WO2000040254A1

WO2000040254A1 - Pharmaceutical composition for oral administration having therapeutic activity on gastrointestinal disorders

Info

Publication number: WO2000040254A1
Application number: PCT/KR1999/000209
Authority: WO
Inventors: Hak Hyung Kim; Jong Wan Lee; Jang Hoon Kweon; Jong Keun Chung
Original assignee: Daewoong Pharmaceutical Co., Ltd.
Priority date: 1998-12-31
Filing date: 1999-04-29
Publication date: 2000-07-13
Also published as: KR20010086297A; AU3444299A; KR100370391B1; CN1175820C; CN1332630A; KR20000046974A

Abstract

Disclosed is a pharmaceutical composition for oral administration having therapeutic activity on gastrointestinal disorders, characterized by comprising at least one selected from the group consisting of aceglutamide aluminum and a mixture of aluminum hydroxide and magnesium hydroxide as active ingredient, and carrageenan as taste masking agent, which can effectively mask a bitter and an astringent taste of active ingredient without involving any additional manufacturing step or cost thereby to improve compliance of patients, to facilitate long-term administration and furthermore, to obtain a physically stable suspension or solution.

Description

PHARMACEUTICAL COMPOSITION FOR ORAL

ADMINISTRATION HAVING THERAPEUTIC ACTIVITY ON

GASTROINTESTINAL DISORDERS

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition for oral administration of aceglutamide aluminum (pentakis(N -acetyl-L-glutam -inato)tetrahydroxytrialuminum, C35Hs Al₃Nιo0₂ ) useful as an anti-ulcerative agent and/or a mixture of aluminum hydroxide and magnesium hydroxide usefiil as an antacid agent. More specifically, the present invention relates to the pharmaceutical composition for oral administration having therapeutic activity on gastrointestinal disorders which comprises aceglutamide aluminum, the mixture of aluminum hydroxide and magnesium hydroxide, or aceglutamide aluminum and the mixture of aluminum hydroxide and magnesium hydroxide as active ingredient, and carrageenan as taste masking agent.

BACKGROUND ART

Aceglutamide aluminum promotes rapid regeneration of damaged gastric mucosa by displaying stimulating activity on production of mucin and constituents of mucosa (Tanaka, H., Gastric cytoprotection of aceglutamide aluminum in rats, Drug Res., 36, 1485-1489(1986)) and recovery of damaged granulation tissue by displaying stimulating activity on formation of granulation (Tanaka, H., Kojima, T. and Marumo, H., Effect of N-acetyl-L-glutamine aluminum complex(KW-HO) on hexosamine content in gastric mucosa, Pharmacometrics 9, 519-522(1975)). It also protects damaged mucosa via its adsorption on mucosa so that mucosa may not be subjected to attack by gastric acid any longer (Brown, S., Mendoza, N., Bertholf, R.L., Ross, R., Wills, M.R. and Savory, J., Absorption of aluminum from aceglutamide aluminum in healthy adult males, Res. Comm. Chem. Pathol. Pharmacol. 53, 105-116(1986)), and eliminates continuously attacking factors against mucosa by displaying sustained antacid activity and inhibitory activity on the effects of pepsin (Harada, M. and Yano, S., Inhibitory effect of an antiulcer agent, N-acetyl-L-glutamine aluminum complex(KW-lOO) and related compounds on gastric erosion and mobility in stressed animals, Pharmacometrics 8, 1-6(1974)). Other than the above-described mechanisms, aceglutamide aluminum is an anti-ulcerative agent which has various mechanisms.

In particular, Korean patent publication No. 96-11773 disclosed that aceglutamide aluminum is administered in combination with antacid agent comprising aluminum hydroxide and magnesium hydroxide in a weight ratio of 1 to 1, wherein a weight ratio of aceglutamide aluminum to the antacid agent is 1 to 1.1 —2.3, thereby to obtain excellent therapeutic effects on digestive ulcers such as gastric or duodenal ulcer.

As dosage forms for oral administration of aceglutamide aluminum, granule which has been marketed in the name of "Glumal" and suspension have been hitherto developed. However, since they have a bitter and an astringent taste of their own, patients are reluctant to take them in the long term and hence, frequently stop taking them in the course of treating ulcers and consequently, a percentage of complete treating is unavoidably lowered. Particularly, granule "Glumal" has been rarely used due to a bitter taste of its own and at the present time, is not marketed any longer. Also, a mixture of aluminum hydroxide and magnesium hydroxide has an astringent taste of its own. Therefore, in order to pharmaceutically manufacture aceglutamide aluminum and/or the mixture of aluminum hydroxide and magnesium hydroxide into orally administrable dosage forms, it is the most important point to effectively mask the bitter and the astringent taste thereof.

To the present time, in order to mask a bitter taste of active ingredient, various methods have been developed, for example, (i) a method wherein sweeteners are employed, (ii) a method for coating active ingredient with water-insoluble agent in order that patients cannot feel its tastes, (iii) as a more recently developed method, a method wherein anesthetic agents against taste cells are employed, and the like.

The method (i) is inexpensive and simple but has problems in that when active ingredient is very bitter, due to a sweet taste of sweetener, it feels much bitterer than sweetener-free agent on the contrary. Also, in the case of aceglutamide aluminum, although attempts were made to mask its astringent taste by combining it with saccharides such as sucrose, sorbitol, aspartame, etc., its astringent taste became reversely stronger and hence, it became more difficult to take. The method (ii) can effectively mask tastes which cause rejection by patients but the unit cost of manufacturing is elevated since it requires additional manufacturing steps and equipments, and yield is inevitably lowered by involving a coating step. In particular, in the case of being manufactured into suspension, it feels like a foreign substance and cannot be comfortably taken. In addition, precipitates are formed and hence, it cannot be taken with an accurate dose. Moreover, its pharmacological effects cannot be rapidly displayed. The method (iii) cannot completely mask tastes and is rarely used due to rejection after being orally administered.

Accordingly, in order that pharmacological effects of aceglutamide aluminum and/or a mixture of aluminum hydroxide and magnesium hydroxide can be maximally displayed, a bitter and an astringent taste thereof should be effectively masked and particularly, in the case of being manufactured into solution or suspension, it is the most important point to maintain physically stable state without precipitates of aceglutamide aluminum, etc.

Carrageenan is a high molecular weight polymer extracted from plant, seaweed or animal collagen and is a hydrocolloid belonging to polysaccharide family. Structure of carrageenan consists of alternating copolymers of -(l→3)-D-galactose and (l→4)-3,6-anhydro-D- or L-galactose. Several members of the family are known; they differ in the amount of sulfate ester and/or other substituent groups they carry, for example, t^'øta-carrageenan, kappa-carrageenan, etc. To the present time, carrageenan has been used as gelling agents, emulsifying agents, stabilizing agents and viscosity builders in foods and non-foods, but especially milk or water systems. However, carrageenan has never been used in combination with aceglutamide aluminum, aluminum hydroxide or magnesium hydroxide for any use and furthermore, has never been used for masking various tastes including a bitter taste or an astringent taste in any case.

DISCLOSURE OF THE INVENTION

The present inventors repeated the extensive studies to develop a novel method by which without involving any additional manufacturing step, a bitter and an astringent taste of aceglutamide aluminum and/or a mixture of aluminum hydroxide and magnesium hydroxide can be effectively masked without any adverse effects on pharmacological activity thereof and particularly, in the case of being manufactured into suspension or solution, precipitates are not formed during a period of preservation after being manufactured to obtain a physically stable dosage form. As a result, they surprisingly found out that by combining aceglutamide aluminum and/or a mixture of aluminum hydroxide and magnesium hydroxide with carrageenan, the bitter and the astringent taste thereof can be effectively masked without involving any additional manufacturing step and cost, and furthermore, suspension or solution thereof can be obtained in a completely dissolved state wherein layers are not formed.

Accordingly, the purpose of the present invention is to provide a pharmaceutical composition for oral administration of aceglutamide aluminum and/or a mixture of aluminum hydroxide and magnesium hydroxide, which can effectively mask a bitter and an astringent taste thereof without involving any additional manufacturing step and cost, thereby to improve compliance of patients, to facilitate long-term administration, and furthermore, to obtain a physically stable suspension or solution thereof.

In order to attain the above-described purposes, the present invention provides a pharmaceutical composition for oral administration having therapeutic activity on gastrointestinal disorders characterized by comprising at least one selected from the group consisting of aceglutamide aluminum and a mixture of aluminum hydroxide and magnesium hydroxide as active ingredient and carrageenan as taste masking agent. In one embodiment of the present invention, the composition may comprise aceglutamide aluminum alone as active ingredient. In another embodiment of the present invention, the composition may comprise aceglutamide aluminum and the mixture of aluminum hydroxide and magnesium hydroxide as active ingredient. In addition, a weight ratio of aluminum hydroxide to magnesium hydroxide is preferably 1 to 1 and a weight ratio of aceglutamide aluminum to the mixture of aluminum hydroxide and magnesium hydroxide is preferably 1 to 1J — 2.3. In a preferable embodiment, the above-described compositions comprise 1 —30 parts by weight of aceglutamide aluminum and 0.01 — 10 parts by weight of carrageenan per 100 parts by weight of the composition.

Also, the composition according to the present invention may comprise the mixture of aluminum hydroxide and magnesium hydroxide as active ingredient. The present composition preferably comprises aluminum hydroxide and magnesium hydroxide in a weight ratio of 1 to 1. And it preferably comprises 20 — 50 parts by weight of the mixture of aluminum hydroxide and magnesium hydroxide and 0.01 — 10 parts by weight of carrageenan per 100 parts by weight of the composition.

The pharmaceutical composition according to the present invention may be pharmaceutically manufactured into a dosage form selected from the group consisting of powder, granule, dry syrup, suspension, solution and chewable tablet in combination with pharmaceutically acceptable excipients. It is preferable that the composition is pharmaceutically manufactured into suspension or solution. In the case of suspension or solution, the composition preferably comprises 0.01 — 0J parts by weight of carrageenan per 100 parts by weight of the composition. More preferably, the composition further comprises sweeteners or aromatics. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail.

According to the present invention, by combining the known aceglutamide aluminum and/or the known mixture of aluminum hydroxide and magnesium hydroxide, which cannot be orally administered easily due to a bitter and an astringent taste thereof, in spite of pharmacological activity thereof effective in treating ulcers, with the known polysaccharide, carrageenan, the bitter and the astringent taste can be effectively masked without involving any additional manufacturing step or cost. The present inventors performed many experiments to find out which polysaccharides can effectively mask the bitter and the astringent taste among many kinds of polysaccharides and as a result, found out that carrageenan only can effectively mask the tastes. Also, they discovered that carrageenan can most effectively mask the bitter and the astringent taste of aceglutamide aluminum, aluminum hydroxide and magnesium hydroxide, among various agents.

According to the present invention, in a pharmaceutical composition for oral administration comprising aceglutamide aluminum, although an amount of aceglutamide aluminum is variable according to its dosage form, it is preferably 1 — 30 parts by weight, more preferably, 2 — 20 parts by weight, per 100 parts by weight of the composition, since within the above range of amount, aceglutamide aluminum is expected to sufficiently display its pharmacological effects.

In addition, a pharmaceutical composition for oral administration of a mixture of aluminum hydroxide and magnesium hydroxide preferably comprises 20 — 50 parts by weight of the mixture of aluminum hydroxide and magnesium hydroxide per 100 parts by weight of the composition.

In a preferable embodiment, the above-described compositions comprise 0.01 — 10 parts by weight of carrageenan, since in the case of more than 10 parts by weight, their viscosity becomes too high and thus, they involve some problems in being pharmaceutically manufactured into dosage forms by conventional methods, and in the case of less than 0.01 parts by weight, due to too small amount of carrageenan, tastes cannot be effectively masked.

Particularly, provided that the present composition comprises aceglutamide aluminum in combination with a mixture of aluminum hydroxide and magnesium hydroxide, according to Korean patent publication No. 96-11773, the content of which is incorporated hereinto by reference, it is preferable that a weight ratio of aluminum hydroxide to magnesium hydroxide is 1 to 1 and a weight ratio of aceglutamide aluminum to the mixture of aluminum hydroxide and magnesium hydroxide is 1 to 1J — 2.3, since excellent therapeutic effects on digestive ulcers can be obtained in the above-described ratios.

The pharmaceutical composition according to the present invention may be pharmaceutically manufactured into various dosage forms, for example, powder, granule, dry syrup, suspension, solution or chewable tablet, in combination with pharmaceutically acceptable excipients, by conventional methods. Carrageenan has characteristic flow, so called "pseudoplastic flow", characterized by without any external stimulus, high viscosity being maintained but with any external stimulus, viscosity being steeply decreased. Therefore, carrageenan is the optimal excipient for suspension wherein suspension stability is important during a period of preservation, or solution. Therefore, provided that the composition according to the present invention is manufactured into suspension or solution, it can be comfortably taken by patients and is stable without precipitates during a period of preservation after being manufactured. In the case of being manufactured into suspension or solution, the present composition preferably comprises 0.01 — 0J parts by weight of carrageenan per 100 parts by weight of the composition. That is, if more than 0J parts by weight of carrageenan is present, the composition will have too high viscosity and thus, lose fluidity, a principal characteristic of liquid dosage forms. If less than 0.01 parts by weight of carrageenan is present, an amount of carrageenan is too small and thus, tastes cannot be effectively masked.

In addition, because liquid dosage forms such as suspension or solution are characterized in that patients feel bitterer or more astringent than solid dosage forms, in the case of suspension or solution, a bitter and an astringent taste are preliminary masked and subsequently, to be rendered to have tastes suitable for taking, it preferably further comprises conventional sweeteners. As sweeteners, sucrose, sorbitol, stevioside or mixtures thereof may be added thereto. In this case, it is preferable that a weight ratio of aceglutamide aluminum to sweeteners is 1 to 1 — 10. To be rendered to have favorable aroma, it may also further comprise conventional aromatics.

EXAMPLES

This invention will be better understood from the following examples. However, one skilled in the art will readily appreciate the specific materials and results described are merely illustrative of, and are not intended to, nor should be intended to, limit the invention as described more fully in the claims which follow thereafter. Example 1

Manufacture of powder of aceglutamide aluminum

Powder of aceglutamide aluminum was manufactured according to a conventional method for manufacturing powder, using the composition as shown in the following table 1.

Table. 1

Example 2 Manufacture of granules of aceglutamide aluminum

Granules of aceglutamide aluminum were manufactured according to a conventional method for manufacturing granules, using the composition as shown in the following table 2.

Table. 2

Example 3

Manufacture of solution of aceglutamide aluminum

Solution of aceglutamide aluminum was manufactured according to a conventional method for manufacturing solution, using the composition as shown in the following table 3.

Table. 3

Example 4

Manufacture of suspension of aceglutamide aluminum and a mixture of aluminum hydroxide and magnesium hydroxide

Suspension of aceglutamide aluminum and a mixture of aluminum hydroxide and magnesium hydroxide was manufactured according to a conventional method for manufacturing suspension, using the composition as shown in the following table 4. Table. 4

Example 5

Manufacture of chewable tablets of aceglutamide aluminum

Chewable tablets of aceglutamide aluminum, a weight of which was 2.5g/tablet, were manufactured according to a conventional method for manufacturing chewable tablets, using the composition as shown in the following table 5. Table. 5

Comparative Example 1

Manufacture of solution of aceglutamide aluminum

Solution of aceglutamide aluminum was manufactured in the substantially same method as in example 3 except that carrageenan was not used.

Comparative Example 2 Manufacture of suspension of aceglutamide aluminum and a mixture of aluminum hydroxide and magnesium hydroxide

Suspension of aceglutamide aluminum and a mixture of aluminum hydroxide and magnesium hydroxide was manufactured in the substantially same method as in example 4 except that carrageenan was not used.

Test Example 1

To test masking effects of carrageenan on aceglutamide aluminum according to the present invention, organoleptic tests were carried out on solutions of aceglutamide aluminum obtained from example 3 and comparative example 1, respectively. Organoleptic tests were proceeded with by two-point contrast method which can be used in judgement of simple differences, indication of differences and selection of quality. Panel participating in the tests consisted of 27 members regardless of sex who had no prejudice on dosage forms according to the present invention. In the case of the above described method, a percentage of a correct answer was 50% and results were tested according to χ test and significance test table of two-point contrast method. In addition, after the members tasted, grade No. 1 was given to a preferable sample and grade No. 2 given to an unpreferable sample. The results were shown in the following table 6.

Table. 6

The results were tested according to significance test table of two-point contrast method, wherein in the case of 27 members, the mininum number of correct answers is 20 in significance level of 5%, and 21 in significance level of 1%, respectively. From the above table 6, the number of correct answers of example 3 was 22, more than 21 which was the minimum number of correct answers in significance level of 1% to show that the composition according to example 3 had remarkably improved tastes over comparative example 1 and effectively masked tastes of active ingredient which caused rejection.

Test Example 2

To test masking effects of carrageenan on aceglutamide aluminum, aluminum hydroxide and magnesium hydroxide according to the present invention, organoleptic tests were carried out in the substantially same method as in test example 2 on suspensions of aceglutamide aluminum and the mixture of aluminum hydroxide and magnesium hydroxide obtained from example 4 and comparative example 2, respectively. The results were shown in the following table 7.

Table. 7

As shown in the above table 7, the number of correct answers on example 4 was 24 to show that the composition according to example 4 had remarkably improved tastes over comparative example 2 and effectively masked tastes of active ingredient which caused rejection.

The pharmaceutical composition according to the present invention can effectively mask a bitter and an astringent taste of aceglutamide aluminum and/or a mixture of aluminum hydroxide and magnesium hydroxide without involving any additional manufacturing step or cost thereby to improve compliance of patients, to facilitate long-term administration and furthermore, to obtain a physically stable suspension or solution.

Claims

WHAT IS CLAIMED:

1. A pharmaceutical composition for oral administration having therapeutic activity on gastrointestinal disorders, characterized by comprising at least one selected from the group consisting of aceglutamide aluminum and a mixture of aluminum hydroxide and magnesium hydroxide as active ingredient, and carrageenan as taste masking agent.

2. The composition according to claim 1, characterized by comprising aceglutamide aluminum as active ingredient.

3. The composition according to claim 1, characterized by comprising aceglutamide aluminum and the mixture of aluminum hydroxide and magnesium hydroxide as active ingredient.

4. The composition according to claim 3, characterized by a weight ratio of aluminum hydroxide to magnesium hydroxide being 1 to 1 and a weight ratio of aceglutamide aluminum to the mixture of aluminum hydroxide and magnesium hydroxide being 1 to 1.1 — 2.3.

5. The composition according to any one of claims 2 to 4, characterized by comprising 1 —30 parts by weight of aceglutamide aluminum and 0.01 — 10 parts by weight of carrageenan per 100 parts by weight of the composition.

6. The composition according to claim 1, characterized by comprising the mixture of aluminum hydroxide and magnesium hydroxide as active ingredient.

7. The composition according to claim 6, characterized by a weight ratio of aluminum hydroxide to magnesium hydroxide being 1 to 1.

8. The composition according to claim 6 or 7, characterized by comprising 20 — 50 parts by weight of the mixture of aluminum hydroxide and magnesium hydroxide and 0.01 — 10 parts by weight of carrageenan per 100 parts by weight of the composition.

9. The composition according to claim 1, characterized by being pharmaceutically manufactured into a dosage form selected from the group consisting of powder, granule, dry syrup, suspension, solution and chewable tablet in combination with pharmaceutically acceptable excipients.

10. The composition according to claim 9, characterized by being pharmaceutically manufactured into suspension or solution.

11. The composition according to claim 10, characterized by comprising 0.01 — 0.1 parts by weight of carrageenan per 100 parts by weight of the composition.

12. The composition according to claim 11, characterized by further comprising sweeteners or aromatics.