Note: Descriptions are shown in the official language in which they were submitted.
5~7
This invention relates to nonsteroidal anti-lnflammatory
compositions containing, as protectants against gastrointentinal
injury caused by said nonsteroidal anti-inflammatory drug
(hereinafter sometimes referred to as NSAID), a protectant selected
from the group consisting of H1 blockers, H2 blockers,
beta-adrenergic agonists, and combinations thereof. More
particularly, it concerns co~positions of this character, that also
contain an alkalizing agent, and a process that uses such
compositions. The terms Hl blockers and H2 blockers are used
herein to refer to the histamine H1- and H2-receptor blockers,
respectively.
Hl blockers, H2 blockers, as well as beta-adrenergic
agonists, have been shown to offer some protection against
gastrointestinal injury that is sometimes caused by the
administration of NSAIDs. These, however, have suffered from some
very distinct disadvantages. Among such advantages is the delay in
relieving the subjective symptoms of gastric distress that is
experienced by individuals who have taken such products.
It has now been found that the aforesaid disadvantages may be
avoided by also incorporating an alk~lizmq
agent in said NSAID composition containing a gastrointestinal
protectant selected from the group consisting of Hl blockers, H2
blockers, beta-adrenergic agonists, and combinations thereof. In
addition, it has been found that by incorporating said alkalizing
agent in the compositons of interest there is often also observed an
improvement in the ability of such compositions to protect against
gastrointestinal injury that may be caused by said NSAIDs.
It has been suggested in the prior art that the
coadministration of cimetidine with an antacid is to be avoided. In
this connection, attention is directed to the "Physicians Desk
Reference", 40th Edition, 1986, page 1726 and AMA Drug
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Evaluations" 5th Edition p. 1267. The latter is prepared and
published by the American Medical Association, Chicago, Illinois. In
contrast to this, applicants did not observe any reduction in efficacy
when the alkalizing agents were coadministered with Hz- or
Hl-blockers and a NSAID.
It has also been reported in prior art that H2-receptor
blocking 2gents or antagonists protect against acetylsalicylic acid
(ASA) induced lesions in certain laboratory anLmals. One such study
is reported in Gastrcenterology Vol. 88, NO~ S part 2~ pol344~ This
reference teaches nothing with regard to the use of an alkalizing agent
as is characteristic of the present invelltion,
Cyproheptadine has been evaluated as a protectant against
~SA-induced gastric 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 at serotonin-
receptor sites ~Goodman and Gilman "The Pharmacological Basis of
Therapeutics", 7th Edition, p. 634). In addition, in the Indian
Journal reference, the ASA and cyproheptadine are not
coadministered but are given serially. This is to be contrasted with
the present invention in which the H2- or H2-receptor blocker or
the beta-adrenergic agonist is coadministered with the ASA.
F~rtherrnore, the treatment with cyproheptadine in ~ccordance with the
Indian reference is reported as not modifying the gastric acidity.
This is also in contrast with the experience in this invention in
which significant modification of gastric acidity takes place with
the administration of ASA and gastroprotectants utilized for
the present p~lrposes. Still a further distinction of the instant
invention over the Indian Journal teaching is the fact that in the
latter cyproheptadine was administered by intraperitoneal injection
prior to the intragastric administration of the ASA. This is to
be contrasted with the fact that the compositions of the present
invention lend themsel~es to oral administration at which time the
NSAID and the Hl- or H2-receptor blocker are coadministered.
Most importantly perhaps, like the other reference discussed above,
the Indian Journal reference nowhere suggests the use nor the
advantages that follow from its use of an alkalizing agent. This, as
will be made cleax below, is an essential feature of the present
invention.
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The NSAIDs form a well-known class of drugs that are
anti-inflammatory ~nalgesics. These have the common property of
inhibiting the formation of prostaglandins, which have a protective
affect on the gastrointestin~l mucosa (Goodman and Gilman "The
Pharmacological Basis or Therapeutics" 7th Edition, p. 67~). It is
because of this inhibiting effect that the oral administration of
drugs of this class may result in gastrointestinal injury and/or
bleeding and is at least part of the problem that the present
invention seeks to reduce or eliminate.
A number of NSAIDs are known in the prior art to which the
present invention has application. The most commonly known group are
the salicylates of which ASA is the prime example. A further
group of NSAIDs that have utility in connection with the instant
invention are the proprionic acid derivatives. Included in this
group are ibuprofen and naproxen. A further group of NSAIDs,
employable herein, are the fenamates and compounds closely related to
them structurally. These may be illustrated by such compounds as
mefenamic acid, meclofenamate sodium, 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~
piro~icam), etc.
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.
A number 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 Hl-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
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nitrate Ealt6); alkylamines (e.g. chlorpheniramine or its maleate
6alt, brompheniramine or its maleate salt); piperazines (e.g.
hydroxyzine or its hydrochloride or pamoate ~alts, cyclizine or its
v,~
hydrochloride or lactate salts, meclizine or its hydrochloride
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-receptors 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 whersin the acid portion may be hydrochloride, maleata,
ascorbate, citrate, pamoate, lactate, tartrate, sulfate, etc.
The quantity of Hl~receptor blocker that will be contained in
the composition of this invention may vary somewhat because of the
variations in the anticholinergic activity that these agents
exhibit. All that is required is that an effective amount be present
so that the Hl-receptor blocker can make its contribution as a
protectant against NSAID-induced gastrointestinal injury.
Similarly, the quantity of H2-receptor blocker in the present
composition may also vary. Again, all that is required is that
amount employed be an effective protectant quantity which will enable
the H2-receptor blocker to play its part as a gastrointestinal
protectant.
A number of beta-adrenergic agonists are known in the prior art
which are useful for the purposes of this invention. Of special
interest are isoproterenol which is a mixed beta-1 and beta-2 agonist
and terbutaline which is a more selective beta-2 agonist. By way of
illustrating other beta-adrenergic agonists that may be employed
herein, the followiny are given: metaproterenol, albuterol,
ritodrine. All of these may be employed as such or as
pharmaceutically acceptable salts.
As with the other active ingredients contained in the
compositions of this invention, the quantity of beta-adrenergic
agonist that will be contained therein may also vary somewhat.
,b Again, all that is required is that it be contained in said
composition in an amount which will enable the beta-adrenergic
agonist to play its part as a gastrointestinal protectant.
As indicated above, it is a feature of the present invention to
incorporate in the instant composition an alkalizing agent. Since
this composition is intended for oral administration, the akalizing
agent employed will be one which is a pharmaceutically acceptable one
that may be tolerated at the concentrations ~t which it is
administered. A number of such alkalizing agents are known in this
- art which are suitable for the present purposes. By way of
illustration, the following may be mentioned: sodium bicarbonate,
magnesium carbonate, calcium carbonate, magnesium oxide, magnesium
hydroxide, magnesium trisilicate, aluminum hydroxide, aluminum
carbonate, potassium bicarbonate, etc.
The ~lantitive relationships of the various components of the
composition of this invention may be expressed on the basis of the
average daily dose of the ingredient contained in the product. This
will take the form of weight of the ingredient per kg of body weight
of the subject per day (e.g. milligrams or grams/kg of body
weight/day). In general, this relationship may be expressed for the
various ingredients as follows:
~a) NSAID: from about 10 mg/kg/day to about 100 mg/kg/day;
preferred range from about 15 mg/kg/day to about 75
mg/kg/day.
(b) H2-receptor blocker (when employed): from about 0.01
mg/kg/day to about lg/kg/day; preferred range from about
0.01 mg/kg/day to about 10 mg/kg/day.
(c) Hl-receptor blocker (when employed): from about 2.5
ug/kg/day to about 500 mg/kg/day; preferred range from
about 0.1 mg/kg/day to about 50 mg/kg/day.
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(d) beta-adrenergic agonist ~when employed): from about
0.30 ug/kg/day to about 500 mg/kg/day; preferred range
from about 0.01 mg/kg/day to about 10 mgtks/day.
(e) alkalizing agent: from about 0.02 mEq/kg/day to about
10 mEq/kg/day; preferred range from about 0.04
mEq/kg/day to about 2 mEq/kg/day.
: The compositions of the present invention may also be madeup in unit dosage forms. Each unit dosage form will be ~ized and
contain the ingredients in such amount that they may be taken
orally in comfortable and convenient manner. Given below are the
quantities of each type of active ingredient, when present in the
composition, that will be contained in each:
TABLE I
mg. per ~nit dose
Ingredient General _
.
NSAID about 200 mg to about 600 mg.
H1 Blocker about 0.01 mg to about 70 mg.
H2 Blocker about 0.5 mg to about 350 rng
Beta-Adrenergic Agonist about 0.7 mg to about 70 mg.
Alkalizing Agent about 2 mEq to about 10 mEq
The present products may be made into capsules, tablets,
powders or caplets and may be film-coated, enteric-coated or
formulated into sustained-release dosage forms or liquid dosage
compositions. When formed into tablets or caplets they may
contain adjuvants that facilitate the tableting of the product or
enhance its elegance or dissolut-on rates. Generally
illustrative of the adjuvants that may be contained in the
various dosage forms encompassed in the present invention, the
following may be mentioned: disintegrating agents, binders,
' ' ", '. ' ' ' ' ' " ' `
~3~S~
lubricants, fillers, glidents, surfactantfi, flavoring ~gents,
sweeteners, solvents, liquid c~rriers, suspending agentc,
preservatives, etc. More particularly, the adjuvant~ that may be
contained in the various dosage forms over and above the active
ingredients are as follow~:
Capl~t and Tablet: Cellulose, lacto~e, corn ~tarch, stearic acid,
water, gelatin, talc, sterotix, magnesium stearate, terra alba,
*
sucrose, agar, pectin, Cab-0-Sil, acaci~, etc.
Cap ule: Spray-dried lactose, dimethylsiloxane, corn starch, water,
magnesium stearate, sucrose, agar, pectin, Cab-0-Sil, etc.
Liquid Dosage Forms: Polyethylene glycol, sucrose, povidone, sodium
citrate, citric acid, flavor, color, quinine, salicylic acid, water,
peanut oil, olive oil, sesame oil, etc.
Sustained-release compositions may contain such things as
glyceryl monostearate or glyceryl distearate.
In addition, these products may also contain other
pharmaceutically active ingredients, such as decongestants, analgesic
adjuvants, antihistamines, expectorants, antitussives, diuretics,
other analgesics, other anti-inflammatory agents, other antipyretics,
other antirheumatics, antioxidants, vasodilators, smooth muscle
relaxants, skeletal muscle relaxants, bronchodilators, vitamins,
trace minerals, amino acids, biological peptides, etc.
The compositions of this invention are useful in treating
conditions and symptoms that are classically treated by the
administration of NSAIDs. These include headache pain, pain and
inflammation associated with arthritis and other systemic diseases,
elevated body temperatures, eto. A variety of regimens may be
employed in treating these conditions in accordance with the present
invention. This will depend upon the particular unit dosage form
that is used in the regimen. In the typical case one to two tablets
will be taken every 4 to 6 hours, as needed.
*Trade M~rk
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The following exasples are given t~ further illuctrate the
present invention. It i6 to be understood, however, that the
invention i6 not limited thereto.
~:,ea~
A oe tylsalicylic acid (ASA)325 mg
Diphenhydramine hydrochloride16.67 mg
Sodium bicarbonate 5 mEg
The above ingredie~ts are mixed in powderod or granular form
and loaded into gelatin capsules.
Example 2
A5A 325 mg
Ranitidine hydrochloride 3.33 mg
Sodium bicarbonate 5 mEq
Prepared as described in Example 1
ExamPle 3
ASA 325 mg
Metaproterenol sulfate 0.83 mg
Sodium bicarbonate 5 mEq
Prepared as described in Example 1
To test the effectiveness of the composition of this invention
in protecting the stomach against NS~ID-induced muscosal injury each
protectant, in co~bination with an alkalizing agent, is administered
orally with ASA in capsules. For purposes of comparison, the
protectant alone or the alkalizing agent alone is administer~d with
the ASA. A standard dose of 975 mg of ASA is administered
with varying doses of protectant and or alkalizing agent.
A11 test formulations are prepared on the day of the tests.
The capsules are placed in the back of the dog's throat. A 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 65F
and 85F and relative hu~idity between 30~ and 80%. Room lights
remain on from 6:00 AM to 4:00 PM.
~'
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Each dog ls trained to ~tand in a stanchion with ~ling 6upport
and to accept a bit tied in tts mouth. A gastroscope is then passed
through the bit into th~ dog 1 8 stomach. This tr~lning 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 ASA is evaluated (as under Test Procedure~. An
acceptable gastric irritation score in the antrum must be S or
greater (on a scal~ of 0-7) 2 hours after dosage.
Food is withheld from test dogs for 24 hours before the test
and durinq 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 2 hours later for gastric
petechiae and signs of bleeding according to the following scale:
O = 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 bleeding 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.
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A base line is est~bl1shed by mea6uring the variou6 parameters
after the ~dministration of 975 mg of ASA The normal resting
stomach has an irritAtion score of O and ~ pH of 5 to 5.5. ASA
given alone, produced injury with score6 of approximately 5.5 after 2
hours. The g~stric pH at this time was about 3.1.
The results of these tests are ~ummarized in Tables II, III and
IV below. Table II summarizes the results obtained with an Hl
blocker and alkalizing agents; Table III the results sbtained with
~2 blockers and an alkalizing agent; and Table IV the results
obtained ~ith beta-adrenergic agonists and al~alizing agents. These
tables also include the data obtained with the protectant or
alkalizing agent alone. With each of the test compositions set
forth in these tables, 975 mg of ASA was simultaneously
administered. The ASA was contained in the same capsule along
with the other test ingredients.
In these tests the active ingredients were administered in the
following forms:
diphenhydramine: lhydrochloride]
ranitidine: [hydrochloride]
cimetidine: Ifree base]
terbutaline: [sulfate~
albuterol: [free base]
isoproterenol: ~hydrochloride~
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