WO2000078307A1

WO2000078307A1 - Orally administrable pharmaceutical preparation having therapeutic effect on gastrointestinal disorders comprising coated ranitidine, bismuth subcitrate and sucralfate

Info

Publication number: WO2000078307A1
Application number: PCT/KR1999/000327
Authority: WO
Inventors: Young-Hyo Yoo; Hak-Hyung Kim; Jong-Wan Lee; Joon-Woo Park; Byung-Soo Jang
Original assignee: Daewoong Pharmaceutical Co., Ltd.
Priority date: 1999-06-21
Filing date: 1999-06-21
Publication date: 2000-12-28
Also published as: KR20020031342A; AU4655199A; CN1354660A; KR100453179B1; CN1173698C

Abstract

Disclosed is an orally administrable pharmaceutical preparation having therapeutic effect on gastrointestinal disorders which comprises as active ingredients ranitidine, bismuth subcitrate and sucralfate, wherein the ranitidine is coated with a coating agent to have a film dissolution time ranging from 20 to 90 minutes.

Description

ORALLY ADMINISTRABLE PHARMACEUTICAL PREPARATION

HAVING THERAPEUTIC EFFECT ON GASTROINTESTINAL

DISORDERS COMPRISING COATED RANITIDINE, BISMUTH

SUBCITRATE AND SUCRALFATE

TECHNICAL FIELD

The present invention relates to a pharmaceutical preparation comprising ranitidine, bismuth subcitrate and sucralfate. More specifically, the present invention relates to a novel orally administrable pharmaceutical preparation which can obtain synergism of ranitidine, bismuth subcitrate and sucralfate by preventing reduction of therapeutic efficacy due to inhibitory action on absorption of ranitidine by sucralfate, when ranitidine, bismuth subcitrate and sucralfate are simultaneously administered per os. The orally administrable pharmaceutical preparation according to the present invention increases absorption rate of ranitidine to thus exhibit remarkably improved therapeutic effect on gastric and duodenal ulcers by synergism of ranitidine, bismuth subcitrate and sucralfate.

BACKGROUND ART

Gastrointestinal disorders such as gastritis, gastric ulcer, duodenitis and duodenal ulcer are caused by various factors. Recently, it has been reported that gastrointestinal disorders are caused by imbalance of aggressive factors such as gastric acid, pepsin and Helicobacter pylori, etc. and defensive factors such as mucus secreted from mucosa, regenerative activity of tissues, improvability of blood circulation.

In order to treat gastrointestinal disorders, as agents for treatment of gastric ulcer by inhibitory action on secretion of aggressive factors, H₂ antagonists such as ranitidine, cimetidine and famotidine were developed hitherto. However, it is known that such agents cannot exhibit sustained therapeutic effect and thus, gastrointestinal disorders recur frequently [The American Journal of Medicine, Volume 91(Suppl. 2A), August 8, 1991].

Bismuth preparations such as bismuth subcitrate and bismuth subsalicylate were developed for treatment of gastrointestinal disorders not only by protecting gastric and duodenal ulcerative lesions by potentiating defensive factors but also by killing Helicobacter pylori [Drugs 36, 132 - 157(1988); Gut 28, 201 -205(1987); The American Journal of Gastroenterology Vol.84, No.3(1989)]. However, it is known that bismuth preparations cannot exhibit antacid effect and alleviatory effect on a pain caused by gastric acid.

Sucralfate is used for treatment of gastritis or gastric ulcer by inactivation of pepsin acting as an aggressive factor and by stimulation of mucus secretion, antacid action, regeneration of mucous cells and prostaglandine secretion. However, it is known that sucralfate cannot be involved in inhibition of acid secretion.

Accordingly, a method for treatment of gastric ulcer characterized by administration of H₂ antagonists in combination with bismuth preparations is disclosed in the European Patent No. 282132 and a method characterized by administration of H₂ antagonists in combination with sucralfate is disclosed in the literature [The American Journal of Medicine, Volume 79(Suppl. 2c), August 30, 1985]. However, therapeutic effect on gastrointestinal disorders according to the above methods are merely insufficient. The present inventors noticed that gastrointestinal function should be normalized on the whole by balance of aggressive factors and defensive factors, in order not only to rapidly treat gastrointestinal disorders, e. g. gastric ulcer, but also to reduce recurrence rate. As a result, they discovered that unexpectedly remarkable therapeutic effect on gastric and duodenal ulcers can be obtained by simultaneous administration of ranitidine among H antagonists, bismuth subcitrate among bismuth preparations and sucralfate to rats(the Korean Publication Patent No. 97-6083).

However, when ranitidine is mixed with bismuth subcitrate, properties of ranitidine are likely to be significantly affected by bismuth subcitrate. Therefore, to separate ranitidine and bismuth subcitrate, ranitidine is manufactured into tablets according to any one of conventional methods, the manufactured tablets are film-coated with hydroxypropyl methylcellulose and glycerin to thus manufacture tablet cores. Then, the film-coated tablet cores are mixed with bismuth subcitrate and sucralfate to thus manufacture double-layer tablets comprising tablet cores.

However, when the double-layer tablets disclosed in the Korean Patent Publication No. 97-6083 were administered per os. to patients, they exhibited unsatisfactory therapeutic effect on gastric ulcer due to reduction of absorption rate of ranitidine by 20 to 30% caused by adsorption of ranitidine by sucralfate, while they exhibited excellent therapeutic effect on duodenal ulcer, i. e. 90% or more of therapeutic efficacy.

More specifically, while bismuth subcitrate and sucralfate exhibit directly their effects in the stomach, ranitidine exhibits its therapeutic effect on gastrointestinal disorders by inhibitory action on secretion of gastric acid after being absorbed in the upper intestine in vivo and then migrating to the stomach along with blood circulation.

In particular, sucralfate is converted into viscous material in gastric juice of acidity and then, coats the walls of the stomach and thus, can protect the walls of the stomach from being attacked by various aggressive factors. As above-described, sucralfate exhibits high viscosity under the acidic condition, e. g. in gastric juice. Hence, the combined use of ranitidine and sucralfate results in adsorption of ranitidine by sucralfate because of high viscosity of sucralfate. As a result, ranitidine cannot migrate to the upper small intestine any longer and absorption rate of ranitidine is reduced by 20 to 30% and consequently, its therapeutic efficacy on gastric ulcer is inevitably reduced to 55 to 65%.

DISCLOSURE OF THE INVENTION

In order to solve the problems as above, the present inventors have performed the extensive studies to enhance therapeutic effect on gastrointestinal disorders of an orally administrable pharmaceutical preparation comprising ranitidine, bismuth subcitrate and sucralfate by increasing absorption rate of ranitidine in vivo. As a result, they surprisingly discovered that if ranitidine is film-coated, wherein the film dissolution time is longer than time required for migration of ranitidine from the stomach to the upper small intestine, it is not adsorbed by sucralfate in the stomach any longer and after migration to the small intestine, it can be absorbed therein to be highly effective for treatment of gastrointestinal disorders even in case of being orally administered by being formulated into various dosage forms such as tablets, capsules or granules, in combination with bismuth subcitrate and sucralfate, and finally, completed the present invention.

Accordingly, an object of the present invention is to provide an orally administrable pharmaceutical preparation comprising ranitidine, bismuth subcitrate and sucralfate which exhibits excellent therapeutic effect on gastrointestinal disorders by preventing adsorption of ranitidine by sucralfate and by increasing absorption rate of ranitidine.

According to the present invention, when ranitidine is orally administered in combination with bismuth subcitrate and sucralfate, it is not eluted to be adsorbed by sucralfate of high viscosity in the stomach but is eluted and disintegrated after migration to the upper small intestine and thereby it can be absorbed at a high rate in vivo to thus enhance therapeutic efficacy of gastric ulcer.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be more specifically explained.

The present invention provides an orally administrable pharmaceutical preparation comprising ranitidine, bismuth subcitrate and sucralfate, which makes it possible that ranitidine migrates to the upper small intestine and is absorbed therein to display inhibitory effect on secretion of gastric juice, while bismuth subcitrate and sucralfate are disintegrated in the stomach immediately after being administered and exhibit rapidly their therapeutic effects on gastrointestinal disorders.

According to the present invention, ranitidine is separated from bismuth subcitrate and sucralfate by being coated with a coating agent, in order not to be denatured by bismuth subcitrate, not to be adsorbed by sucralfate and to be absorbed at a high rate in the small intestine. More specifically, ranitidine is coated with a coating agent and subsequently, the coated ranitidine is mixed with bismuth subcitrate and sucralfate to being pharmaceutically manufactured into an orally administrable formulation containing ranitidine, bismuth subcitrate and sucralfate. After the preparation of the present invention is administered, bismuth subcitrate and sucralfate are immediately eluted and then, ranitidine is exposed to gastric juice in the stomach. If the coated ranitidine is eluted and disintegrated in the stomach before it migrates to the small intestine, it is adsorbed by sucralfate of high viscosity. Therefore, in order to be efficiently absorbed in vivo, it is important not to be eluted and to successfully migrate to the small intestine. As a result of various experiments in the present invention, when ranitidine is administered to the empty stomach, it migrates to the upper small intestine 20 to 30 minutes after entry into the stomach and it completes passage through the upper small intestine, 70 to 90 minutes after being administered.

Consequently, ranitidine is coated to have a film dissolution time of 20 to 90 minutes, more preferably, 30 to 70 minutes, in gastric juice of acidity, in order not to be adsorbed by sucralfate in the stomach and to be absorbed after migration to the small intestine.

According to the present invention, in order to adjust the film dissolution time of ranitidine ranging from 20 to 90 minutes in gastric juice, the film dissolution time was measured by placement of the film coated ranitidine in a beaker in which 0.07M of HC1 was contained at a temperature of 37°C . The film dissolution time was evaluated by measuring a period of time after which ranitidine was visually inspected for the first time along with dissolution of the film.

The pharmaceutical preparation according to the present invention is characterized in that ranitidine is coated with a coating agent to have a film dissolution time ranging from 20 to 90 minutes as evaluated in the above-described test, which can prevent ranitidine from being denatured by bismuth subcitrate and being adsorbed by sucralfate in the stomach to thus increase absorption rate of ranitidine.

In the present invention, ranitidine is coated with a coating agent according to any one of conventional methods which are known in the art, in a conventional coating machine, for example, Manesty Accela cota, Driam coater or Hi-coater. The coated ranitidine may be dried by being allowed to stand in the coating machine or by being transferred to a dry oven or a high-temperature drier. A coating agent which is used for coating ranitidine must have a film dissolution time of 20 minutes or longer in gastric juice of acidity, i. e. in 0.07M of HC1, or must be dissolved in the small intestine of alkalinity or neutrality without being dissolved under the acidic condition. Representative examples of such coating agent are enteric-coating agents such as hydroxypropyl methylcellulose phthalate, Eudragit L. S. alone or in combination with another cellulose base polymer which may be used in both of water-soluble and water-insoluble solvent systems(e. g. hydroxypropoxy and methyl ether based on cellulose substrate such as Sepifilm 002), alkyl cellulose which may be used in water-soluble solvent systems(e. g. methylcellulose, hydroxypropyl methylcellulose), or polymeric material which can form a film such as Eudragit E.

The coating agent may contain excipients selected from the group plasticizers, e. g. propylene glycol, Myvacet, glycerol, sorbitol, glycerol triacetate, diethyl phthalate or triethyl citrate; preservatives, e. g. methyl or propyl hydroxybenzoate; and colorant, e. g. titanium dioxide containing crimson lakes or ferric oxide. These excipients can facilitate the coating procedure and improve the shape of film.

The coating agent may be preferably used in an amount of 0.1 to 10.0% by weight based on the weight of ranitidine. If less than 0.1% by weight, the film is dissolved in gastric juice and then, ranitidine is eluted before migration to the small intestine and is adsorbed by sucralfate. If more than 10.0% by weight, the film dissolution is delayed and ranitidine pass through the upper small intestine without being eluted to be absorbed in the small intestine.

According to the present invention, two methods are provided for manufacture of orally administrable dosage forms by coating ranitidine with a coating agent.

According to a method of the present invention, ranitidine is manufactured into granules according to any one of conventional methods and then, the granules are coated with a coating agent to obtain film-coated granules. Thereafter, the film-coated granules are mixed with bismuth subcitrate and sucralfate, in combination with one or more pharmaceutically acceptable carriers or excipients to obtain granules, tablets or capsules comprising the film-coated granules of ranitidine.

According to another method of the present invention, tablet cores containing ranitidine are manufactured according to any one of conventional methods and then, the tablet cores are coated with a coating agent to obtain film-coated tablet cores containing ranitidine. Thereafter, the film-coated tablet cores are mixed with bismuth subcitrate and sucralfate in combination with one or more pharmaceutically acceptable carriers or excipients to obtain double-layer tablets comprising tablet cores.

Granules, tablets, capsules and double-layer tablets comprising tablet cores may be manufactured according to any one of conventional methods known in the art, and may comprise one or more pharmaceutically acceptable carriers or excipients, for example, binders, e. g. pregelatinized corn starch, poly vinyl pyrrolidone or hydroxypropyl methylcellulose such as HPMC 5 or 6; fillers, e. g. starch, lactose, microcrystalline cellulose or calcium phosphate; disintegrators, e. g. potato starch, sodium starch glycolate, skim soybean extracts, cross-linked polyvinyl pyrrolidone or cross-linked carboxymethylcellulose; lubricant or glidant, e. g. hydrogenated vegetable oil, talc or silica, or humectant, e. g. sodium lauryl sulfate.

In general, the orally administrable preparation of the present invention may comprise 1 to 2 parts by weight of ranitidine, 2 to 4 parts by weight of bismuth subcitrate and 6 to 12 parts by weight of sucralfate based on the total weight of preparation, preferably, 50 to 300 mg of ranitidine, 100 to 400 mg of bismuth subcitrate and 300 to 1200 mg of sucralfate, and more preferably, 50 — 150 mg of ranitidine, 100 to 200 mg of bismuth subcitrate and 300 to 600 mg of sucralfate.

The preparation of the present invention may be preferably administered once or twice a day, with a unit dose of 50 to 150 mg as ranitidine. However, the unit dose may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the preparation of the present invention.

The present inventors identified that the orally administrable preparation can completely resolve the problems that absorption rate of ranitidine is reduced by sucralfate, to thus enhance the absorption rate of ranitidine and to exhibit excellent therapeutic effect on gastric disorders by synergism of ranitidine, bismuth subcitrate and sucralfate

EXAMPLES

The present 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 granules comprising coated granules of ranitidine

A. Manufacture of coated granules of ranitidine

1) Manufacture of granules of ranitidine

A mixture of 84 mg of ranitidine hydrochloride(75 mg as ranitidine), 6 mg of microcrystalline cellulose, 8 mg of calcium carboxymethylcellulose and 1 mg of hydroxypropyl cellulose was added q. s. to ethanol solution. The thus obtained mixture was kneaded and the kneaded mixture was manufactured into granules according to a conventional method. Thereafter, the granules were divided into 20 mesh passages and 32 mesh residues. 2-1) Film coating

A mixture of 4 mg of hydroxypropyl methylcellulose, 1 mg of ethyl cellulose, 0.17 mg of glycerin was added q. s. to ethanol solution to prepare a film coating composition. The granules manufactured in 1) were film coated with the coating composition according to a conventional method to manufacture film-coated granules of ranitidine.

2-2) Enteric coating

A mixture of 7.3 mg of hydroxypropyl methylcellulose phthalate, 1.8 mg of purified shellac and 0.9 mg of Myvacet was added to a solution of methylene chloride and isopropanol in distilled water to prepare an enteric coating composition. The granules manufactured in 1) were enteric coated with the coating composition according to a conventional method to prepare enteric-coated granules of ranitidine.

B. Manufacture of granules of bismuth subcitrate and sucralfate

A mixture of 300 mg of sucralfate, 100 mg of bismuth subcitrate, 2.83 mg of microcrystalline cellulose and 14 mg of hydroxypropyl cellulose was added to distilled water and the whole mixture was granulated in a high-velocity mixer and the granulated mixture was dried to manufacture granules comprising sucralfate and bismuth subcitrate.

C. Manufacture of granules comprising coated granules of ranitidine

The granules manufactured in B. were mixed with 104.17 mg of the film-coated or enteric-coated ranitidine granules(75 mg as ranitidine) manufactured in 1) to obtain granules comprising coated granules of ranitidine. Example 2

Manufacture of capsules comprising coated granules of ranitidine

521 mg of granules manufactured in example 1 were filled in capsules according to a conventional method to thus manufacture capsules comprising coated granules of ranitidine.

Example 3

Manufacture of tablets comprising coated granules of ranitidine

600 mg of tablets were manufactured according to a conventional method using a mixture of 104.17 mg of the film-coated granules of ranitidine(75 mg as ranitidine) manufactured in example 1. A, 300 mg of sucralfate, 100 mg of bismuth subcitrate, 53.83 mg of microcrystalline cellulose, 30 mg of lactose, 10 mg of carboxymethylcellulose and 2 mg of magnesium stearate.

Example 4

Manufacture of double-layer tablets comprising coated tablet cores of ranitidine

A. Manufacture of coated tablet cores of ranitidine

1) Manufacture of tablet cores of ranitidine

84 mg of ranitidine hydrochloride(75 mg as ranitidine), 6 mg of microcrystalline cellulose and 1 mg of hydroxypropyl cellulose were mixed and the mixture was added to ethanol solution. The whole mixture was kneaded and granulated according to a conventional method. The granulated mixture was dried and sieved. The granules were mixed with 8 mg of carboxymethylcellulose and 2 mg of magnesium stearate and the whole mixture was compressed into tablet cores of ranitidine. 2-1) Film coating

A mixture of 3 mg of hydroxypropyl methylcellulose, 1 mg of ethyl cellulose, 0.8 mg of titanium dioxide, 0.4 mg of talc and 0.2 mg of polyethylene glycol was added to ethanol solution to prepare a film coating composition. The tablet cores of ranitidine manufactured in example 1. A were coated with the coating composition according to a conventional method to manufacture film-coated tablet cores of ranitidine.

2-2) Enteric coating

A mixture of 7.2 mg of hydroxypropyl methylcellulose phthalate and 0.8 mg of Myvacet was added to a solution of acetone and ethanol to prepare an enteric coating composition. The tablet cores of ranitidine manufactured in 1) were coated with the coating composition according to a conventional method to manufacture enteric-coated tablet cores of ranitidine.

B. Preparation of granules of bismuth subcitrate and sucralfate

A mixture of 300 mg of sucralfate, 100 mg of bismuth subcitrate, 86.46 mg of microcrystalline cellulose and 20 mg of hydroxypropyl cellulose was added to ethanol solution. The whole mixture was kneaded and then, the kneaded mixture was granulated and dried according to a conventional method to manufacture granules of sucralfate and bismuth subcitrate.

C. Manufacture of double-layer tablets comprising tablet cores of ranitidine

The granules of bismuth subcitrate and sucralfate manufactured in B. were mixed with 20 mg of calcium carboxymethylcellulose and 4 mg of magnesium stearate. The thus obtained mixture was manufactured into double-layer tablets comprising tablet cores according to a conventional method, in combination with 106.4 mg of the film- or enteric-coated tablet cores of ranitidine hydrochloride(75 mg as ranitidine).

D. Coating

A mixture of 6.5 mg of hydroxypropyl methylcellulose, 1.7 mg of titanium dioxide, 0.9 mg of talc and 0.34 mg of polyethylene glycol was added to ethanol solution to prepare a film coating composition. The double-layer tablets manufactured in C. were film coated with the film coating composition to obtain film-coated double-layer tablets.

Comparative example

Manufacture of double-layer tablets comprising tablet cores of ranitidine

Double-layer tablets comprising tablet cores of ranitidine were manufactured using a mixture of 84 mg of ranitidine hydrochloride(75 mg as ranitidine), 300 mg of sucralfate, 100 mg of bismuth subcitrate, 3.5 mg of microcrystalline cellulose, 14.0 mg of hydroxypropyl methylcellulose, 17 mg of carboxymethylcellulose, 11 mg of magnesium stearate, 14. 5 mg of hydroxypropyl methylcellulose, 5.1 mg of glycerin and 0.9 mg of titanium dioxide, according to the method disclosed in preparation 4 of the Korean Patent Publication No. 97-6083.

Test Example 1

Measurement of a film dissolution time in gastric juice of acidity of 0.07

M HC1

Film-dissolution times of the double-layer tablets manufactured in example 4 and the comparative example were measured as follows. 0.07 M of hydrochloric acid solution at 37 °C was contained in a beaker and thereto were added the double-layer tablets manufactured in example 4 and the comparative example, respectively. Thereafter, the film-dissolution times was evaluated by measuring a period of time after which the film was dissolved and ranitidine was visually inspected for the first time, respectively. The results are shown in the following table 1.

Table 1.

Film-dissolution times in gastric juice of acidity of 0.07 M HC1 (10 tablets)

As shown in the above table 1, film-dissolution times of the double-layer tablets manufactured in example 4 were longer than 30 minutes, while the films of the double-layer tablets prepared in the comparative example were rapidly dissolved and their film-dissolution times were shorter than 8 minutes.

Test Example 2 Measurement of absorption rate of ranitidine in case of being orally administered in vivo

In order to identify whether or not absorption of ranitidine is inhibited in case of administration of the preparation according to the present invention to the human body, the blood concentrations of ranitidine were measured with the lapse of time in 18 of healthy men of an age of 25 to 30. The results are shown in the following table 2. Table 2.

Changes in blood concentrations of ranitidine and pharmacokinetic parameters in case of oral administration to the human body.

*: significance level with the double-layer tablets of the comparative example; P < 0.05

As shown in the above table 2, the double-layer tablets according to the present invention exhibited significantly increased AUC and maximum blood concenrration(Cmax) in comparison with those according to comparative example. Therefore, ranitidine is expected to be efficiently absorbed in case of administration of the preparation according to the present invention.

Test Example 3

Therapeutic effect on gastric ulcer in vivo

In order to evaluate therapeutic effect on gastric ulcer of the preparation of the present invention, the granules manufactured in example 1 were administered per os. for six weeks to the volunteers of an age of 20 to 50 suffering from gastric ulcer, the diameter of which ranged from 10 to 25 mm. Complete treatment of gastric ulcer was determined by endoscopy. The results are shown in the following table 3. Table 3. Therapeutic effect on gastric ulcer in the human body.

As shown in the above table 3, the double-layer tablets and granules of the present invention exhibited remarkably improved therapeutic effect on gastric ulcer in comparison with the double-layer tablets of the comparative example.

As can be seen from the results of test examples 1 to 3, the orally administrable pharmaceutical preparation of the present invention which comprises ranitidine, bismuth subcitrate and sucralfate, wherein the ranitidine is coated with a coating agent to have a film-dissolution time ranging from 20 to 90 minutes, exhibit excellent therapeutic effect on gastrointestinal disorders by completely resolving the problem of the prior art that ranitidine cannot be efficiently absorbed in vivo by adsorption by sucralfate in the stomach. Consequently, according to the present invention, unexpectedly remarkable therapeutic effect on gastric ulcer can be obtained by synergism of ranitidine, bismuth subcitrate and sucralfate.

Claims

WHAT IS CLAIMED:

1. An orally administrable pharmaceutical preparation having therapeutic effect on gastrointestinal disorders which comprises as active ingredients ranitidine, bismuth subcitrate and sucralfate, wherein the ranitidine is coated with a coating agent to have a film dissolution time ranging from 20 to 90 minutes.

2. The preparation according to claim 1, wherein the film dissolution time ranges from 30 to 70 minutes.

3. The preparation according to claim 1, wherein ranitidine is coated with the coating agent of 0.1 — 10.0% by weight based on the weight of ranitidine.

4. The preparation according to claim 3, wherein the coating agent is selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose and Eudragit.

5. The preparation according to claim 3, wherein the coating agent is an enteric coating agent.

6. The preparation according to claim 5, wherein the enteric coating agent is hydroxypropyl methylcellulose phthalate or Eudragit E. S.

7. The preparation according to claim 1, wherein the preparation is pharmaceutically manufactured into granules, capsules, tablets or double-layer tablets comprising coated tablet cores.

8. The preparation according to claim 7, wherein the coated tablet cores are manufactured by mixing ranitidine with pharmaceutically acceptable carriers or excipients to manufacture tablet cores and coating the tablet cores with the coating agent.