JPS58109411A - Nifedipine composition for solid preparation - Google Patents

Abstract

PURPOSE:The titled composition that is made by dissolving a mixture of nifedipine, a specific pH-depending type macromolecular binder and a plasticizer for the binder in an organic solvent, mixing the solution with a porous substance and evaporating the solvent, thus showing improved elution and absorption. CONSTITUTION:(A) Nifedipine, (B) a pH-depending type macromolecular binder dissolving in a pH of 5-7 or higher, preferably selected from hydroxypropylmethylcellulose phthalate, carboxymethylcellulose and methyl methacrylate/ methacrylic acid copolymer, and (C) a plasticizer for the binder, especially glycerol ester are mixed and dissolved in an organic solvent, preferably combined with a porous substance selected from magnesium metasilicatealuminate, aluminum silicate and finely powdery silica. Then, the organic solvent is evaporated to produce titled composition with improved elution and absorption properties of nifedipine without causing the reduction in the acculmulated elution with time.

Description

DETAILED DESCRIPTION OF THE INVENTION [Regarding the lJ composition, particularly for nifedipine,
This invention relates to a nifedipine solid preparation composition containing a voice-dependent solubility polymeric binder that dissolves at a temperature of 7 or more, a plasticizer for the binder, and a porous substance.

Since nifedipine has extremely low solubility in water and gastrointestinal fluids (approximately 10 pg/ml), this problem must first be resolved when formulating it. For this reason, ever since nifedipine was created.

Most of the preparations on the market to date are preparations in which a polyethylene glycol (hereinafter abbreviated as PEG) solution of nifedipine is filled into soft capsules. These soft capsules have a large dosage form compared to a single dose of herbal medicine, and have the drawback that not only is the manufacturing process complicated, but the timing at which they begin to be released in the body is not constant. As these drawbacks were pointed out, development of solid preparations became active, and many dosage forms have already been disclosed and proposed.

The German Patent Publication (DT) was the first of these.

-os, 2. litθ4♂19-British Patent No. 1'l!
;) The specification describes a method in which nifedipine is dissolved in PEG in the presence of a surfactant, and a solid additive, mainly cellulose powder, is added to the hot solution to obtain a dry powder. (Heat mixing method) The basic concept regarding nifedipine solid preparations is disclosed.

Various solid nifedipine preparations have been proposed, some of which have already been put into practical use.

These specifications include information on the dissolution properties of nifedipine and the formation of coprecipitates, for example, JP-A No. 1+-23/O.
Otsu-7/θ6/2, 5t-AIAI No.9, etc.)
, Surface adsorption of P E Gl solution onto porous materials (for example, JP-A-Sho t+-+pθ34I!Sho 3'l-9!;7
2/2/), or a combination of both concepts (formation of a thin layer of solid solution on the surface of a porous material, for example, JP-A Shoj Goo 2θ/27; JP-A No. 37). ing.

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 adopted.

On the other hand, in JP-A-56-93/Hiroshi, a pH-dependent soluble binder is used, and polyethylene oxide (hereinafter referred to as PEO), PEG with a degree of polymerization exceeding 2θθ to 3θ0, is used.
) has 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 had formed a solid dispersion with nifedipine served to promote the dissolution of nifedipine into water or gastrointestinal fluids at the beginning of the dissolution test, but over the course of one hour, the binder itself began to dissolve. becomes competitive with the dissolution of nifedipine, leading to redeposition of the latter.

3- This results in a decrease in cumulative elution amount. Also.

PEG or surfactants added to the binder do not help prevent nifedipine redeposition.

Furthermore, preparations are formed by solid dispersion in a hydrophilic polymeric binder, or by forming such a solid dispersion as a thin layer on the surface of a porous material.

If this is stored under humid conditions, the elution characteristics will deteriorate over time. This fact is already known in Chem and Pharm.

BuII, 2/ /7/! ; C/91/) and was reported in the July 25, 2016 issue of ``Pharmaceutical Factory.'' Also, formulations obtained using p!

Similar facts were confirmed.

Based on the above knowledge, the present inventors completed the invention as described in claim 1 at the beginning. That is, according to the present invention, a mixture of ÷ fuedipine, a pH-dependent soluble polymeric binder that dissolves at pH 3 to 7 or higher, and a plasticizer for the binder is dissolved in an organic solvent, and this is dissolved in a porous material. A solid preparation composition of nifedipine is provided, which is obtained by supporting the V-organic solvent on the nifedipine and distilling off the organic solvent.

The polymeric binder is preferably hydroxypropyl methyl cellulose phthalate (HPMCP).

Carboxymethylethyl cellulose (CMEC).

and methyl methacrylate/methacrylic acid copolymer (
commercially available under the trade names Eudragit L and S).

It has a solubility pH of 5 to 7 or higher and is commonly used as a base for enteric film coatings.

The plasticizer for the binder is one commonly used to impart a smooth film-forming ability to these bases, and in the present invention, esters of glycerin, particularly glycerin triacetate, are preferred.

On the other hand, a porous substance has a large specific surface area, and allows a bond of nifedipine and a binder to be adsorbed and supported on its surface. Magnesium metasilicate aluminate, aluminum silicate and pulverulent silica, which are usually obtained by spray drying, are preferably used and serve to improve the elution characteristics of the conjugate.

The composition of the present invention is disclosed in the above-mentioned Japanese Patent Application Laid-open No.
When compared to the exemplary long-acting nifedipine formulation disclosed in No. I, the only difference is the use of a porous material in place of PEO in the latter. However, this exemplary composition and the composition of the present invention.

They are completely different in their elution and absorption characteristics.

This will be clarified in the dissolution test described below. Furthermore, due to the clever combination of its components, the composition of the present invention allows at least 50% of the nifedipine to dissolve in the stomach!
θ% can be designed to subsequently elute 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.

To produce the composition of the present invention, a mixture of nifedipine, a polymeric binder, and a plasticizer is first dissolved in an all-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.

Means such as spray drying may also be used to remove the solvent.

Usually, the mixed slurry is dried as it is for 5 minutes, and the particles are adjusted to the desired size and sieved to obtain fine particles.

The present invention will be explained in more detail below with reference to Examples and Control Examples.

EXAMPLE Of the composition shown in the following table (in terms of weight of ingredients per unit dose), nifedipine, binder and plasticizer were mixed in an organic solvent (ethanol:acetone=l:/).

Only in the case of CMEC, ethanol:dichloromethane=l
:/,-approximately 0.3 tsl per dose unit),
A porous substance as an adsorption/dispersion agent was added to this, and the mixture was gently kneaded, the solvent was distilled off, and the mixture was dried to obtain fine particles.

In addition, control preparations shown in part of the following table were manufactured by similar operations. Of these, B uses a binder with a low elution pH, and No. 7 uses JP-A-Sho 3g-! This is an example in No. 931q.

Control Experiment i) 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 (displayed below) were obtained.

Elution tester = 3θOml beaker (with a blade propeller) Elution solution 2 Japanese Pharmacopoeia 1st and 2nd solution (2θ0x
t) Sample: nifedipine amount 20~temperature for each preparation
Degree: 3700! °c Stirring: 21.3r, p, m.

Quantitative method: Absorbance (3jOnm) measurement (sample solution taken at each time and filtered with a Millipore filter (θ15-μ)) (Left below) From Table 2, all formulations with prescription number /-j It can be seen that the second liquid has satisfactory elution characteristics. On the other hand, the formulation with prescription number B shows extremely good dissolution characteristics in the first solution for the first 70 minutes, but after that,
It can be seen that nifedipine began to recrystallize and the elution characteristics deteriorated, and that satisfactory elution characteristics were not obtained in the second solution at any time during the measurement period.

Compared to other oral preparations, granules or fine granules move extremely smoothly through the gastrointestinal tract, passing from the stomach to the intestines in a short period of time.

It is difficult to say that the formulation with prescription number B is actually more preferable than the formulation with prescription number B/-j.

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.

ii) Blood concentration: A thin layer of a solid solution of nifedipine and polyvinylpyrrolidone was added to the formulation of Formulation No. 1 of the Example of the present invention, the formulation of Formulation No. Preparation formed on the surface of lactose, "Pharmaceutical Factory", 1932
(Refer to pages 73-16 of the issue of June 2, 2016) and the product name “
Regarding the preparation (commercially available under "Adalard") in which a PEG solution of nifedipine is filled and held in a soft gelatin capsule, a Heakle male weighing around 1 okq.
A dose of 9 was administered to the head (crossover) at /q/, and lθ minutes, 20 minutes, tio minutes, and 60 minutes after administration.

Blood was collected at 20 minutes, 21 Io minutes, and 360 minutes, and the amount of nifedipine contained was measured by gas chromatography.

As a result, no significant difference was observed among the t test preparations in any of the maximum blood concentration, effective blood concentration maintenance time, and area under the curve.

ii) Dissolution test after change over time: Formulations of formulation number/, '1.3 and 6 were prepared at qθ°c.

12- After storing for about 7 weeks under conditions of relative humidity 7j,
Results of a test conducted under the same conditions as ii) above.

The dissolution characteristics of formulations with formulation numbers 1 and j were almost unchanged from those originally.

On the other hand, for the formulation with prescription number DA, although the pattern of the dissolution characteristic curve did not change from the initial one, a decrease of approximately /j'lA was observed over the entire test period.

Furthermore, it was confirmed that the dissolution characteristics of the formulation with prescription number B were reduced by approximately 3θ coefficient.

On the other hand, the above-mentioned "Shipamid" shows a very significant decrease in dissolution characteristics (about 100 ml) under storage conditions at 20'C and relative humidity of 700°C (as described in the above-mentioned "Pharmaceutical Factory"). (See Figure 6).

l 3-

Claims (1)

[Claims] l) A mixture of nifedipine, IIH, a voice-dependent polymeric binder soluble in 5- to 7 or more and a plasticizer for the binder is dissolved in an organic solvent and mixed into a porous material. A nifedipine solid preparation composition obtained by distilling off the organic solvent. 2) The nifedipine solid formulation composition according to claim 1), wherein the polymeric binder is selected from the group consisting of hydroxypropyl methyl cellulose phthalate, carboxymethyl ethyl cellulose, and methyl methacrylate/methacrylic acid copolymer. thing. 3) The nifedipine solid preparation composition according to claim 1), wherein the plasticizer is a glycesin ester. 1) The nifedipine solid dosage composition according to claim 1), wherein the porous material is selected from the group consisting of magnesium aluminate metasilicate, aluminum silicate, and finely divided silica.