PL168421B1 - Method of obtaining a pharmaceutic composition for treating stomach disorders - Google Patents

Abstract

Buffered pharmaceutical compositions for the local treatment of gastric disorders comprising a histamine H2-receptor antagonist in intimate admixture with a bioadhesive material.

Description

The present invention relates to a process for the preparation of a pharmaceutical composition for the treatment of gastric disorders. The invention relates to the local treatment of gastric disorders, in particular acute gastric disorders such as dyspepsia, heartburn and gastritis as well as gastric ulcer and peptic ulcer, by the oral administration of pharmaceutical compositions containing a histamine H2 receptor antagonist obtained by the method of the invention. These compositions are specifically tailored to be sent through the stomach wall to H2 receptors in the parietal cells.

Histamine H2 receptor antagonists, e.g. cimetidine, ranitidine, nizetidine and famotidine, reduce acid secretion by acting directly on acid-secreting parietal cells located in the gastric gland on the gastric wall.

Although histamine H2 receptor antagonists are significantly effective in the treatment of many gastric disorders, particularly peptic ulcers and gastric ulcers, there are some patients who do not respond to treatment. Furthermore, the time lag between administration and onset of action limits the potential benefit of histamine H2 receptor antagonists in the treatment of acute, spontaneously resolving gastric disorders.

A significant proportion of patients suffering from gastric and peptic ulcers are assessed as non-responders and not responding to conventional histamine H2 receptor antagonist therapy (Walker et al., Frequent non-response to histamine H2-receptor antagonists in cirrhotics; Gut., 30, 1105) -9 (1989); and Brack et al., Clinical Failures with cimetidine; Surgery, 88 (3), 417-24).

In addition, the known poor response to treatment with histamine H2 receptor antagonists, shown by hypersecretory patients, e.g., dangerously ill, with multiple

168 421 (L. Martin et al., Failure of cimetidine prophylaxis in the critically ill; Arch. Surg., 114, 492-6 (1979)) or with Zollinger-Ellison syndrome (BGStabile et al., Failure of histamine H2 -receptor antagonist therapy in Zollinger-Ellison syndrome; AJ Surg., 145, 17-23 (1983)) forces to look for alternative methods of treatment, especially the use of proton pumping inhibitors.

Histamine H2 receptor antagonists are potentially beneficial in the self-treatment of acute, self-limiting gastric disorders such as hyperacidity. However, due to their slow onset of action, they do not meet the user's requirements for rapidly alleviating disease symptoms.

Moreover, it should be remembered that using high horizontal doses for rapid symptom relief is not appropriate for over-the-counter use. In fact, it is desirable to reduce the standard therapeutic dose in the case of self-treatment.

Co-administration of histamine H2 receptor antagonists and other pharmaceutically active substances, including sucralfate and other antacids, has been studied. The rationale for co-administration with an antacid is that the antacid provides rapid relief of symptoms of excessive gastric acidity by neutralization, while the H 2 histamine receptor antagonist acts independently by inhibiting acid secretion from the parietal cells.

However, the fact is well known (G. Bodemar et al., Lancet, 1444-445 (1979); GWMihaly et al., BMJ, 285, 998-9 (1982); JHLin et al., BJClin Pharmacol. , 24,551-3 (1987)), that when histamine H2 receptor antagonists are co-administered with a neutralizing agent, especially a highly acid-neutralizing agent, a significant reduction in the plasma bioavailability of the histamine H2 receptor antagonist is often observed. Therefore, the use of a histamine H2 receptor antagonist-antacid combination is generally contraindicated.

Particular attention has been paid to bio-adhesive materials as the basis for the controlled drug release. They can be sent to specific drug administration sites, which prolongs their residence time and ensures optimal contact with the absorbing surface. Many different types of bioadhesive materials, both natural and synthetic, can be used to form controlled drug release systems.

Sucralfate is a basic aluminum sulphate sucrose complex with ulcer healing and buffering properties. According to the literature, sucralfate acts to form a bio-adhesive gel structure which is believed to form a local protective barrier. Sucralfate has been reported not to interfere with the absorption of histamine H2 receptor antagonists. Clinical trials have shown that combination therapy masks the potential benefits.

EP-A-0 286 781 (Heumann Pharma) describes cell-protective and gastrointestinal preparations which are a combination of a histamine H 2 antagonist and an antacid, which preparations are capable of functional cell protection. They have been found to protect cells functionally but have a relatively low antacid effect.

European Patent EP-AO 403 048 (W amer-Lambert), published on December 19, 1990, describes a medicinal composition containing sucralfate and a therapeutically effective amount of a drug that is (a) practically insoluble in water, or (b) a mixture a water-soluble drug and a release retardant, thereby forming a practically water-insoluble drug. In a preferred embodiment, the drug belongs to the group of antacids and antiulcer drugs, among others. Compositions containing sucralfate and an antacid, and sucralfate and an anti-ulcer drug are described as cell protective preparations useful in the treatment of peptic ulcers by forming an ulcer-adherent protective gel barrier.

EP-A-O 193 400 (Reckitt and Colman) describes pharmaceutical compositions which are mixtures of a histamine H2 receptor antagonist and sodium polyacrylate in a weight ratio of 10: 1 to 1:10. The compositions are described as being for use in the treatment of gastritis or gastroduodenal ulcers. Compositions can

168,421 contain an antacid. The use of a neutralizing agent is intended to reduce the viscosity of the liquid composition as described herein, which provides some degree of viscosity control in the preparation of pourable liquid formulations.

In U.S. Patent No. US No. 4,615,697 (Robinson) discloses a controlled release composition comprising an effective amount of a therapeutic agent and a bioadhesive material which is a water-insoluble, water-swellable, fibrous, cross-linked polymer containing carboxyl functional groups. Controlled release compositions are described as being adhered to the skin or mucosa in the presence of water. Cimetidine is given as an example of a drug.

Treatment with histamine H2 receptor antagonists is systemic, i.e., the histamine H2 receptor antagonist is delivered to the parietal cell receptors from the blood.

International Patent Application No. PCT / GB91 / 00953 describes the oral treatment of gastric disorders by using a histamine H2 receptor antagonist in combination with an antacid, which facilitates local delivery of the antagonist to parietal cell receptors in the wall. Increasing the bioavailability of the histamine H2 receptor antagonist increases its ability to reduce acid secretion as compared to the administration of the antagonist alone.

The enhancement of the acid secretion-reducing capacity is recognized as being beneficial in the treatment of patients with peptic ulcer disease, in particular hypersecretory patients and in the treatment of non-responsive patients. It also shortens the start-up phase until a single dose has been triggered and allows for self-treatment of acute gastric disorders such as those caused by hyperacidity.

It has been found that a mixture of a histamine H2 receptor antagonist with a bio-adhesive, e.g. sucralfate, buffered to about the pKa of a histamine H2 receptor antagonist, allows effective treatment of gastric disorders by delivering the antagonist topically directly to the parietal cells of the gastric wall.

The method of the invention consists in mixing the bio-adhesive and the histamine H2 receptor antagonist and buffering to obtain a pH value practically equal to the pKa value of the histamine H2 receptor antagonist with an antacid. The pharmaceutical composition according to the invention is used to treat gastric disorders by administering to sufferers an effective amount of a topically acting pharmaceutical composition which is an intimate mixture of the H2-histamine receptor antagonist and bioadhesive substances, the components of which form an in situ bioadhesive complex. The pharmaceutical composition according to the invention is an intimate mixture of a histamine H 2 antagonist, a bio-adhesive and a buffering agent that allows the pH to be kept practically equal to the pKa of the antagonist.

The composition according to the invention produces an in situ bioadhesive complex which enables the antagonist to be delivered to the stomach walls.

The bioadhesive material used in the method of the invention are both natural and synthetic materials, capable of adhering to biological surfaces such as mucous membranes. Examples of bio-adhesive substances are natural gums, plant extracts and synthetic materials such as sucralfate, cellulose derivatives and derivatives of acrylic acid and methacrylic acid, e.g. cross-linked copolymers of acrylic acid and methacrylic acid, available under the trade names CARBOPOL and POLYCARBOPHIL.

The compositions according to the invention are buffered by the addition of a buffering component which is a suitable pH equilibrating antacid capable of neutralizing the acid for a gastric residence time such as to maintain an appropriate pH value practically equal to the pKa of the histamine H 2 antagonist. .

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It should be noted that when the bio-adhesive is sucralfate, which exhibits buffering properties, it may also function as a buffering agent in the pharmaceutical composition.

Such a method of delivering the histamine H2 receptor antagonists to the site via the gastric mucosa is particularly advantageous for the treatment of acute, spontaneously resolving gastric disorders such as hyperacidity. It is understood that treatment with H2-RA fails in Zollinger-Ellison syndrome due to too low levels of the drug at the H2-receptors in the parietal. Delivery of a composition according to the invention to the treatment site, increasing the drug concentration at the H2 receptors of the parietal cells and making the histamine H2 receptor antagonist effective at low doses, is considered particularly beneficial in the treatment of the disorders in question.

The histamine H2 receptor antagonists in the compositions of the invention are cimetidine, ranitidine and famotidine, preferably cimetidine and ranitidine, in particular cimetidine. PKa values for known histamine H 2 receptor antagonists are readily available from pharmacological publications.

Likewise, the above parameters for suitable buffering agents are readily available to those skilled in the art. Suitable buffering agents for the method of the invention include aluminum hydroxide, magnesium hydroxide, co-dried gel aluminum hydroxide-magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium aluminum silicate, magnesium trisilicate, sodium bicarbonate, calcium carbonate, bismuth carbonate, metal salts alkali metals of citric, tartaric, benzoic, sorbic and phosphoric acid, and mixtures of the foregoing.

Other suitable antacids can be selected on the basis of a pharmacokinetic analysis of the acid secretion reducing capacity of the selected histamine H2 receptor antagonists using a pharmacokinetic model based on a modified standard two compartment model. By introducing further compartments, separately describing the stomach and intestine, and a compartment describing the transport between tissues, a compartment representing the receptors of the parietal cell tissue and the gastric lumen, the above model can be used to describe the pharmacokinetics of a selected histamine H2 receptor antagonist. Such a model demonstrates a reduction in the local bioavailability of the histamine H 2 receptor antagonist in the parietal tissue receptor compartment as a function of gastric secretion and increasing the local bioavailability in the parietal tissue receptor compartment as a function of local gastric absorption as well as their dependence on gastric pH. The pH levels in the stomach are changed with an antacid. Hence, the suitability of any antacid can be determined by knowing the equilibrium values for pH, antacid capacity, and gastric residence time.

The usual histamine H2 receptor antagonist therapy is systemic therapy and the drug is distributed through the blood stream to all parts of the body. Therefore, it should be borne in mind that all body tissues other than the target body are exposed to the drug. An advantage of the drug delivery system to the selected site is that lower doses can be used and pharmacological doses do not reach undesired tissues.

The secretion of the histamine H 2 antagonist into the lumen of the stomach from the receptors of the parietal cell tissue reduces the local bioavailability of the antagonist, while gastric absorption of this antagonist at the receptors of the parietal cell tissue increases its local bioavailability. An advantageous feature of the method according to the invention is the possibility of using reduced dose levels of the histamine H2 receptor antagonist by buffering this antagonist in the gastric environment, which effectively reduces the secretion of the antagonist into the gastric lumen, increases gastric lumen absorption, and increases the residence time of the antagonist in the gastric environment due to the formation of a bio-adhesive complex. .

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The dosage of a histamine H2 receptor antagonist may be selected on the basis of its potency, body weight, and degree of disorder. For example, when the antagonist is cimetidine or ranitidine, it may be used in an amount of from about 1 mg to 800 mg per dose unit, typically from about 5 to 50 mg, e.g. 5, 10, 15, 20 or 25 mg.

It should also be noted that treatment with the present composition results in a faster onset of action, which makes it particularly suitable for the treatment of acute gastritis.

In a further aspect of the invention, the amount of neutralizing agent in a given composition is independent of the dose of the histamine H2 receptor antagonist.

The bio-adhesive, e.g., sucralfate, may be present in an amount from about 100 mg to 1500 mg / dose, typically from about 800 mg to 1200 mg, e.g., 1000 mg. This dosage relates to compositions in which sucralfate acts as a buffering ingredient and which contain no other buffering agent.

In case the composition contains a non-buffering bioadhesive material or if, in addition to sucralfate, another buffering agent is added, the amount of the latter is optimally selected to obtain a pH value practically equal to the pKa value of the histamine H2 receptor antagonist.

A feature of the buffering agent is that it has two roles. On the one hand, it is an antacid and alleviates symptoms of excessive gastric acidity, and on the other hand, and more importantly, it serves as a suitable buffering carrier to increase the absorption of the histamine H2 receptor antagonist. The dose of the buffering agent may be adjusted to obtain both effects.

A suitable dose of magnesium hydroxide is from about 150 mg to 3000 mg, preferably from about 300 mg to 1500 mg, e.g. from about 300 mg to 600 mg.

A suitable dose of aluminum hydroxide is from about 180 mg to 3600 mg, preferably from about 360 mg to 1800 mg, e.g. from 360 mg to 720 mg. A suitable dose of sodium bicarbonate is from about 400 mg to 8,000 mg, preferably from about 800 mg to 4000 mg, e.g. from about 800 mg to 1600 mg.

The compositions prepared by the process of the invention may also contain pharmaceutically acceptable carriers. Compositions for oral administration may be solid or liquid, and may take the form of, for example, tablets, capsules, powders or suspensions. The compositions may be prepared by mixing the drug substances with pharmaceutically acceptable carriers, and may additionally contain, if desired, pharmaceutically acceptable adjuvants such as, but not limited to, thickening agents, preservatives, dyes or flavoring agents.

The invention is illustrated by the following examples. Although sucralfate is used as the bio-adhesive in the examples, this is not a limitation. Any substance with bioadhesive properties, natural or synthetic, can be used in the compositions according to the invention.

In the following examples, cimetidine with a pKa of 6.8 and 7.1 and ranitidine with a pKa of 8.2 and famotidine with a pKa of 6.5 were used to adjust the pH of each composition to the antagonist pKa listed.

Example 3 illustrates the release of cimetidine as a function of sucralfate. It proves that cimetidine can be released sufficiently at pH values of 6.0 and 7.5, which correspond to the pKa values of cimetidine.

Example I. Deposition of Cimetidine in Sucralfate

Cimetidine solutions at pH 2.5 and concentrations ranging from 0 to 200 mg / ml were prepared. To 50 ml of each cimetidine solution, 2 g of sucralfate was added and then 1M hydrochloric acid was added until a good paste was obtained.

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Results

Cimetidine mg / ml Paste quality The appearance of the supernatant 0 Okay clear 50 Okay clear 100 Okay clear 125 Okay clear 150 bad cloudy suspension 200 does not form cloudy suspension

The above results demonstrate that cimetidine concentrations below 150 mg / ml are the most favorable for deposition. The paste is not homogeneous at concentrations above 150 mg / ml.

Example II. Deposition and release of cimetidine.

The level of deposition of cimetidine in sucralfate and the release of cimetidine into solution was determined as a function of time. Concentrations of 0.25, 50, 75, 100 and 125 mg / ml were tested in 50 ml aliquots.

Method.

A weighed amount of cimetidine was added to 30 ml of 0.1 M hydrochloric acid, the solution was stirred with a magnetic stirrer. A pH electrode was inserted into the solution and 1 M hydrochloric acid was added until a clear solution was obtained (pH 2.5). The volume was adjusted to 50 ml and a sample of 200 (i.

2 g of sucralfate (Katsura) was added to the solution with stirring to form a suspension, then 200 µM hydrochloric acid was added in portions until a paste was obtained. Stirring was continued until a clear supernatant was obtained. A 200 µl sample of the supematant was taken.

The supernatant was decanted and a cimetidine paste with sucralfate was obtained.

50 ml of 0.1 M hydrochloric acid was added to the paste, the mixture was stirred for 10 minutes, and a 200 μ sample was taken. Again 50 ml of 0.1M hydrochloric acid was added and a 200 μ sample was taken. A third portion of 0.1M hydrochloric acid (pH 1.5) was added and the mixture was placed on a rotary shaker (GFL., 3017), shaking at 3/4 maximum speed. 200 μl samples were taken after 1, 5, 15, 30 and 45 minutes and then after 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours.

After the end of the experiment, 5 ml of 5M hydrochloric acid was added to dissolve the sucralfate. The resulting solution was diluted and the total final sucralfate content was determined.

Each of the 200 μ samples taken during the experiment was determined as follows. The 50 μ sample was transferred to a vial and 1.95 ml of 0.1M hydrochloric acid was added. Further, the samples were diluted with the required amount of water. The optical density at 218 nm was determined against distilled water (blank).

Release of cimetidine (corrected data)

Time (minutes) Cimetidine concentrations (mg / ml) 0 25 50 75 100 125 01 0.0 0.05 0.06 0.187 0.507 0.680 05 0.0 0.086 0.166 0.249 0.609 0.945 15 0.0 0.138 0.314 0.549 0.966 1.734 thirty 0.0 0.193 0.519 0.738 1.364 2,120 45 0.0 0.237 0.645 0.948 1.691 2.488 60 0.0 0.274 0.743 1.107 1.942 2.828 90 0.0 0.323 0.855 1.43 2.337 3.494 120 0.0 0.363 0.935 1.665 2.675 3.868 150 0.0 0.382 1.039 1.969 2.865 4.220 180 0.0 0.406 1.13 2,176 3.203 4.448 210 0.0 0.438 1.162 2.285 3.419 4.596 240 0.0 0.439 1.185 3.012 3.438 4.497

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Deposition of cimetidine

Cimetidine (mg / ml) Total amount of cimetidine added Total amount of cimetidine in paste % deposited of total added 0 0.0 0.0 - 25 1175.5 59.35 5.05 50 2399.0 121.45 5.06 75 3497.0 166.0 4.75 100 4,613.0 225.75 4.89 125 5207.5 263.75 5.06

At each concentration of cimetidine, approximately 5% by weight of the available cimetidine is deposited in the sucralfate. Visual observations show that the homogeneity of the paste is disturbed when the concentration of cimetidine is exceeded by 75 mg / ml. Stirring breaks up the pieces of paste.

The release data show that the release from sucralfate is a diffusion process.

Example III. Effect of pH on the release of cimetidine from sycralfate pastes

The rate of cimetidine release from sucralfate was determined as a function of pH at pH values of 1.5, 3.0, 4.5, 6.0, and 7.5. The experiment was carried out using a concentration of cimetidine of 50 mg / ml and 1 g of sucralfate.

Theoretical pH values 1.5 3.0 4.5 6.0 7.5 Total amount of cimetidine (mg) 1.079 1.082 1.117 1.105 1.045 Initial pH value 1.69 3.23 4.64 6.12 7.54 PH value after 5 hours 3.21 3.17 4.57 6.18 7.66

The following table shows the release data as a function of the% of total cimetidine embedded in sucralfate paste.

Time (minutes) PH value 1.5 3.0 4.5 6.0 7.5 01 6.95 6.65 5.28 9.41 6.32 05 12.6 19.50 14.50 11.31 6.96 15 21.87 31.89 23.63 15.48 11.20 thirty 32.16 37.15 27.48 19.91 15.98 45 42.08 42.79 29.45 25.16 21.44 60 51.62 44.82 32.86 28.69 26.69 90 68.39 50.09 39.21 34.93 35.89 120 83.5 57.02 41.99 40.0 45.26 150 94.16 61.28 46.46 47.87 54.74 180 104.54 65.25 48.97 52.04 63.83 210 111.21 68.69 52.28 56.29 72.63 240 119.55 70.06 54.43 60.27 81.24

The presented results show that the greatest release of cimetidine from the paste occurs at pH 1.5. As the pH increases, the amount of cimetidine released decreases to pH 4.5. Above this pH the release increases again.

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Example IV. Powder preparations

The ingredients are dry mixed under controlled temperature and humidity conditions using standard equipment.

Example V-VI. Pills

The antacids are granulated or spray dried in the usual manner. The granules, the histamine H2 receptor antagonist and the bio-adhesive are mixed together with conventional tableting additives, fillers and flavorings. The obtained blend is tableted using a conventional machine.

Example VII. Liquid suspensions

Commercially available slurries of algae hydroxide and magnesium hydroxide are added to the mixture of thickeners. The resulting mixture is mixed with the histamine H2 receptor antagonist, bio-adhesive, and preservatives and flavors.

Example IV. Powders

Preparation no 1 2 3 4 5 6 7 8 9 10 11 Sukralfat 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 Cimetidine 1-100 - - 1-100 - - 1-100 - - 1-100 - Ranitidine - 1-100 - - 1-100 - - 1-100 - - 1-100 Famotidine - - 1-20 - - 1-20 - - 1-20 - - Sodium bicarbonate 1500 1750 2000 750 875 1500 1500 1750 2000 - - Citric acid - - - - - - 1000 1225 1400 - - Tartaric acid - - - - - - 600 70 800 - - Flavoring agent 1 1 1 1 1 1 1 1 1 1 1 Sugar powder 500 500 500 500 500 500 500 500 500 500 500

(all amounts in mg) Example 5 Tablets

Preparation no 12 13 14 15 16 17 18 19 twenty 21 22 Sukralfat 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 Cimetidine 1-100 - - 1-100 - - 1-100 - - 1-100 - Ranitidine - 1-100 - - 1-100 - - 1-100 - - 1-100 Famotidine - - 1-20 - - 1-20 - - 1-20 - - Aluminum hydroxide 700 800 750 350 400 375 - - - - - Magnesium hydroxide 700 800 750 350 400 375 - - - - - Calcium carbonate - - - - - - 800 900 1000 - - Starch 100 100 100 100 100 100 100 100 100 100 100 Sugar powder 250 250 250 250 250 250 250 250 250 250 250 Flavoring agent 2 2 2 2 2 2 2 2 2 2 2

168 421 Example V

Preparation no 12 13 14 15 16 17 18 19 twenty 21 22 Povidone (polyvinylpyrrolidone) 10 10 10 10 10 10 10 10 10 10 10 Magnesium stearate twenty twenty twenty twenty twenty twenty twenty twenty twenty twenty twenty

(all amounts in mg)

Example VI. Tablets containing an antacid

Preparation no 23 24 25 26 27 28 29 thirty 31 Sukralfat 1000 1000 1000 1000 1000 1000 1000 1000 1000 Cimetidine 1-100 - - 1-100 - - 1-100 - - Ranitidine - 1-100 - - 1-100 - - 1-100 - Famotidine - - 1-20 - - 1-20 - - 1-20 Sodium bicarbonate 1000 1000 1000 2000 2000 2000 Magnesium aluminum silicate 100 100 100 200 200 200 - - - Hydrocalcite 125 125 125 250 250 250 250 250 250

(all amounts in mg)

Example VII. Liquid suspensions

Preparation no 32 33 34 Sukralfat 1000 1000 1000 Cimetidine ' 1-100 - - Ranitidine - 1-100 - Famotidine - - 1-20 Magnesium hydroxide 350 400 375 Aluminum hydroxide 350 400 375 Sodium bicarbonate 750 875 1000 Sorbitol solution 3000 3000 3000 Preservatives 4.5 4.5 4.5 Flavorings 10 10 10 Thickeners 45 45 45 Water how much do you need

(all amounts in mg)

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Claims (6)

Patent claims A method for the preparation of a pharmaceutical composition for the treatment of gastric disorders by mixing a histamine H2 receptor antagonist and a bio-adhesive, characterized by mixing a bioadhesive substance and a histamine H2 receptor antagonist and buffering with an antacid to obtain a pH value practically equal to the pKa value of the histamine receptor antagonist H2. 2. The method according to p. The method of claim 1, wherein the histamine H2 receptor antagonist is cimetidine, ranitidine or famotidine. 3. The method according to p. The method of claim 2, wherein the histamine H2 receptor antagonist is cimetidine. 4. The method according to p. The process of claim 3, wherein the amount of cimetidine in one dose is 1 to 800 mg. 5. The method according to p. The process of claim 4, wherein the amount of cimetidine in one dose is 5 to 50 mg. 6. The method according to p. The method of claim 1, wherein the composition is buffered with aluminum hydroxide, magnesium hydroxide, co-dried gel of aluminum hydroxide and magnesium carbonate, magnesium carbonate, magnesium oxide, magnesium trisilicate, sodium bicarbonate, calcium carbonate, bismuth carbonate, magnesium aluminum silicate, alkali metal salts of citric acid , tartaric acid, benzoic acid, sorbic acid, or phosphoric acid, or mixtures of the foregoing antacids.