JP2002087966A - Elution-regulated particle for medicinal preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicinal preparation in which an elution regulation is provided for a medicine having a high solubility at a pH in the stomach of a healthy person such as clarithromycin or a medicine being unstable at the pH in the stomach of the healthy person. SOLUTION: The particles for a medicinal preparation are obtained by spraying and solidifying for granulation by using (A) the medicine having a high solubility at the pH in the stomach of the healthy person or the medicine being unstable at the pH, in the stomach of the healthy person, (B) one kind or more than 2 kinds selected from a group consisting of a glycerol fatty acid ester, stearyl alcohol, stearic acid, macrogols, a paraffin and a sucrose fatty acid ester and (C) an acrylic acid-based polymer.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to pharmaceutical particles in which the dissolution of a drug is controlled.

[0002]

2. Description of the Related Art Drugs that are highly soluble at the pH of the stomach of healthy individuals, such as clarithromycin, which is known as an excellent antibiotic, are drugs that dissolve quickly in the stomach and are excellent in immediate action. . However, the acidity in the stomach is weak in patients with anacidity and the dissolution is insufficient, so that the effects of these drugs are sometimes insufficient.

On the other hand, an acid-labile drug is degraded by the acid in the stomach when administered orally and its effect becomes insufficient, so that it is difficult to prepare an easily administrable oral drug. In many cases, the dosage form was difficult to administer.

[0004]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a drug having a high solubility at the gastric pH of a healthy subject or a drug unstable at the gastric pH of a healthy subject in a stable effect for all patients. It is intended to provide an oral preparation which is easy to administer.

[0005]

According to the present invention, if a drug administered orally is not eluted in the acidic region of the stomach but can be eluted near the neutrality of the intestine, a stable drug effect can be obtained even in anacidic patients. As a result of various studies, it was considered that an acid-labile drug could be used as an oral drug. completed.

That is, the present invention relates to (A) a drug having high solubility at the gastric pH of a healthy subject or a drug unstable at the gastric pH of a healthy subject. (B) glycerin fatty acid ester, stearyl alcohol, stearic acid and macrogol. One or more selected from the group consisting of paraffin and sucrose fatty acid ester. (C) Acrylic polymer-based particles obtained by spray coagulation and granulation.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the pH of the stomach of a healthy person is
The drug having high solubility in the above is a drug which is mainly dissolved in the stomach when administered orally, and in the present invention, clarithromycin can be mentioned as a particularly preferred drug.
In the present invention, a drug unstable in the stomach pH of a healthy person is a drug which, when administered orally in a general preparation, is degraded by the stomach pH and becomes ineffective.

As the component (B) of the present invention, glycerin fatty acid esters are particularly preferred. Here, the glycerin fatty acid ester is one in which glycerin and a fatty acid are ester-bonded. Representative examples of glycerin fatty acid esters include monoglycerides and triglycerides.

[0009] Formulations made only with monoglyceride can rapidly elute the drug under acidic conditions, while formulations made with triglyceride alone can suppress drug elution. It can be. Also, by preparing and combining the pharmaceutical particles produced only with monoglyceride and the pharmaceutical particles of the present invention as separate granules, it is possible to obtain a formulation having both immediate effect of dissolving in the stomach and certainty of dissolving in the intestine. Is also possible.

The fatty acids constituting the esters of glycerin fatty acid esters are behenic acid, stearic acid, oleic acid,
Palmitic acid, myristic acid, lauric acid and the like are preferred.

The component (C) of the present invention is preferably a carboxyvinyl polymer.
Those having a molecular weight of 100,000 to 6,000,000 are particularly preferred.

In the present invention, the amount of component (B) is preferably at least 0.5 part by mass, more preferably at least 1 part by mass, even more preferably at least 2 parts by mass with respect to 1 part by mass of component (A).

If the amount is less than 0.5 part by mass, not only the dissolution control is insufficient, but also the viscosity of the dispersion becomes high, and the work at the time of production becomes difficult.

In the present invention, the compounding amount of the component (C) is
0.0001 to 0.25 parts by mass, preferably 0.001 to 0.2 parts by mass, more preferably 0.01 to 0.18 parts by mass, per 1 part by mass of component (B).

In the present invention, the amount of the component (A) is preferably 60% by mass or less, more preferably 45% by mass,
The following is more preferable, and the content is more preferably 30% by mass or less. Here, the less the amount of the component (A), the easier the elution control becomes. However, if the amount is too small, a large amount of the drug is required to produce a medicinal effect. The amounts of the components are determined.

In the particles for pharmaceutical preparation of the present invention, additives used in the production of general oral preparations can be appropriately used within a quantitative and qualitative range that does not impair the effects of the present invention.

The pharmaceutical particles of the present invention need to be produced by spray coagulation granulation in order to obtain fine and highly bioavailable pharmaceutical particles with controlled dissolution.

Here, the spray coagulation granulation is classified into one of the granulation methods generally called melt granulation, and a liquid or a suspension is sprayed to cool a droplet to form a spherical or spherical particle. This is a method for obtaining granular solid particles. This method is characterized in that no organic solvent is used, and differs from spray drying, which is a typical example of the melt granulation method, in that it is cooled.

The pharmaceutical particles of the present invention are usually produced as follows. First, it was heated and melted above the melting point (B)
The preparation of the present invention can be obtained by dispersing the component (A) in the components and performing spray coagulation and granulation under general spray conditions.

In the case of production by spray coagulation granulation, if the suspension in the production component has a large particle size, it may become clogged in a pipe at the time of spraying, or the component may not be uniformly dispersed in the produced pharmaceutical particles. For this reason, the particle diameter of the particles in the warm suspension component is usually 20 μm or less, preferably 10 μm or less. For this reason, it is necessary to pulverize the solid that is not melted by heating or the solid that is not dissolved in the carrier for spray coagulation and granulation that has been heated and melted to reduce the particle diameter. From this viewpoint, when an additive is added, an enteric base, a plasticizer, and the like which are easily dissolved in the component (B) of the present invention are most preferable from the viewpoint of operability and uniformity.

The thus obtained particles for pharmaceutical preparations may be used as they are or as necessary, for example, excipients, disintegrants, binders, lubricants, antioxidants, coating agents, coloring agents, flavors. Add a flavoring agent, surfactant, plasticizer, etc.
Ordinary solid preparations such as powders, granules, capsules, tablets, dry syrups and the like can be obtained through ordinary preparation steps.

[0022]

Industrial Applicability According to the present invention, it has become possible to provide particles for sustained-release preparations having excellent dissolution controllability and good bioavailability. Further, the present invention makes it possible to control the bioavailability (BA), and furthermore to show the excellent effects of stomach-soluble drugs such as clarithromycin even in patients with anacidity. It became possible to obtain.

[0023]

The present invention will be described below in more detail with reference to examples and test examples. The glycerin fatty acid ester used was monoglycerin fatty acid ester containing stearic acid as a main fatty acid and having a monoglyceride content of 90% or more (Sunsoft 8000: trade name). 101 (product name) was used. The spray dryer used was a CL-12 type (Okawara Koki Co., Ltd.).

Example 1 400 g of triglycerin fatty acid ester was added at about 100 ° C.
And 100 g of carboxyvinyl polymer (Carbopol 971P: trade name) was dispersed therein. 100 g of clarithromycin was further dispersed in the mixture. Using a spray drying apparatus,
Spray coagulation and granulation were performed under the conditions of an inlet temperature of 100 ° C. and a rotating disk of 20000 rpm to obtain pharmaceutical particles. ,

Example 2 650 g of stearyl alcohol was melted at about 90 ° C., and 50 g of carboxyvinyl polymer (Carbopol 971P: trade name) was dispersed therein. 300 g of clarithromycin was further dispersed in the mixture.
This dispersion was spray-coagulated and granulated using a spray-drying device under the conditions of an inlet temperature of 90 ° C. and a rotating disk of 10,000 rpm to obtain particles for pharmaceutical preparation.

Example 3 100 g of glycerin fatty acid ester was melted at about 120 ° C., and Eudragit E100 (trade name) 3 was added thereto.
0 g was dispersed and dissolved. A solution obtained by adding 30 g of a carboxyvinyl polymer to 320 g of a hardened oil melted at about 120 ° C. and 200 g of clarithromycin were dispersed therein.

The obtained dispersion was applied to a rotary disk at 12000 rp using an spray dryer.
Spray coagulation and granulation were performed under the conditions of m to obtain particles for preparation.

Comparative Example 1 400 g of glycerin fatty acid ester was melted at about 100 ° C., and 100 g of clarithromycin was dispersed therein. This dispersion was spray-coagulated and granulated using a spray-drying device under the conditions of an inlet temperature of 80 ° C. and a rotating disk of 20000 rpm to obtain particles for pharmaceutical preparation.

Comparative Example 2 400 g of triglycerin fatty acid ester was added at about 100 ° C.
And 100 g of clarithromycin was dispersed therein. This dispersion was spray-coagulated and granulated using a spray-drying device under the conditions of an inlet temperature of 100 ° C. and a rotating disk of 20000 rpm to obtain particles for pharmaceutical preparation.

Test Example 1 The pharmaceutical particles produced in Example 1 and Comparative Example
The dissolution test was conducted according to the revised Japanese Pharmacopoeia regulations. Buffers at pH 4.0 and 6.8 were used as elution media.

Table 1 shows the results of the dissolution rate 60 minutes after the start of the test.
FIG. 1 shows the results of the transition of the elution rate over time, FIG. 2 shows the results of Comparative Example 1, and FIG. 3 shows the results of Comparative Example 2.

[0032]

[Table 1] As is clear from the results, it was found that the particles for pharmaceutical preparations of the present invention were suppressed from eluting in an acidic region and eluted near neutrality.

[Brief description of the drawings]

FIG. 1 is a graph showing the elution rate of Example 1 over time, with the horizontal axis representing time and the vertical axis representing elution rate.

FIG. 2 is a graph showing the elution rate of Comparative Example 1 over time, in which the horizontal axis represents time and the vertical axis represents elution rate.

FIG. 3 is a diagram showing the elution rate of Comparative Example 2 over time, in which the horizontal axis represents time and the vertical axis represents elution rate.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/14 A61K 47/14 47/32 47/32 47/34 47/34 A61P 31/04 A61P 31 / 04 (72) Inventor Toshio Yajima 3-24-1, Takada, Toshima-ku, Tokyo F-term (reference) 4C076 AA32 BB01 CC32 DD37H DD41H DD46H DD66H EE06H EE09H FF31 FF63 4C086 AA01 AA02 EA13 MA01 MA52 MA52 NA03 NA12 ZB35

Claims (5)

[Claims] 1. A drug having high solubility at the gastric pH of a healthy subject or a drug unstable at a gastric pH of a healthy subject. B) Glycerin fatty acid ester, stearyl alcohol, stearic acid, macrogol, paraffin. And at least one member selected from the group consisting of sucrose fatty acid esters and (C) acrylic acid-based polymers by spray coagulation and granulation. 2. The pharmaceutical particles according to claim 1, wherein the component (A) is clarithromycin. 3. The particles for pharmaceutical preparation according to claim 1, wherein the component (C) is a carboxyvinyl polymer. 4. The pharmaceutical particles according to claim 1, wherein the component (B) is a glycerin fatty acid ester. 5. A glycerin fatty acid ester, stearyl alcohol, stearic acid, macrogol, paraffin and sucrose fatty acid ester.
A method for controlling the dissolution of a drug, which comprises spraying and coagulating and granulating a seed or two or more kinds thereof and an acrylic acid polymer.