JPH031288B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a method for producing easily absorbable preparations of nifedipine, and more specifically, fine particles (hereinafter referred to as fine particle carriers) obtained by granulating a water-soluble pharmaceutical additive are combined with nifedipine and polyvinyl granules. The present invention relates to a method for producing an easily absorbable nifedipine fine granule preparation, which is coated with a solid solution consisting of pyrrolidone (hereinafter referred to as PVP). Prior art and problems to be solved by the invention Nifedipine (dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl))
-3,5-pyridinedicarboxylate) is one of the typical angina treatment drugs, but since angina attacks can occur without warning, patients should always carry the drug with them and take emergency medication in the event of an attack. The drug must be easy to take, rapidly and fully effective. However, nifedipine normally has a melting point of 170
It is a crystal with a temperature of ~174℃ and is extremely poorly soluble in water.
Therefore, even if the powder is made into a normal granule preparation or fine granule preparation, it is poorly absorbed in the body and cannot meet the above-mentioned rapid effect. Various measures have been proposed to improve this malabsorption property of nifedipine. One method is to dissolve nifedipine in polyethylene glycol and fill capsules with this solution (see Japanese Patent Application Laid-open No. 28621/1983). However, in this case, the capsules are relatively large and are not easy to take, and the manufacturing technology is complicated. On the other hand, as a general method for making a poorly absorbed drug easily absorbable, it is known to disperse the poorly absorbed drug in a water-soluble polymeric substance such as PVP or polyethylene glycol to form a solid solution [for example, journal of Pharmaceutical Sciences, Vol. 55, pp. 1323-1324 (1966)],
It has also been shown that absorption is improved when this solid solution method is applied to nifedipine [see Third International Adalate Symposium, pp. 33-41 (1976)]. Furthermore, it has also been proposed to obtain a solid preparation (powder preparation) by dissolving nifedipine and PVP in an organic solvent (e.g., methyl alcohol, methylene chloride, etc.) and distilling off the organic solvent from the solution (Unexamined Patent Publication No. (See Publication No. 54-2316). However, conventional methods using these solid solutions are not fully satisfactory in terms of the quality of the resulting preparations and the manufacturing technology. In other words, in the conventional method, nifedipine and
A binder and excipients are added and kneaded as necessary to an organic solvent solution of PVP, and this kneaded product is subjected to operations such as granulation, drying, pulverization, and sizing using conventional methods to form the desired product. However, there are the following drawbacks or points that should be improved. (1) First, the solubility in water and absorption in the body of the conventional formulation (formulation of Comparative Example A described later) are still not sufficient, as shown by the curve in FIG. 1 and Table 1. (2) Uniformity of drug content and uniformity of particle size distribution are both important requirements for fine particle formulations. Fine granule preparations must be composed of particles with uniform drug content and shapes within a certain range. However, the conventional method is difficult to satisfy the above requirements and is not efficient. That is, (a) In the conventional method, when the organic solvent is distilled off from the kneaded product, the solid solubility of nifedipine segregates as the organic solvent evaporates, resulting in non-uniform content of nifedipine in the product. Using such products, it is very difficult to obtain granules with uniform nifedipine content. (b) The particle size distribution of fine particles obtained during granulation, drying, pulverization, etc. using conventional methods is broad, and a considerable amount of non-specified fine particles are produced as by-products, and the yield of within-specified fine particles may exceed 90%. Can not. Means for Solving the Problems The easily absorbable nifedipine fine granule preparation of the present invention is manufactured according to the following steps. (1st step) Lactose, sucrose, glucose, D-mannitol 1
Fine particles (hereinafter referred to as fine particle carrier) are produced using a seed or two or more species (hereinafter referred to as excipient) and a water-soluble binder. (Second Step) Nifedipine and polyvinylpyrrolidone in a weight ratio of 1:2 to 1:5 are dissolved in an organic solvent capable of dissolving both to produce a solution (hereinafter referred to as a solid solution solution). (Third step) The solid solution solution obtained in the second step is sprayed onto the fine particles obtained in the first step and dried to coat the surface with the solid solution of nifedipine and polyvinylpyrrolidone. Each step will be explained below. First, both the fine particle carrier in the first step and the fine particles that are the final preparation in the third step are used in the Japanese Pharmacopoeia (9).
Particle size range defined in the General Regulations for Pharmaceutical Products (75% of the total amount passes through the No. 32 sieve and remains on the No. 150 sieve. In addition, less than 5% of the total amount remains on the No. 32 sieve, and 200 10% or less of the total amount passes through the No. sieve.) However, the present invention is not limited to these fine particles, but also includes preparations that are substantially equivalent thereto. Now, in the first step, an excipient and a water-soluble binder such as hydroxypropylcellulose, hydroxymethylpropylcellulose, polypynylpyrrolidone, polyvinyl alcohol, gum arapia, gelatin, etc. are blended, and preferably, an alkyl sulfate ester, This is carried out by blending an anionic surfactant such as dialkyl sulfosuccinate and granulating it into fine particles according to a conventional method. As the granulation method, any commonly used method such as wet granulation, dry granulation, fluidized bed granulation, or rolling granulation may be applied, but fluidized bed granulation or rolling Most preferred is the granulation method. The amounts of excipients and binders used may be the same as in the usual case, but when a surfactant is further added, it is preferably about 2 to 5% of the total amount charged. Surfactants have the effect of promoting wet disintegration of the preparation upon administration and providing a pleasant feeling of administration. Next, the solid solution solution in the second step is mixed with nifedipine.
PVP preferably in a weight ratio of 1:2 to 1:5,
Both are prepared by dissolving them in a common organic solvent at a ratio of 1:3. At this time, if the amount of PVP used for nifedipine is less than the above range, when the solid solution solution is sprayed onto the fine particle carrier and dried to form a film of nifedipine solid solution on the surface, nifedipine will precipitate in crystal form and cause in the body. Reduces absorption. On the other hand, if the amount of PVP used exceeds the above range, the absorption of nifedipine in the body will not improve much and the dosage of the preparation will increase unnecessarily, which is not preferable. The PVP used in the present invention has an average molecular weight of 10,000 to 400,000, preferably 10,000 to 200,000, particularly preferably 10,000 to 50,000. In addition, as a solvent for the solid solution solution, chloroform,
Examples include dichloromethane, acetone, methanol, ethanol, etc., with ethanol and dichloromethane being particularly preferred. The amount of solvent used in the solid solution solution varies depending on the type of solvent and the molecular weight and amount of PVP used, but is usually 1.2 to 1.5 times the amount required to dissolve nifedipine. Subsequently, in a third step, the fine-grained carrier must be precisely and uniformly coated with the nifedipine solid solution. Therefore, while maintaining the fine particle carrier in a fluid state, a predetermined amount of the solid solution solution is uniformly sprayed onto the fine particle carrier and dried. Specifically, it is convenient to carry out the spray coating operation in a fluidized bed granulator, a tumbling granulator, or a centrifugal fluid coating apparatus used for the production of ordinary granules and fine granules. Conditions in this case, such as the amount of spray per unit time, processing temperature, fluidity of the fine particle carrier, etc., can be the same as those for producing ordinary granules. By adopting such a coating method, it is possible to accurately and uniformly coat with a predetermined amount of nifedipine solid solution while preventing the fine particle carriers of the raw material from being crushed and mutually bonded. Moreover, the operation is easy and the work efficiency is good. be. The preparation of the present invention obtained as described above is extremely excellent in quality. That is, as shown in Table 2 below, the nifedipine content for each particle size is uniform, and the particle size distribution is sharp, so the required amount of nifedipine can be administered accurately. Next, the preparation of the present invention has excellent solubility in water as shown by the curve in FIG. 1, and as shown in Table 1, the absorption of nifedipine in the body has been significantly improved. Furthermore, in the present invention, only a water-soluble substance is used as a fine particle carrier, so no insoluble matter is left behind when taking it. This, combined with the sharpness of the particle size distribution mentioned above, makes the preparation of the present invention have a pleasant feeling when taken. It can be said that it is an extremely good formulation. The first effect of the present invention is that it provides an excellent nifedipine preparation as described above, but another effect is that the preparation can be manufactured effectively and accurately. In other words, the conventional method of kneading nifedipine solid solution, binder, and excipient in an organic solvent, followed by granulation, drying, and sizing results in considerable loss as mentioned above, and the yield of the final preparation generally exceeds 90%. However, in the present invention, the fine particle carrier prepared in advance is coated with the nifedipine solid solution, so there is no loss associated with granulation, and the yield of the final preparation is at least 95%.
Usually 97% to 98%. Furthermore, in the present invention, the desired formulation can be obtained simply by coating the fine particle carrier prepared in the first step with a solid solution solution, so the operation is simple and accurate results can always be obtained. A more detailed explanation will be given below with reference to Examples and Comparative Examples. In addition, the elution test for water and the blood concentration measurement in the examples were conducted according to the methods described below. In addition, all parts refer to parts by weight. [Elution test for water] A method is used in which the USPX dissolution test device (manufactured by Toyama Sangyo) is connected with a flow cell attached to a dual-wavelength spectrophotometer (manufactured by Hitachi) with a tube, and the eluate is continuously refluxed with a pump. Using. Use 500 ml of distilled water as the eluent, and add 37
Using a 4-blade stirring propeller while maintaining the temperature at ±0.5℃
Stirred at a speed of 150 rpm. A sample equivalent to 50 mg of nifedipine was added to this eluate, and the difference in absorbance between 325 nm and 500 nm was measured over time to determine the elution amount. [Blood Concentration Measurement] A sample equivalent to 10 mg of nifedipine was orally administered to six beagle dogs (weight 8 to 12 kg) that had been fasted overnight, and the blood concentration was measured. Blood was collected at 30, 60, 120, and 240 minutes after administration, and the plasma nifedipine concentration was determined by ECD gas chromatography. Example 1 Inventive Example 1 and the corresponding formulations of Comparative Examples A and B were prepared as follows. Example 1 of the present invention Formula: Lactose 930 parts Hydroxypropyl cellulose 20 parts PVP (average molecular weight 40000) 40 parts Nifedipine 10 parts Total 1000 parts Operation: Fluidized bed granulation dryer [Glatt-OKawara WSG-1 model] . 930 parts of lactose was added to a solution containing 20 parts of hydroxypropyl cellulose dissolved in 500 parts of water. After granulation and drying, the granules were sieved through a 32-mesh sieve to make them fine. A granular carrier was obtained. Next, 40 parts of PVP and 10 parts of nifedipine were dissolved in 600 parts of ethanol, and this solution was added to the previously obtained fine particle carrier 950 in a fluidized bed granulation dryer set at 60°C.
Spray and coat the area (spray rate 100ml/
min), and after drying, it was sieved through a 32-mesh sieve. 32 The mesh residue was forced through a sieve and mixed with the sized product. Comparative Example A (Extrusion granulation of nifedipine solid solution) Prescription: Same as inventive example 1 above. Procedure: To 930 parts of lactose, add 20 parts of hydroxypropylcellulose, 40 parts of PVP, and 10 parts of nifedipine dissolved in 300 parts of warm ethanol, and after kneading with a universal mixer (Shinagawa Kogyo, Model 8DMV-R),
Extrusion granulation using a 0.5 mm screen, 60
Shelf dried at °C. This was sieved using a 32-mesh sieve, and the 32-mesh residue was forcibly sieved and mixed with the sized product. In the case of this method, it was often observed that ethanol evaporated during extrusion granulation, making granulation difficult, so granulation was continued by adding a small amount of ethanol each time. Comparative Example B (Extrusion granulation of nifedipine crystal powder) Prescription: Same as Example 1 of the present invention. Procedure: In a mixture of 930 parts of lactose, 40 parts of PVP and 10 parts of crystalline powder of nifedipine (100 ml), add 20 parts of hydroxypropyl cellulose to 190 parts of water.
After kneading with a multipurpose mixer, the mixture was extruded and granulated using a 0.5 mm screen, and dried on a shelf at 60°C. This was sized using a 32 mesh sieve, and the 32 mesh residue was forced through the sieve and mixed with the sized product. Now, the above-mentioned invention example 1, comparative example A, and comparative example B
A water dissolution test was conducted on the formulation, and the results are shown in FIG. In FIG. 1, the curve shows the dissolution curve of the formulation of Inventive Example 1, the curve shows the dissolution curve of the formulation of Comparative Example A, and the curve shows the dissolution curve of the formulation of Comparative Example B, respectively. Furthermore, for the formulation of Invention Example 1 and Comparative Example A, the blood concentration at the time of administration to beagle dogs, the particle size distribution of the formulation, and the nifedipine content by particle size were measured, and the results were reported in the first It is shown in Table (Blood concentration of Nifedipine) and Table 2 (Particle size distribution and Nifedipine content by particle size).

【table】

[Table] The theoretical content is 1%.
As is clear from Figure 1, the preparation obtained by the method of the present invention (invention 1, curve) has extremely good dissolution properties in water, with almost 100% of nifedipine dissolving in the preparation within a few minutes. Moreover, it stably maintains a high concentration (supersaturated state) that is approximately 10 times the saturation concentration (approximately 10 μg/ml), whereas in the case of the formulation made by the conventional method (Comparative Example A, curve), nifedipine is only slightly Only about 1/2 of the amount is eluted, and even after elution, there is a tendency to immediately precipitate as poorly soluble crystals. The difference between these two formulations lies in their absorption in the body, that is, the blood concentration (first
It is clearly shown in Table 1 that in the formulation of Example 1 of the present invention, nifedipine quickly reaches a high blood concentration after administration, and the area under the blood concentration curve (AUC) also shows a sufficient value. In the case of the conventional method (Comparative Example A), the blood concentration does not reach a level at which an effective therapeutic effect can be expected. Further, as shown in Table 2, the fine granules of the present invention are extremely excellent in uniformity (particle size distribution, nifedipine content distribution). That is, first, in the particle size distribution, Invention Example 1
For this formulation, the amount passing through 200 meshes is as low as 2%.
Japanese Pharmacopoeia's general regulations for fine granules (32 meshes remaining; 5% or less; 32-150 meshes remaining; 75% or more;
200 meshes (10% or less), the entire quantity (100%) is a passing product. On the other hand, the formulation of Comparative Example A had a large amount of 21% passing through 200 meshes, and did not pass the fine granule specification.
Therefore, in order to pass the fine granule specification, at least about 11% of the amount passing through 200 meshes must be removed, and a passing product cannot exceed 90%. Next, the formulation of Example 1 of the present invention is also excellent in the distribution of nifedipine content. As shown in Table 2, nifedipine is 200
It tends to be unevenly distributed in high concentrations in fine powders such as those that pass through the mesh. In the formulation of Example 1 of the present invention, the amount passing through 200 meshes is small and the nifedipine content is not so high, so the nifedipine content distribution as a whole formulation is excellent in uniformity. On the other hand, in the formulation of Comparative Example A, the amount that passed through 200 meshes was as high as 21%, and the nifedipine content rate in this area was high, so a large amount of nifedipine was unevenly distributed in this area, and as a result, the amount that passed through 32 to 150 meshes was high. The nifedipine content is low and the nifedipine content distribution as a whole formulation is extremely non-uniform. Example 2 Regarding the usage ratio of nifedipine and PVP in the second step of the present invention, formulations of Invention Example 2, Invention Example 3, and corresponding Comparative Example C and Comparative Example D were prepared below. Invention Examples 2 and 3 In the same manner as Invention Example 1 of Example 1, lactose 750
A fine particle carrier was prepared consisting of 200 parts of D-mannitol and 30 parts of hydroxypropyl methylcellulose. Nifedipine and PVP (average molecular weight
40000): 20 parts: 40 parts (Invention Example 2 and 20 parts:
A solution prepared by dissolving 60 parts (invention example 3) in 1000 parts of ethanol was sprayed and coated using a fluidized bed granulation dryer so that the nifedipine content was 2% (temperature 60°C, spray rate 100ml). /min) After drying
The grains were sorted using a 32 mesh sieve. 32 The mesh residue was forced through a sieve and mixed with the sized product. Comparative Example C and Comparative Example D Nifedipine and PVP 20 parts:0 parts (Comparative Example C)
A fine granule was obtained in the same manner as in Inventive Example 2, except that the ratio of 20 parts to 30 parts (Comparative Example D) was used. The above four types of fine granules were examined for their dissolution properties in water, and the results are shown in Figure 2. In FIG. 2, curves ~ are respectively Invention Example 2 (curve), Invention Example 3 (curve), and Comparative Example C.
(curve) and the formulation of Comparative Example D (curve) i.e. nifedipine and PVP at 20:40, 20:60,
The dissolution curves of the formulations obtained by coating with solutions dissolved in the ratio of 20:0 and 20:30 (parts) are shown. As is clear from FIG. 2, the preparations of the present invention (Inventive Examples 2 and 3) exhibit extremely high dissolution of nifedipine, but when the amount of PVP used does not reach twice that of nifedipine (Comparative Example C, In Comparative Example D), a stable solid solution film was difficult to form and the dissolution of nifedipine was reduced. Example 3 Particularly regarding the third step of the present invention, a formulation of the present invention was prepared by using another coating method instead of the spray drying method in Example 1 of the present invention. That is, PVP (average molecular weight
40000) and 10 parts of nifedipine dissolved in 500 parts of dichloromethane were coated using the following method. Invention Example 4 Coating using a fluidized bed granulation dryer: Coating and granulation were carried out in the same manner as in Invention Example 1 of Example 1, except that the temperature was 40° C. and the spray rate was 80 ml/min. Example 5 of the present invention Coating using a centrifugal fluid coating device: 950 parts of the fine particle carrier was placed in a centrifugal fluid coating device, and the above solution was sprayed and coated at a temperature of 40°C and a spraying rate of 25 ml/min. After drying, the coating was passed through a 32 mesh sieve. The grains were sorted. 32 The mesh residue was forced through a sieve and mixed with the sized product. A water dissolution test was conducted on the formulations obtained in Examples 4 and 5 of the present invention, and the results are shown in FIG. In FIG. 3, the curve and the curve represent Invention Example 4 (curve) and Invention Example 5, respectively.
(Curve) shows the dissolution curve of nifedipine in the formulation. As is clear from FIG. 3, all of these formulations of the present invention exhibited excellent nifedipine dissolution properties.

[Brief explanation of the drawing]

Figures 1 to 3 are diagrams showing the nifedipine dissolution test results of the preparations; Figure 1 shows the data of Invention Example 1, Comparative Example A, and Comparative Example B;
The figures show data for Inventive Examples 2 and 3, Comparative Example C and Comparative Example D, and FIG. 3 shows data for Inventive Examples 4 and 5.

Claims (1)

[Claims] 1 The following manufacturing process: (1st step) 1 of lactose, sucrose, glucose, D-mannitol
Produce fine granules using the seed or two or more and a water-soluble binder. (Second step) Dissolve nifedipine and polyvinylpyrrolidone in a weight ratio of 1:2 to 1:5 in an organic solvent that can dissolve both. Producing a solution (3rd step) The solution obtained in the 2nd step is sprayed onto the fine particles obtained in the 1st step, and the surface is coated with a solid solution of nifedipine and polyvinylpyrrolidone by drying. A method for producing a characterized easily absorbable nifedipine fine granule preparation.