JPH06502855A - Composition containing antihistamine H↓2 receptor antagonist and bioadhesive - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Compositions containing antihistamine H2 receptor antagonists and bioadhesives The present invention provides The present invention relates to the treatment of disorders and pharmaceutical compositions useful therein. More specifically, the present invention , drug delivery/histamine H2-receptor antagonist contained within the stem. gastric disorders, particularly indigestion, heartburn and Concerning the topical treatment of acute gastric disorders such as gastritis, and gastric and peptic ulcers. Ru. Compositions for use in the present invention are particularly suitable for use across the gastric wall and on parietal cell receptors. It is adapted for local delivery to H2-receptors.

Histamine H2-receptor antagonists, such as cimetidine, ranitidine, nizetidine and famotidine, which acts directly on the acid-secreting parietal cells located within the gastric glands in the stomach wall. This reduces acid secretion.

Histamine H2-receptor antagonists are effective in treating many gastric disorders, especially peptic ulcers and gastric ulcers. treatment is very effective, but there are certain groups of patients who do not respond to treatment. Ru. In addition, the time lag between administration and onset of action is important for the treatment of acute self-limiting gastric disorders. limiting the effectiveness of histamine H2-receptor antagonists in

The majority of gastric and peptic ulcer patients, referred to as immune non-responders, are treated with conventional histamines. Unresponsive to MinH2-receptor antagonist therapy. (Walker et al.: Frequent unresponsiveness to histamine H2-receptor antagonists in cirrhosis (Fre quentnon-response to histarnine H2-r ecceptor antagonists in cirrhotic sword j; Guts Cut, 30.1105-9.1989: and Bra Cck A, et al., Clinical failure with cimetidine res with cietidine): surgery ), 88(3), 417-24).

In addition, hypersecretory patients, such as critically ill multiple injury patients (Mar. tinL) et al. Failure of cimetidine prophylaxis in critical condition cimetidine prophylaxis in the critical ally 1ll): Archives of Sarnely (Arch, S urg, ), 114.492-6.1979) or Patients suffering from Son syndrome (Stable) B, G, et al. Histamine H2-reception in Zolinzjaer-Ellison syndrome Failure of histamine H2-r ceptor antagonist therapy in Zollin g ■ Chichi | E1lison syndrome); American Journal of Sa -J.E. (Am, J.

Histamine H2-reception by Surg, ), 145.17-23.1983) The known poor response to receptor antagonists has led to the use of alternative treatments, most notably proton pumps. Developed the use of inhibitory factors.

Histamine H2-receptor antagonists are effective in treating acute self-limiting gastric disorders such as hyperacidity. It is effective in self-medication. However, their slow onset of action is not expected to meet consumer demands for prompt release of cargo.

Furthermore, the use of high doses in an attempt to achieve rapid relief of symptoms It will be understood that it is not suitable for non-prescription use. In fact, standard treatment A reduction from the administered dose may be desirable for self-medication.

Contains histamine H2-receptor antagonists and sucralfate and other antacids. The simultaneous administration of other pharmaceutically active substances has been investigated. Principles of coadministration with antacids The theoretical interpretation is that antacids also provide rapid relief from symptoms of excessive acidity by neutralization. On the other hand, histamine H2-receptor antagonists inhibit acid secretion from parietal cells. It is to act independently by

However, histamine H2-receptor antagonists can be used as antacids, especially those with high acid-neutralizing ability. When administered concomitantly with antacids, histamine H7-receptor antagonists increase the plasma biological It is well known that a substantial reduction in availability is often observed (poudoma - Bodemar G, et al., Lancet, 1.4 44-445.1979: Mihaly G, W ) et al., Brittany Medical Journal (B, M, J,), 285 ．． 998-9.1982 Nilin J.H. et al. , Briti/U Journal of Cylinical Pharmalogy (B, J, Clin, P harmacol, ), 24.551-3.198 7). Therefore, histamine H7-receptor antagonist-antacid compositions are generally prohibited. To show one's death.

Bioadhesives have attracted much attention as platforms for controlling drug delivery. ing. They target specific drug administration sites, prolong residence time, and increase absorption surface area. can ensure optimal contact with the Many species, both natural and synthetic Various types of bioadhesives can be used to design controlled drug delivery systems. Wear.

Sucralfate is a basic sucrose sulfate ester with ulcer healing and buffering properties. aluminum salt. According to the literature, sucralfate is a topical protective barrier. It acts by forming a bioadhesive gel structure that appears to provide a It turned out that. Sucralfate interferes with the absorption of histamine H2-receptor antagonists It was reported that there was no. Clinical studies show that combination therapy can be effective Indicated.

EP-A-0286781 (Heumann Phano a)) is a histamine H2-receptor antagonist and provides functional cytoprotection Pharmaceutical preparations with a cytoprotective effect on the gastrointestinal tract, containing a mixture of antacids capable of relating to things.

Sucralfate has been identified as an example of an antacid. It requires functional cells It is disclosed as providing protection but having relatively low acid neutralizing effectiveness.

EP-A-0403048 (Wahchira) published on December 19, 1990 Warner-Lambert) contains sucralfate and comprising a therapeutically effective amount of a drug, the drug being a) substantially water-insoluble; b) a mixture of a water-soluble drug and a release-retarding substance which, upon mixing, is substantially water-free; Pharmaceutical compositions that form soluble drugs are disclosed. In a preferred embodiment, the drug is selected from the group consisting of antacids and anti-ulcer drugs, among others. Skrullfur Composition consisting of To Plus Antacid and Sucralfate Plus Anticrushing Agent The product is useful in the treatment of peptic ulcers by forming a protective gel barrier that adheres to the ulcer. It is disclosed as a cell protection composition.

EP-A-0193400 (Reckit Colman)) contains histamine H2- with a weight ratio of 101 to 1.10. A pharmaceutical composition comprising a mixture of a receptor antagonist and sodium polyacrylate has been disclosed. It is shown.

The composition is disclosed for use in the treatment of gastritis or gastro-duodenal ulcers. ing. The composition may include an antacid. The use of antacids can reduce the viscosity of liquid compositions. to some extent in the design of easily flowable liquid preparations. provides viscosity control.

US 4,615.697 (Robinson) has drug an effective amount of a therapeutic agent, and a water-swellable bioadhesive; A controlled release composition comprising an insoluble fibrous crosslinked carboxine functional polymer is disclosed. ing. The controlled release composition is disclosed to adhere to skin or mucous membranes in the presence of water. It is. Cimetidine is mentioned as an example of a drug.

Current treatments using histamine H2-receptor antagonists act systemically.

That is, histamine H2-receptor antagonists are transported from the blood to parietal cell receptors. Ru.

International Patent Application No. PCT/GB91100953 describes histamine H2-receptor antacids and antacids to promote local delivery of body antagonists to parietal cell wall receptors. Oral treatment of gastric disorders using a histamine H2-receptor antagonist has also been disclosed. ing. Increased gastric wall receptor site bioavailability of histamine H7-receptor antagonists is a human drug that reduces acid secretion compared to histamine H2-receptor antagonists alone. Increases the potency of stamine H2-receptor antagonists.

Increased acid-hypersecretion ability is important for treatment of ulcer patients, especially those with hypersecretion, and for diagnosis in non-responders. In the treatment of these patients, such as gastric disorders due to hypercyanic acid It is said to be excellent in reducing the onset period of single-dose self-medication for acute gastric disorders. Disclosed.

pKa or histamine H7-receptor antagonist and histamine H2-receptor antagonist A homogeneous mixture consisting of a buffered bioadhesive, e.g. sucralfate, in its vicinity. The compound is a local depressant of histamine H2-receptor antagonists directly to parietal cell receptors in the gastric wall. Provides a useful treatment for gastric disorders mediated through recovery.

Therefore, the present invention provides that the composition is formulated as a homogeneous mixture and that the bioadhesive and and histamine H2-receptor antagonist form a bioadhesive complex in situ, Histamine H2-receptor antagonists locally target the gastric wall and one composition provides optimal buffering to a pH that is substantially the same as the pKa of the histamine H2-receptor antagonist. Histamine H2- for the formulation of a drug for the treatment of gastric disorders characterized by giving Provides for the use of an orally administrable pharmaceutical composition comprising a receptor antagonist and a bioadhesive do.

In addition, the present invention provides a histamine H2-receptor antagonist and in 5 in situ biological contact. a homogeneous mixture of bioadhesives forming an adhesive complex; and a histamine H2-receptor Consists of a buffering component to provide a pH substantially the same as the pH of the antagonist's pKa gastric disorders resulting from oral administration to the affected person of an effective amount of a locally acting pharmaceutical composition; Provide a method of treatment for harm.

In a further aspect, the invention provides a histamine H2-receptor antagonist and a biological agent. A homogeneous mixture of adhesives, as well as the pH and actuality of the pKa of the histamine H2-receptor antagonist. A topical agent for the treatment of gastric disorders consisting of a buffered component to provide a qualitatively identical pH. Provides a pharmaceutical composition for use.

゛The bioadhesive used in the composition of the present invention can be used in contact with biological surfaces such as mucous membranes. Includes both natural and synthetic substances that can be worn. As an example of bioadhesive natural rubber and plant extracts as well as sucralfate and cellulose derivatives. , acrylic acid and methacrylic acid derivatives, such as the trade names CARBOPOL and Crosslinked acrylic and methacrylic available under POLYCARBOPHIL Synthetic materials such as acid copolymers may be mentioned.

Compositions for use in the present invention preferably contain histamine H2-receptor antagonists. A pH profile over time that provides a local pH level that is substantially the same as the pH of the agent's pKa. A buffer that is an antacid with an equilibrium pH 1 acid neutralizing ability and gastric retention time value that provides a Optimum buffering is achieved through the use of buffering components.

If the bioadhesive is sucralfate, which has buffering properties, the It will be appreciated that it may function as a stimulant component.

This study of local transport of H6-receptor antagonists through the gastric mucosa has shown that gastric acid It is particularly useful in the self-medication of acute self-limiting gastric disorders such as gastric overload.

H2-RA treatment is difficult due to low levels of drug at Hl-receptors in parietal cells. It is understood to fail in Nsha-Ellison syndrome. Parietal cell H2-reception Increases drug concentration in the body, making histamine H2-receptor antagonists effective at lower doses The topical delivery of the present invention may be particularly useful in treating these disorders. It seems to be that.

Histamine H2-receptor antagonists for use in the compositions of the invention include , cimetidine, ranitidine and famotidine, preferably cimetidine and ranitidine. Mention may be made of nitidine, especially cimetidine. Known histamine H2-receptor antagonists pKa values for are readily available from pharmaceutical publications.

Similarly, the above parameters for suitable buffering components are known in the art. It is readily available to those skilled in the art. Preferred for use in compositions of the invention As a buffering agent, aluminum hydroxide, magnesium hydroxide, aluminum hydroxide Umu magnesium carbonate dry gel, magnesium carbonate, magnesium oxide, silicon magnesium aluminum acid, magnesium trisilicate, sodium bicarbonate, carbonate Calcium, bismuth carbonate, citric acid, tartaric acid, benzoic acid, sorbic acid and Mention may be made of alkali metal salts of phosphoric acids as well as mixtures thereof.

Additional suitable antacids have a pharmacokinetic model based on a modified standard two-component model. Drugs with acid secretion-lowering ability of histamine H2-receptor antagonists selected using del The selection may be made by kinetic analysis. Further to describe the stomach and intestines separately Introduction of compartments that represent the parietal cell tissue receptor compartments The model was selected with respect to the movement of tissue compartments and intragastric squeeze volumes. used to describe the pharmacokinetics for histamine H2-receptor antagonists. obtain. The model shows that the parietal cell tissue receptor compartment as a function of gastric emptying. reduced local bioavailability of histamine H2-receptor antagonists in Local organisms in the parietal cell tissue receptor compartment as a function of gastric absorption They show increased biological availability and their dependence on gastric pH. Stomach pH level is antacid Affected by drugs. Thus, the relationship between equilibrium pH, acid neutralization capacity and gastric retention time The suitability of a given antacid can be determined by inserting known values.

Conventional histamine H2-receptor antagonist therapy acts systemically, with the drug passing through the bloodstream. distributed to all parts of the body. Therefore, it is understood that non-target body tissues are exposed to the drug. will be done. The advantages of locally targeted drug delivery-7 stems are , lower doses can be used, thus ensuring that pharmaceutically relevant doses do not reach non-target tissues. That's a good thing.

Excretion of histamine H2-receptor antagonist from parietal cell tissue receptors into the gastric lumen is an antagonist. of histamine H2-receptor antagonists, while reducing the local bioavailability of Gastric absorption into parietal cell tissue receptors increases the local bioavailability of the antagonist. Book An advantageous feature of the invention is that it buffers the histamine H2-receptor antagonist in the gastric environment. effectively reduces antagonist excretion into the gastric lumen, increases absorption from the gastric lumen, Histamine H2-receptors in the gastric environment by forming bioadhesive complexes Reduced dose hiss brought about by increasing the residence time of the antagonist Efficacy of using tamin H2-receptor antagonists.

The dose of the histamine H3-receptor antagonist will depend on the efficacy of the antagonist based on body weight. , and the severity of symptoms. For example, histamine H2-receptor When the antagonist is cimetidine or ranitidine, about 1 to 8 doses per dosage form. 0019, typically about 519 to 5019, such as 5.10.15.20 or There may be an amount of 25 votes and 9 votes.

Furthermore, treatment with the compositions of the invention makes them particularly suitable for the treatment of acute gastritis. provides a more rapid onset of action.

A further aspect of the invention provides that the amount of antacid present in a given composition is - It is unaffected by the dose of receptor antagonist.

Bioadhesives, e.g., sucralfate, contain approximately 100 soybeans per dosage form. 00*9, typically present in an amount of about 800u to 1200me, e.g. 1000-9. It's okay to exist.

These doses are based on the and compositions that do not contain additional buffering agents.

If the composition contains a bioadhesive that does not have buffering capacity or in addition to sucralfate, If the buffer contains an additional buffering agent, the amount of buffer is equal to or greater than that of the histamine H2-receptor antagonist. is optimally selected to provide a pH that is substantially the same as the pH of the pKa.

It is a feature of the buffering component that it plays a dual role. In one aspect, In the permissive mode of action of antacids, immunity from symptoms of excessive gastric acidity due to neutralization bring a load. In a second and more important aspect, histamine H2-receptor antagonists It serves to act as a suitable buffering excipient to enhance the absorption of the antidrug. buffer The dosage of the softening agent can be selected to achieve both effects.

A suitable dosage range for magnesium hydroxide is about 15019-3000- 9, e.g. about 30019-1500n, e.g. 300we-600-q .

Suitable dosage ranges for aluminum hydroxide include 180 g to 3600 g; For example, 360u~1800, for example, 360~720~9.

A suitable dosage range for sodium bicarbonate is about 400 u to 8,00 u (be , for example, about 800 to 4000 to 9, for example about 800 to 160,019 be.

Compositions for use in the invention may contain a pharmaceutically acceptable carrier. stomach. The composition may be, for example, a tablet, capsule, powder, suspension or dispersion. They may be formulated for oral administration in solid or liquid form. Thus, the composition , further optionally a pharmaceutically acceptable adjuvant, including, inter alia, a thickening agent; Pharmaceutically acceptable excipients containing preservatives and coloring and flavoring agents It may be formulated by mixing with other agents.

Certain pharmaceutical compositions for use in the present invention are novel and, as such, of the present invention. It will be understood that this forms further embodiments.

The following examples illustrate the invention.

Such examples include, but are limited to, sucralfate as a bioadhesive. It's not a thing. Substances with bioadhesive properties, whether natural or synthetic, are may be incorporated into compositions for use in the field of light.

1) Cimetidine solutions of H2,5 were prepared with concentrations ranging from O to 200 u/ml. . Sucralfate (2 g) was added to 50 volumes of each methidine solution. good bae IM HCr was added until a paste was formed.

0 Good Transparent 50 Good Transparent 100 Good Transparent 125 Good Transparent 150 inferior residence cloudy qfi fluid 200 Not a paste Cloudy suspension liquid The result is less than 130mg/*i The cimetidine concentration is shown to be the most favorable for entrapment. 15 Concentrations higher than 0.019/寞1 affect the integrity of the paste.

Entrapment of cimetidine into sucralfate and entrapment into solution The amount of trapped cimetidine released was measured as a function of time.

The amount of cimetidine studied was 0.25.50.75.100 in 3Qmr volume. and 125 leaves/iris.

Pre-weighed cimetidine was added to 0.1M hydrochloric acid (30u). The solution was stirred magnetically. Mixed using a stirrer.

Insert a pH probe into the solution and add 1M salt until a clear solution (pH 2,5) is obtained. Added acid. The capacity was set to 50ml. A 200 μl sample was removed.

Add sucralfate (2gex Katsura) while stirring; Dispersed. Add LM HCl to 200 μl aliquot until paste formation occurs. Added.

Stirring was continued until the supernatant became clear. A 200 μl sample of supernatant was removed.

The supernatant was drained leaving the cimetidine/sucralfate paste.

Add 0,1M HCt (50ir), stir the mixture for 10 seconds, and sample 2 00 μl was taken out. Additionally, sample 5Qwi of 0.1M HCA was added. trial 200 μl of the sample was taken out. 0゜IM　HCA 3rd sample 5 (hl　(pH 1,5') was added.

The resulting mixture was placed on a 3/4 maximum speed orbital shaker (GFL, 3017).

1.5.15.30 and 45 minutes later, and 1.1.5.2.2.5.3.3 After 5 and 4 hours, 200 μl aliquots were removed.

At the end of the experiment, 5M H(:j'(5ir) was added to dissolve sucralfate. This final solution was diluted and the total final concentration of sucralfate was determined.

200μi of each sample taken throughout the experiment was assayed as follows: .

A 50 μ sample was transferred to a vial and 1.95 ml of O,LM HCl was added. place If desired, it was further diluted with distilled water. at 218mm compared to distilled water blank. Optical density was measured.

Nometidine release (corrected data) 1 time point i Nometidine concentration (Ten 9/117ri 11 75 3497.0 16 6.0 4.75'÷ At each nmethinone concentration, approximately 5% by weight of the available nometidine is converted to sucralfate. Entrapped. Visual observation shows that the paste integrity is 75 mq/m1 or more. was shown to be inhibited by cimetidine release. Pieces of the paste mass are broken up by stirring. Destroyed.

The release data indicate that release from sucralfate is a diffusion process.

Example 3 ? pH effect on cimetidine release from cralfate paste pH 1, 5, Sucralfate as a function of pH at 3,0,4,5,6,0 and 7.5 The rate of cimetidine release was measured. The experiment consisted of using a solution of water at a concentration of 50 mq/xl. It was carried out using tidine and 1 g of sucralfate.

Theoretical pH value 1.5 3.0 4.5 6.0 7.5 Total amount (mg) 1.079 1.0 82 1.117 1.105 1.045 The table below shows sucralfate pace Figure 2 shows release data as a function of % of total amount of cimetidine endramped in .

The results show that the release of 7methinone from the paste exposed to pH 1.5 was maximum. Show that something is true. As the pH increases, the amount of nometidine released decreases until I) H45. Do a little. At higher pHs, the amount released increases again.

The ingredients are dry conditioned under controlled temperature and humidity conditions using conventional equipment. granulate or spray dry the active antacid ingredient. The granules, histamine The H2-receptor antagonist and bioadhesive are combined with conventional tabletting aids, fillers and additives. Compounded with philic adjuvants, the formulation is compressed into tablets in conventional machines.

Commercially available aluminum hydroxide and magne/ram hydroxide! F! cloudy liquid Enter it as Add these active W& suspensions to the thickener premix. Next The resulting mixture was treated with a histamine H2-receptor antagonist, a bioadhesive and a preservative. Also, if desired, it is blended with a flavoring agent.

Example 7 Liquid suspension (All amounts are ■9) international search report teamCT/lsAI2111m+oowmwwlt+ww12teu+2 8αshi1+ international search report G[+9102063 SA　53494 Continuation of front page (72) Inventor: Koch, Mark United Kingdom Lee Katy 13.0 DD, Weybridge, St. George's Avenue (no address displayed) SmithKline Beecham Co. Consumer Brang (72) Inventor: O'Mallane, John Nidward, UK, Sully Katie -13.0D, Weybridge, St. George's Avenue (No. (No location indicated) SmithKline Beecham Consumer Brands

Claims (13)

[Claims] 1. The composition is formulated as a homogeneous mixture, whereby the bioadhesive and the Tamin H2-receptor antagonist forms a bioadhesive complex in situ and The min H2-receptor antagonist is locally targeted to the gastric wall; the composition is optimally buffered. to provide a pH substantially the same as the pKa of the histamine H2-receptor antagonist; This increases local levels of histamine H2-receptor antagonists at parietal cell receptors. Histamine H2 for formulation of a drug for treating gastric disorders characterized by increased - Use of an orally administrable pharmaceutical composition consisting of a receptor antagonist and a bioadhesive. 2. The composition has a pH substantially the same as the pKa of the histamine H2-receptor antagonist. Equilibrium pH, acid neutralizing capacity, resulting in a pH profile over time that provides local pH levels The use according to claim 1, optimally buffered with an antacid having gastric retention time values. 3. Use according to claim 1 or 2 for the treatment of gastric disorders in ulcer patients. 4. For the treatment of patients who do not respond to conventional histamine H2-receptor antagonist therapy Use according to claim 3. 5. 4. Use according to claim 3 for the treatment of acid hypersecretion patients. 6. 3. Use according to claim 1 or 2 for the single-dose treatment of acute gastric disorders. 7. Histamine H2-receptor antagonists are cimetidine, ranitidine, or famotidine. 7. The use according to any one of claims 1 to 6, which is a 8. 8. The use according to claim 7, wherein the histamine H2-receptor antagonist is cimetidine. 9. Claim 8, wherein the dose of cimetidine is 1 to 800 mg per dosage form. use. 10. Claim 9, wherein the dose of cimetidine is 5 to 50 mg per dosage form. use. 11. Composition is aluminum hydroxide, magnesium hydroxide, aluminum hydroxide - Magnesium carbonate dry gel, magnesium carbonate, magnesium oxide, trisilicate Magnesium, sodium bicarbonate, calcium carbonate, bismuth carbonate, alkaline silicate Minium magnesium, citric acid, tartaric acid, benzoic acid, sorbic acid or phosphorus Claims buffered with an alkali metal salt of an acid, or a combination of any of the aforementioned antacids. Use according to any one of items 1 to 10. 12. a homogeneous mixture of a histamine H2-receptor antagonist and a bioadhesive; and Equilibrium pH, acid neutralization capacity and gastric residence time values are the pK of histamine H2-receptor antagonists. of a pharmaceutical composition comprising a buffering component that provides a pH level substantially the same as the pH of a. A method for treating gastric disorders comprising orally administering an effective amount to an affected person. 13. a homogeneous mixture of a histamine H2-receptor antagonist and a bioadhesive; and Equilibrium pH, acid neutralization capacity and gastric residence time values are the pK of histamine H2-receptor antagonists. for the treatment of gastric disorders, comprising a buffering component that provides a pH level substantially the same as that of a. Pharmaceutical composition.