Note: Descriptions are shown in the official language in which they were submitted.
~3~3~ ~ 5
The Effect of a Combination of a Beta-Adrenergic
Agonist and Certain Histamine Hl- andtor H2
Receptor Blockers on Gastrointestinal Injury
Producsd by Nonsteroidal Anti-Inflammatory
Compositions.
This invention relates to non~teroidal anti-~nflammatory
compositions containing, as protectants against ga trointestin~l
injury cau~ed by said nonstzroidal anti-inflammatory drugs
(hereinafter referred to as NSAID~, combination~ of a beta
adrenergic agonist and hi6t2mine-raceptor blocker6 ~elected from
the group consi6ting of H1-and H2-blockers and mixtures
thereof. The compositions of this invention are useful in
treating condition~ and 6ymptoms that are clas6ically treated by
th~ administration of NSAIDs, e.g., headache pain, pain and
inflammation associated with arthritis ana other sy~temic
diseases, elevated body temperatures, etc.
Aspirin snd other NSAIDs have lony 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. Thi6 becomes a particular
problem where large and sustained doses of NSAIDs must be given
to control the s~mptoms, 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 beta-
adrenergic agonist and a histamine-receptor blocker selected from
the group consisting of histamine Hl-, H2-receptor blockers
and mixtures thereof is administered concurrently with said
NSAID.
~r~!3~
An aspect of this invention is as follows:
A nonsteroidal anti-inflammatory composition having
reduced potential for gastrointestinal injury comprising
an anti-inflammatory amount of a nonsteroidal anti-
inflammatory agent acting synergistically with a
protective amount of a protectant comprising a beta-
adrenergic agonist and a ~istamine receptor blocking
component selected from the group consisting of histamine
Hl-receptor blockers, and histamine H2~receptor blockers,
and a combination of histamine Hl- and H2-receptor
blockers.
As pointed out in U.S. Patent 4996571, Hl-and H2-
receptor blockers ~orm two well-known and distinct
classes of pharmacologically active drugs that serve as
hlocking agents for histamine at Hl- and H2- receptor
sites, respectively. Histamine-receptor sites have been
differentiated on the basis of the classas of
antihistamines that can serve to block thesa sites. The
fact that a drug is identified as an antihistamine
-la-
~3 ,
`` ;~3~
does not nece6sarily mean that it will be effective in blocking
all the known histamine-receptor ~ites but may, in fact, be
selective so that it will act at one site e.g. Hl site but not
At another, e.g., ~2 site.
It has been reported in prior art that H2-receptor blocking
agent6 protect against aspirin-induced lesions in certain
laboratory animals. One such ~tudy 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 gastrointe6tinal injury
(Indian J. Med. Res. 1980, 71, p. 926-32). Although
cyproheptadine may have some Hl-receptor antagonist properties,
it does not act exclusively at the Hl-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 Hl- and H2-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 H1-and/or H2-receptor blockers.
-- 2 --
~3~ 3~;i
Numbers of Hl-and H2-receptor blockers are known in the
prior art which are useful for the purposes of the present
invention. By way of illustrating the H1-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
H2-receptor blockers that may be advantageously used in the
practice of this invention, the following are given: cimetidine,
ranitidine, famotidine, etc.
The Hl-and H2-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 beta-
adrenergic receptor sites. These receptor sites are of two
types, referred to as the,~ , and ~ 1 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 ~ 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.
3~3~
The NSAIDs al60 form a well-known class of drugs that are
anti-inflammatory analgesic6. These have the common property of
inhibiting the formation of prostaglandins which have a
protective affect on the gastrointestinal mucosa. See Goo~man
and Gilman "The Pharmacological Basis for Therapeutics" 7th
Edition, p. 678. It iB 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 NSAIDæ 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, ie 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 ~alt. 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); etc.
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 Hl-and/or
H2-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, etc.
~3~3~39~i
The quantity of Hl-receptor blocker that will be con-
tained in the composition of this invention may vary somewhat.
All that is required is that an effective amount be present 60
that the Hl-receptor blocker can make its contribution as a
protectant against NSAID-indueed gastrointestinal injury.
Similarly the quantity of H2-receptor blocker in the
present composition may also vary. Again, all that i8 required
is that the amount employed be an effective quantity that will
enable the H2-receptor blocker to play its part as protectant.
The quantity of beta-adrenergic agonist that will be con-
tained in the present composition may vary somewhat. Again, all
that is required i6 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 invçntion.
The NSAID will be contained in the ~omposition of this
invention at concentrations at which it is generally found in
therapeutic NSAID compositions intended for oral administration~
This will usually be a pharmaceuticallly acceptable analgesic/
anti-inflammatory dose.
The quantitative relationship of the NSAID, the beta-
adrenergic agonist, and the histamine H1-and/or H2 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
Hl-and H2-receptor blockers are those that apply when the
Hl or H2 blocker is employed. When a combination of the Hl
and H2 blocker is utilized the amount of each contained in the
product will be adjusted.
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~3~.?~39~
Table I
In~redient General Ranqe Preferred Ran~e
low ~9~ low high
NSAID10 mg/kg/day - 100 mg/k~/day15 my/kg/day - 75 mg/kg/day
.
Beta-~drenergic
Agonist 0.3 ug/kg/day - 500 mg/kg/day 0.01 mg/kg/day - l0 my/kg/day
Histamine Hl-
Receptor Blocker
(when employed)2.5 uy/kg/day - 500 mg/kg/day 100 ug/kg/day - 50 mg/kg/day
.
Histamine H2-
Receptor Blocker
(when employed)l0 ug/kg/day - 1 g/kg/day 0.01 mg/kg/day - 10 mg/kg/day
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 sp~cified
for the histamine H1-and H2-receptor blockers are those that apply when
the Hl blocker or the H2 blocker is employed. When a combination of
the H1 and H2 blockers is utilized the amount of each in the product
will be adjusted.
Table II
INGREDIENT UNIT DOSAGE
mg/dose
NSAID 200mg - 600 mg
Beta-Adrenergic 0.7 mg - 70 mg
Agonist
~ ~ . .
Histamine H1 - 0.01 mg - 70 mg
Receptor Blocker
(when used)
_
Histamine H2 ~ 0.5 mg - 350 mg
Receptor Blocker
(when used~
.. _ _ . _ _ , .
~1.3~13~3~S
, .
Depending upon the dosag~ ~orm ~mployad, the products of this
invention may also contain other adjuvants that may be useful in
formulating or admini~tering the particular dosage form. Thus
~or example, when administered as a tablet, the product6 of this
invention may also contain lubxicants, excipient6, binding
agents, disintegrating agents, flavoring agents, etc. In
addition, these products may also contain other pharmaceutically
active ingredients such as: decongestant~, analgesic adjuvants,
expectorants, antitussives, diuretics, other analgesic6, other
anti-infl D atory agents, antipyretics, anti-rheumatic~,
anti-oxidants, vasodilators, smooth musclerelaxants, skeletal
muscle relaxants, b~onchodilators, 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 m~dium or as
powders packaged in suitable paper envelopes.
,, .
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. _ _. _ _ .................... . .. . .. .. ..
The following experiments were carried out to test the
effectiveness of the combination of beta-adrenergic agonists with
histamine Hl--or H2-receptor blbckers in protecting the
stomach against NSAID-induced gastrointestinal injury. In these
studies the histamine H1_receptor blocker employed was
diphenhydramine and it was used in the form of its HCl salt. The
histamine H2 receptor blocker utilized was ranitidine al60
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
H1- and H2-receptor blockers and the beta- adrenergic
agonists were te~ted separately along with the standard do~e of
975 mg of aspirin for purposes of comparison with the irritation
results obtained from the combination of the beta-adrenergic
.
,` `
.
,
.. ~ 1.3~3~'g~
~gonist with the histamine ~1- or H2-receptor blocker when
al~o administered with the standard test dose of 975 mg of
aspirin.
The stomach lining of dog~ is examined endoscopically and
rated as to the degree of injury. ~he 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 te~ts.
The capsules are placed in the back of the dog'~ 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 ~ex 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 i6
maintained between 55F and 8SF 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 awa~ from the kennel. Fasted dogs of
either sex are examined gastroscopically to ensure that their
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: ~ _ g
~ ~f.;~ 9S
6tomachs have normal healthy mucosal linings. The dogs are dosed
orslly with test formulations, which ~re flu~hed into their ,
stomach6 with 50 ml of deionized water. They are then
re-examined two and four hours l~ter for gastric petechiae and
other sign6 of bleeding according to the following scale:
O = uniform, pale ~o dark pink muco~a
1 = darker pink or blotchy mucosa
2 = petechiae and/or light red streaks
3 = few small lesions
4 = many or connected small lesion6 (6triations)
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 ~core.
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 O
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.
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~.~q.~3~Y3~j
, . ~ - ! ` T ;: '
T lo III
Nonsteroidal Anti-inflammatory Composition6 Protected Ag~in6t
Gastrointestinal Injury with a Combination of Certain Beta - Adrenergic
Receptor Agonists and Histamine Hl-RPceptor Blockero
Data Summary
2-H~ur Data
Irrit~tion
~ Score _ pH
Aspirin 975 mg 8 5.5 3.3
Terbutaline 1.25 mg + Aspirin 975 mg 4 4.0 2.9
2.50 mg ~ Aspirin 975 mg 4 2.0 3.8
5.00 mg + Aspirin 975 mg .8 1.4 4.0
" lO.0 mg + Aspirin 975 mg 5 1.2 4.6
Diphenhydramine 12.5 mg + Aspirin 975 mg 4 5.5 1.4
" 25.0 mg + Aspirin 975 mg 4 5.75 2.1
" 50.0 mg + Aspirin 975 mg 4 4.0 3.6
Terbutaline 2.5 mg + Diphenhydramine
50 mg + Aspirin 975 mg 4 4.50 2.8
Terbutaline 5.0 mg + Diphenhydramine
25 mg ~ Aspirin 975 mg 4 1.75 4.4
Terbutaline 5.0 mg + Diphenhydramine
50 mg + Aspirin 975 mg 4 0.0 5.4
~;
- ~l31~!3S~
T~ble IV
Nonsteroidal Anti-inflammatory Composition Protected Against
Gastrointe6tinal Injury with a Combination of C~rtain Beta-
Adrenergic Agonist~ and Histamine H2-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
" 2.5 mg ~ Aspirin 975 mg 4 2.0 3.8
" S.0 mg + Aspirin 975 mg 8 1.43 4.0
" 10.0 mg + Aspirin 975 mg 5 1.2 4.6
Ranitidine 10 mg + Aspirin 975 mg 6 3.50 5.3
" 20 mg ~ Aspirin 975 mg 8 1.88 5.9
" 50 mg + Aspirin 975 mg 6 0.67 6.1
Terbutaline 5 mg + Ranitidine 10 mg
+ Aspirin 975 mg 4 0.0 4.8
Terbutaline 5 mg + Ranitidine 5 mg
+ Aspirin 975 mg 4 1./5 4.1
Terbutaline 2 mg ~ Ranitidine 5 mg
Aspirin 975 mg 4 1.75 4.3
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