JPS618A - Nifedipin-containing drug preparation - Google Patents

Abstract

PURPOSE:To obtain a drug preparation satisfying quick dissolution as well as slow releasing properties, by adding a surfactant to nifedipine to obtain a quick- dissolution granule, preparing a slow-releasing granule by pulverizing a part of the quick-dissolution granule and adding an organic polymeric binder thereto, an d combining both granules by a particular method. CONSTITUTION:Nifedipine is added with a surfactant (e.g. sodium laurylsulfate, polyacrylic acid, etc.) to obtain the first granule dissolving quickly when brought into contact with peptic liquid and exhibiting the rapid activity. A part of the first granule is finely pulverized, and mixed with an organic polymeric binder (e.g. ethyl cellulose, glycerol fatty acid ester, etc.) to reduce the disintegration property or dissolving property and obtain the second granule exhibiting slow- releasing property. Both granules are mixed together and coated with an enteric coating to form a core, and the mixture of both granules are applied to the core to obtain the objective drug preparation. Quick dissolution effect can be attained by the disintegration of the coating layer before the duodenum, and the slow- releasing property can be exhibited after the duodenum by the core layer.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a nifedipine-containing preparation that satisfies both rapid dissolution and sustained release properties.

[Prior Art] Nifedipine is a so-called calcium ion antagonist that has a coronary vasodilatory effect and blocks the influx of Ca ions into cells, which is essential for smooth muscle contraction, and is an extremely useful angina treatment agent. Therefore, it is widely used in practical use. Furthermore, since the powder is a drug that exhibits rapid effects once absorbed into the body, it has the advantage of being quite effective even in emergencies such as attacks of angina pectoris. However, on the other hand, it had the drawback of lacking long-lasting medicinal efficacy. It is also known that when nifedipine is orally administered in solid form, absorption from the gastrointestinal tract is extremely slow and bioavailability is also low.

Therefore, research was carried out with the desire to improve the absorbability of nifedipine as much as possible.
As seen in JP-A No. 206612 and JP-A-56-32293, a method has been reported in which nifedipine is prepared by dissolving it in an appropriate solvent. However, since nifedipine has a short half-life in the blood and is metabolized at a relatively fast rate, it was unreasonable to expect long-term drug efficacy from a single administration. In fact, currently marketed nifedipine-containing preparations are quite effective in emergencies such as angina attacks, but they can be used to prevent or prevent attacks that occur when taking the drug is difficult, such as while sleeping. Patients with angina pectoris must always be in fear of such attacks, as they cannot be controlled. Therefore, there has been a desire for a mutualfedibin preparation that not only exhibits immediate effects with a single administration, but also can be expected to maintain its medicinal effects over a long period of time.

[Problem that the invention attempts to solve] However, as mentioned above, oral nifedipine.

Absorption is not improved by pulverization according to conventional methods or addition of conventional additives or even wetting improvers added for the purpose of improving absorption, and bioavailability is also low, so it does not work immediately after administration. However, no preparation has yet been realized that can exhibit clinical efficacy over a long period of time.

In addition, general long-acting preparations are expected to have many medical benefits, such as reducing the number of drug administrations, reducing side effects on the gastrointestinal tract, etc., and maintaining the duration of action. However, most of the long-acting preparations that have been developed to date emphasize only drug elution control, and there are very few long-acting preparations that are expected to have immediate effects immediately after administration. It was thought that it forced the expression of sexuality. In addition, microencapsulation methods are known as preparations that are expected to be effective immediately after administration, and are usually prepared by filling granules prepared by various elution control methods into hard capsules, etc. However, in this method, the residence time and distribution of the drug in the gastrointestinal tract depended on the dispersion of the particles, which tended to result in non-uniformity, and was not necessarily suitable for long-lasting preparations. For these reasons, it was necessary to develop a new formulation technology for nifedipine preparations used for angina pectoris that would sufficiently exhibit both immediate and sustained effects after administration.

[Technical means for solving the problem] The nifedipine-containing preparation provided here as one that meets the above purpose is a first granulated product prepared by adding a surfactant to nifedipine, and a first granulated product prepared by adding a surfactant to nifedipine. It contains a second granule prepared by crushing a part of the first granule and further adding an organic polymer adhesive, and the mixture of the first granule and the second granule is enterically coated. The gist is that the core layer is coated with a mixture of the first granules and the second granules to form a coating layer.

[Effects] The effects of each component in the nifedipine preparation of the present invention will be described as follows.

Since the first granulated product is a mixture of nifedipine and a surfactant, after oral administration, it is rapidly dissolved by contact with digestive juices and exhibits fast-acting properties based on its fast-dissolving properties.

There are no particular restrictions on the type or amount of surfactant that satisfies these conditions, or on the blending method, but representative examples of suitable surfactants include Porin Rube-1-1.
80, sodium lauryl sulfate, polyoxyl stearate 40. Examples include polyacrylic acid, which may be used alone or in combination of two or more. Note that it is desirable that the nifedipine blended into this be as finely divided as possible in view of the purpose of increasing rapid solubility.

Since the second granules contain an organic polymeric fixing agent, the nifedipine is strongly fixed to each other, thereby reducing disintegration or solubility, and thereby exhibiting sustained release properties or sustainability. There are no particular restrictions on the type or amount of the organic polymer adhesive used here, as well as on the blending method, but representative examples of suitable organic polymer adhesives include hydroxypropyl methyl cellulose phthalate, ethyl cellulose, and glycerin. Fatty acid esters, shellac, etc. are exemplified, and these may be used alone or in combination.
It should be noted that the nifedipine blended with this must be a part of the first granulated material, which means that once it is released from the fixation, it quickly enters the digestive juices. Since it needs to be dissolved in a surfactant, it must be mixed with a surfactant in advance. If so, nifedipine, which originally has poor solubility, will be excreted from the body without being dissolved at all, and there will be no time for it to exert its medicinal effect.

As mentioned above, the first point of the present invention is that it is divided into two types of granules: first granules: fast-dissolving second granules: sustained release, but the present invention does not stop there. These sites of action are mainly the stomach, pre-fatty intestine (stomach, -difatty intestine, etc.)
Care has also been taken to separate the area into which it acts, and the area where it acts after the 72 fat yang (small intestine, large intestine, colon, rectum, etc.). In other words, the part that acts after the second fatty acid intestine is the core layer formed by mixing the first granules and the second granules and applying an enteric coating, and The portion to be acted upon before the intestine is a coating layer formed by coating the first granulated material and the second granulated material around the core layer. The core layer may be once compressed into a tablet, and the coating layer may be further coated.

In other words, the coating layer disintegrates before the 12th fatty intestine, but since the fast-dissolving first granules and sustained-release second granules are mixed in this layer, the fast-dissolving first granules are disintegrated in this area. and sustained release properties. The enteric coated nuclear layer is -
It disintegrates only after reaching the bifatty intestine, but since the first granules, which are quickly soluble, and the second granules, which are sustained release, are mixed, this region also contains fast dissolution and sustained release granules. As a result, quick dissolution and sustained release properties are exhibited evenly throughout the drug.

There are no restrictions on the material for the enteric coating formed on the core layer, and all commonly used materials can be used, but representative examples include hydroxypropyl methyl cellulose phthalate, ethyl cellulose, glycerin fatty acid ester, Shellac and the like can be mentioned.

Although the basic components and effects thereof of the nifedipine preparation according to the present invention have been clarified through the above explanations,
Next, supplementary explanation will be given regarding the composition and formulation means of the formulation of the present invention.

The means for producing the first and second nuclear granules is not limited, and may include a method of kneading and granulating the first and second nuclear granules, a method of dispersing them in a volatile liquid and spraying them, or Other general-purpose granulation methods can be used. As mentioned above, the core layer may be compressed into tablets, but if necessary, a surfactant may be further added to form the core layer into a spherical or round shape after kneading, or simple compression molding may be used. Regarding the coating layer, a protective coating made of hydroxypropyl methyl cellulose, macrogol, tar pigment, titanium oxide, etc. may be formed, taking into consideration the photostability of nifedipine.

In the present invention, excipients, disintegrants, binders, lubricants, and brightening agents can be added within the ranges commonly used for granulation and compression molding. In addition, the blending ratio of the surfactant and organic polymer fixing agent blended in the present invention varies depending on the degree of surfactant and fixing ability; therefore, it should not be strictly prescribed, but it should be noted that the proportions are particularly representative. Regarding 1 part by weight of nifedipine, the amount of sodium lauryl sulfate is 0.
1 to 2.0 parts by weight, preferably 0.1 to 0.5 parts by weight,
Polysorbate 80. Polyoxyl stearate 40.
For polyacrylic acid etc., o, o01 to 1 part by weight,
Preferably 0.01 to 0.5 parts by weight, and as a fixing agent, 0.01 to 1.0 parts by weight per 1 part by weight of nifedipine.
Preferably 0. 1 to 0.5 parts by weight of O is suitable. The distribution ratio of nifedipine to the coating layer and the core layer is preferably 2-8:8-2, more preferably 7-5:3-5 based on the total weight of nifedipine. Further, the elution rate of nifedipine in each layer can be controlled by increasing or decreasing the amount of the fixing agent, but it is also possible to control the nifedipine mixing ratio in the coating layer and the core layer as described above.

Note that the sustained release preparation of the present invention is manufactured in a conventional manner.

However, this is a typical formulation example, and the present invention is not limited thereto. First, micronized nifedipine was mixed uniformly with lactose, sodium lauryl sulfate, polyacrylic acid, etc., and then polysorbate 80
．． Polyoxyl stearate 40 dissolved in an aqueous hydroxypropylcellulose solution is added, kneaded, and dried (first granulated product). A portion of this material is then crushed and pulverized. After dissolving hydroxypropyl methylcellulose phthalate, ethyl cellulose, glycerin fatty acid ester, and shellac in a mixed solvent such as methylene chloride and ethyl alcohol, the finely divided product is dispersed and granulated by a spray granulation method to form a powder (second granulated product). ), carboxymethyl cellulose calcium, crystalline cellulose, magnesium stearate, etc. are added to the mixture of the first granules and the second granules, and tablets are manufactured by compression molding. Subsequently, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, glycerin fatty acid ester, etc. are dissolved in a mixed solvent of methylene chloride and ethyl alcohol, and then coated on the tablet to form a core layer. In addition, other excipients, binders,
Add a lubricant, coat around the core layer, and compression mold.
The tablet has a double structure. Further, this molded tablet is coated with a film layer composed of hydroxypropylcellulose, macrogol, titanium oxide, tar pigment, etc. to produce a film-coated tablet.

[Example] Example 1 A core layer was manufactured according to the composition shown in Table 1. That is, a mixture of nifedipine, lactose, crystalline cellulose, polyacrylic acid, and sodium lauryl sulfate, and a solution of polysorbate 80 and polyoxyl stearate 40 dissolved in a 5% hydroxypropyl cellulose aqueous solution are granulated by a kneading method and dried ( After pulverizing 50% by weight of the dry product (first granulated product), hydroxypropyl methyl cellulose phthalate and glycerin fatty acid ester.

Ethyl cellulose is mixed with methylene chloride, ethyl alcohol (
1: The above-mentioned micronized product is added to the solution in the mixed solvent of 1) and granulated by a spray granulation method (second granulated product). After mixing these granulated products, hydrogenated oil and magnesium stearate are added. and compress into 45 mg tablets. Subsequently, the compressed tablets were film-coated with a solution of hydroxypropyl methylcellulose phthalate, glycerin fatty acid ester, and ethyl cellulose in methylene chloride and ethyl alcohol (1:1) to form a 50-g core layer.

Next, a first granulated product and a second granulated product were manufactured according to the compositions shown in Table 2. Then, the two are mixed, Neusilin (manufactured by Fuji Chemical Co., Ltd., registered trademark) and magnesium stearate are added and mixed well, and each tablet weighing about 200 mg is compressed so as to coat the core layer. Subsequently, film coating was performed using a conventional method using a solution of 7% hydroxypropyl methylcellulose in ethyl alcohol with macrogol 6000, titanium oxide, and tar pigment added to form an orange dry-coated tablet with a double structure containing 20 g of nifedipine. I got it.

Table 1 Table 2 Example 2 A formulation was prepared in the same manner as in Example 1 so as to satisfy Table 3 (composition of core layer) and Table 4 (composition of coating layer).

Table 3 Table 4 These formulations were tested in the following manner.

(1) Dissolution test Based on the dissolution test method of Pharmacopoeia No. 10, using 900 ml of test solutions (1st solution, 2nd solution) at 37°C, take the number corresponding to 20 mg of nifedipine from each sample and use the paddle method. I went. Take test liquid 51 at regular intervals, 0.457
After filtration with a TM membrane filter, absorbance was measured at a wavelength of 339 nm. However, the test using the second liquid was conducted only for formulations in which residue was observed 2 hours after the start of the test.

(2) Blood concentration test Using 3 groups of 6 rabbits, each sample was treated as nifedipine at 20%
The number of doses corresponding to mg was taken and taken with 20ff11 of water, and blood was collected from the ear vein at regular intervals. After protein removal from blood, nifedipine was extracted and determined by high performance liquid chromatography.

Chromatography conditions: Column: ZBb6HO [IS 4.6cmφX15c
m Column temperature: Room temperature Mobile phase: 0.01M methyl alcohol pH 8, 1 sodium hydrogen phosphate solution (45:55 volume ratio) Column pressure 120 kg/cm2 Flow rate: 1.
Oml/ll1in Detector Nishimatsu 5PD-2A Sensitivity: 0.01 AVFsJnFs Wavelength: 254
nm Chart speed: 25 mm/min Sample: Nifedipine The results of the dissolution test for the preparation obtained in Example 1 are shown in FIG. 1, and the results of the blood concentration test are shown in FIG. As a result, it was confirmed that the formulation of the present invention is extremely excellent in rapid dissolution and long-lasting properties.

[Effects of the Invention] The nifedipine-containing preparation of the present invention can fully exhibit rapid dissolution and sustained release properties, and is effective not only when taken during an attack but also when taken before going to bed to prevent an attack.

[Brief explanation of the drawing]

FIG. 1 shows the dissolution rate curve of nifedipine, and FIG. 2 shows the blood concentration of nifedipine.

Claims (1)

[Claims] A first granulated product prepared by adding a surfactant to nifedipine, and a second granulated product prepared by pulverizing a part of the first granulated product and further adding an organic polymer adhesive, A coating layer is formed by coating a mixture of the first granules and second granules around a core layer formed by enterically coating a mixture of the first granules and second granules. A nifedipine-containing preparation characterized by: