JPH0566364B2 - - Google Patents

Description

[Detailed description of the invention]

[Field of Application of the Invention] The present invention relates to a method for improving the dissolution rate of poorly soluble drugs, and more specifically, in order to improve the bioavailability of poorly soluble drugs, the present invention relates to a method for improving the dissolution rate of poorly soluble drugs. The present invention relates to a method for improving the dissolution rate of poorly soluble drugs, which comprises kneading and kneading with a mixing roll machine at room temperature or heating, or further heating the kneaded product obtained by kneading and kneading at room temperature. [Background of the Invention] When a poorly soluble drug is orally administered, it is difficult to be absorbed in the gastrointestinal tract, making it impossible to achieve effective medicinal efficacy or rapid efficacy. Increasing the solubility of poorly soluble drugs has traditionally been considered to be particularly important for increasing bioavailability and expecting effective drug efficacy and rapid efficacy, and various methods have been known to improve solubility. It is being These methods are detailed in Setsuo Yoshiyanagi, Chemistry, 31 , 881 (1977). All of these methods have advantages and disadvantages, and problems still remain in their practical application. Among these methods, the solid dispersion method is particularly noteworthy.
This is defined as a method of preparing one or more drugs by dispersing them in monomolecular form in an inert carrier, and is described by WLChiu & S.Riegelman, J.Pharm.
Sci., 60 , 181 (1971). Its manufacturing methods include a melting method by heating and melting, and a solvent method in which the drug and water-soluble polymer are dissolved in a solvent, and then the solvent is removed to obtain a solid composition in which the drug is dispersed and amorphized in a polymer matrix. (Also called coprecipitation method. Hereinafter referred to as coprecipitation method). However, heating the drug until it melts tends to cause deterioration of the drug, and the coprecipitation method also has the problem of residual solvent, so there is room for improvement. In addition, a method has recently been reported in which a poorly soluble drug and crystalline cellulose are co-pulverized using an ultrafine mill such as a ball mill to amorphize them, and it has been shown that when this method is used, the dissolution rate of the drug is significantly increased. [Nakai et al., Journal of Powder Engineering Society, 10 , 473 (1979),
No. 54-29565]. However, this method has limitations on the amount of drug that can be contained in the drug formulation, and requires grinding for several tens of hours until it becomes amorphous.This method not only lacks convenience, but also tends to lead to drug deterioration, which may affect the drug formulation. It was thought that there would be negative effects, and improvements were desired. Therefore, as a result of intensive research into improving the method of improving the dissolution rate of poorly soluble drugs, the present inventors found that the method of kneading is simply kneading with a heated roll mixer at room temperature or at a temperature lower than the melting point of the poorly soluble drug used. This significantly improves the dissolution rate of poorly soluble drugs, and when the kneaded product obtained by kneading and kneading at room temperature is heated to a temperature lower than the melting point of the poorly soluble drug, the dissolution rate increases compared to that obtained by kneading and kneading at room temperature. The present invention was completed based on the finding that the performance of the present invention can be further improved. [Object of the Invention] One of the objects of the present invention is to mix a poorly soluble drug and a specific water-soluble polymer base in a heated roll mixer at room temperature or at a temperature lower than the melting point of the poorly soluble drug used. It consists in kneading and kneading. The second object of the present invention is to knead and knead a poorly soluble drug and a specific water-soluble polymer base using a roll mixer at room temperature, and then heat the mixture at a temperature lower than the melting point of the poorly soluble drug. An object of the present invention is to provide a method for improving the dissolution rate of poorly soluble drugs. Another object of the present invention is to further add other pharmaceutical additives to the preparation or composition obtained by such a method to prepare powders, fine granules, tablets, pills, capsules, etc. for oral administration. The aim is to provide it as a solid preparation. [Structure of the Invention] The method for improving the dissolution rate of a poorly soluble drug according to the specified invention includes a poorly soluble drug, polyvinylpyrrolidone,
One or more water-soluble polymer bases selected from the group consisting of polyvinyl alcohol, methylcellulose, polyethylene glycol, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, gum arabic, dextrin, gelatin, pectin, and lactose. The composition is kneaded using a roll mixer under heating at room temperature or at a temperature lower than the melting point of the poorly soluble drug used. The method under room temperature is simply referred to as the roll mixing method, and the method under heating is simply referred to as the hot roll mixing method. Furthermore, the method of the dependent invention of the present invention further comprises heating the kneaded material obtained by the roll mixing method of the specified invention at a temperature lower than the melting point of the poorly soluble drug used. . This method is hereinafter simply referred to as a heat treatment method. (Poorly Soluble Drug) The sparingly soluble drug used in the present invention refers to a drug that has low solubility in water and is poorly absorbed in the gastrointestinal tract when used in ordinary oral preparations. Such drugs include poorly soluble anti-inflammatory agents such as phenacetin, poorly soluble anticonvulsants such as phenytoin, poorly soluble inotropes such as dietoxin and digoxin, poorly soluble coronary vasodilators such as nifedipine, and poorly soluble coronary vasodilators such as diazepam. Soluble psychoactive agents, cholic acid-based cholatenic or gallstone dissolving agents such as chenodeoxycholic acid,
Examples include steroid compounds such as prednisolone, cortisone, hydrocortisone, and dexamethasone, as well as other sulfur drugs, griseofulvin, γ-tocopherol, and rifampicillin. (Water-soluble polymer base) The water-soluble polymer base used in the present invention is one that improves the dissolution rate of poorly soluble drugs by roll mixing, hot roll mixing, or heat treatment. Examples include the above-mentioned specific water-soluble polymer bases whose effects have been confirmed. There are various molecular weights of water-soluble polymer bases, and the intended purpose of the present invention can be achieved with any molecular weight, but if the molecular weight exceeds 100,000, the solubility will be slightly lower. Therefore, the base material preferably has a molecular weight of up to about 100,000.
Particularly preferred are polyethylene glycols having a molecular weight of up to 4000, which are liquids or low molecular weight solids. Further, although polyvinyl alcohol and the like in the base of the present invention can have any degree of saponification, the intended purpose of the present invention can be achieved, but a higher degree of saponification is relatively advantageous. Furthermore, the degree of polymerization of the base is not an important rate-limiting factor in improving the dissolution rate, but as the degree of polymerization increases, the solubility gradually decreases, so the degree of polymerization
Up to 2000 are advantageously used. (Roll mixer) The roll mixer used in the present invention consists of horizontal two-axis rolls, and the bulk powder is fed between the rolls that rotate inwardly, and is kneaded and kneaded by the rotation of the rolls. Any device is fine. This type of roll mixer is not currently available in commercially available medical formulation equipment (including laboratory use).
Although it is somewhat similar in shape to a roller compactor, it does not produce granules, so its purpose is completely different. In the embodiment of the present invention, an open horizontal two-roll type mixing roll used for kneading and kneading such as rubber mastication, which is widely used in the field of rubber industry, is used. A tray was provided to collect and re-supply the powder, and the rotation of the rolls was motorized. A schematic structural diagram of this device is shown in FIG. A shows its front view, B shows its side view, and roll machine 1
Two parallel rolls (front roll 4, rear roll 5) mounted on a frame 2 are provided close to each other,
The rotation of the motor 12 causes them to rotate inwardly relative to each other. The mixing roll machine heats or cools the rubber when kneading it, so the rolls are hollow and allow water or steam to pass through.The hot roll mixing method of the present invention requires heating. Although this configuration can be used as is, it is not necessarily limited to this configuration. In addition, in order to continuously manufacture the formulation or composition of the present invention, it is necessary to install a device that automatically collects the powder that falls between the rolls and re-feeds it to the rollers, although this is not currently commercially available. Alternatively, it is preferable to use a device in which two horizontal rolls are mounted in multiple stages and the kneaded material is recovered at the bottom of the device. Additionally, there are Banbury mixers that are not open type roll mixers. This is designed for the purpose of kneading in a gas stream and does not need to be used for this purpose in the present invention. However, since the roll mixer of the present invention handles powder and scattering of powder during the manufacturing process is a problem, it is not limited to an open type, but naturally includes a closed system device. The spacing between the rolls is appropriately set in consideration of the conditions such as the poorly soluble drug used, the base material, and the dosage form, but is usually set in the range of 3/100 to 6 m/m and adjusted using a push boat. Regarding the material and hardness of the roll, chilled rolls, nickel steel, or hard chromium ore rolls having a Rockwell hardness of 70 to 65 degrees are commonly used, and are also suitable for achieving the purpose of the present invention. (Kneading and kneading) The time for kneading and kneading is set appropriately taking into consideration the production scale, the poorly soluble drug used, the water-soluble polymer base, etc., but usually 30 minutes to 3 hours is sufficient. . As is clear from the experimental results of the present invention,
In all experimental systems, it can be carried out in about 1 hour and sufficient effects can be achieved. The mixing ratio of the water-soluble polymer base to the poorly soluble drug used is 24:1 or more (approximately 0.042 times or more),
Preferably, the ratio is 1:1 or more (1:1 or more). Even when the drug content of the composition of the present invention is 16% or more (~1:5 in terms of the above-mentioned kneading ratio), the solubility does not decrease significantly, and in this respect, it is far superior to known pulverization methods. advantageous to In addition, kneading and kneading as used in the present invention refers to an operation of strongly kneading powder or solids with a liquid or a highly viscous substance, and ultimately achieves ultramicroscopic homogeneous mixing. . On the other hand, co-grinding refers to a mechanical operation in which two components are divided into solid substances using mechanical and dynamic forces, thereby reducing the particle size and increasing the solid surface area. are essentially different. Further, it will become clear from the experimental examples described later that kneading and kneading is essentially different from mere uniform mixing and blending. (Heating) If heating is performed at or near the melting point of a poorly soluble drug, the drug may melt and cause deterioration of the drug. The purpose of the present invention cannot be achieved. Therefore, in the present invention, "heating at a temperature lower than the melting point of the poorly soluble drug used" means heating at a temperature at which the poorly soluble drug used does not melt. Nifedipine-polyvinylpyrrolidone (weight ratio 5:1) subjected to hot roll mixing method (Example 4 (b))
In a powder sample of fenidipine, the melting point of 170
It has been confirmed that the dissolution rate is significantly increased by kneading for 1 hour at a temperature of 90-100°C, which is much lower than ~174°C. Thus, it is desirable to select a heating temperature as low as possible below the melting point of the drug and at a temperature that can improve the dissolution rate. (Heat treatment method) Heat treatment of the kneaded product kneaded and kneaded at room temperature can also be performed using a roll mixer, but since there is no need to further roll the kneaded product, it is possible to collect the kneaded product from the roll mixer and use it. It is preferable to carry out the treatment by transferring to an appropriate heat treatment apparatus. The setting of the heating temperature is exactly the same as the above-mentioned hot roll mixing method. For example, the melting point of phenacetin is 134-135°C, but in the system of phenacetin-polyvinylpyrrolidone (weight ratio 1:5) of Example 2 of the present invention, the melting point is 90°C.
It was found that by heating at 5°C, the dissolution rate was further increased compared to the kneaded product kneaded at room temperature. In the examples, a constant temperature dryer, which is commonly used in this field, is used as the heat treatment equipment, but it is possible to achieve the purpose of the heat treatment method of the present invention, and to avoid causing undesirable changes in quality, etc., particularly for formulation. It can be of any structure or scale as long as it does not (Formulation) Formulation using the method for improving dissolution rate of the present invention involves combining a poorly soluble drug and a water-soluble polymer base, or, if necessary, additionally adding coloring agents, flavoring agents, flavoring agents, bulking agents, etc. Adding additives, kneading and kneading with a roll mixer at room temperature or under heating, or heat-treating the kneaded product at room temperature to form a powder directly, or mixing a poorly soluble drug and a water-soluble polymer base at room temperature or under heating. Add additives for formulations, such as coloring agents, flavoring agents, flavoring agents, fillers, disintegrants, etc., to the powder obtained by kneading under heating or heat-treating the kneaded material at room temperature, depending on the dosage form, etc. This is carried out by preparing solid preparations for oral administration such as powders, fine granules, granules, tablets, pills, capsules, etc. by a conventional method. [Effect of the present invention] It was confirmed by the following experimental method that the preparation or composition obtained by applying the method of the present invention exhibits an excellent dissolution rate. (Measurement of dissolution rate) (1) Powder sample 200 mg of the powder sample obtained in Example (100 meshes in total) was added to the water in Step 3 at 37°C with stirring, and the concentration of the dissolved poorly soluble drug was measured at 10 mm. The absorbance at a characteristic wavelength (245 nm for phenacetin) was continuously recorded through the flow cell using a spectrophotometer (Toshiba Beckman, Specter 20), and the dissolution rate was estimated from the slope of the obtained straight line. This value was determined as the average value of five or more samples of the same sample. (2) Tablet Using the tablet (200 mg) obtained in Example, the disintegration test method of the Japanese Pharmacopoeia was applied. (Experimental Results) (1) Table 1 shows the experimental results of the phenacetin-polyvinylpyrrolidone powder samples and heat-treated powder samples of Examples 1 and 2. It should be noted that 16% polyvinylpyrrolidone content indicates a blending ratio of 5:1, and 84% indicates a weighed ratio of 1:5. The same applies to the following experimental system.

【table】

[Table] The graph created based on this data is
As shown in the figure. , , and indicate the dissolution rate curves corresponding to the methods in the table above, respectively. The same reference numerals will be used in the drawings showing the experimental results below. (2) The experimental results of the phenacetin-polyvinylpyrrolidone tablets obtained in Example 1 are shown in FIG. (3) The experimental results of the phenytoin-polyvinylpyrrolidone powder sample obtained in Example 3 are shown in FIG. (4) The experimental results of the phenytoin-polyvinylpyrrolidone tablet obtained in Example 3 are shown in FIG. (5) The experimental results of the nifedipine-polyvinylpyrrolidone tablet obtained in Example 4(a) are shown in FIG. 6(a). Further, the experimental results of the hot roll mixing method and the roll mixed powder samples obtained in Example 4*(a) and (b) are shown in FIG. 6(b). shows the dissolution rate curve of the hot roll mixed sample. (6) The experimental results of the indomethacin-polyvinylpyrrolidone powder sample obtained in Example 5(a) are shown in FIG. 7(a). (7) Indomethacin (100
The experimental results for the polyvinylpyrrolidone powder sample are shown in FIG. (8) The experimental results of the griseofulvin-polyvinylrilopidone tablet obtained in Example 6 are shown in FIG. (9) Table 2 shows the dissolution rates of tablet and powder samples of phenacetin and various water-soluble polymer bases obtained by the roll mixing method of the present invention. The weight ratio is phenacetin:
The ratio of various water-soluble polymer bases is 1:5.

【table】

【table】

[Table] (9) The influence of the molecular weight of the water-soluble polymer base on the dissolution rate was confirmed using tablet and powder samples (Example 1) of phenacetin-polyvinylpyrodone (weight ratio 1:5). The results are shown in Table 3.

[Table] (10) The influence of the degree of saponification of the water-soluble polymer base on the dissolution rate was confirmed using a powder sample (Example 7) of phenacetin-polyvinyl alcohol (weight ratio 1:5). The results are shown in Table 4.

[Table] Regarding the effect of the viscosity of the water-soluble base on the dissolution rate, when we confirmed the effect of the viscosity of the water-soluble base on phenacetin-methylcellulose (weight ratio 1:5), the dissolution rate was the best at 1500 cps, and dissolution was poor at lower viscosities. It turned out that the speed was a little slower. In addition, regarding the influence of the degree of polymerization of the polymer base, although no particular difference is observed between phenacetin and polyvinyl alcohol (polymerization ratio 1:5), as the degree of polymerization increases, the dissolution rate gradually decreases. Up to 2000 is advantageous. (11) The experimental results of the griseofulvin-polyvinylpyrrolidone-polyethylene glycol powder sample obtained in Example 17 are shown in FIG. (12) The experimental results of the nifedipine-polyvinylpyrrolidone-polyethylene glycol powder sample obtained in Example 18 are shown in FIG. (Discussion) As is clear from the above experimental results, the roll mixing method and hot roll mixing method of the present invention are superior to the simple physical mixing method and the coprecipitation method, which is currently recognized as the most practical method. Therefore, it is practical in achieving an improvement in dissolution rate. Further, when the heat treatment method of the present invention is used, a preparation or a composition for a preparation can be obtained which has a higher dissolution rate than a kneaded product obtained by the roll mixing method. Therefore, the method for improving the dissolution rate of the present invention is essentially different in a technical sense from mere mixing, compounding, etc. in a pharmaceutical preparation. In the case of tablets, although the influence of the disintegration of the tablet itself cannot be ignored, the method for improving the dissolution rate of the present invention was recognized as the most effective technical means for achieving the object of the present invention. X-ray diffraction patterns were confirmed for samples with various blending ratios of phenacetin-polyvinylpyrrolidone obtained by the roll mixing method, heat treatment method, simple physical mixing method, or coprecipitation method of the present invention (No. 9
and Fig. 10), the blending ratio is 1:1, 1:2,
In the 1:3 roll mix sample, it was observed that some parts were amorphous and some crystals were present, and in the 1:5 roll mix sample, it was observed that the roll mix sample was completely amorphous, while in the 1:2 roll mix sample, it was observed that the sample was completely amorphous. It is observed that the sample obtained by further heat-treating the roll mixed sample of 1 is also completely amorphized. Therefore, the fact that the dissolution rate can be significantly improved in any of the above blending ratios in the method of the present invention is thought to be largely due to the surfactant effect of the base, and that effect is due to the surface active effect of the base material. It is recognized that this phenomenon appears more prominently in the kneaded mixture in which the drug and the base interact more closely than in other cases. That is, it is considered that the roll mixing operation dramatically increases the contact area between the drug and the base due to its compaction effect, and greatly improves the so-called "wetting" of the surface of the drug powder. In addition, in the case of the present invention, the amorphization of the drug is considered to be based on the lattice misalignment of the crystal, and it is considered that kneading, heating, and interaction between the drug and the base cause this lattice misalignment. Ru. Therefore, it is recognized that pulverization, as conventionally recognized, is not an important factor in improving the solubility of poorly soluble drugs. The method of the present invention can improve solubility in a short time by kneading, without co-pulverizing the drug and base material, which requires a large load and a long time, and can reduce the drug content. This is an excellent method that was able to achieve a reduction of 10% or more for the first time. Furthermore, the present invention is a method that does not require a solvent or heating to the extent of melting, and in this sense, it can be said to be a simple and optimal method for formulation, and has great industrial value. Examples are given below, and drugs and bases that improve solubility and means for improving solubility will be explained in detail. Note that, as is clear from the above experimental examples, the present invention is a technology that can be generalized, and is not limited to only those described in the examples. [Example] Example 1 Phenacetin (pharmaceutical product) and polyvinylpyrrolidone (PVPK-30, manufactured by Wako Pure Chemical Industries, Ltd.) were each weighed so as to have an arbitrary weight ratio, and each bulk powder was prepared. The compound is fed onto the horizontal rolls of a heated roll machine for plastic kneading [laboratory horizontal two-roll kneader (mixing roll, manufactured by Eto Seisakusho)], which rotates 1 to 2 times per second, and the mixture is passed between the rolls. The fallen material was collected in a saucer, and kneaded (roll mixing) at room temperature for 1 hour while being re-supplied onto the roll.The kneaded material was collected and dried under vacuum at room temperature for 3 hours.Phenacetin-Polyvinyl X of kneaded mixtures of pyrrolidone in ratios of 1:1, 1:2, 1:3, and 1:5, respectively
The ray diffraction pattern was confirmed using a GF2025 X-ray diffraction measuring device manufactured by Rigaku Denki Co., Ltd. (Figure 9) (Control) (1) Physical mixing method Phenacetin and polyvinylpyrrolidone were mixed in the same weight ratio as in the roll mixing method. take,
This bulk powder mixture was thoroughly mixed in a mortar for 15 to 20 minutes and dried under vacuum at room temperature for 3 hours. (2) Weigh phenacetin and polyvinylpyrrolidone in the same weight ratio as in the roll mixing method, dissolve them in methylene chloride, evaporate the solvent under reduced pressure at room temperature, collect the precipitated solid, and dissolve it under vacuum. It was dried for 3 hours at room temperature. In addition, for the solubility test, 200 mg of a powder sample with a grain size that passes through 100 mesh was used.
The material was molded under a pressure of 2 tons/cm ² . Figure 10 shows the X-ray diffraction data of those obtained by the coprecipitation method at blending ratios of 1:2 and 1:3, and those obtained by the physical mixing method at a blending ratio of 1:5. [f, g, h] shown in [f, g, h]. Example 2 The powder sample obtained in Example 1 was left standing in a constant temperature dryer at 90±5° C. for 1 hour to obtain a heat-treated sample.
Control and solubility test samples were prepared under identical conditions. The X-ray diffraction pattern of a heat-treated powder sample with a blending ratio of 1:2 is shown in FIG. 10 [e]. Example 3 Processed in the same manner as in Example 1, with a blending ratio of 3:1,
Phenytoin-polyvinylpyrrolidone powders and tablets of 1:1, 1:3 and 1:5 were obtained. The same applies to controls. Example 4 (a) Processed in the same manner as in Example 1, with a blending ratio of 1:
1, 1:3, 1:5 and 1:9 nifedipine-polyvinylpyrrolidone powders and tablets were prepared. As a control, tablets were prepared using a physical mixing method and subjected to a solubility test. (b) Set the temperature when mixing the rolls to 90-100℃ instead of room temperature.
A heated roll mixed powder sample was obtained by processing in exactly the same manner as in (a) except that the temperature was set at ℃. Example 5 (a) Processed in the same manner as in Example 1, with a blending ratio of 24:
1, 12:1, 5:1, 3:1, 1:1, 1:
1.5, 1:3 and 1:5 indomethacin-polyvinylpyrrolidone powders were prepared. For controls, the mixing ratio was 5:1, 1:1,
1:3 and 1:5, 24:1 by coprecipitation method,
12:1, 5:1, 3:1, 1:1, 1:3 and 1:5 were prepared. (b) Indomethacin-polyvinylpyrrolidone powder was obtained in exactly the same manner as in (a) except that the indomethacin content was 100 mg and the blending ratio of 1:1.5 was not prepared. Example 6 Processed in the same manner as in Example 1, with a blending ratio of 5:1,
Tablets of 1:1, 1:3, 1:5 and 1:19 griseofulvin-polyvinylpyrrolidone were prepared. For controls, 5:1 and 1:19 by coprecipitation method.
The same procedure was followed except that the sample was not prepared. Examples 7 to 16 In the same manner as in Example 1, powders and tablets were obtained in which phenacetin and various water-soluble polymer bases were prepared at a blending ratio of 1:5. For polyvinyl alcohol, in order to confirm the influence of saponification degree and polymerization degree, various degrees of saponification and polymerization were used, and for polyethylene glycol [and polyvinylpyrrolidone Example 1], the influence of molecular weight was confirmed. Therefore, methylcelluloses of various molecular weights were used, and methylcelluloses of various viscosities were prepared to examine the effect of viscosity. Example 7 Phenacetin-Polyvinyl Alcohol Example 8 Phenacetin-Polyethylene Glycol Example 9 Phenacetin-Methylcellulose Example 10 Phenacetin-Hydroxyethylcellulose Example 11 Phenacetin-Hydroxypropylcellulose Example 12 Phenacetin-Carboxymethylcellulose Example 13 Phenacetin-Gum Arabic Example Example 14 Phenacetin-gelatin Example 15 Phenacetin-Dextrin Example 16 Phenacetin-Lactose Example 17 Polyethylene glycol in the same manner as in Example 1
Griseofulvin-polyvinylpyrrolidone-polyethylene glycol kneaded product containing 10% of 1500 (mixing ratio 8:37:5, 5:13:2, 17:28:5, 5:
4:1, 33:12:5, 15:3:2, 42:3:5)
was prepared. As a control, the blending ratio was 8:37:5, 5:13:
A coprecipitate of the above three components of 2, 5:4:1 and 15:3:2 was prepared and subjected to a solubility test. Example 18 Polyethylene glycol was prepared in the same manner as in Example 1.
Nifedipine-polyvinylpyrrolidone-polyethylene glycol kneaded product containing 10% of 1500 (blending ratio 9:81:10, 8:37:5, 5:13:2, 5:4:
1,15:3:2) was prepared. As a control, a coprecipitate was prepared using the three components in the same mixing ratio as described above and subjected to a solubility test.

[Brief explanation of the drawing]

Figure 1 is a schematic structural diagram of the roll mixer used in the present invention, where A is a front view, B is a side view, Figure 2 is a phenacetin-polyvinylpyrrolidone powder sample, and Figure 3 is a tablet thereof. , Figure 4 shows a powder sample of phenytoin-polyvinylpyrrolidone, Figure 5 shows its tablets, Figure 6A shows nifedipine-polyvinylpyrrolidone tablets, and Figure 6B shows nifedipine-polyvinyl obtained by roll mixing method and hot roll mixing method. Figure 7 shows the dissolution rate test results for a pyrrolidone powder sample, Figure 7A shows an indomethacin-polyvinylpyrrolidone powder sample, Figure 7B shows an indomethacin (100 mg)-polyvinylpyrrolidone powder sample, and Figure 8 shows the results of a griseofulvin-polyvinylpyrrolidone tablet. 9 shows the phenacetin-polyvinylpyrrolidone powder sample obtained by the roll mixing method of Example 1, and FIG. 10 shows the phenacetin-polyvinylpyrrolidone powder sample obtained by the control of Example 1 and Example 2. Figure 11 shows the X-ray diffraction charts of each phenacetin-polyvinylpyrrolidone powder sample obtained by the heat treatment method of Example 17.
Figure 12 shows the dissolution rate test of the 3-component roll mixture (powder) of griseofulvin-polyvinylpyrrolidone-polyethylene glycol obtained in Example 18. ) are shown respectively. In Figure 1, 1 ...Roll mixer, 2...Frame, 3...Cap, 4...Front roll, 5...
...Rear roll, 6, 7...Roll shaft box, 8...Saucer, 9...Stock guide, 10...Safety bar, 11...Bull gear, In Figures 2 to 8,...Roll mixing method ,…
...heat treatment method, ...physical mixing method, ...coprecipitation method,
...The dissolution rate curve of the product obtained by the hot roll mixing method is shown in Fig. 9, a...The weight ratio of phenacetin and polyvinylpyrrolidone is 1:1, b...1:
2, c...1:3 and d...1:5 are the diffraction patterns obtained by the roll mixing method. The diffraction pattern obtained by the method was divided into f...1:2 and g...
The diffraction pattern of the one obtained by the coprecipitation method at 1:3 and the diffraction pattern of the one obtained by the physical mixing method at h...1:5 are shown, respectively.

Claims (1)

[Claims] 1. A poorly soluble drug, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, polyethylene glycol, hydroxyethylcellulose,
One or more water-soluble polymer bases selected from the group consisting of hydroxypropyl cellulose, carboxymethyl cellulose, gum arabic, dextrin, gelatin, pectin, and lactose at room temperature or at the melting point of the poorly soluble drug used. 1. A method for improving the dissolution rate of a poorly soluble drug, which comprises kneading and kneading with a roll mixer under heating at a temperature lower than that of the above. 2. Poorly soluble drugs, polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, polyethylene glycol, hydroxyethylcellulose,
one or more water-soluble polymer bases selected from the group consisting of hydroxypropyl cellulose, carboxymethyl cellulose, gum arabic, dextrin, gelatin, pectin, and lactose;
1. A method for improving the dissolution rate of a poorly soluble drug, which comprises kneading and kneading with a roll mixer at room temperature and then heating at a temperature lower than the melting point of the poorly soluble drug used.