JPS60252411A - Composition for soft capsule having long-term storage stability - Google Patents

Abstract

PURPOSE:To prepare a soft capsule agent storable for a long period without causing the reaction of the drug content with gelatin and the precipitation of the crystal, by using an modified gelatin as a base, and compounding with a hydrolyzed product of reduced starch and/or propylene glycol. CONSTITUTION:A soft capsule agent storable for a long period without causing the lowering of the solubility nor the deterioration of the appearance can be prepared by compounding (A) base material comprising a modified gelatin, preferably a gelatin wherein the amino group in the molecule is protected with acetyl group, propionyl group, benzoyl group, phthaloyl group and/or succinoyl group, more preferably the above gelatin having a bloom strength of 100-250 and a viscosity of 10-100cps (60 deg.C) with (B) hydrolyzed product of reduced starch and/or (C) propylene blycol. The weight ratio A:C is preferably 1:(1-0.2) or the amounts of the component A, the component C and water are 30-60 pts.wt., 10-40pts.wt. and 20-50pts.wt., respectively.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compositions for long-term storage stable soft capsules.

[Description of prior art]

Conventionally, it has been known that gelatin is used as a base material for soft capsules, and glycerin, nrubitol, etc. are blended as water retaining agents and softeners, and a sol solution prepared by adding water and dissolving the gelatin is used as the outer shell of soft capsules.

However, when the capsule contents are, for example, special drugs, especially those containing aldehyde groups, they easily react with the amine groups of the gelatin used, and the reaction (crosslinking) forms macromolecules. It was accepted that it would. However, the formation of this macromolecule has led to drawbacks such as the insolubility of the capsule product or its failure to disintegrate within the pharmacopoeially prescribed disintegration time. It was particularly undesirable for such a phenomenon to occur when a long-term accelerated test was conducted under the conditions of 1 ItO 0 C and 75% R, H, which are essential for applying for a manufacturing license for a drug.

Furthermore, when nrbitol as described above was used as an additive to the base material, crystals thereof were deposited on the surface of the resulting capsules, which significantly deteriorated the appearance of the final product.

The present invention was made to improve the drawbacks of stiffness, and surprisingly has the advantage of having long-term storage stability.

[Configuration of the present invention]

The present invention is a composition in which modified gelatin is used as a corresponding gelatin, and reduced starch hydrolyzate and/or zoropylene glycol is blended in order to achieve various predetermined effects of the present invention. be.

In the present invention, "modified gelatin" refers to gelatin in which an amine group is side-chained with a known appropriate securing group. Examples of the protecting group include an acetyl group, a propionyl group, a hendiyl group, a phthal group, and a succinic acid group. In the present invention, protection with an acetyl group is particularly desirable.

As a mere example, ME retention by organic acids is described as follows.
It is desirable to use acetic anhydride, succinic anhydride, phthalic anhydride, etc., and of course they may be used in the form of reactive derivatives if necessary.

This type of modified gelatin is called acetylated gelatin, succinated gelatin or phthalated gelatin, and is easily available on the market.

By the way, it is said that the solubility of such modified gelatin in the digestive tract is slightly slower than that of modified gelatin. However, when the capsule is made into a soft capsule, the seam is the first to rupture and the drug solution is released, so such a delay is not a particular problem.

On the other hand, the pharmacopoeia 1st solution (sodium chloride θq, special grade hydrochloric acid (35%), 23.6- to 100- by adding water, 2 da, θ- and water to make 100- It has been found that gelatin has a pH of about 1.2 mm and solubility in hot water is better than that of ordinary gelatin. Furthermore, other physical properties, such as surface strength, specific gravity, viscosity characteristics of aqueous solution, adhesive properties, etc., are almost the same as ordinary gelatin, and no particular problem is observed in the production of Hoka capsules.

In the present invention, the term "reduced starch hydrolyzate" refers to a mixture of monosaccharides to polysaccharides or straws obtained by reductive decomposition of various starchy substances.

More specifically, it consists of monosaccharides, trisaccharides, trisaccharides, and tetrasaccharides, or a mixture thereof, and PO
- Multiplicative sum ■ and u1 Nisii 20. They are easily available under trade names such as Nis-E 30, Nis-E 37, Nis-E 10θ, and Uniton.

Such a reduced starch hydrolyzate is used in a ratio of /θ to left θ (weight ratio), preferably 70 to 3o, based on 100 parts of modified gelatin.

The "propylene glycol" used in the present invention is described in the Japanese Pharmacopoeia (9th revision, D-77). Zoropylene glycol is used at a ratio of 77 to 73 JCM per 10 grams of modified gelatin. More preferably, it is used in a ratio of 30 to 700.

An example of the implementation of the present invention is as follows. First, 3 parts of propylene glycol, 1 part of purified water, and 33 parts of Oimoto starch hydrolyzate were added to the modified gelatin/θO part, stirred, and heated in a dissolution pot with warm water under vacuum to obtain a uniform sol solution pressure. A sol solution for forming a soft capsule shell is obtained. The dissolving time normally required depends on the type of equipment used.
- within the time range.

For the purpose of coloring, the above composition is further added with a pigment of 0.05 to 7.
0% by weight (based on composition), 0 preservatives for storage stability
．． The weight may be /~0.3%.

Next, this sol solution is poured onto the casting drum of a known rotary die punching type soft capsule manufacturing machine while adjusting the thickness using an applicator to prepare a film of a constant thickness, and then cool-dried. Blow air on it to form a film of uniform thickness.

Next, the two glued films are sandwiched between symmetrical rotating metal molds, and while being molded to form a soft capsule shell, the medicine contained in the capsule is filled with a drug injection device, such as vegetable oil/37119. Mixed solution of oxamidine/Hiroki, vegetable hydrogenated oil/gq and surfactant 3cm 300cm
is pressurized and filled into the outer shell of the soft capsule, and at the same time, the outer shell of the soft capsule is welded and closed by rotating one mold, and a soft capsule is punched out.

When this is dried in a hot air rotary dryer, soft capsules containing the above mixed solution 3θ0■ are produced.

[Effects of the composition of the present invention]

Normally, after oral administration, soft capsules are quickly dissolved in gastric juices and absorbed into the body by the outflow of the contents, but this dissolution time is determined by pharmacopoeial disintegration tests, and The disintegration time is said to be less than 20 minutes.

Therefore, when capsules are manufactured by filling the drug with a group that reacts with 41m gelatin, after long-term storage or under 3-
In the disintegration test after 2 or 6 months of accelerated stability testing, the solubility of the capsule was markedly deteriorated, and in extreme cases, the pharmacopoeial disintegration test method [Japanese Pharmacopoeia (Strategy Revised) B-, 2
, 5"'7] may require 20 minutes or more to dissolve.

Furthermore, when sorbitol is used in a gelatin formulation, white crystals may form on the surface of the capsule film after long-term storage or accelerated stability tests, significantly impairing the appearance and causing the capsule to lose its commercial value.

The composition of the present invention improves or eliminates these drawbacks.

The present invention will be explained below with reference to Examples.

Example/ Succinated gelatin was used as modified gelatin, while ordinary gelatin (medical gelatin S) was used for comparison.
#/3θ), sol solutions for capsules were prepared according to the above-mentioned dissolution method using the following formulations.

Next, using these sol solutions for capsules, soft capsules containing vegetable oil, Chinese herbal medicine, surfactants, hydrogenated vegetable oil, etc., either alone or in a mixed solution (filling @ t300), are placed in a rotary machine using the above-mentioned method. Manufactured by die punching method.

Then, it was sealed in a glass bottle and left to stand under conditions of 410° C. and 73% R,H. After 3 years and 2 months had elapsed, the disintegration properties were measured based on the pharmacopoeial disintegration test method. (Japanese Pharmacopoeia Revised P-S-J57) The obtained results are summarized in Table/.

Medicinal solution / Medicinal solution - 1 vegetable oil 300 ■ Vegetable oil 737 ~ (wheat germ oil) Chinese herbal medicine (Oya!,, 7). ,
, v Vegetable hydrogenated oil /g~ From the table, it can be seen that the capsule composition of the present invention has excellent long-term storage stability.

Example 4 4t/7 parts of succinated gelatin, 777 parts of zoropylene glycol, and reduced starch hydrolyzate//The components of the soft capsule outer shell of Otsu part were accurately weighed, 330 parts of purified water was added, and the mixture was stirred. I put it in a melting pot. Then the θ~ri0
The mixture was dissolved under a temperature condition of 0.degree. C. while degassing using a vacuum pump to obtain a sol solution. Next, using this sol solution, using the previously described known capsule manufacturing machine (rotary die punching method), the drugs contained in the capsule were 20 parts by weight of eleutherococ, 20'HfS, d-α-tocopherol, Soft capsules were obtained in which a medicinal solution of 700 parts of wheat germ oil, 10 parts of lecithin, and 700 parts of safflower oil was mixed and stirred and filled into the capsule.

No change was observed in this capsule as a result of the long-term stability test described in Examples.

Example 3 Acetylated gelatin 'l'12 was prepared in the same manner as in Example 3.
A sol solution was prepared by adding 733 parts of the reduced starch hydrolyzate and 733 parts of the reduced starch hydrolyzate and 733 parts of f-robylene glycol as soft capsule shell components, and adding 2 parts of purified water.

Next, by the same method as in Example A, soft capsules containing 3θ0x of a mixed solution of 7 parts of 4002 g of polyethylene glycol, 3 parts of nifedipine, a part of glycerinda, and a part of water were produced. This capsule lasts for a long time.
It didn't change.

Example ≠ Two different types of reduced starch hydrolysates were mixed in a proportion of 7 parts and 102 parts of ZO4, respectively.
A sol solution was prepared by mixing 2 parts of 11t4' of talized Zetia to form a soft capsule shell component, and adding 262 parts of purified water to this 7IA.

Next, in the same manner as in Example 2, soft capsules containing a mixed solution of vegetable soybean oil, ginseng extract, and natural vitamin E, 300-=7, were manufactured.

This capsule did not change over time.

Claims (5)

[Claims] (1) A composition for long-term storage stable soft capsules, which is based on modified gelatin and contains a reduced starch hydrolyzate and/or propylene glycol. (2) The composition for long-term storage-stable soft capsules according to claim (1), wherein the modified gelatin is gelatin in which an acetyl group or an amino group in the zogelatin molecule is substituted as a protective group. (3) Modified gelatin has a bloom strength of 70
0~20, viscosity/θ~100 centipoise (O℃)
A long-term storage stable soft capsule composition according to claim (1). (4) The composition for long-term storage-stable soft capsules according to claim (1), wherein the weight ratio of the reduced starch hydrolyzate to propylene glycol is in the range of /:/ to /: 0.2. (5) weight ratio of 30 to 60 parts of modified gelatin;
The long-term storage stable soft capsule composition according to claim (1) or (2), which contains 70 to 0 parts of propylene glycol and 20 to 50 parts of water.