JPH0220610B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a nifedipine pharmaceutical composition with improved dissolution and absorption properties, and particularly to nifedipine with improved dissolution and absorption properties.
This invention relates to a nifedipine solid preparation composition containing a pH-dependent soluble polymeric binder that dissolves at temperatures of 7 to 7 or higher, a plasticizer for the binder, and a porous material. Nifedipine has extremely low solubility in water and gastrointestinal fluids (approximately 10 μg/ml), so this problem must first be resolved when formulating it. For this reason, since nifedipine was created, many of the commercially available preparations to date have been preparations in which a polyethylene glycol (hereinafter abbreviated as PEG) solution of nifedipine is filled into soft capsules. These soft capsules have the disadvantage that the dosage form is large compared to a single dose of the main drug, the manufacturing process is complicated, and the timing of release in the body is not constant. As these drawbacks have been pointed out, solid preparations have been actively developed, and many dosage forms have already been disclosed and proposed. The German patent publication (DT-OS 2400819 = British Patent No. 1456618), which first appeared among these, describes nifedipine in the presence of a surfactant.
A method of obtaining a dry powder by dissolving nifedipine in PEG and adding solid additives, mainly cellulose powder, to the hot solution (heat mixing method) is disclosed, and the basic concept of nifedipine solid preparations is presented. ing. Following this, numerous patent applications were published and
Various solid preparations of nifedipine have been proposed, some of which have already been put into practical use. These specifications describe solid dispersion (formation of a solid solution or coprecipitate) in a hydrophilic solid binder that has good compatibility with nifedipine as a means to improve the dissolution properties of nifedipine, such as JP-A-1986-1996-1.
2316, No. 56-110612, No. 56-68619, etc.),
Surface adsorption of PEG solutions onto porous materials (e.g.
JP-A-54-44034, JP-A-54-95721, etc.), or a combination of both concepts (formation of a thin layer of solid solution on the surface of a porous material, such as JP-A-54-20127,
No. 54-46837, etc.) have been disclosed. In order to obtain a solid dispersion, in addition to the heating mixing method described above, a method of dissolving both nifedipine and a dispersion medium in a third solvent and then distilling this off (solvent distillation method) is generally employed. On the other hand, in JP-A-56-49314, a PH-dependent soluble binder is used, and polyethylene oxide (hereinafter referred to as PEO) with a degree of polymerization exceeding 200 to 300 is used.
Long-acting formulations combined with PEG) have also been proposed. However, these solid preparations are still not necessarily satisfactory in terms of dissolution and absorption of nifedipine. In other words, the binder that forms a solid dispersion with nifedipine serves to promote the dissolution of nifedipine into water or gastrointestinal fluids at the beginning of the dissolution test, but over time, the binder itself dissolves. comes to compete with the dissolution of nifedipine, leading to redeposition of the latter and thus a reduction in the cumulative elution amount. Also, PEG or surfactants added to the binder do not help prevent redeposition of nifedipine. Furthermore, preparations made by solid dispersion in a hydrophilic polymeric binder, or by forming a thin layer of the solid dispersion on the surface of a porous material, can be stored under humidified conditions over time. Elution characteristics deteriorate. This fact has already been confirmed by Chem.Pharm.Bull.
211715 (1981) and reported in the May 25, 1955 issue of Pharmaceutical Factory. Furthermore, the same fact was confirmed for preparations obtained using a PH-dependent binder having a relatively low dissolution PH, as shown in the control example below. Based on the above knowledge, the present inventors have completed the invention as described in the claims at the beginning. That is, according to the present invention, a mixture of nifedipine, a PH-dependent soluble polymeric binder that dissolves at pH 5 to 7 or higher, and a plasticizer for the binder is dissolved in an organic solvent, and this is dissolved in a porous material. After carrying it,
A nifedipine solid preparation composition obtained by distilling off the organic solvent and having the following characteristics is provided. The polymeric binder is preferably hydroxypropyl methyl cellulose phthalate (HPMCP),
carboxymethylethylcellulose (CMEC),
and methyl methacrylate/methacrylic acid copolymers (commercially available under the trade name Eudragit L and S), which have a solubility pH of 5 to 7 or higher and are usually used as enteric film coating materials. It is frequently used as a drug. The plasticizer for the binder is one commonly used to impart smooth film-forming ability to these bases, and in the present invention, glycerin esters, particularly glycerin triacetate, are preferred. On the other hand, the porous material has a large specific surface area, and allows the combined product of nifedipine and the binder to be adsorbed and supported on its surface. Magnesium aluminate metasilicate, aluminum silicate and pulverulent silica, which are usually obtained by spray drying, are preferably used and serve to improve the elution characteristics of the binder. The composition of the present invention is disclosed in the above-mentioned Japanese Patent Application Laid-open No. 56-49314.
The only difference is the use of a porous material in place of PEO in the latter, when compared to the exemplary long-acting nifedipine formulation disclosed in the latter. However, this exemplary composition and the composition of the present invention are
They are completely different in their elution and absorption characteristics. This will be clarified in the dissolution test described below. Furthermore, the composition of the present invention, by virtue of the clever composition of its constituent components, can contain at least 50% of nifedipine.
% can be designed to dissolve in the stomach and 40% subsequently in the small intestine. Moreover, it does not have the disadvantage that the cumulative elution amount decreases over time, which is the case with formulations using hydrophilic polymeric binders or some acid-soluble PH-dependent binders. In producing the composition of the present invention, a mixture of nifedipine, a polymeric binder, and a plasticizer is first dissolved in an organic solvent, such as a mixed solvent of alcohol and acetone or dichloromethane, and a porous material is added thereto. After mixing, the solvent is distilled off. Although methods such as spray drying can be used to remove the solvent, usually the mixed slurry is dried as it is.
If desired, the particles are adjusted and sieved to obtain fine particles. The present invention will be explained in more detail below using Examples and Control Examples. Examples The compositions shown in the following table (expressed by weight of ingredients per unit dose) were prepared using nifedipine, a binder and a plasticizer in an organic solvent (ethanol: acetone = 1:
For 1 CMEC, dissolve in ethanol:dichloromethane = 1:1 (approximately 0.36 ml per unit dose), add a porous substance as an adsorption/dispersion agent, mix gently, and evaporate the solvent and dry. Fine grains were obtained. In addition, control preparations shown in part of the following table were manufactured using the same procedure. Of these, 6 use a binder with a low elution pH, and 7 is exemplified in JP-A-56-49314. [Table] Control experiment Dissolution: Each of the above formulations was individually subjected to a dissolution test under the following conditions, and the measurement results summarized in Table 2 (expressed as %) below were obtained. Elution tester: 300ml beaker (with 4-blade propeller) Eluent: Japanese Pharmacopoeia liquid 1 and liquid 2 (200ml)
ml) Sample: Nifedipine amount 20 mg for each formulation Temperature: 7 ± 0.5°C Stirring: 263 r.pm Assay method: Absorbance (350 mm) measurement (sample taken at each time and passed through a Millipore filter (0.45 μ) Solution) [Table] [Table] From Table 2, it can be seen that all the formulations of formulation numbers 1 to 5 have satisfactory dissolution characteristics in the second solution. On the other hand, the formulation with prescription number 6
In the second solution, the dissolution characteristics were very good for the first 10 minutes, but after that, nifedipine began to recrystallize and the dissolution characteristics deteriorated, and in the second solution, the dissolution characteristics were satisfactory at any time during the measurement period. It can be seen that no elution characteristics were obtained. Compared to other oral preparations, granules or fine granules move through the gastrointestinal tract extremely smoothly and are transferred from the stomach to the intestines within a short period of time. It is hard to say that it is actually more preferable than the formulation. In addition, the formulation No. 7, in which PEO was substituted for magnesium aluminate metasilicate in the formulation No. 1, exhibited extremely undesirable elution characteristics in both the first and second liquids. . This did not change even when the measurement time was extended to 2 hours. Blood concentration: Preparation No. 1 of the Example of the present invention, Preparation No. 6 as a control example, commercially available preparations under the trade name "Sepamid" (a thin layer of a solid solution of nifedipine and polyvinylpyrrolidone was added to the surface of the lactose). Preparations formed on the above, "Pharmaceutical Factory" May 25, 1980, No. 13-
(See page 16) and a formulation commercially available under the brand name "Adalat" (a formulation in which a PEG solution of nifedipine is filled and held in a soft gelatin capsule) were administered to 8 beagles (crossover) weighing approximately 10 kg. , administered in an amount of 1 mg/Kg, and after administration
10 minutes, 20 minutes, 40 minutes, 60 minutes, 120 minutes, 240 minutes and
Blood was collected at each time of 360 minutes, and the amount of nifedipine contained was measured by gas chromatography. As a result, in terms of maximum blood concentration, effective blood concentration maintenance time, and area under the curve, these four
No significant differences were observed between the individual test preparations. Dissolution test after change over time: The formulations of formulation numbers 1, 4, 5 and 6 were heated at 40°C.
After being stored for about 12 weeks under conditions of relative humidity of 75%,
As a result of conducting a test under the same conditions as above), the dissolution characteristics of formulations No. 1 and No. 5 were almost unchanged from those at the beginning. On the other hand, for formulation No. 4, although the turn of the dissolution characteristic curve did not change from the initial one, a decrease of approximately 15% was observed over the entire test period. Furthermore, it was confirmed that the dissolution characteristics of the formulation No. 6 were reduced by approximately 30%. On the other hand, the above-mentioned "Sepamitsudo" has a temperature of 20℃ and a relative humidity of 75℃.
%, and under storage conditions for 6 weeks, there was a very significant decrease in elution characteristics (approximately 40%) (see the above description of "Pharmaceutical Factory" (Figure 6)).

Claims (1)

[Scope of Claims] 1. A mixture of nifedipine, a PH-dependent polymeric binder selected from the group consisting of hydroxypropylmethylcellulose phthalate, carboxymethylethylcellulose, and methyl methacrylate/methacrylic acid copolymer, and a glycerin ester. A solid preparation composition of nifedipine obtained by dissolving in an organic solvent, mixing with a porous substance, and then distilling off the organic solvent. 2. The nifedipine solid preparation composition according to claim 1, wherein the porous material is selected from the group consisting of magnesium aluminate metasilicate, aluminum silicate, and finely powdered silica.