JP2586922B2 - Non-steroidal anti-inflammatory compositions protected against gastrointestinal tract damage by combination of certain H1 and H2 receptor blockers - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to NSAID compositions containing a protective agent against gastrointestinal damage caused by non-steroidal anti-inflammatory drugs (hereinafter referred to as NSAIDs). More particularly, the present invention relates to compositions of the type described above which use certain combinations of histamine receptor blockers as protective agents. The compositions of the present invention are useful for the treatment of conditions and conditions that have been treated by the classical administration of NSAIDs, such as pain and inflammation associated with headache, arthritis and other systemic diseases, increased body temperature, and the like.

Aspirin and other NSAIDs have been the most popular drugs for the treatment of individual pain, inflammation and fever for many years. However, one of the drawbacks is gastrointestinal tract damage and / or bleeding that is sometimes associated with its administration. This is a particular problem when large and sustained doses of NSAID must be administered to control the symptoms, for example, in the treatment of arthritis.

The combination of histamine receptor blocker, especially when a combination of H ₁ and H ₂ receptor blockers to NSAID administered simultaneously, NSA
It was found that ID-induced gastrointestinal damage was significantly reduced.

As pointed out in U.S. Pat. No. 4,996,571, H ₁
- and H ₂ - receptor blocker, H ₁ - and H ₂ - to form a group of apparent pharmacologically active drug at the receptor sites in the two known which act as blockers of histamine, respectively I have. 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 means that it is necessarily effective at blocking all known histamine receptor sites, but that it may in fact be selective, acting at one site for example H ₁ site, but do not act at other sites such as H ₂ site.

In the prior art, H ₂ - receptor blockers in certain laboratory animals have been reported to protect against aspirin-induced damage. One of the studies is Gastroenterology, Vol. 88, No. 5, Part 2, 13
It is reported on page 44. It has also been reported that cyproheptadine has been evaluated as a protective agent against aspirin-induced gastrointestinal damage [Indian J. Med. Res (Indian J. Med. Res.), 1980, 71, 926-32
page〕. Cyproheptadine Some H ₁ - has the receptor antagonism, this thing is not to act limited connexion to H ₁ receptor site, acts rather to block serotonin receptor sites preferentially I do.

Apart from the above points, the present invention differs significantly from the teachings in the Indian Journal. To give one example in this document, aspirin and cyproheptadine are not co-administered as in the present invention. Furthermore, treatment with cyproheptadine in this document is reported not to alter the acidity of gastric juice, contrary to the observations made in connection with the present invention. Furthermore, in the Indian literature, cyproheptadine was administered by intraperitoneal injection prior to intragastric administration of aspirin. In contrast, the compositions of the present invention have been adapted for oral administration, NSAID and combined H ₁ during the administration - and H ₂ - are coadministered receptor blockers.

As further detailed below, Yotsute to using the further certain combinations of an H ₁ and H ₂ histamine receptor blockers, as defined in the text, these two things NSAID
It has been found to act synergistically in the protective effect against induced gastrointestinal damage. This is an unexpected result and is not expected based on the state of the art.

Known useful H ₁ and H ₂ receptor blockers are numerous prior art for the purposes of the present invention. However, H ₁ and all even必et sushi receptor blockers is not equally effective in the practice of the present invention. Effective must also show anticholinergic effects.

H ₁ which can be used in the present invention - To illustrate receptor blockers,
These include: Ethanolamine (eg, diphenhydramine or its hydrochloride; carbinoxamine or its maleate); Ethylenediamine (eg, tripelamine or its hydrochloride or citrate); Alkylamine (eg, chlorphenila) And / or piperazine (eg, hydroxyzine or its hydrochloride or pamoate salt, cyclidine or its hydrochloride or lactate, etc.). H that can be advantageously used in the practice of the present invention ₂ - include the following can be cited as illustrative of the receptor blockers. Cimetidine, ranitidine, famotidine and the like.

In general, any combination of H ₁ and H ₂ receptor blockers as described above are useful for purposes of the present invention. However, it has been found H ₁ and H ₂ receptor blockers certain combinations are particularly effective. That is, chlorpheniramine plus ranitidine diphenhydramine plus
The combination of ranitidine, chlorpheniramine plus cimetidine and diphenhydramine plus cimetidine is the combination of choice in the present invention.

The H ₁ -and H ₂ -receptor blockers may be used in their base form or in the form of their pharmaceutically acceptable salts. When used as salts, these usually have an acid moiety of hydrochloric acid, maleic acid, ascorbic acid, citric acid, pamoic acid (pamoic acid).
ic), lactic acid, tartaric acid and the like.

NSAIDs also form a well-known class of drugs that are anti-inflammatory analgesics. They have a common property of inhibiting the formation of prostaglandins having a protective action on the gastrointestinal mucosa. Goodman and Gilma
n), "The Pharmacological Basis Foa.
Therapeutics ”(“ The pharmacological Basis
for Therapeutics "), 7th edition, page 678. The propensity of this group of drugs to cause gastrointestinal tract damage and / or bleeding is due to this inhibitory effect, and The present invention is at least part of the problem sought to be reduced or eliminated.

Many NSAIDs to which the present invention can be applied are known in the prior art. The most commonly known group is salicylate, with aspirin being the most important example. Another group of NSAIDs that have utility in connection with the present invention are propionic acid derivatives. This group includes, for example, ibuprofen and naproxen. Yet another group of compounds that can be used in the present invention
NSAIDs are phenamates and compounds that are very similar in structure. These can be exemplified by compounds such as, for example, mefenamic acid, sodium meclofenamic acid and diclofenac and its sodium salt. The NSAIDs related to the present invention include indole derivatives (eg, indomethacin), pyrrole alkanoic acid derivatives (eg, tolmetin); pyrazolone derivatives (eg, phenylbutazone); oxicams (eg, piroxicam); .

In the practice of the present invention, NSAIDs and histamine-
It is contemplated that the receptor blocker will be administered simultaneously in the usual product form. The essential components of such products are histamine H ₁ -and / or H ₂ -receptor blockers, and
NSAID. In addition, these products may contain other ingredients which vary widely depending on the particular dosage form of the product, such as tablets, capsules, powders, suspensions and the like.

The amount of H ₁ -receptor blocker contained in the composition of the present invention can vary slightly. All that is required is that an effective amount be present, whereby the H ₁ -receptor blocker
It can make its contribution as a protective agent against NSAID-induced gastrointestinal damage.

Similarly, the amount of the composition of the present invention may also vary. again,
All that is required, the amount used is H ₂ - is that it is an effective amount to allow to play the role of receptor blockers as a protective agent.

The amount of β-adrenergic agent contained in the composition of the present invention can vary. Again, all that is required is that it is present in an amount sufficient to act as a protective agent against NSAID-induced gastrointestinal damage when used with other active ingredients that form part of the compositions of the present invention. It is doing.

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

NSAID contained in the product of the present invention, and histamine H ₁
- and H ₂ - Quantitative relationship receptor blockers can be expressed Te cowpea these components mean daily dose for example mg / body weight kg / day. In this case, the average daily dose for the components has a numerical value in the range shown in the following table.

The daily dosage form of the product of the invention is formulated for normal oral administration. The daily dose of each is about 200-600 mg of NSAID, H
₁ receptor blocker about 0.1-70mg and H ₂ receptor blockers 0.5
It is about 350 mg. In formulating these products, pharmaceutically acceptable doses of the components within the above ranges are used.

Depending on the dosage form used, the product of the invention may also contain other adjuvants useful for formulating or administering a particular dosage form. So, for example, when administered as a tablet,
The products of the present invention may contain lubricants, additives, binders, disintegrants, flavors and the like. In addition, these products may contain other pharmaceutically active ingredients such as depressants, analgesics, expectorants, antitussives, diuretics, other analgesics, other anti-inflammatory, antipyretic, antirheumatic agents. , Antioxidants, vasodilators,
It may contain smooth muscle relaxants, skeletal muscle relaxants, bronchodilators, vitamins, trace minerals, amino acids and biological peptides.

The product of the present invention can take various forms. As indicated in the preamble, the product of the invention may be in the form of a tablet. However, it may be filed NSAID and H ₁ and H ₂ receptor blocker in or ingestible capsule such as gelatin capsule in NyuTsuta powder or granules. The products of the present invention may also be prepared as suspensions or solutions of the active ingredients in a suitable liquid medium, or alternatively as powders in suitable paper packets.

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

Example 1 Aspirin 325 mg Ranitidine hydrochloride 3.33 mg Chlorpheniramine maleate 3.33 mg The above ingredients are mixed in powder or granular form and filled into gelatin capsules.

Example 2 Aspirin 325 mg Cimetidine hydrochloride 16.67 mg Chlorpheniramine maleate 3.33 mg Prepared as described in Example 1.

Example 3 Aspirin 325 mg Cimetidine hydrochloride 3.33 mg Diphenhydramine hydrochloride 16.67 mg Prepared as described in Example 1.

NSAID-To protect the stomach against induced gastrointestinal damage,
Histamine H ₁ - and H ₂ - to test the effectiveness of the combination of receptor blockers, and separate H ₁ - and H ₂ - for comparison with some protection obtained Te cowpea receptor blockers, the following The experiment was performed. In these studies, H ₁ and H ₂ receptor blockers used in the form of the following salts. That is, ranitidine
HCl, diphenhydramine HCl, chlorpheniramine maleate, cimetidine HCl. Standard dose of aspirin 975mg
Is orally administered to dogs together with the following treatments (a) to (h). The dog's allogeneic wall is examined endoscopically and evaluated for damage. The results are tabulated according to the methodology described below.

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

Adult male or female beagle dogs are selected for testing. The dogs are individually housed in stainless steel gauges on the grid floor to allow the passage of waste. Room and laboratory room temperatures are maintained between 65 ° F. and 85 ° F. and 30% -80% relative humidity. The room lights will be on from 6 am to 4 pm.

Each dog is trained to stand on a stanchion bar with a strap support and to accept a hook tied to its mouth. Insert the endoscope into the dog's stomach through the hook. This training takes 10 days to 2 weeks for most dogs.

To determine whether a dog is suitable for the purpose of the test,
The stomach is examined for normal mucosa and the stomach reactivity to the NSAID is evaluated (as in the test procedure). Acceptable dogs must have a cavity gastric irritation score of 5 or more 2 hours after dosing.

Remove food from the test dog 24 hours before the test and during the test,
And water is taken as appropriate. Move the dog to a restraint area that has been separated from the kennel. Male or female fasted dogs are examined endoscopically to confirm that the stomach lining has normal, healthy mucosal lining. Dogs are dosed orally with the test formulation, which is flushed into the stomach with 50 ml of deionized water. Then, after 2 and 4 hours, reexamine for gastric petechiae and other signs of bleeding according to the following criteria.

0 = uniform, pale to dark pink mucosa 1 = darker pink or spotty mucous membrane 2 = petechiae and / or bright red streaks 3 = few small injuries 4 = many or connected Minor injury (linear) 5 = small major injury 6 = many major injury 7 = major hemorrhagic injury The extent of injury at each treatment and at each time is calculated as the average gastric stimulation score.

In addition to the endoscopic observation of the gastric mucosa of each dog, the quantitative characteristics of the gastric fluid are recorded and the pH is measured on the gastric fluid. These are all performed 2 hours after administration of the test compound.

Baseline is established by measuring various parameters after administration of 975 mg aspirin alone. A resting normal stomach has a stimulation score of 0 and a pH of 5-5.5. Aspirin alone produces a lesion of about 5.6 score after 2 hours, at which point gastric pH is about 3.1.

After 4 hours, these values are 4.0 for the stimulator and the pH is about 4.7. This indicates that a certain amount of healing occurred between the second and fourth hours after administration.

The results of these tests are summarized in the table below for the 2-hour damage data.

Inspection of these data, as compared to when used alone H ₁ or H ₂ receptor blocker, respectively, H ₁ and
A combination of H ₂ receptor blocker understood that the protection by synergistic significantly greater when used in conjunction with aspirin can be obtained.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Randy J. Coslo East Windsor Edison Drive 605, New Jersey, USA 605

Claims (8)

(57) [Claims] 1. An analgesic or anti-inflammatory amount of a non-steroidal anti-inflammatory drug (NSAID) selected from the group consisting of aspirin and a pharmaceutically acceptable salt thereof; and (b) (i) diphenhydra An H ₁ receptor blocker selected from the group consisting of min and pharmaceutically acceptable salts thereof; and (ii) an H ₂ receptor selected from the group consisting of cimetidine, ranitidine, famotidine and pharmaceutically acceptable salts thereof. A nonsteroidal anti-inflammatory composition comprising a protective amount of a body-blocking agent. 2. The composition according to claim 1, wherein the H ₂ receptor blocker is ranitidine or a pharmaceutically acceptable salt thereof. 3. The composition according to claim 1, wherein the H ₂ receptor blocker is cimetidine or a pharmaceutically acceptable salt thereof. Wherein H ₂ receptor blockers famotidine or composition range set forth in claim 1, wherein the pharmaceutically acceptable Patent salts claims. 5. A composition based on the weight of the patient to be administered, NSAID is present in an amount of about 10-100 mg / kg / day, H ₁ receptor blockers about 2.5μg- about 500 mg / kg _2. The composition of claim 1, wherein the H2 receptor blocker is present in an amount of about 10 [mu] g to about 1 g / kg / day. 6. NSAID is present in an amount of from about 200-600, present in an amount of from about 0.1-70mg is H ₁ receptor blockers, and present in an amount of H ₂ receptor blocker about 0.5-350mg A composition according to claim 1 wherein 7. NSAID is aspirin 975 mg, H ₁ receptor blockers are Ziv-ene Hydra Min HCl 50 mg, and H ₂
3. The composition according to claim 2, wherein the receptor blocker is 10 mg of ranitidine HCl. 8. NSAID is aspirin 975 mg, a H ₁ receptor blockers Ziv ene Hydra Min HCl 50 mg, and H ₂
4. The composition according to claim 3, wherein the receptor blocker is cimetidine HCl 50 mg.