[Title of the invention]

Gelatin capsules and gelatin compositions for forming capsule coating

[Technical Field]

[0001]

This invention relates to a gelatin capsule wherein insolubilization with the lapse of time is difficult to occur and mechanical strength reduction is minimized, as well as a novel gelatin composition which is used for the preparation of the same.

[Prior Art]

[0002]

Capsules may be handled as one calculation unit like tablets and have advantages in that drugs are less

deteriorated because of no need for compression step unlike tablets and capsules may be prepared even in the case where molding of drugs is difficult. Hard capsules are prepared by using gelatin as a base and adding thereto plasticizers, coloring agents, etc. Soft capsules are prepared by adding a relatively large amount of plasticizers to a gelatin base, whereby there is formed a pharmaceutical preparation which is abundant in elasticity and flexibility (Non-patent document 1) .

[0003]

However, since gelatin of a main component for a capsule coating has amino groups, there has been presented the problem that change over time such as cross-linking or polymerization may occur during a prolonged storage to cause insolubilization and, as a result, a delayed release of the packed drug, in the case where a resin containing an aldehyde-type component is used as a package, or where capsules may comprise the drugs or excipients containing an aldehyde group or capable of producing aldehyde by

degradation with the lapse of time (hereinafter collectively referred to as insolubilization-inducing substances), such as reducing sugars, macrolide antibiotics, etc.

[0004]

Moreover, the gelatin coating of hard gelatin capsules contains a water content of around 15% in environments of 50%RH, which may provide gelatin with moderate flexibility and strength as a plasticizer. However, if the water content is lowered, the coating becomes hard and brittle so as to lose elasticity and capsules are easy to crack. For the purpose of improving this drawback, it was studied to add polyethylene glycol (hereinafter referred to as PEG) to gelatin so that the strength could be remarkably enhanced at a low water content (Non-patent document 2) . However, there has been presented the problem that PEG may be also oxidized with the lapse of time to generate aldehyde, which may act as insolubilization-inducing substances to cause gelatin capsules to be insolubilized .

[0005] In order to solve these insolubilization problems, there have hitherto been made various studies. For instance, it is known that the resins not containing aldehyde components are applied onto the surface of a package contacting with capsules (Patent document 1), that aminoacetic acid is incorporated into packing materials for capsules to prevent the aldehyde in the packing materials from its reacting with amino groups in the gelatin of packing materials for hard capsules, thereby reducing insolubilization (Patent document 2), or that amino compounds such as collagen peptides having a molecular weight of 500-10,000 are blended into packing materials to prevent the aldehyde in the packed materials from its reacting with amino groups in the gelatin of packing materials for soft capsules, thereby reducing insolubilization (Patent document 3) .

[0006]

Moreover, for improving the outer shell of capsules, it is known that ammonium sulfate, ammonium hydrogensulfate , glutamic acid, aspartic acid, etc is added to gelatin

(Patent document 4), that a polypeptide having a molecular weight of around 5,000-10,000 is added to gelatin at 15-70% to depress the reaction of aldehyde with gelatin (Patent document 5) , that a succinylated gelatin, wherein the amino acid lysine residue (-NH ₂ ) causing insolubilization is chemically modified, is used for hard capsules (Patent documents 6 and 7), soft capsules (Patent document 8), etc.

[0007] Among these various methods, it is the most fundamental solution to stabilize the capsule outer shell itself.

However, the use of a succinylated gelatin results in the reduction in mechanical strength of a coating; in particular, in the case of a hard capsule having a thickness of only around 100 micrometers, there is presented the problem that capsules become easier to crack as compared with the prior art products, whereby practical use comes to be difficult (Patent document 7), or, in the case where a polypeptide having a molecular weight of 5,000-10,000 is used, there is presented the problem that shape retention of products may be reduced if added in a large amount (Patent document 5) . As a result, these methods have been not always satisfactory.

[0008]

As mentioned above, when a water-soluble polymeric

substance such as a polypeptide having a smaller molecular weight is used for depressing the reaction of gelatin with insolubilization-inducing substances, mechanical strength is reduced even if the insolubilization thus induced may be prevented. Then, it has been originally placed in the course of inconsistency that the above results shall be compatible with each other, in the light of physicochemical properties of polymers.

[Prior art documents]

[Patent Documents]

[0009]

[Patent document 1] Japanese Utility Model Kokai No. HEI7-13761

[Patent document 2]

Japanese Patent Kokai No. 2000-26282

[Patent document 3]

Japanese Patent Kokai No. 2003-55263

[Patent document 4]

Japanese Patent Kohyo No. HEI10-509470

[Patent document 5]

Japanese Patent Publication No. HEI6-2665

[Patent document 6]

Japanese Patent Kokai No. HEI7-252138

[Patent document 7]

Japanese Patent Kokai No. HEI6-72862

[Patent document 8]

Japanese Patent Kokai No. 2000-44465

[Non-Patent Documents]

[0010]

[Non-patent document 1]

"Comprehensive Galenical Pharmacy" (written in Japanese) , Written and Edited by Yuichi SUGIYAMA and Keiji YAMAMOTO, NANZANDO, Published on April 3, 2000, pages 456-457

[Non-patent document 2]

"Polymer reviews - The structures and properties of solid gelatin and the principles of their modification"

(Polymer, 1983, Vol. 24, June, 651-666)

[Summary of the Invention]

[Problems to be Solved by the Invention] [0011]

It is the object of this invention to provide a gelatin capsule which is prevented from the insolubilization of a capsule coating with the lapse of time and also retains mechanical strength, as well as a novel gelatin composition which is used for the preparation of the same.

[Means to Solve the Problems]

[0012]

The present inventors have made various studies to solve the above-mentioned problems and, as a result, have found out that, in the case where capsules are prepared by using a novel gelatin composition which is prepared by blending a low molecular weight gelatin (a decomposed product of gelatin with a molecular weight of 6,000-26,000) with a common gelatin at 5-10 percent by weight in terms of a total amount of gelatin (which is the sum of the weight of a common gelatin (with an average molecular weight of two hundred thousand) and the weight of a low molecular weight gelatin) , there can be obtained practical capsules wherein insolubilization of capsules by insolubilization-inducing substances can be depressed and mechanical strength is not reduced, and these capsules are practically provided with an improved solubility even after a prolonged storage. In view of the fact that polypeptides having a molecular weight of over 10,000 have hitherto been considered to exert less effect of preventing insolubilization with the lapse of time (Patent document 5), it is surprising that such effects can be accomplished by using a low molecular weight gelatin having a molecular weight ranging from 6,000 to 26,000.

Moreover, this invention provides ideal hard capsules which are difficult to be insolubilized by using the low molecular weight gelatin at the rate as defined above, even when PEG is added to gelatin for enhancing strength of hard capsules in a low water content. In this case, there can be obtained capsules by adding PEG having an average molecular weight of 2,600-25,000 at 2-5 percent by weight in terms of a total amount of gelatin.

[Effect of the Invention]

[0013]

According to this invention, hard or soft capsules are prepared by using as a raw material a gelatin composition wherein a low molecular weight gelatin is blended with a common gelatin at 5-10 percent by weight in terms of a total amount of gelatin, whereby insolubilization of capsules caused by insolubilization-inducing substances can be prevented and, in particular, ideal hard capsules without any loss in mechanical strength can be provided.

[Embodiments of the Invention]

[0014]

This invention will be more fully explained below.

In the capsules of this invention, a composition

comprising the common gelatin depicted below and blended with the low molecular weight gelatin is used as a basic raw material, and additives or methods for the preparation of capsules may be selected depending on whether the desired capsules may be of a hard type or a soft type. First, raw materials for the preparation will be explained below.

1. Raw materials

(1) Gelatin

The common gelatin for preparing capsules includes an acid-treated gelatin prepared by acid treatment of pigskin etc., an alkali-treated gelatin prepared by alkali treatment of bovine bones etc., and it is composed of a polypeptide chain of a molecular weight of about one hundred thousand (a -chain), its dimer ( j3 -chain), trimer (γ-chain) and a polypeptide chain obtained by hydrolysis thereof, and it has an average molecular weight of about two hundred thousand.

In preparing the capsules of this invention, there may be used any of the gelatins obtained by acid- or alkali- treatment, and a mixture thereof may be also used.

[0015]

(2) Low molecular weight gelatin

The low molecular weight gelatin as used in this invention is referred to the decomposition product of a gelatin which has a molecular weight distribution ranging from 6,000 to 26,000, preferably 6,000 to 24,000, more preferably 12,000 to 24,000 when analyzed by a gel permeation chromatography.

The low molecular weight gelatin may be prepared by subjecting collagen to heat decomposition, acid or alkali decomposition or enzymolysis with protease and then separating and purifying the gelatin having the above- defined molecular weight distribution.

Moreover, the low molecular weight gelatin has a gelling ability. The term "gelling ability" as used herein is meant to be an ability of solidifying to a jelly-like solid state through sol-gel transition when a temperature of an aqueous solution is lowered.

A content of the low molecular weight gelatin is in a range of from 5-25 percent by weight, preferably 5-10 percent by weight in terms of a total amount of gelatin (which is the sum of the weight of a conventional gelatin and the weight of a low molecular weight gelatin) . The insolubilization-prevention effect will become less in the case of less than 5 % by weight, and, in the case of more than 25 percent by weight, the viscosity of a gelatin solution will be lowered so as not to be suited for

preparing capsules having a prescribed thickness by the existing capsule manufacturing machine. Consequently, the above-defined range is preferable.

[0016]

(3) PEG

According to this invention, there can be provided ideal hard capsules which are difficult to be inzolubilized even if polyethylene glycol (PEG) is added, and to be reduced in mechanical strength even at a low water content. The PEG to be added to the gelatin raw material is not particularly critical, and it is used with an average molecular weight of preferably from 2,600 to 9,300, more preferably from 2,600 to 3,800, since mechanical strength of capsules may be remarkably improved.

[0017]

The preferred PEG may be available as the product with a trade name "Macrogol 4000". An amount of this PEG to be added is not particularly critical, and it is suitable to use the PEG at 2-15 percent by weight, preferably 2-10 percent by weight, more preferably 2-5 percent by weight in terms of the above-mentioned total amount of the gelatin raw material (gelatin) . In the case of less than 2 percent by weight or not less than 15 percent by weight, any

improvement in mechanical strength is not realized or, rather, mechanical strength may be sometimes reduced.

[0018]

(4) Other additives

In preparing the capsules of this invention, to the raw material for the outer shell (gelatin) may be further added conventional additives to be blended. For instance, there may be added if necessary food dyes, titanium oxide, sodium lauryl sulfate, surfactants such as fatty acid esters, etc. in the case of hard gelatin capsules, or food dyes, glycerol, sorbitol, ethyl paraoxybenzoate, etc. in the case of soft gelatin capsules.

[0019]

2. Materials to be packed The gelatin capsules may be preferably employed as an encapsulating material in the field of drugs or foods, but this is not critical. The capsules may be also similarly applied, for example, to quasi drugs or cosmetics.

[0020]

3. Manufacture of capsules

Manufacture of the capsules according to this invention can be performed by using a gelatin composition for forming a capsule coating containing a low molecular weight gelatin and applying a conventional process for the manufacture of capsules. For hard capsules, there may be used a dipping method, wherein gelatin and a low molecular weight gelatin having a gelling ability are dissolved and pigments etc. are mixed to form a coating solution, dipping a mold into the solution to adhere the gelatin solution and drying until a water content is reached to 15-18%, etc. For soft capsules, there may be used a rotary method or a double-nozzle method, wherein to a solution of gelatin and a low molecular weight gelatin having a gelling ability is added a plasticizer such as glycerol, sorbitol, etc. to form a base and encapsulating a drug in a liquid state in the base and molding to a certain shape.

[Example]

[0021]

[Example 1]

With an alkali-treated gelatin having an average molecular weight of about two hundred thousand was blended a low molecular weight gelatin (having a molecular weight ranging from 6,000 to 26,000) at a rate of 0.5, 5, 10 or 25 % by weight to form gelatin mixtures. 1.5 kg of each of the gelatin mixtures thus formed was completely dissolved in 2.9 kg of water to prepare a uniform gelatin solution with a concentration of 34%. This solution was maintained at 50°C, thoroughly defoamed and then the solution viscosity for each solution was measured using a rotational viscometer at 4000 rpm. The results are shown in Table 1.

[0022]

Table 1

Low molecular weight gelatin content Measured viscosity in capsule coating [%] [mPa- s]

0 1355

5 1332

10 1285

25 515

[0023]

A viscosity of the gelatin solution, with which the low molecular weight gelatin was admixed at 0-10%, was not less than 1000 mPa-s, and then capsules could be prepared with a prescribed thickness in the existing capsule-manufacturing machine. However, a viscosity of the gelatin solution, with which the low molecular weight gelatin was admixed at 25%, was extremely lower than 1000 mPa- s, and then this gelatin solution was not suited for the use in the existing capsule- manufacturing machine.

[0024]

[Example 2] To the gelatin solution prepared by Example 1 and having a low molecular weight gelatin content of 0, 5 or 10% was added water to adjust the respective solution viscosities up to such a viscosity that is convenient for molding of capsules by means of a trial manufacturing machine for hard capsules. In the solution for forming capsules thus prepared was dipped a mold for capsule molding to prepare hard capsules of Size No. 2. Into the capsules thus prepared was packed acetaminophen powder and solubility of the capsules was measured according to the dissolution test prescribed in the Japanese Pharmacopoeia (the JP) (a paddle method, 50 rpm, water, 37°C). The results are shown in Table 2.

Into each of unused remaining capsules was packed lactose powder, which is one of aldehydes, and the packed capsules were stored in unpackaged state for 3 weeks in environments at 40°C and 75% RH to accelerate insolubilization . After the packed material in the capsules after the storage was repacked with acetaminophen powder and then solubility of the capsules was measured according to the dissolution test prescribed in the JP (a paddle method, 50 rpm, water, 37°C). The results are shown in Table 3.

[0025]

Table 2: Before starting storage

Low molecular Dissolution Dissolution Dissolution weight gelatin [%] in 15 [%] in 30 [%] in 45 content in capsule min . min . min .

coating [ % ]

Reference- 1 0 40.9 73.2 90.3

Capsule A 5 41.7 76.3 91.0

Capsule B 10 49.3 80.1 92.9 [0026]

Table 3: After storage

Low molecular Dissolution Dissolution Dissolution weight gelatin [%] in 15 [%] in 30 [%] in 45 content in capsule min . min . min .

coating [ % ]

Reference- 1 0 33.3 54.2 68.7

Capsule A 5 39.0 62.8 81.5

Capsule B 10 40.3 69.3 83.8

[0027]

As shown in Table 3, both of Capsule A and Capsule B, which contained the low molecular weight gelatin at the respective blending rates of 5% and 10%, showed a higher dissolution after storage and a greater improvement in the lowering of solubility of capsules, as compared with

Reference-1 having the low molecular weight gelatin of 0%.

[0028]

[Example 3]

The capsule-forming solution prepared by Example 2 was applied onto a plain polyvinyl chloride plate by means of an applicator for film-forming to form a gelatin film having a dried film thickness of 0.1mm. The film was measured for a film-breakage energy by means of a pendulum impact tester (manufacture by CAPSUGEL) (mean value of measurements n=10) .

Moreover, Reference-2 film was prepared in the similar procedures using the above-mentioned gelatin solution, to which a titanium oxide coloring material was further added at 2%, and then incorporated in this test, in order to reproduce white-colored capsules blended with titanium oxide, which have been very often employed in the relevant market. The films to be tested were placed in a box previously maintained at 10%RH to 50%RH for one week to reduce a water content in the films. The results are shown in Table 4.

[0029]

Table 4

50%RH 20%RH 10%RH

Reference-1 (transparent) 26 24 24

Reference-2 (white-colored) 22 17.5 12.5

Film A 26 24 24

Film B 26 23 22

[0030]

It was shown that both of Film A and Film B, which contained the low molecular weight gelatin at the respective blending rates of 5% and 10%, have a sufficiently superior strength, as compared with Reference-1 and Refetrence-2 having the low molecular weight gelatin at 0%.

[0031]

[Example 4]

Using a common gelatin alone (Reference-3 ) , a blend of a common gelatin with Macrogol 4000 (drug in the JP) at 2.5% or 5% (Reference-4 and Reference-5) , and a blend of a common gelatin with the low molecular weight gelatin used in

Example 1 in a content of 5% by weight or 10% by weight (Capsule C and Capsule D) , the capsule-forming solutions were prepared according to the procedures described in Example 2. A mold for forming capsules was dipped into each of the capsule-forming solutions to form hard capsules.

Into the capsules thus formed was packed a tocopherol nicotinate preparation (a pharmacologically equivalent fine granule drug to Juvela-N® manufactured by Eisai Co., Ltd.) . The packed capsules were stored for 4 weeks in environments at 50°C and 75% RH . A disintegration time for the capsules before and after storage was measured according to the disintegration test in the JP. The test results are shown in Table 5 and Table 6.

[0032]

Table 5 : Before starting storage

Content of low PEG blending Opening Dissolving molecular rate (%) time of time of weight gelatin capsules capsules

(%)

Ref erence- 3 0 0 Omin .51sec . 3min .42sec .

Ref erence- 4 0 5 lmin . OOsec . 9min .15sec .

Ref erence- 5 0 2.5 lmin .18sec . 4min .5sec .

Capsule C 5 2.5 lmin .28sec . 3min . Usee .

Capsule D 10 2.5 Omin .51sec . 2min .40sec .

[0033]

Table 6 : After storage

Content of low PEG blending Opening Dissolving molecular rate (%) time of time of weight gelatin capsules capsules

(%)

Ref erence- 3 0 0 lmin .53sec . 9min .4 lsec .

Ref erence- 4 0 5 lmin .4 lsec . 13min .42sec .

Ref erence- 5 0 2.5 2min .30sec . lOmin .31sec .

Capsule C 5 2.5 lmin .24sec . 6min .2sec .

Capsule D 10 2.5 Omin .52sec . 4min .29sec .

[0034]

Hard capsules blended with PEG showed longer capsule opening time and dissolving time, since insolubilization proceeded during storage. However, changes in opening time were hardly observed and also delay in dissolving time was depressed by blending the low molecular weight gelatin into the outer shell of capsules.

[Industrial Applicability]

[0035] As mentioned above, the capsules according to this invention do not bring about delayed disintegration with the lapse of time and can maintain a sufficient mechanical strength even if insolubilization-inducing substances may be present in packaged products or packing materials or raw materials for capsules. Consequently, the capsules

according to this invention are extensively useful as an improved product for the existing gelatin capsules in the relevant field, in which it is required to maintain capsule contents and simultaneously secure the dissolution thereof, such as drugs, foods, dietary supplements, etc.