JPH01197444A - Effect of combination of beta-adrenergic agent to damage of digestive tract generated by non-steroidal anti-inflammatory composition and certain kind of histamine h1-and/or h2-receptor blocker - Google Patents

Abstract

PURPOSE: To obtain a nonsteroidal antiinflammatory drug(NSAID) composition protective to digestive tract damage induced by NSAID, containing a combination of a β-adrenergic agent with histamine H1 and/or H2 receptor blocker(s). CONSTITUTION: This composition contains (A) an antiinflammatory amount of a NSAID such as aspirin or ibuprofen and (B) a protective amount of a protective agent composed of B1 : a β-adrenergic agent (e.g. terbutaline) and B2 : a histamine H1 receptor blocker (e.g. diphenhydramine) and/or histamine H2 receptor blocker (e.g. ranitidine). The average daily doses of the above active ingredients, based on the body weight (kg) of a patient to be administered, are as follows: A: 10-1000mg/kg, B1 : 0.30μg to 500mg, and B2 as the H1 receptor blocker: 2.5μg to 500mg; or A: 10-70mg, B1 : 0.01-10mg, and B2 as the H2 receptor blocker: 0.1-50mg.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides β-adrenergic mulberry and H.
The invention relates to a non-steroidal anti-inflammatory composition containing a combination of histamine-receptor blockers selected from the group consisting of -1 and H2-blockers and mixtures thereof. Compositions of the invention are useful in treating conditions and symptoms classically treated by the administration of N5AIDs, such as headaches, pain and inflammation associated with arthritis and other systemic diseases, elevated body temperature, and the like.

Aspirin and other N5AIDs have been the most popular drugs for treating pain, inflammation and fever in individuals for many years. However, one of the drawbacks is the gastrointestinal injury and/or bleeding that sometimes accompanies its administration. This requires large and sustained doses of N5A to control symptoms, for example in the treatment of arthritis.
This poses a particular problem when ID must be administered.

When a combination of β-adrenergic mulberry and a histamine receptor blocker selected from the group consisting of histamine H1-1H2-receptor blockers and mixtures thereof is administered simultaneously with N5AID, the induced gastrointestinal damage is significantly reduced compared to NSA. It was found that

As pointed out in U.S. Pat. No. 4,996,571, Hz- and Hz-receptor blockers are two well-known classes of blockers of histamine that act as blockers of histamine at Hl- and H,- receptor sites, respectively. They form a group of pharmacologically active drugs. Histamine receptor sites have been classified based on the group of antihistamines that can act to block these sites. The fact that a drug is identified as an antihistamine does not necessarily mean that it is effective in blocking all known histamine receptor sites, but may be selective in nature, resulting in One part, for example H
, but not at other sites, such as the H2 site.

In the prior art, Hz-receptor blockers have been reported to protect against aspirin-induced damage in some fed animals. One of these studies is reported in Gastroenterology, Volume 88, No. 5, Part 2, Page 1344. It has also been reported that cyprohebutadine has been evaluated as a protective agent against aspirin-induced gastrointestinal injury [Indian, J., Met.

Shiy, (Indian J, Mad, Re@,), 1
980, 71, pp. 926-32]. Sibroheptadine has some H14 receptor antagonism, but this does not act only at the HI receptor site;
Rather, it acts to preferentially block serotonin receptor sites (Goodman and Giman, The Pharmacological Basis of Therapeutics).
armaceutical Ba5is of The
rapeutics), 7th edition, page 1344.

Apart from the foregoing, the present invention differs more significantly from the teachings in the Indian Journal. The first example in this document is that aspirin and cyprohebutadine are not co-administered, as in the present invention. Furthermore, treatment with sibrohebutadine in this document was reported not to alter the acidity of gastric fluid, contrary to the observations made in connection with the present invention. Furthermore, in this Indian document, cyprohebutadine was administered by intraperitoneal injection prior to intragastric administration of aspirin. On the contrary, the compositions of the present invention are adapted for oral administration, during which administration N5AID and the combination Hl- and Hl-
A z-receptor blocker is being administered concurrently.

Furthermore, the prior art disclosed in the preamble describes the essential features of the present invention, namely histamine H1- and/or
There is no suggestion of the use of β-adrenergic agonists in combination with z-receptor blockers.

Many Hl- and H2-receptor blockers useful for the purposes of the present invention are known in the prior art. Examples of Hl-receptor blockers that can be used in the present invention include the following. Ethanolamines (e.g. diphenhydramine or its hydrochloride; carpinoxamine' or its maleate); ethylenediamines (e.g. triberenamine or its hydrochloride or citrate); alkylamines (e.g. chlorpheniramine or its maleate); maleate, prompheniramine or its maleate);
and piperazine (eg, hydroxyzine or its hydrochloride or pamoate salt, cyclizine or its hydrochloride or milk salt, etc.). Examples of H2-receptor blockers that can be advantageously used in the practice of the present invention include the following: cimetidine, ranitidine, famotidine, and the like.

H8- and H2-receptor blockers may be used in their base form or in the form of their pharmaceutically acceptable salts. When in the form of salts, these salts have common acid moieties such as hydrochloric acid, maleic acid, ascorbic acid, citric acid, and hamoin F (p
ammoic), lactic acid, tartaric acid, etc.

They form a fairly well-defined group of pharmaceutically active compounds characterized by their action on β-adrenergic activity and by stimulating β-adrenergic receptor sites. These receptor sites are of two types, termed β1 and β2 sites. Acts at either or both types of β-adrenergic sites.

Numerous beta-adrenergic agents are known in the art that are useful for the purposes of the present invention. Of particular interest is β2
The agonist terbutaline
). Examples of other β-adrenergic agents that can be used in the present invention include the following. Ingloterenol, metaproterenol, and albutyrol. Any of these can be used by itself or as a pharmaceutically acceptable salt.

N5AID#-i also forms a well-known group of drugs that are anti-inflammatory analgesics. These have the common property of inhibiting the formation of prostaglandins, which have a protective effect on the gastrointestinal mucosa. See Gutdman and Gilman, The Pharmacological Basis for Therapeutics, 7th edition, p. 678. It is because of this inhibitory effect that oral administration of this group of drugs tends to result in gastrointestinal injury and/or bleeding, a problem that the present invention seeks to reduce or eliminate. At least in part.

Many N5AIDs are known in the prior art to which the present invention can be applied. The most commonly known group is the salicylates, with aspirin being the most important example. Another group of N5AIDs that have utility in connection with the present invention are zolopionic acid derivatives. This group includes, for example, ibuprofen and naproxen. A further group of N5AIDs that can be used in the present invention are compounds that are very similar in structure to zenamate. These can be exemplified by compounds such as mefenamic acid, sodium metallofenamic acid and diclofenac and its sodium salt. In addition, as those belonging to the N5AID group to which the present invention relates, indole derivatives (e.g., indomethacin),
Examples include pyrrole alkanoic acid derivatives (eg, tolmetin); pyrazolone derivatives (eg, phenylbutacin); oxicams (eg, piroxicam); and the like.

In the practice of the present invention, it is contemplated that N5AID, beta-adrenergic and histamine-receptor blockers are administered simultaneously in conventional product form. Essential ingredients of such products are histamine H1- and/or H1-receptor blockers, β-adrenergic agonists and NSAIDs. In addition to this, these products are available in special dosage forms of the product such as tablets, capsules, powders,
It may also contain other ingredients depending on the amount, such as a suspending agent.

The amount of Hl-receptor blocker contained in the compositions of the invention can vary slightly. All that is required is that an effective amount exist so that the H,-receptor blocker can make its contribution as a protective agent against N5AID-induced gastrointestinal damage.

Similarly, the amount of the composition of the invention may also vary. Again, all that is required is that the buds used be in an effective amount to enable the H2-receptor blocker to perform its role as a protective agent.

The amount of β-adrenergic agonist contained in the compositions of the invention can vary. Again, all that is required is that it be present in an amount sufficient to act as a protective agent for N5AID-induced gastrointestinal damage when used in conjunction with the other active ingredients forming part of the compositions of the present invention. That's what I'm doing.

N5AID Fi is included in the compositions of the invention at concentrations commonly present in therapeutic N5AID compositions intended for oral administration. This is usually a pharmaceutically acceptable analgesic/anti-inflammatory dose.

N5AID, β-adrenergic agonist and histamine H,- and/or H2 contained in the product of the invention
- The quantitative relationship of receptor blockers can be expressed in terms of the average daily dose of these components, for example Cape/Kf/day. These relationships are shown in Table I below, with quantitative and preferred ranges specified therein. The range specified for histamine H1- and H2-receptor blockers is Hl
Or, it is the range to be screened when using an H2 blocker. When using a combination of Hl and H2 blockers, adjust the amount of each included in the product.

Table ■ N5AID 1□-100□15≠1-75□ Single dose forms for the present invention are formulated for conventional oral administration. The range of amounts of each component is listed in Table 3 below. The ranges specified for histamine H1- and H2-receptor blockers are the ranges applicable when using H1 blockers or H2 blockade systems. When using a combination of Hl and H2 blockers, adjust the t of each in the product.

Table ■ N5AID 200■-600111iJβ-
Adrenergic agent 0.7η-70 Histamine H8-receptor blocker (when used) 0.01
++v-70 ■ Histamine H2-receptor blocker (when used)
Depending on the dosage form used, the products of the invention may also contain other adjuvants useful in formulating or administering the particular dosage form. Thus, for example, when administered as a tablet, the product of the invention may contain lubricants, additives, binders, disintegrants, flavoring agents, and the like. In addition, these products may contain other pharmaceutically active ingredients, such as decongestants, analgesics, expectorants, antitussives, diuretics, other analgesics, other anti-inflammatory agents, antipyretics, antirheumatic agents, It may contain antioxidants, vasodilators, smooth muscle relaxants, skeletal muscle relaxants, bronchodilators, vitamins, trace minerals, amino acids and biological peptides.

As indicated in the preamble, the products of the invention may be in the form of tablets. However, the toner may also be formulated as a caplet or in the form of a powder or granules in an ingestible capsule, such as a gelatin capsule. The products of the invention also contain the active ingredients in a suitable liquid medium. The drug may be prepared as a liquid or alternatively as a powder packed in suitable paper packets.

Next, the present invention will be explained in more detail with reference to Examples. However, it is clear that the invention is not limited to these examples.

Example 1 Aspirin 325 119 Diphenhydramine Hydrochloride 16.67q The above ingredients are mixed in powder or granule form and filled into gelatin capsules.

Example 2 Aspirin 325 1119 Ranitidine Hydrochloride 3.331Ni Example 1
Prepared as described in .

Example 3 Aspirin 325 11q Metaproterenol peach salt 01831N? Prepared as described in Example 1.

Dosage 2 capsules every 4 hours as needed. Do not exceed 8 capsules in 24 hours and do not administer to children below t7'c12 o unless directed by a physician.

The following experiments were conducted to test the effectiveness of the combination of a β-adrenergic agonist and a histamine Hw-F'1Hz-receptor blocker in protecting against N5AID-induced gastrointestinal damage. In these studies, the histamine H1-receptor drug used was diphenhydramine, which was used in its hydrochloride form. The histamine H2-receptor blocker used was ranitidine;
It was also used in the form of its hydrochloride. The illustrative beta-adrenergic agonist of the invention used in this study was terbutaline. This product was used as a base.

A standard dose of aspirin, 975η, is administered orally to obtain pincer marks of gastrointestinal injury. Histamine H, - and H
2-receptor blockers and β-adrenergic agonists with the standard dose of aspirin, 975■; - For comparison with the stimulation results obtained in combination with receptor blockers, the stomach lining of the dogs tested separately is examined with an endoscopic cast and the degree of damage is assessed.The results are presented below. The methodology is shown in the table.

All test formulations are prepared on the day of the test. Place the capsule in the back of your dog's throat. A gastric catheter with a funnel is placed in the dog's stomach and 50 ml of deionized water is administered.

Select a healthy male or female peagle for testing.

Dogs are housed individually in stainless steel cages with a grid floor to allow waste to pass through.
Maintain 5 to 85 below and relative humidity 30 to 80%. Murogen will be lit from 6 a.m. to 4 p.m.

Each dog is trained to stand on a sling frame and to accept a bit tied to its mouth. Insert the endoscope into the dog's mouth through the bit.

This training takes 10 days to 2 weeks for most dogs.

To determine whether a dog is suitable for the purpose of the study, its stomach should be examined for normal mucosa and its N5AID
Assess the pre-reactivity to (as in the section on test procedures).

Acceptable dogs must have a cavity gastric irritation score of 5 or higher 2 hours after dosing. Food must be removed from the dog for 24 hours before and during the test.
And drink water as needed. Move the dog to a restraining area away from the kennel. The male fc examines a fasted female dog with an endoscope to confirm that the stomach lining has a normal and healthy mucosal lining. Dogs are dosed orally with the test formulation and flushed with 50 tons of deionized water. Then re-examine gastric petechiae and other bleeding signs after 2 and 4 hours according to the following criteria.

0 = uniform, pale to basic pink mucosa 1 = darker pink or blotchy mucosa 2 = petechiae and/or bright red streaks 3 = few small lesions 4 = numerous creases or Connected small lesions (striae) 5=few large lesions 6=many large lesions 7=large hemorrhagic lesions The degree of injury at each treatment and each time is calculated as an average gastric irritation score.

In addition to endoscopic observations of each dog's gastric mucosa, the quantitative characteristics of the gastric fluid are recorded and the pH of the gastric fluid is measured.

All of these are conducted 2 hours after administration of the test compound.

A baseline is established by measuring various parameters after administering Aspirin 975■ alone. A normal helmet at rest has an irritation score of O and a pH of 5-5.5. Aspirin produces lesions with a score of about 5.6 after 2 hours, and the solution pH at this point is about 3.1.

Table ■ Aspirin 975 Cape 8 5.
5 3.3 Terbutaline 1.29η + Aspirin 9
75mp 4 4.0 191 2.5
0 Cape + I 975 Cape 4 ZO3,8〃
5.0ωη+ 975 Cape 8 1.4
4. Otr 10.0■+p 975*
5 1.2 4.6 Diphenhydramine 12.
5+η+aspirin 975Hi4 5.5
1.47F 25.0■+ 〃975ni4
5.75 2. ．． 1# 50.0■+
〃975η 44゜03.650■+Asbiri: /9
7F)+Iv Table ■

Claims (1)

[Claims] 1. Anti-inflammatory amount of non-steroidal anti-inflammatory agent, and β-
Adrenergic agents and histamine H_1-receptor blockers and histamine H_2-receptor blockers and histamine H_1-receptor blockers and histamine H_2-
A non-steroidal anti-inflammatory composition having reduced efficacy against gastrointestinal injury characterized in that it includes a protective amount of a protective agent consisting of a histamine receptor blocking component selected from the group consisting of combinations of receptor blockers. . 2. The histamine-receptor blocking component is histamine H_
The composition according to claim 1, which is a 1-receptor blocker. 3. The composition according to claim 2, wherein the non-steroidal anti-inflammatory agent is aspirin or ibuprofen. 4. The composition according to claim 3, wherein the non-steroidal anti-inflammatory agent is aspirin. 5. The β-adrenergic agent is terbutaline and a pharmaceutically acceptable salt thereof, and the histamine H_1-receptor blocker is diphenhydramine or a pharmaceutically acceptable salt thereof. Composition according to item 4. 6. A composition according to any one of claims 1 to 5, wherein the amount of each component present is sufficient to provide an average daily dose of the various components: (a) the non-steroidal anti-inflammatory agent, about 10-100 m
g/Kg/day, (b) the β-adrenergic agonist, about 0.30 μg/day;
Kg/day to about 500 mg/Kg/day, (c) the histamine H_1-receptor blocker, about 2.5
μg/Kg/day to about 500 mg/Kg/day. 7. A composition according to any one of claims 1 to 5, wherein the amount of each component present is sufficient to provide an average daily dose of the various components: (a) the non-steroidal anti-inflammatory agent, about 10-75 mg;
/Kg/day, (b) the β-adrenergic agonist, about 0.01-10
mg/Kg/day, (c) the histamine H_2-receptor blocker, about 0.1
-50mg/Kg/day. 8. The composition according to any one of claims 1 to 5, which is in a daily dosage form and contains the following ingredients per daily dose: (a) the non-steroidal anti-inflammatory agent, about 200-600
mg, (b) said β-adrenergic agonist, about 0.7-
70 mg, (c) about 0.01-70 mg of said histamine H_1-receptor blocker. 9. The histamine-receptor blocking component is histamine H_
2. The composition according to claim 1, which is a 2-receptor blocker. 10. The composition according to claim 9, wherein the non-steroidal anti-inflammatory agent is aspirin or ibuprofen. 11. The composition according to claim 10, wherein the non-steroidal anti-inflammatory agent is aspirin. 12. Claim 11, wherein the β-adrenergic agent is terbutaline or a pharmaceutically acceptable salt thereof, and the histamine H_2-receptor blocker is ranitidine or a pharmaceutically acceptable salt thereof. Composition of. 13. The composition of any one of claims 9 to 12, wherein the amount of each component present is sufficient to provide an average daily dose of the various components: (a) The non-steroidal anti-inflammatory drug, about 10-100 mg
/Kg/day, (b) the β-adrenergic agonist, about 0.30 μg/day;
Kg/day to about 500 mg/Kg/day, (c) the histamine H_2-receptor blocker, about 10μ
g/Kg/day to about 1 g/Kg/day. 14. The composition of any one of claims 9 to 12, wherein the amount of each component present is sufficient to provide an average daily dose of the various components: (a) the non-steroidal anti-inflammatory agent, about 15-75 mg;
/Kg/day, (b) the β-adrenergic agonist, about 0.01-10
mg/Kg/day, (c) the histamine H_2-receptor blocker, about 0.0
1-10mg/Kg/day. 15. The composition according to any one of claims 9 to 12 in a daily dosage form containing the following ingredients per daily dose: (a) the non-steroidal anti-inflammatory agent, about 200-600
mg, (b) said β-adrenergic agonist, about 0.7-
70 mg, (c) about 0.5-350 mg of said histamine H_2-receptor blocker.