroxypropylcellulose of Example 1 were prepared with the composition shown in Table 2.

Comparative Examples 2 and 3
The low-substituted hydroxypropyl cellulose of Example 1 was replaced with low-substituted hydroxypropyl cellulose (L-HPC) (hydroxypropoxyl group 10.9% by mass, average particle size 44 μm, specific surface area 0.92 m ² / g, loose bulk density. 0.44 g / ml, angle of repose 39 degrees, elastic recovery rate 3.8%, swelling volume increase rate 250%, swelling volume increase rate 200% / min). Granules were produced.

Table 2 shows the results of observing the flow state of the granulated product during the granulation process in the granulated product of each formulation. In the evaluation of fluidity, “excellent” has particularly good fluidity, “good” has good fluidity, “poor” has somewhat poor fluidity, blocking in the layer (powder stays in the layer and does not flow) ) There is an indication of occurrence, “impossible” means that the fluid is blocked in the bed and cannot flow.
As shown in Table 2, the granules of Examples 1 to 3 using Samples 1 to 3 were excellent in fluidity, but in Comparative Example 1 or 2, the granules were compared with Examples 1 to 3. The liquidity was inferior. Moreover, in the comparative example 3, since the fluidity | liquidity of the granulation powder fell in the process and blocking generate | occur | produced in the layer, it was impossible to granulate to the last.

Drug dissolution of Examples 1 to 3 and Comparative Examples 1 and 2 About the granulated product obtained in Examples 1 to 3 and Comparative Examples 1 and 2, 1800 mg of granulated product (containing 90 mg as nifedipine) was The test was conducted in accordance with the 15th revised dissolution test paddle method. The conditions for the dissolution test were 100 rpm and 900 ml of water as the test solution. For reference, 90 mg of nifedipine powder was also tested in the same manner. The results are shown in Table 3.
All of the granulated products of Examples 1 to 3 showed higher elution properties than the granulated product of the comparative example. On the other hand, in the granulated product of Comparative Example 2, although the dissolution property was improved as compared with the case where the disintegrant was not added (Comparative Example 1), the degree was smaller than that of the Example. Conversely, when there are many disintegrants (Comparative Example 3), blocking occurred during fluidized bed granulation and it was difficult to perform good granulation.
From the above, the granulated product of the solid dispersion of the present invention was recognized to have a rapid and high drug dissolution property.

Examples 4 to 6 and Comparative Examples 4 and 5
The granulated product prepared in Examples 1 to 3 was used as a tableting powder, and 0.5 mass% of magnesium stearate as a lubricant was added to the tableting powder and mixed. A rotary tableting machine (Kikusui Seisakusho Co., Ltd.) Vergo) produced 201 mg tablets at a molding pressure of 20 kg / cm ² (Examples 4 to 6). As a comparative example, tablets were produced in the same manner as in Example 4 using the granulated product prepared in Comparative Examples 1 and 2 as a tableting powder (Comparative Examples 4 and 5). The obtained tablets were subjected to hardness and disintegration tests, and the results are shown in Table 4.
The tablets obtained in Examples 4 to 6 showed appropriate hardness and excellent disintegration. On the other hand, in the tablets obtained in Comparative Examples 4 and 5, although the appropriate hardness was obtained, the disintegration time was delayed.

Drug dissolution characteristics of Examples 4 to 6 and Comparative Examples 4 and 5 About 1809 mg of tablets (containing 90 mg as nifedipine) obtained by Examples 4 to 6 and Comparative Examples 4 and 5, dissolution tests similar to those of Examples 1 to 3 Went. For reference, 90 mg of nifedipine powder was also tested in the same manner. The results are shown in Table 5.
The tablets obtained in Examples 4 to 6 obtained results comparable to the dissolution rate from the granulated product. On the other hand, when the low-substituted hydroxypropylcellulose as a disintegrant was not added (Comparative Example 4) and the tablets obtained by Comparative Example 5, almost no improvement in dissolution was observed.
From the above, it was confirmed that the solid dispersion tablet of the present invention had excellent disintegration property and rapid and high dissolution property.

Examples 7-10
Table 6 shows the same amount of nifedipine, hydroxypropylmethylcellulose (HPMC), lactose (Pharmatose manufactured by DMV) and corn starch (Corn Starch W manufactured by Nippon Food Processing Co., Ltd.) shown in Table 6 in the same manner as in Examples 1 to 3. Granules were obtained at the mixing ratio shown in FIG.

  Table 6 shows the results of observing the flow state of the granulated product during the granulation process in the granulated product of each formulation. In the flow state evaluation, “excellent” means particularly good fluidity, “good” means good fluidity, and Examples 7 to 10 show good fluidity.

Drug Elution Characteristics of Examples 7 to 10 About the granulated product obtained in Examples 7 to 10, 1800 mg of granulated product (containing 90 mg as nifedipine) was evaluated in the same manner as in Examples 1 to 3. The results are shown in Table 7.
All of the granulated products of Examples 7 to 10 showed rapid and high drug dissolution properties.

Examples 11 and 12
The granulated product prepared in Examples 7 and 8 was used as a tableting powder, and 0.5% by mass of magnesium stearate as a lubricant was added to the tableting powder and mixed, and the same as in Examples 4-6. Tablets were produced by this method (Examples 11 and 12). The obtained tablets were subjected to hardness measurement and disintegration test in the same manner as in Examples 4 to 6, and the results are shown in Table 8.
The tablets obtained in Examples 11 and 12 showed appropriate hardness and excellent disintegration.

Drug dissolution characteristics of Examples 11 and 12 About 1890 mg of tablets of Examples 11 and 12 (containing 90 mg as nifedipine), dissolution tests from tablets were performed using the same method as in Examples 4-6. The results are shown in Table 9.
The tablets obtained in Examples 11 and 12 showed results comparable to the drug dissolution rate from the granulated powder. Moreover, the improvement of the elution property was seen by increasing the addition amount of a disintegrating agent.
From the above, it was confirmed that the solid dispersion tablet of the present invention had excellent disintegration property and rapid and high dissolution property.

Claims (8)

A solid preparation of a solid dispersion containing a hardly soluble drug, a water-soluble polymer and a disintegrant, wherein the hardly soluble drug is “almost insoluble” or “extremely” defined in the 15th revision of the Japanese Pharmacopoeia with respect to water. A polymer that is said to be “dissolvable” and whose water-soluble polymer falls under the category of “extremely soluble”, “easily soluble” or “slightly soluble” as stipulated in the 15th revision of the Japanese Pharmacopoeia. The disintegrant is a low-substituted hydroxypropyl cellulose having an average particle diameter of 10 to 100 μm, an angle of repose of 42 ^° or less, and a specific surface area measured by the BET method of 1.0 m ² / g or more. A solid formulation of a solid dispersion.   The solid preparation of the solid dispersion according to claim 1, further comprising an excipient.   The solid preparation of the solid dispersion according to claim 1 or 2, wherein the disintegrant is a low-substituted hydroxypropyl cellulose having 5 to 16% by mass of hydroxypropoxyl group.   The solid preparation of a solid dispersion according to any one of claims 1 to 3, wherein the disintegrant is a low-substituted hydroxypropyl cellulose having a loose bulk density of 0.30 g / ml or more.   The solid preparation of a solid dispersion according to any one of claims 1 to 4, wherein the disintegrant is a low-substituted hydroxypropylcellulose having an elastic recovery rate of 7% or less when compression-molded at a compression pressure of 50 MPa.   The solid dispersion according to any one of claims 1 to 5, wherein the disintegrant is a low-substituted hydroxypropyl cellulose having a swelling volume increase rate of 300% or more upon water absorption and a swelling volume increase rate of 100% / min or more. A solid formulation of the body. The solid preparation of a solid dispersion according to any one of claims 1 to 6 , wherein the water-soluble polymer is selected from alkyl cellulose, hydroxyalkyl cellulose, hydroxyalkyl alkyl cellulose, polyvinyl alcohol and polyvinyl pyrrolidone. As a disintegrant, a sparingly soluble drug is added to a low-substituted hydroxypropylcellulose powder having an average particle size of 10 to 100 μm, an angle of repose of 42 ^° or less, and a specific surface area measured by the BET method of 1.0 m ² / g or more. spraying the dispersed or dissolved water soluble polymer solution, granulation, Ri Na comprise drying, flame-soluble drug is "practically insoluble" is defined in the Japanese Pharmacopoeia fifteenth against water Or it is a drug said to be “extremely insoluble”, and the water-soluble polymer is “extremely soluble”, “easily soluble” or “slightly soluble” as defined in the 15th revision of the Japanese Pharmacopoeia with respect to water. method for producing a solid preparation of the corresponding polymer der Ru solid dispersion.