Effect of a combination of a terbutaline, diphenhydramine and ranitidine composition on gastrointestinal injury produced by nonsteroidal anti-inflammatory compositions

Pharmaceutical composition and process for administering NSAIDs with a combination of beta-adrenergic agonist and certain H.sub.1 -and H.sub.2 -receptor blockers which protect against injury to the gastrointestinal tract. Said composition being terbutaline, diphenhydramine and ranitidine.

This invention relates to nonsteroidal anti-inflammatory compositions 
containing, as protectants against gastrointestinal injury caused by said 
nonsteroidal anti-inflammatory drugs (hereinafter referred to as NSAID), 
combinations of a beta-adrenergic agonist and histamine-receptor blockers 
selected from the group consisting of H.sub.1 -and H.sub.2 -blockers and 
mixtures thereof. The compositions of this invention are useful in 
treating conditions and symptoms that are classically treated by the 
administration of NSAIDS, e.g., headache pain, pain and inflammation 
associated with arthritis and other systemic diseases, elevated body 
temperatures. 
Aspirin and other NSAIDs have long been the most popular drugs for the 
management of pain, inflammation and fever in individuals. However, one of 
the drawbacks is the gastrointestinal injury and/or bleeding that 
sometimes accompanies their administration. This becomes a particular 
problem where large and sustained doses of NSAIDs must be given to control 
the symptoms, as for example, in the case of the management of arthritis. 
It has now been found that NSAID-induced gastrointestinal injury can be 
significantly reduced when a combination of a betaadrenergic agonist and a 
histamine-receptor blocker selected from the group consisting of histamine 
H.sub.1 -, H.sub.2 -receptor blockers and mixtures thereof is administered 
concurrently with said NSAID. 
As pointed out in U.S. Pat. No. 4,496,511, H.sub.1 - and H.sub.2 -receptor 
blockers form two well-known and distinct classes of pharmacologically 
active drugs that serve as blocking agents for histamine at H.sub.1 - and 
H.sub.2 - receptor sites, respectively. Histamine-receptor sites have been 
differentiated on the basis of the classes of antihistamines that can 
serve to block these sites. The fact that a drug is identified as an 
antihistamine does not necessarily mean that it will be effective in 
blocking all the known histamine-receptor sites but may, in fact, be 
selective so that it will act at one site e.g. H.sub.1 site but not at 
another, e.g., H.sub.2 site. 
It has been reported in prior art that H.sub.2 -receptor blocking agents 
protect against aspirin-induced lesions in certain laboratory animals. One 
such study is reported in Gastroenterology Vol. 88, No. 5 part 2. p. 1344. 
It has also been reported that cyproheptadine has been evaluated as a 
protectant against aspirin-induced gastrointestinal injury (Indian J. Med. 
Res. 1980, 71, p. 926-32). Although cyproheptadine may have some H.sub.1 
-receptor antagonist properties, it does not act exclusively at the 
H.sub.1 -receptor sites but rather acts predominantly to block the 
serotonin receptor sites. (Goodman and Gilman, "The Phamacological Basis 
of Therapeutics," Seventh Edition, p. 634). 
Aside from the above, the present invention has further significant 
distinctions from the teachings in the Indian Journal. For one thing in 
this reference the aspirin and the cyproheptadine are not coadministered, 
as would be the case in the present invention. Furthermore, the treatment 
in this reference with cyproheptadine is reported as not modifying the 
gastric acidity and is contrary to the observations made in connection 
with the present invention. Moreover, in the Indian, reference the 
cyproheptadine was administered by intraperitoneal injection prior to the 
intragastric administration of the aspirin. In contrast, the compositions 
of the present invention lend themselves to oral administration, at which 
time the NSAID and the combination H.sub.1 - and H.sub.2 -receptor 
blockers are coadministered. 
Moreover, there is nothing in the prior art cited above to suggest the 
essential feature of the present invention, namely the use of the 
combination of a beta-adrenergic agonist along with the histamine H.sub.1 
-and/or H.sub.2 -receptor blockers. 
Numbers of H.sub.1 -and H.sub.2 -receptor blockers are known in the prior 
art which are useful for the purposes of the present invention. By way of 
illustrating the H.sub.1 -receptor blockers that may be employed herein, 
mention may be made of the following: ethanolamines (e.g. diphenhydramine 
or its hydrochloride salt; carbinoxamine or its maleate salt); 
ethylenediamines (e.g. tripelennamine or its hydrochloride or citrate 
salts); alkylamines (e.g. chlorpheniramine or its maleate salt, 
brompheniramine or its maleate salt); and piperazines (e.g. hydroxyzine or 
its hydrochloride or pamoate salts, cyclizine or its hydrochloride or 
lactate salts, etc.). To exemplify the H.sub.2 -receptor blockers that may 
be advantageously used in the practice of this invention, the following 
are given: cimetidine, ranitidine, famotidine. 
The H.sub.1 -and H.sub.2 -receptor blockers may be used in the form of 
their bases or in the form of their pharmaceutically acceptable salts. 
When employed as salts, these will usually be acid-addition salts wherein 
the acid portion may be hydrochloric, maleic, ascorbic, citric, pamoic, 
lactic, tartaric, etc. 
The beta-adrenergic agonists also form a fairly well-defined class of 
pharmaceutically effective compounds that are characterized by the fact 
that they act by stimulating betaadrenergic receptor sites. These receptor 
sites are of two types, referred to as the .beta..sub.1, and .beta..sub.2 
sites. Beta-adrenergic agonists may act on one or the other or on both 
types of sites. 
Numerous beta-adrenergic agonists are know in the prior art which are 
useful for the purposes of this invention. Of special interest is 
terbutaline which is a .beta..sub.2 agonist. By way of illustrating other 
beta-adrenergic agonists that may be employed herein, the following are 
given: isoproterenol metaproterenol, and albuterol. All of these may be 
employed as such or as pharmaceutically acceptable salts. 
The NSAIDs also form a well-known class of drugs that are anti-inflammatory 
analgesics. These have the common property of inhibiting the formation of 
prostaglandins which have a protective affect on the gastrointestinal 
mucosa. See Goodman and Gilman "The Pharmacological Basis for 
Therapeutics" 7th Edition, p. 678. It is because of this inhibiting effect 
that the oral administration of drugs of this class tends to result in 
gastrointestinal injury and/or bleeding and is at least part of the 
problem that the present invention seeks to reduce or eliminate. 
Numbers of NSAIDs are known in the prior art to which the present invention 
has application. The most commonly known group is the salicylates of which 
aspirin is the prime example. A further group of NSAIDs that has utility 
in connection with the instant invention is the proprionic acid 
derivatives. Included in this group are, for example, ibuprofen and 
naproxen. Still a further group of NSAIDS, employable herein, is the 
fenamates and compounds closely related to them structurally. These may be 
illustrated by such compounds as mefenamic acid, meclofenamate sodium, and 
diclofenac and its sodium salt. Also belonging to the class NSAIDs with 
which the present invention is concerned are the indole derivatives (e.g. 
indomethacin); pyrrole alkanoic acid derivatives (e.g. tolmetin); 
pyrazalone derivatives (e.g. phenylbutazone); oxicams (e.g. piroxicam). 
It is contemplated that in the practice of the present invention the NSAID, 
the beta-adrenergic agonist, and the histamine-receptor blocker or 
blockers will be administered concurrently in a convenient product form. 
The essential ingredients of such products will be the histamine H.sub.1 
-and/or H.sub.2 -receptor blocker, the beta-adrenergic agonist, and the 
NSAID. Over and above this, these products may also contain other 
ingredients which will, to a large extent, depend upon the particular 
dosage form of the product, e.g., tablets, capsules, powders, suspensions. 
The quantity of H.sub.1 -receptor blocker that will be contained in the 
composition of this invention may vary somewhat. All that is required is 
that an effective amount be present so that the H.sub.1 -receptor blocker 
can make its contribution as a protectant against NSAID-induced 
gastrointestinal injury. 
Similarly the quantity of H.sub.2 -receptor blocker in the present 
composition may also vary. Again, all that is required is that the amount 
employed be an effective quantity that will enable the H.sub.2 -receptor 
blocker to play its part as protectant. 
The quantity of beta-adrenergic agonist that will be contained in the 
present composition may vary somewhat. Again, all that is required is that 
it be present in sufficient amount to function as a protectant for 
NSAID-induced gastrointestinal injury when employed with the other active 
ingredients that form part of the composition of this invention. 
The NSAID will be contained in the composition of this invention at 
concentrations at which it is generally found in therapeutic NSAID 
compositions intended for oral administration. This will usually be a 
pharmaceutically acceptable analgesic/ anti-inflammatory dose. 
The quantitative relationship of the NSAID, the beta-adrenergic agonist, 
and the histamine H.sub.1 -and/or H.sub.2 -receptor blockers contained in 
the products of the present invention may be expressed in terms of the 
average daily dose of these ingredients, e.g., mg/kg of body weight/day. 
These relationships are set forth in Table I below, the general and 
preferred ranges being specified therein. The ranges specified for the 
histamine H.sub.1 -and H.sub.2 -receptor blockers are those that apply 
when the H.sub.1 or H.sub.2 blocker is employed. When a combination of the 
H.sub.1 and H.sub.2 blocker is utilized the amount of each contained in 
the product will be adjusted. 
TABLE I 
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General Range Preferred Range 
Ingredient 
lowhigh lowhigh 
__________________________________________________________________________ 
NSAID 10 mg/kg/day-100 mg/kg/day 
15 mg/kg/day-75 mg/kg/day 
Beta-Adrenergic 
0.3 .mu.g/kg/day-500 mg/kg/day 
0.01 mg/kg/day-10 mg/kg/day 
Agonist 
Histamine H.sub.1 - 
2.5 .mu.g/kg/day-500 mg/kg/day 
100 ug/kg/day-500 mg/kg/day 
Receptor Blocker 
(when employed) 
Histamine H.sub.2 - 
10 .mu.g/kg/day-1 g/kg/day 
0.01 mg/kg/day-10 mg/kg/day 
Receptor Blocker 
(when employed) 
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The unit dosage forms for the present invention will be formulated for 
convenient oral administration. The range of the quantities of each 
ingredient is set forth in Table II below. The ranges specified for the 
histamine H.sub.1 -and H.sub.2 -receptor blockers are those that apply 
when the H.sub.1 blocker or the H.sub.2 blocker is employed. When a 
combination of the H.sub.1 and H.sub.2 blockers is utilized the amount of 
each in the product will be adjusted. 
TABLE II 
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UNIT DOSAGE 
INGREDIENT mg/dose 
______________________________________ 
NSAID 200 mg-600 mg 
Beta-Adrenergic 
0.7 mg-70 mg 
Agonist 
Histamine H.sub.1 - 
0.01 mg-70 mg 
Receptor Blocker 
(when used) 
Histamine H.sub.2 - 
0.5 mg-350 mg 
Receptor Blocker 
(when used) 
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Depending upon the dosage form employed, the products of this invention may 
also contain other adjuvants that may be useful in formulating or 
administering the particular dosage form. Thus for example, when 
administered as a tablet, the products of this invention may also contain 
lubricants, excipients, binding agents, disintegrating agents, flavoring 
agents. In addition, these products may also contain other 
pharmaceutically active ingredients such as: decongestants, analgesic 
adjuvants, expectorants, antitussives, diuretics, other analgesics, other 
anti-inflammatory agents, antipyretics, anti-rheumatics, anti-oxidants, 
vasodilators, smooth musclerelaxants, skeletal muscle relaxants, 
bronchodilators, vitamins, trace minerals, amino acids, and biological 
peptides. 
As indicated above, the products of the present invention may assume the 
form of tablets. However, they may also be formulated as caplets or be in 
powdered or granular form contained in edible capsules such as gelatin 
capsules. The present products may also be made up as suspensions or 
solutions of the above ingredients in a suitable liquid medium or as 
powders packaged in suitable paper envelopes.

The following examples are given to further illustrate the present 
invention. It is to be understood, however, that this invention is not 
limited thereto. 
EXAMPLE 1 
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Aspirin 325 mg 
Diphenhydramine hydrochloride 
16.67 mg 
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The above ingredients are mixed in powdered or granular form and loaded 
into gelatin capsules. 
EXAMPLE 2 
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Aspirin 325 mg 
Ranitidine hydrochloride 
3.33 mg 
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Prepared as described in Example 1. 
EXAMPLE 3 
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Aspirin 325 mg 
Metaproterenol sulfate 
0.83 mg 
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Prepared as described in Example 1. 
Dosage 
Two capsules every 4 hours as needed. Do not exceed 8 capsules in 24 hours 
or give to children 12 or under, unless directed by a physician. 
The following experiments were carried out to test the effectiveness of the 
combination of beta-adrenergic agonists with histamine H.sub.1 - or 
H.sub.2 -receptor blockers in protecting the stomach against NSAID-induced 
gastrointestinal injury. In these studies the histamine H.sub.1 -receptor 
blocker employed was diphenhydramine and it was used in the form of its 
HCl salt. The histamine H.sub.2 -receptor blocker utilized was ranitidine 
also employed in the form of its HCl salt. The beta-adrenergic agonist, 
exemplary of the present invention that was used in this test, was 
terbutaline. This was employed as the base. 
A standard dose of 975 mg of aspirin is administered orally to obtain a 
benchmark for gastrointestinal injury. The histamine H.sub.1 - and H.sub.2 
-receptor blockers and the beta- adrenergic agonists were tested 
separately along with the standard dose of 975 mg of aspirin for purposes 
of comparison with the irritation results obtained from the combination of 
the beta-adrenergic agonist with the histamine H.sub.1 - or H.sub.2 
-receptor blocker when the administered with the standard test dose of 975 
mg of aspirin. 
The stomach lining of dogs is examined endoscopically and rated as to the 
degree of injury. The results are summarized in the tables following the 
description of the methodology which is given immediately below. 
All test formulations are prepared on the day of the tests. The capsules 
are placed in the back of the dog's throat. A stomach catheter, with 
funnel attached, is positioned in the dog's stomach and 50 ml of deionized 
water is administered. 
Healthy adult beagle dogs of either sex are selected for testing. Dogs are 
housed individually in stainless steel cages with grid floors to allow 
excreta to pass through. Room temperature in the holding rooms and test 
laboratories is maintained between 65.degree. F. and 85.degree. F. and 
relative humidity between 30% and 80%. Room lights remain on from 6:00 AM 
to 4:00 PM. 
Each dog is trained to stand in a stanchion with sling support and to 
accept a bit tied in its mouth. A gastroscope is then passed through the 
bit into the dog's stomach. This training requires ten days to two weeks 
in most dogs. 
To determine whether a dog is suitable for test purposes, its stomach is 
examined for a normal mucosa, and its gastric responsiveness to NSAID is 
evaluated (as under Test Procedure). An acceptable dog must have a gastric 
irritation score of 5 or greater, in the antrum 2 hours after dosage. 
Food is withheld from test dogs for 24 hours before the test and during the 
test and water is allowed ad lib. The dogs are moved into a holding area 
away from the kennel. Fasted dogs of either sex are examined 
gastroscopically to ensure that their stomachs have normal healthy mucosal 
linings. The dogs are dosed orally with test formulations, which are 
flushed into their stomachs with 50 ml of deionized water. They are then 
re-examined two and four hours later for gastric petechiae and other signs 
of bleeding according to the following scale: 
0=uniform, pale to dark pink mucosa 
1=darker pink or blotchy mucosa 
2=petechiae and/or light red streaks 
3=few small lesions 
4=many or connected small lesions (striations) 
5=few large lesions 
6=many large lesions 
7=massive hemorrhagic damage 
Severity of injury for each treatment and at each time is calculated as the 
mean gastric irritation score. 
In addition to the endoscopic observation of the gastric mucosa of each 
dog, a qualitative description of gastric fluid is recorded and a pH 
measurement is made of the gastric fluid. All of these are done 2 hours 
after administration of the test product. 
A base line is established by measuring the various parameters after the 
administration of 975 mg of aspirin by itself. The resting normal stomach 
has an irritation score of 0 and a pH of 5 to 5.5. Aspirin produces injury 
which scores at approximately 5.6 after 2 hours and the gastric pH at this 
time is about 3.1. 
TABLE III 
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Nonsteroidal Anti-inflammatory Compositions Protected Against 
Gastrointestinal Injury with a Combination of Certain Beta - 
Adrenergic Receptor Agonists and Histamine H.sub.1 -Receptor 
Blocker: 
Data Summary 
2-Hour Data 
Irrita- 
tion 
(N) Score pH 
______________________________________ 
Aspirin 975 mg 8 5.5 3.3 
Terbutaline 1.25 mg + Aspirin 975 mg 
4 4.0 2.9 
Terbutaline 2.50 mg + Aspirin 975 mg 
4 2.0 3.8 
Terbutaline 5.00 mg + Aspirin 975 mg 
8 1.4 4.0 
Terbutaline 10.0 mg + Aspirin 975 mg 
5 1.2 4.6 
Diphenhydramine 12.5 mg + Aspirin 975 mg 
4 5.5 1.4 
Diphenhydramine 25.0 mg + Aspirin 975 mg 
4 5.75 2.1 
Diphenhydramine 50.0 mg + Aspirin 975 mg 
4 4.0 3.6 
Terbutaline 2.5 mg + Diphenhydramine 
4 4.50 2.8 
50 mg + Aspirin 975 mg 
Terbutaline 5.0 mg + Diphenhydramine 
4 1.75 4.4 
25 mg + Aspirin 975 mg 
Terbutaline 5.0 mg + Diphenhydramine 
4 0.0 5.4 
50 mg + Aspirin 975 mg 
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TABLE IV 
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Nonsteroidal Anti-inflammatory Composition Protected Against 
Gastrointestinal Injury with a Combination of Certain Beta- 
Adrenergic Agonists and Histamine H.sub.2 -Receptor Blockers. 
Data Summary 
2-Hour Data 
Irritation 
(N) Score pH 
______________________________________ 
Aspirin 975 mg 8 5.5 3.3 
Terbutaline 1.25 mg + Aspirin 975 mg 
4 4.0 2.9 
Terbutaline 2.5 mg + Aspirin 975 mg 
4 2.0 3.8 
Terbutaline 5.0 mg + Aspirin 975 mg 
8 1.43 4.0 
Terbutaline 10.0 mg + Aspirin 975 mg 
5 1.2 4.6 
Ranitidine 10 mg + Aspirin 975 mg 
6 3.50 5.3 
Ranitidine 20 mg + Aspirin 975 mg 
8 1.88 5.9 
Ranitidine 50 mg + Aspirin 975 mg 
6 0.67 6.1 
Terbutaline 5 mg + Ranitidine 10 mg + 
4 0.0 4.8 
Aspirin 975 mg 
Terbutaline 5 mg + Ranitidine 5 mg + 
4 1.75 4.1 
Aspirin 975 mg 
Terbutaline 2 mg + Ranitidine 5 mg + 
4 1.75 4.3 
Aspirin 975 mg 
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