JPH05507695A - new treatment - 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] new treatment The present invention relates to the treatment of gastric diseases and pharmaceutical compositions used therein. more specific The present invention provides an oral pharmaceutical composition comprising an H2-recebuter antagonist and an antacid. acute diseases such as acid indigestion, heartburn and gastritis, and Concerning the treatment of gastric diseases including ulcerative ulcers.

Histamine H2-recebuter antagonists, such as cimetidine, ranitidine, nizatidine Famotidine and famotidine act directly on the acid-secreting parietal cells in the gastric glands in the stomach wall to release acid. decreases secretion.

Histamine H2-recebuterant antagonists are very effective in various gastric diseases, especially peptic ulcers. However, there are certain groups of patients who do not respond to treatment. Taking more The time lag between Limiting the promising benefits of stamine H2-recebuter antagonists.

A large proportion of peptic ulcer patients who are considered non-responders are treated with normal histamine H2- unresponsive to receptor antagonist therapy (Walker et al., often seen in cirrhosis). Frequent non-response to histamine H2-receptor antagonist Sponse to histamine H2-receptor anta gonists in cirrhotics): Gut, 30.1105 -9.1989; and A. Brack et al. Treatment ineffectiveness of Nidimethicin (C1in ical failures with cimetidine): Surg. ery, 88(3), 417-24).

Furthermore, patients with hyperacidity, such as patients with severe multiple wounds (L, Martin et al. Failure of cimetidine's prophylactic effect in critically ill patients etidine prophylaxis in the critical Arch, Surg, Shell 4.492-6.1979) or Patients with Zollinger-Ellson syndrome (B, G, 5tabile et al.: Hiss in Solinger-Ellison syndrome Failure of histamin H2-recebuter antagonist treatment mine H2-receptor antag.

nis therapy in 2o11inger-Ellison syn drome: Am, J, Surg.

145, 17-23.1983) Histamine H7-Recebuter Antagonist Treatment The low response to - led to the use of pump inhibitors.

Histamine H2-receptor antagonists are effective in acute and self-limiting gastric diseases, e.g. It has promising advantages as a self-administered questionnaire for hypersomnia. However, the slow onset of its action , it is impossible to meet consumers' demands for rapid disappearance of symptoms.

Moreover, increasing the dose to quickly eliminate symptoms is not recommended for use without a prescription. It will be understood that it is not appropriate to use In fact, it is less than the standard treatment volume. It would be desirable for a self-administered form to have no amount.

Co-administration of histamine H2-receptor antagonists and antacids has been investigated.

The rationale for coadministration is that antacids quickly relieve symptoms of gastric excess acidity by neutralizing them. whereas histamine H2-receptor antagonists inhibit acid secretion from parietal cells. acts independently by suppressing the

However, histamine H2-receptor antagonists can be used as antacids, especially those with strong acid-neutralizing ability. When administered with antacids, histamine H2-receptor antagonists often It is well known that bioavailability in plasma is substantially reduced (G, B Odemar et al., Lancet, 1. 444-445. 1979: G, W , Mihaly et al., B. Mj., 285. 998-9, 1982: J. H, Lin et al., B, J, Cl1n, Pharmacol, 24.551-3.　 1987).

Histamine H2-xebuta-antagonist/antacid combinations are therefore generally It is contraindicated. This contraindication for the combination of histamine H1-xeta-antagonists/antacids is Standard 2 Comparator Shows Reduced Systemic Absorption of Stamine H2-Recebuter Antagonists This is supported by pharmacological absorption model experiments using a treatment model.

Surprisingly, histamine H2-receptor antagonists and antacids (even strong acids) Even with antacids that have neutralizing properties, the combination resulting in enhanced bioavailability of histamine H2-recebuter antagonists in Therefore, compared to the case of histamine H2-recebuter antagonist alone, the histamine It was found that the acid secretion suppressing ability of the H2-receptor antagonist was enhanced. This synergy The fruit is the treatment of gastric diseases, especially the treatment of so-called "non-responders" and the treatment of patients with acute gastric diseases. It is advantageous as a control ticket.

The invention therefore consists of a histamine H7-receptor antagonist and an antacid. 1. An orally administrable pharmaceutical composition comprising: a histamine H2-receptor antagonist; Provides a pH change over time that provides a local pH level substantially equal to the pH level of Ka. The antacid is characterized in that it has an equilibrium pH 1 acid neutralizing ability and gastric retention time that can provide The present invention provides use of the pharmaceutical composition for producing a medicament for treating gastric diseases. wall thin Local doses of histamine H2-receptor antagonists in cell receptors have been This increases the ability of the histamine H2-recebuter antagonist to suppress acid secretion.

Increased ability to suppress acid secretion is important for the treatment of ulcer patients, especially those with gastric hyperacidity, and those diagnosed as non-responders. It is advantageous in treating patients with severe symptoms and also reduces the starting time in unit doses. Therefore, it is useful as a self-management sheet for acute gastric diseases, especially gastric diseases caused by hyperacidity. be.

The present invention also provides a pharmaceutical composition comprising a histamine H2-receptor antagonist and an antacid. composition, whose equilibrium pH 1 acid neutralizing ability and gastric retention time are imparting a pH level substantially equal to the pH level of the pKa of the Sebutar antagonist; A method for treating gastric diseases comprising orally administering an effective amount of the pharmaceutical composition to a patient. provide.

In yet another aspect, the invention provides a histamine H1-receptor antagonist and an antacid. A pharmaceutical composition for use in the treatment of gastric diseases, comprising: 1 acid neutralization ability and gastric residence time pKa of histamine H2-receptor antagonist To provide a pH level that is substantially equal to that of an H.

Histamine H! used as the composition of the present invention! - Recebuter antagonists are Includes tidine, ranitidine and famotidine, preferably cimetidine and Includes ranitidine, especially cimetidine. Known histamine H2-receptor antagonists The pKa value of an antidrug is readily available from the pharmacological literature.

Similarly, the above parameters of suitable antacids are also readily known to those skilled in the art. Ru. Suitable antacids for use in the compositions of the invention include aluminum hydroxide, hydroxide Magnesium chloride, aluminum hydroxide-magnesium carbonate co-dried gel, carbonate mug nesium, magnesium oxide, magnesium aluminum silicate, magnesium oxide Resilicate, baking soda, calcium carbonate, bismuth carbonate, citric acid, tartaric acid, rest Contains alkali metal salts of aromatic acid, sorbic acid and phosphoric acid and combinations thereof. be caught.

A more suitable antacid is based on a modification of the standard two-compartment model. Selected histamine H2-receptor antagonists using pharmacokinetic models can be selected by pharmacokinetic analysis of its ability to inhibit acid secretion. stomach and intestines Introducing separate compartments to represent cells separately and further habituate the tissue of the cells. Using the movement between the tissue compartment representing the gastric compartment and the gastric pouch, Select the model and evaluate the pharmacokinetics of the histamine H1-recebuter antagonist. It can be used to express something. This model is a histamine H2-receptor antagonist. Local bioavailability of antibiotics in the tissue receptor compartment of habit cells Furthermore, the tissue reservoir compartment of habit cells decreases as a function of gastric emptying. Increase in local bioavailability at the site as a function of local biology and Demonstrate their dependence on gastric pH. Stomach pH levels are affected by antacids.

Therefore, substituting known values for equilibrium pH 1 acid neutralizing capacity and gastric residence time. This allows us to assess the suitability of any antacid.

Dosing levels for histamine H2-recebuter antagonists are based on the weight of the selective antagonist. It can be determined by effectiveness and severity of symptoms. For example, if the antagonist When it is thidine, it generally contains approximately 25 to 400 mg per unit dosage form, especially Approximately 50 to 200 mg of cimetidine is included.

Histamine H7-receptor antagonist is excreted from the tissue receptors of habit cells into the stomach pouch. This decreases the local biological availability of the antagonist. On the other hand, histami H2-receptor antagonists are absorbed into the receptors by gastric absorption into the receptors. Local bioavailability increases. An advantage of the present invention is that antacids and histamine H 2- Synergistic effect with receptor antagonist, i.e. effectively suppresses the excretion of antagonist into the stomach pouch Histamine H2 by inhibiting and increasing absorption from the stomach pouch - It is expected that the dosage of receptor antagonists will be reduced.

Treatment with the compositions of the invention results in a more rapid onset of action, which indicates that It will also be appreciated that these compositions are particularly suitable for the treatment of acute gastritis.

Another aspect of the invention is that the content of the antacid in any composition is equal to or less than the amount of histamine H7- It is independent of the dose of the receptor antagonist.

A dual role is a characteristic of antacid components. On the one hand In the already recognized mode of action of antacids, they treat symptoms caused by excessive acidity in the stomach. Eliminates by neutralization.

In the second aspect, and more importantly, the biological It serves as an excipient with appropriate buffering properties for biological availability.

The dose of antacids should be determined to achieve the desired acid neutralizing effect and also to reduce histamine H2-lysebu. It is said to provide a pH level substantially equal to the pH level of the pKa of the tar antagonist. The antacid component can be selected to serve as a buffering excipient.

A suitable dosage range for magnesium hydroxide is approximately 150 mg to 3000 mg; For example approximately 3'OOm'g 1500mg, for example approximately 300mg to 60 It is 0 mg.

A suitable dosage range for aluminum hydroxide is approximately I 80mg to 3600mg , for example approximately 360 m’g to 1800’ mg, for example approximately 360 mg? and 720 mg.

A suitable dosage range for baking soda is approximately 400 mg to 8000' mg, e.g. 800mg to 4000mg, for example approximately 800mg to 1600mg .

Compositions for use in the invention may also include a pharmaceutically acceptable carrier.

The composition can be in solid or liquid form for oral use, such as tablets, capsules, powders, suspension straws, It may also be formulated as a dispersion lid. The composition is therefore in a pharmaceutically acceptable excipient. If desired, pharmaceutically acceptable adjuvants (particularly swelling agents, (including preservatives, colorants and fragrances) can be added to formulations. Certain pharmaceutical compositions using the invention are novel and form another aspect of the invention. It is understood that it is something like that.

The present invention will be explained in detail in the following examples.

powder formulation The ingredients are blended dry while controlling temperature and humidity using regular equipment. Ta.

tablet did. The granules and histamine H1-recebuterant antagonist are combined with conventional tabletting aids and fillers. Blend with fillers and taste modifiers and compress the blend with conventional equipment. .

suspension Aluminum hydroxide and magnesium hydroxide were obtained as commercial suspensions. this The active suspension was added to the premixed swelling agent. Furthermore, the resulting mixture is mixed with histamine. Blended with H2-recebuter antagonist and appropriate amounts of preservatives and flavors.

antacid combination tablets (All numbers are in milligrams) (All numbers are in milligrams) summary Simultaneous combination of histamine H1-receptor antagonists and antacids to treat gastric diseases Administration.

Copy and translation of written amendment) Submission (Article 184-8 of the Patent Law) December 8, 1992

Claims (13)

[Claims] 1. Orally available, consisting of histamine H2-receptor antagonists and antacids. 2. A pharmaceutical composition, wherein the antacid is the histamine H2-receptor antagonist p It also changes pH over time to give a local pH level substantially equal to the pH level of Ka. , an equilibrium pH, an acid neutralizing ability, and a gastric retention time. Use of a pharmaceutical composition for the manufacture of a medicament for treating gastric diseases. 2. Local levels of histamine H2-receptor antagonists in habit cell receptors increases, thereby increasing the ability of histamine H2-receptor antagonists to suppress acid secretion. Use according to claim 1, characterized in that it strengthens. 3. The use according to claim 1 or 2 for the treatment of gastric disease in patients with ulcerative cancer. 4. For the treatment of patients who do not respond to conventional histamine H2-receptor antagonist therapy. 4. The use according to claim 3. 5. 4. Use according to claim 3 for the treatment of patients with gastric hypersecretion. 6. Use according to claim 1 or 2 for the treatment of acute gastric diseases for one-time administration. . 7. Histamine H2-recebuter antagonists are cimetidine, ranitidine or famo The use according to any of the preceding claims, which is tidine. 8. Claim 7, wherein the histamine H2-recebuter antagonist is cimetidine. use. 9. Cimetidine dose levels are 25 to 400 mg per unit dosage form , the use according to claim 8. 10. Cimetidine dosage levels range from 50 to 200 mg per unit dosage form. 10. The use according to claim 9. 11. Antacids include aluminum hydroxide, magnesium hydroxide, and aluminum hydroxide / Magnesium carbonate co-dried gel, magnesium carbonate, magnesium oxide, magne Cium trisilicate, baking soda, calcium carbonate, bismuth carbonate, magnesium silicate aluminum, citric acid, tartaric acid, benzoic acid, sorbic acid or phosphoric acid. Any preceding which is a combination of alkali metal salts or antacids of any of the above. Use as claimed in any of the claims. 12. A pharmaceutical composition comprising a histamine H2-receptor antagonist and an antacid. Therefore, the equilibrium pH, acid neutralizing ability, and gastric residence time of the histamine H2-lysebu the pharmaceutical agent that provides a pH level substantially equal to the pH level of the pKa of the tar antagonist; A method of treating gastric disorders comprising orally administering to a patient an effective amount of a pharmaceutical composition. 13. Consists of histamine H2-receptor antagonists and antacids, whose equilibrium pH , acid neutralization ability and gastric residence time, the pKa of the histamine H2-receptor antagonist for use in the treatment of gastric disorders, imparting a pH level substantially equal to that of Pharmaceutical composition.