JPS60255719A - Preparation of nifedipine sustained release pharmaceutical - Google Patents

Abstract

PURPOSE:To obtain the titled pharmaceutical useful as a remedy for angina pectoris, by incorporating and copulverizing a copulverized fine powdery composition obtained from a salt, e.g. magnesium silicate or Mg2CO3, etc. with casein and nifedipine with an enteric coating agent and a plasticizer, and dry granulating the resultant mixture. CONSTITUTION:One or more selected from magnesium silicate, Mg2CO3, dried aluminum hydroxide gel, etc. are copulverized with casein and nifedipine to give a fine powdery composition, which is then incorporated with an enteric coating agent, e.g. cellulose acetate phthalate, a plasticizer, e.g. PEG, and copulverized. The resultant copulverized mixture is then dry granulated. A higher fatty acid ester e.g. sucrose ester of a fatty acid, may be further used in addition to the above-mentioned enteric coating agent and plasticizer for the above-mentioned fine powdery composition. Thus, the aimed solid nifedipine pharmaceutical having ready absorbability and sustained release property can be obtained without using an organic solvent.

Description

[Detailed description of the invention]

The present invention relates to a method for producing a novel solid formulation of nifedipine. More specifically, the present invention relates to a method for producing a nifedipine formulation that is easily absorbed and has excellent durability. Nifedipine has excellent coronary vasodilatory and antihypertensive effects, and is therefore a substance used clinically as a therapeutic agent for angina pectoris, hypertension, and the like. Since nifedipine crystals are poorly soluble in water and difficult to absorb from the gastrointestinal tract, various types of easily absorbable preparations have been proposed. For example, there is a method in which nifedipine is dissolved in liquid polyethylene glycol and this solution is filled into soft capsules (Japanese Patent Publication No. 34048/1982), and a method in which nifedipine is formulated as a solid solution (Japanese Patent Application Laid-open No. 54-1988).
-2316) is the first. The preparation manufactured by this method increases the plasma concentration of nifedipine quickly after administration and has a rapid onset of action, but its short half-life prevents heart attack in the early morning, and the rapid increase in plasma concentration It is not suitable for the purpose of preventing the occurrence of side effects or sustaining the antihypertensive effect, and from this point of view, a long-lasting preparation that suppresses the rapid release of nifedipine to an appropriate therapeutic plasma concentration is desired. The present inventors previously related to a solid preparation of nifedigin,
As a result of extensive research into improving its dissolution properties, we selected magnesium from the group consisting of magnesium silicate, magnesium carbonate, dry aluminum hydroxide gel, magnesium oxide, magnesium aluminate metasilicate, synthetic hydrotalcite, and alumina magne/rum hydroxide. By containing a fine powder composition obtained by co-pulverizing one or more of the above and casein in a mixed state with Ni-no-e and Y-pin, a solid preparation with extremely excellent dissolution properties of Ni-e-no-hi 0/ is provided. (Patent application 1986-210617)
No.), the present invention further improves the method for producing solid preparations of the above-mentioned Japanese Patent Application No. 57-210617,
In addition to improving the absorption of nifedipine crystals, which are poorly soluble, the drug maintains a plasma concentration at a level where a therapeutic effect can be expected for a long period of time after a single dose, which in turn reduces the number of drug administrations. The present invention provides a novel method for producing a solid nifedipine preparation that can reduce the burden on patients. Below, the method for manufacturing the novel nifedipine formulation according to the present invention is detailed. The first method for producing a solid preparation of nifedipine according to the present invention comprises magnesium silicate, magnesium carbonate, dry aluminum hydroxide, magnesium 7ium oxide, magnesium aluminometasilicate, synthetic hydrotalcite and alumina magne hydroxide/ 1 selected from the group consisting of rum
A fine powder composition obtained by co-pulverizing a powder or two or more and casein with nifedipine in a mixed state (7) is further co-pulverized with an enteric liquid ~ agent and i +] plastic agent in a mixed state. The second method of the present invention consists of forming the composition into granules or fine granules by dry granulation.The second method of the present invention is to add a high-quality fine powder to the finely powdered composition described above in addition to an enteric coater, a tunic agent, and a plasticizer. It consists of co-pulverizing them in a mixed state using a fatty acid ester, and forming the resulting composition into granules or fine granules by a dry granulation method. Granules obtained by these methods, To commercialize Hoso Ahi, it can be filled into capsules and used as capsules.
An excipient may be added to the granules or granules, and the mixture may be compressed and molded using a tablet machine to form a tablet. Generally, for powder grinding, mortar and pestle, hammer mill,
Although methods using ball mills, jet mills, etc. are known, it is preferable to use a moving ball mill for both operations in the manufacturing method of the present invention. The above fine powder composition (roma, magne silicate l1, magnene carbonate l2, dry-retaining aluminum hydroxide gel, magne oxide/
A product obtained by co-pulverizing casein and one or more selected from the group consisting of magnesium aluminate metagenate, synthetic hydrotalcite, alumina hydroxide, and magnesium in a mixed state with nifedipine. This is one of the essential requirements of the present invention. In other words, even if all of the same components as those of the above-mentioned fine powder composition are ground separately and mixed together, the intended purpose of improving the dissolution of nifedipine cannot be achieved. not achieved. The mixing ratio of the components of the fine powder composition of L fertilizer varies depending on the type of components used, but when magnesium silicate is used alone, Tracing Niphelipin 1
Casein is more than 1 part by weight, 1 part by weight
．． The amount of magnesium silicate is 0.2 to 9 parts by weight, preferably 0.3 to 5 parts by weight. When preparing this fine powder composition, adding water-soluble saccharides such as glucose, fructose, mannitol, sorbitol, xylitol, maltose, lactose, and sucrose as excipients facilitates the co-pulverization operation. As a result, the amount of casein, magnesium silicate, and other components used can be reduced. For example, 1 part by weight of nifedipine? j When 6 parts by weight of L-lactose is used as an excipient, 0.1 part by weight or more of casein, preferably 0.2 to 10 parts by weight, and 0.15 to 7 parts by weight of magnesium silicate.
The purpose can be achieved by using a weighing section, preferably a 0.15 to 3 slide section. In the method of the present invention, for the above-mentioned fine powder composition,
Next, an enteric coating agent and a plasticizer are co-pulverized in a mixed state. Examples of enteric coating agents include cellulose acetate phthalate, hydroxyzolobyl methyl cellulose phthalate, and methyl methacturic acid co-modifier. Examples include polyvinyl acetate phthalate, cellulose acetate succinate, and styrene-maleic acid copolymer. These can be used alone or as a mixture of two or more. =T Examples of plasticizers include polyethylene glycol, triacetyl 7, polyoxyethylene 7 sorbitano monooleate, zoropylene glycol, and acetylated monoglycerides. These can be used alone or as a mixture of two or more. The above enteric coating agent is 1 part by weight or more, preferably 1.3 to 2.3 parts by weight, based on 1 part by weight of the above fine powder composition, and the above oT molding is 0.1 m@part or more. , preferably 0.13 to 0.38 parts by weight. The higher fatty acid esters used in the second method of the present invention include sucrose fatty acid esters,
Examples include nrubitan fatty acid ester and glycerin fatty acid ester. The amount of higher fatty acid ester used is 2% or more, preferably 6% or more, based on the total amount of other components.
~] It is 2 yen. The above-mentioned fine powder composition is co-pulverized with each of these components in a mixed state, and the resulting composition is granulated by a granulation method to form granules or fine particles. Polyethylene glycol is one of the preferred plasticizers, but it is solid at room temperature and has a molecular weight of 4.
000 to 20,000 is suitable. Further, as the higher fatty acid ester, sucrose fatty acid ester is one of the preferable ones, and those having HLB 1 to 8 and preferably HLB 1 to 2 are suitable. The elution rate of nifedipine can be controlled by increasing or decreasing the amount of higher fatty acid ester added. Conventionally, one method for producing long-acting preparations has been to control the release of crude drugs by coating the surfaces of granules, fine granules, and tablets with enteric-coated polymer compounds or oils and fats. ing. However, these methods are difficult to solve by dissolving enteric polymer compounds, oils, etc. in organic solvents.
This is a method in which a film coating is applied to the surface of the core granules, fine granules, and tablets, and since a very large amount of solvent is used in these coating processes, it is necessary to reduce the impact of the solvent remaining in the product on the human body. In consideration of this, and from the viewpoint of saving energy and energy for removing organic solvents, there has been a demand for a method θ that does not use a solvent. The method of the present invention is an extremely excellent method for providing a nifedipine solid preparation that is easily absorbable and has excellent durability without using any organic solvent. Since the granules or fine granules obtained by the method of the present invention are not coated only on the surface of the granules as in the case of conventional methods, there is no fear that the film will peel off and the effect will be impaired. When compressed and molded, even after the tablet has disintegrated and dispersed, it exhibits the same effects as granules before tabletting. Next, examples of the present invention will be shown, but the present invention is not limited to these examples. Example 1 Nifedipine 30g, casein (for food additive) 459
and magnesium silicate (Japanese Pharmacopoeia) 309 were co-pulverized using a vibrating ball mill (Model MB-1 manufactured by Chuo Kakoki Kogyo). The co-pulverization operation was carried out by placing 200 alumina balls with a diameter of 20 mm and 40 BA of alumina balls with a diameter of 30 mm into an alumina container with a capacity of 3.41 mm, and pulverizing them for 120 minutes. To 42g of this co-pulverized material,
Cellulose acetate phthalate (Japanese Pharmacopoeia) 84,1. T?
Liethylene glycol 6000 (Japanese Pharmacopoeia) 14
．． After adding 13.2 g of 4.9 and/yosaccharide fatty acid ester (HLB 2 , food additive Dai-Kogyo Seika Co., Ltd.) and co-pulverizing the mixture using a vibrating ball mill, the resulting composition was dry granulated. Machine (Roller contactor made by Freund Sangyo (
The mixture was made into granules of 16 to 30 meth/yu using a commercial TF-156 model). The obtained granules were made into hard capsules by filling 128 square centimeters of each capsule with 10 square centimeters of nifedipine using a capsule filling machine. Example 2 16~: Genmetsu/Yu granules 3. produced by the method of Example 1.
Using 2 and 9, 1.05 kg of lactose and 2.45 kg of cornstarch were mixed therewith, and granules were produced using a dry granulator (Roller Konono (Cutter TF-156 type) manufactured by Freund Sangyo Co., Ltd.).The obtained 20- 50 horns/yu granules 3.
5kg, Kalhoki/Methyl cell

[''-su (Gotoku Pharmaceutical Table NSN5-300) 075 and Sterium Phosphate Magne/
0.05 kg of Phenobin was added and mixed evenly, and a rotary tablet press (HT-AP38S-Tll type manufactured by Hata Tekkosho Co., Ltd.) was used to prepare tablets each weighing 300~ and containing 10 μg of phenobin. Below, the results of various tests on the nifedipine solid preparation obtained by the method of the present invention are shown. Experimental Example 1 When the granules obtained by the manufacturing method of Example 1 were tested according to the Japanese Pharmacopoeia (RPX) dissolution test method 2 ($9 method), it was found that the granules gradually swelled over a period of about 12 hours. It was confirmed that Nihue:) Hin elutes. Figure 1 shows the granules (A+ and Nifuezibi 7) obtained by the manufacturing method of Example 1.
30g, casein 45.9 and magnesium silicate 30
12 g under the same conditions as Example 1 using a vibrating ball mill.
To 70 g of the pulverized material co-pulverized for 0 minutes, 184 g of lactose and 239 g of co-pulverized stearate were added and mixed evenly, and the mixture was processed using a dry granulator (roller compactor manufactured by Freund Sangyo Co., Ltd.).
The elution curve of 16-30 mesh granules () 3) manufactured using TF-156 type) is shown. The dissolution test was conducted as follows. As a test liquid p) 16.8! J acid buffer 900 ml
While keeping the temperature at 370.5°C,
Inject the amount of sample corresponding to 10 mW, and
Rotate at 0 Or, p, m, collect the eluate at regular intervals, and filter it through a membrane filter (paresiZeo, 8
zt). Take 5 ml of the filtrate, extract with ether, distill off the ether, and add 5 ml of ethanol.
ml was added and quantified by ultraviolet absorption likelihood method (wavelength: 36 Ontn). Experimental Example 2 Addition of sucrose fatty acid Ni-Al (Ill, B 2 , for food additives, manufactured by Dai-Kogyo Sehin Co., Ltd.) h1゛ and Nino-r
The relationship between the dissolution rate was measured. Nihuenobin Oni) 9
A pulverized product obtained by co-pulverizing 45 g of casein and magnesium silicate;
129, cellulose acetate phthalate 84.9, polynylene glycol 600014.4 g/3 Ja! ! The addition ratio of fatty acid 1 stellate (HLT32) was changed as shown in Table 1, and the amount of 16 to 30 horns/yu was prepared according to the manufacturing method of Example 1.
Table l kl, sucrose fatty acid esters with compositions in, b, C, d (
Regarding the granules made with the addition ratio of HLB 2 ) [
1 Hydrocopoeia (', rpx) dissolution test method 2 (・g
When a test was conducted using the dollar method, it was confirmed that the elution rate of -C niphenopine could be appropriately controlled by increasing or decreasing the amount of sucrose fatty acid ester (HLI'l 2 ) added. Note that the elution test was conducted in the same manner as in Experimental Example 1. In FIG. 2, the dissolution curves of nifedipine in granules having compositions a, b, c, and d are shown as indicated by L. Experimental Example 3 Six healthy adult males were orally administered one capsule each containing 10 μl of retanifedibine obtained by Example I VC, and changes over time in plasma nifedipine concentration were measured. The control formulation was a commercially available product, nifedipine]O
A soft capsule containing mq was used. The results are shown in FIG. 3 as a plasma concentration transition curve (graph). The plasma concentration time course curve showed the average value of 6 subjects. In FIG. 3, the vertical axis represents the concentration of nifedipine in plasma (unit: the amount of nifedipine in 1 me of plasma (n, 9) J), and the horizontal axis represents the elapsed time after injection of the nifedipine preparation. Based on these results, the capsules obtained by the manufacturing method of Example]
As shown by the -.- line +Al, the drug was gradually absorbed after administration, and niphragm was observed in the plasma even 12 hours later. The χ1 radiation preparation is absorbed quickly after administration, as indicated by the −mu line (Bl), but the preparation of Example 1/
7. The duration is shorter than that of capsules inhaled. The results of Experimental Example 1, Experimental Example 2, and Experimental Example 3 demonstrated that the preparation obtained by the method of the present invention is a novel solid preparation of nifedipine that has a long-lasting effect. Experimental Example 4 For the granules obtained by the manufacturing method of Example 1, the first solution (pH 1, 2) and the second solution (pH 6, 8) of the Japanese Pharmacopoeia (JPX) disintegration test method were used as test solutions. (
When a test was conducted using the dissolution test method 2 (the ξ dollar method) of JPX, it was confirmed that in the first liquid, it was slightly dissolved, and in the second liquid, it was gradually dissolved. The elution test was conducted as follows. Using the first solution (pH 1, 2) and second solution (pH 6, 8) of the Japanese Pharmacopoeia (JPX) disintegration test method as the test solution, 37
:ho, while maintaining the temperature at 5°C, add an amount of sample corresponding to nifedipine l0Tn9, ・e$10°r, l),
The eluate was collected at regular intervals and filtered using a membrane filter (pore 5 size 0.8μ). A portion of the filtrate was taken, extracted with ether, the ether was distilled off, ethanol 5ae was added, and the amount was determined by ultraviolet absorption spectrophotometry (wavelength: 360 nm). FIG. 4 shows the elution curves of the granules obtained by the manufacturing method of Example 1 in the first and second liquids.

[Brief explanation of drawings]

Figures 1 and 2 are graphical representations of the dissolution test results for nifedipine solid preparations. Figure 1 is a diagram showing the dissolution curve obtained from the dissolution test of the granules described in Experimental Example 1, where III@ is the dissolution amount (ch) and the horizontal axis is the dissolution time (hr).
The amounts dissolved at each dissolution time are shown. In the figure, -・-ke shows the elution curve of granules (Al,
The elution curve of granules (B) is shown. Figure 2 shows the compositions of Table 1 described in Experimental Example 2), b, c.
, d, granules a, b, (·, (1 showing the dissolution curve obtained from the dissolution test of 1)], and the vertical and horizontal axes are the same as in Figure 1. Figure 3 is The following is a concentration change curve showing the results of measuring the change in the concentration of Nihuedibino in the plasma of a healthy male using the capsule obtained by the method of the present invention described in Experimental Example 3 and a commercially available soft capsule as a control preparation. It is a diagram showing
The vertical axis shows plasma concentration (ng/me), and the horizontal axis shows time (hr). In the figure, =·-ke shows the plasma nifedibine concentration transition curve of the capsule preparation obtained by the method of the present invention, and -mu- shows the plasma nifedibine concentration transition curve of the commercially available soft capsule preparation, which is the control preparation. / Shows the concentration transition curve. Figure 4 shows the Japanese Pharmacopoeia (JP) granules described in Experimental Example 4.
X) First liquid (pH 1, 2) and second liquid (pH 6, 8)
In the figure showing the elution curve of
It is similar to the figure. In the figure, -mu1 is the first liquid (1) HI
, 2), and -Kenichi decreases the elution curve in the second liquid (pH 6, 8). Patent applicant: Takada Pharmaceutical Co., Ltd. Figure 1 90 granule dissolution curve time (hrl Time (hr) 1←□ Preparation of the present invention → pair It [tlIITll Figure 2 Dissolution IfrR conversion time by Noyosaccharide fatty acid J step fhr) Time ihrl

Claims (5)

[Claims] (1) One or two selected from the group consisting of magnesium silicate, magnesium carbonate, dry aluminum hydroxide, magnesium oxide, 1 cum of magnesium aluminate metasilicate, synthetic hydrotalcite, and alumina/magnesium hydroxide. A fine powder composition obtained by co-pulverizing the ingredients and casein in a mixed state with nifedipine is further co-pulverized in a mixed state with an enteric coating agent and a plasticizer, and the resulting composition is A method for producing a long-acting preparation containing nifedipine, which comprises dry granulation. (2) Magnesium silicate, magnesium carbonate, dry aluminum hydroxide gel, magnesium oxide, red aluminate metasilicate, synthetic hydrotalcite, and alumina hydroxide. A fine powder composition obtained by co-pulverizing one or more selected from the group consisting of magnesium and casein together with nifedipine is further mixed with a highly soluble covering agent, a plasticizer, and a higher fatty acid ester. 1. A method for packaging a long-acting preparation containing nifedipine, which comprises co-pulverizing the resulting composition in a mixed state, and dry granulating the resulting composition. (3) The enteric coating material is one selected from cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, methyl methacrylic acid copolymer, polyvinyl acetate phthalate, cellulose acetate phthalate, and styrene maleic acid copolymer. or 2 inserts 1-
The method according to claim 1 or 2, which is a mixture of. (4) The above plasticizer is polynibufunglycol, triacetin, polyoxyethylene norvicune monooleate,
The method according to claim 1 or a 2, which is selected from propylene glycol and acetylated monoglycerides. (5) The method according to claim 2, wherein the higher fatty acid ester is selected from polysaccharide fatty acid ester, nrubitan fatty acid ester, and glycerin fatty acid ester.