JP2000302679A - Composition for soft capsule packing and soft capsule - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a soft capsule having high bioavailability, useful for treating stomach ulcer, or the like, by dissolving an effective amount of famotidine in a polyethylene glycol liquid at the vicinity of normal temperature to give a composition for a soft capsule packing and forming and packing the composition into a soft capsule. SOLUTION: An effective amount of famotidine[N-sulfamoyl-3-(2- guanidinothiazol-4-ylmethylthio)propionamidine] is dissolved in a polyethylene glycol liquid at the vicinity of normal temperature to give a composition for a soft capsule packing containing glycerol and/or water, which is formed and packed into a soft capsule. A gelatin or a chemically modified gelatin is used as the coat of the soft capsule. The amount of <=20 wt.% of the formotidine can be contained in the soft capsule based on the total weight of the soft capsule contents.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION This invention is an invention relating to pharmaceutical soft capsule preparation, particularly, relates to a soft capsule formulation and those soft capsules fill composition of famotidine is H ₂ receptor antagonists is there.

[0002]

BACKGROUND ART Famotidine (famotidin: N-sulfamoyl-3- (2
- click Bu Anishi Bu Nochiaso Bu --4-ylmethylthio) prop On'amijin, hereinafter FAM abbreviated] is, H ₂ receptor antagonists represented by the following chemical formula (H ₂ blocker - used as) gastric ulcer, for the treatment of gastritis Is a useful drug (Japanese Patent Publication No. 60-561)
No. 43). FAM is a compound that hardly dissolves in a solvent having a pH of neutral or higher, and thus is administered mainly as a tablet or powder during treatment.
7 to 5.7 injections have been developed, but injections require slow administration and are only used in the early stages of treatment,
After that, the treatment is switched to tablets or powder. And FAM bioavailability is 37%
(Applied pharmacology, 27 (1) P.73 (198
4)). Therefore, diversification of treatment methods (application means) and development of new dosage forms having high bioavailability are desired.

The chemical structural formula of FAM

Embedded image

The applicant of the present invention is a manufacturer whose main business is to manufacture soft capsule preparations used in the fields of pharmaceuticals, foods, cosmetics and the like. Has features such as the following 1) to 6) which are generally not found in other dosage forms (PHARM. TECH. JAP
AN, Vol.8 No.11 p.95-101 (1992)). 1) It shows excellent bioavailability. 2) Excellent content uniformity and low weight deviation. 3) Low oxygen permeability and good stability of contents. 4) Prescription study is easy and development can be shortened. 5) Dispersible drugs can be handled as oils or suspensions, and are highly safe in operation. 6) It is excellent in form beauty such as appearance and shape.

As for FAM, as described above, tablets, powders and injections have already been developed and put to practical use as pharmaceuticals, but the use of injections is limited. On the other hand, a filling composition for soft gelatin which has recently been contained in a semi-solid substance comprising a polyalkylene glycol (PAG) having an average molecular weight of about 600 or less and cellulose ether for thickening (Japanese Patent Application Laid-Open No. -1
No. 82426), a preparation comprising a two-phase semi-solid phase containing a drug in both phases and a gelatin shell (Japanese Patent Application Laid-Open No. 10-182437), and an average molecular weight of about 6
Pharmaceutical composition in which a drug is suspended in a gel containing a polyalkylene glycol, water and a gelling agent.
No. 253411) has been proposed.

[0006] However, the preparations according to these proposals are all based on the theme of "semi-solidifying or gelling the polyalkylene glycol as the base of the contents". This gelled or semi-solidified PAG (eg, polyethylene glycol:
(Hereinafter abbreviated as PEG)) (see Examples). Further, in the formulation described in the examples listed in each gazette, after the PEG is heated to a high temperature (110 to 120 ° C.) enough to boil to perform gelling or semi-solidification, In addition, a method of adding a drug (FAM) under heating or heating is adopted, and the soft capsule preparation prepared by that method cannot be said to have the above-mentioned characteristics of the soft capsule. Thus, when this formulation method is applied to FAM, there are many problems to be improved as described below.

1) An additive such as hydroxypropyl cellulose or sodium acetate as a gelling or semi-solidifying agent is added to the base (PAG) to form a viscous liquid.
Since AM is added, the uniformity of FAM is poor. 2) Since the treatment is performed at a high temperature, the FAM is likely to be degraded (such as a decrease in the content). 3) Since the heating and cooling steps are included, the operation is complicated and takes time, which inevitably leads to an increase in cost. 4) Since the content is solid, the disintegration time (disintegration time is a disintegration test method specified in the Japanese Pharmacopoeia,
This is the time from the start of the test until no "sample residue" is observed. ) Becomes longer.

[0008] 5) Since the concentration of the medicinal ingredient is about 5% at the maximum, if it is attempted to contain 10 mg of FAM per capsule, the weight of the content becomes 200 mg or more, and furthermore, FA
To contain 20 mg of M, the content weight is 400
When the amount is over mg, the capsule dosage form becomes large. 6) FAM is difficult to maintain uniformity because it does not dissolve in vegetable oil which is a typical base for soft capsules. In addition, FAM may settle.

[0009]

SUMMARY OF THE INVENTION The present invention aims to develop a new formulation in which high bioavailability is expected along with diversification of means for applying FAM.

[0010]

Means for Solving the Problems The present inventor has developed a new formulation of FAM in order to solve the above problems,
An effective amount of FAM is dispersed in polyethylene glycol (PEG), one of the bases for soft capsules, at room temperature and sufficiently uniformly.
It was found that it is possible to dissolve and soften the capsule. The present invention has been made based on such findings. That is, the present invention provides a novel famotidine-containing soft capsule comprising the following and a composition for filling the soft capsule. A soft capsule prepared by filling a soft capsule with a composition for filling a soft capsule obtained by dissolving an effective amount of famotidine in polyethylene glycol which is liquid at about normal temperature. The soft capsule according to the above, wherein the composition for filling a soft capsule contains glycerin and / or water. A composition for filling a soft capsule prepared by dissolving an effective amount of famotidine in liquid polyethylene glycol at around normal temperature. The composition for filling a soft capsule as described above, wherein the composition for filling a soft capsule contains glycerin and / or water. Hereinafter, the present invention will be described in detail.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The composition for filling a soft capsule according to the present invention comprises a chemically modified gelatin such as gelatin or succinated gelatin which is usually used as an outer shell of the soft capsule, a plasticizer such as glycerin or sorbitol, An oval or spherical soft capsule is formed by molding and filling using a film agent prepared by melting in water, together with a coloring agent and a preservative added as necessary. As the production method, any of the following rotary method and dropping method, which are typical production methods of soft capsules, can be applied (Igusa et al., Development of Pharmaceuticals, Vol. 5 Soft capsules, pages 121 to 135, see Hirokawa Shoten (issued on H1.11.10)).

A) Rotary method: In the rotary method, first, the coating agent is formed into a pair of continuous belt-shaped sheets by utilizing the gelatinization ability of gelatin, and a pair of cylindrical molds (die rolls) which rotate the band-shaped sheets. Between the injection segment, from the injection segment, the piston interlocks with the rotation of the die roll, intermittently and quantitatively injects the contents, the strip-shaped sheet is formed by the die pressure of the injected contents by the liquid pressure of the injected contents. It bulges along the hole, and a predetermined amount of the content is enclosed, and at the same time, is cut out and adhered at the joint of the film to be molded into a soft capsule. This molded soft capsule is made into a final product after drying and washing steps.

B) Dropping method: Since the soft capsules obtained by the present dropping method have no seams unlike the soft capsules obtained by the rotary method, "seamless capsules" (seamless capsul) are used.
Also called e). According to the manufacturing method, a coating liquid composed of a gelatin liquid or the like is dropped from an outer nozzle and a chemical liquid from an inner nozzle into a medium such as liquid paraffin to form a concentric cylindrical liquid flow. The two-layer concentric cylindrical liquid flow is a two-layer liquid droplet composed of the outer skin and the contents due to the interfacial tension acting between the outer liquid flow and the inner liquid flow. Become Then, the soft capsule thus produced is separated from the medium by the inclined sieve, and then is commercialized through washing, drying steps and the like. Further, it can also be manufactured by a dropping method using a triple nozzle method. This triple nozzle method is different from the above-mentioned double nozzle method in that when the coating (gelatin) liquid from the outer nozzle and the content liquid from the inner nozzle come into contact with each other, the water in the coating liquid is deprived and the high concentration gelatin liquid is removed. In the event that problems such as hardening of the coating liquid at the nozzle tip or deterioration of the liquid from the nozzle occur, an intermediate nozzle is provided between the outer nozzle and the inner nozzle, and a hydrophobic substance ( This is a method of forming a soft capsule having a three-layer structure composed of an outer skin, an intermediate layer, and contents by flowing an intermediate layer).

The FAM can be incorporated up to about 20% by weight based on the total weight of the soft capsule contents. This means that various soft capsules having different FAM contents per capsule can be prepared depending on the purpose of treatment. If the FAM content exceeds 20% by weight, FAM tends to precipitate, which is not preferable. As the base for the contents in the present invention, polyethylene glycol (PEG) which is liquid at around normal temperature is used. PEG is an addition polymer of ethylene oxide and water and generally has the chemical formula HOCH
₂ (CH ₂ OCH ₂ ) _n CH ₂ OH and several types are commercially available depending on their average molecular weight. Suitable as a base of the soft capsule of the present invention are Macrogol 300 (pharmaceutical rule), Macrogol 400 (JP) and Macrogol 600 (pharmaceutical rule), among which Macrogol 300 which is liquid at room temperature. (Drug rule) and Macrogol 400 (JP) are suitable.

As the base for the contents of the soft capsules, vegetable oils such as soybean oil, olive oil, wheat germ oil, medium-chain fatty acid triglyceride (MCT), beeswax, monoacylglycerin (monoglycol) and the like. Oils and fats such as beef tallow, lard, cacao butter and the like, or a mixture thereof at around normal temperature are used as a base. Generally, vegetable oil and MCT having 6 to 10 carbon atoms are often used. However, since these bases hardly dissolve FAM or are in a gel or solid state, they are unsuitable as bases for FAM because of a long disintegration time. Next, the present invention will be described in more detail by way of examples. The present invention is not limited by these examples.

[0016]

EXAMPLES (Examples 1 to 3) Spherical soft capsules were obtained using the known rotary soft capsule manufacturing apparatus according to the formulations shown in Table 1 below. The contents are
In each case, a transparent solution was obtained only by mixing and stirring each component.

[Table 1] Table 1

[0017]

Comparative Examples (Comparative Examples 1 to 3) The formulation of the film and the method of producing the soft capsules were in accordance with Examples 1 to 3, and the contents used were those shown in Table 2 below. In Comparative Example 1, each component was mixed and stirred. It did not dissolve when heated.
Comparative Examples 2 and 3 were prepared using beeswax or monoglia at 70 ° C.
The mixture was heated to 80 ° C. and melted. Vegetable oil was added to the mixture, followed by stirring. FAM was added to the mixture, followed by stirring and dispersion.

[0018]

[Table 2] Table 2

[0019]

[Test Example] [Test Example 1] (Observation of appearance) The appearance of each of the soft capsules produced in the above Examples and Comparative Examples was observed. Table 3 shows the results.
As is clear from Table 3, Examples 1 to 3 of the present invention were all excellent in transparency and appearance in comparison with Comparative Examples. The soft capsules of the present invention all have a pale yellow color, which is derived from the gelatin used as the coating base.

[0020]

[Table 3] Table 3

[Test Example 2] (Disintegration test) A disintegration test was carried out based on the Japanese Pharmacopoeia, and the time until the residue disappeared was measured. Table 4 shows the results.
Shown in

[Table 4] Table 4

[0022]

As will be apparent from the detailed description above, the present invention has the following effects by soft encapsulation of FAM. B) Since FAM is encapsulated in a liquid state, FAM
It is expected that the homogeneity of FAM will be maintained and that the bioavailability of FAM will be improved. B) Since encapsulation can be performed without performing heat treatment, F
Less degradation of AM and other capsule contents. C) Since heating and cooling are not required, the operation is simple, it takes no time, and the cost is advantageous. D) Since the contents are liquid, the film dissolution time is almost equal to the disintegration time, and the disintegration time is shorter than in the case of gel or semi-solid. E) Since FAM can be contained up to 20% by weight, the size of the soft capsule preparation can be reduced. Also,
The choice of FAM concentration per capsule is expanded.

Claims (4)

[Claims] 1. A soft capsule, wherein a composition for filling a soft capsule in which an effective amount of famotidine is dissolved in polyethylene glycol which is liquid at around normal temperature is formed and filled in a soft capsule. 2. The soft capsule according to claim 1, wherein the composition for filling a soft capsule contains glycerin and / or water. 3. A composition for filling a soft capsule, which is obtained by dissolving an effective amount of famotidine in polyethylene glycol which is liquid at about normal temperature. 4. The composition for filling a soft capsule according to claim 3, wherein the composition for filling a soft capsule contains glycerin and / or water.