United States Patent [191
`Lukacsko et al.
`
`[11]\ Patent Number:
`[45] Date of Patent:
`
`4,757,060
`Jul. 12, 1988
`
`[54] NON-STEROIDAL ANTI-INFLAMIVIATORY
`COMPOSITIONS PROTECTED AGAINST
`GASTROINTESTINAL INJURY WITH A
`COMBINATION OF CERTAIN H1 AND H2,
`RECEPTOR BLOCKERS
`[75] Inventors: Alison B. Lukacsko, Robbinsville;
`Randy J. Koslo, East Windsor;
`Joseph J. Piala, Metuchen, all of NJ.
`Bristol-Myers Company, New York,
`NY.
`[21] Appl. NO.: 867,882
`[22] Filed:
`Apr. 29, 1986
`
`[73] Assignee:
`
`[63]
`
`Related US. Application Data
`Continuation-impart of Ser. No. 836,264, Mar. 4, 1986,
`abandoned.
`
`[51] Int. Cl.4 ................... .. A61K 31/60; A61K 31/62;
`A61K /615
`
`[52] US. Cl. .................................. .. 514/160; 514/161;
`‘514/162
`[58] Field of Search ...................... .. 514/160, 162, 161
`[56]
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,401,665 8/1983 Sheinaus et a1. .................. .. 514/162
`
`' OTHER PUBLICATIONS
`Chem. Abst 93 (l980)-l91l7K & 94 (1981)-24923V.
`Primary Examiner-Stanley J. Friedman
`Attorney, Agent, or Firm—Morton S. Simon
`[57]
`ABSTRACT
`A pharmaceutical composition and process for adminis
`tering non-steroidal drugs which are protected against
`injury to the gastrointestinal tract by a combination of
`certain H1 and H2 receptor blockers.
`'
`
`17 Claims, No Drawings
`
`

`

`1
`
`NON-STEROIDAL AN'I'I-INFLANHVIATORY
`COMPOSITIONS PROTECTED AGAINST
`GASTROINTESTINAL INJURY WITH A
`COMBINATION OF CERTAIN H1 AND H2,
`RECEPTOR BLOCKERS
`
`5
`
`35
`
`4,757,060
`2
`the present ‘invention. Moreover, the cyproheptadine
`was administered by intraperitoneal injection prior to
`the intragastric administration of the aspirin. In contrast
`to this the compositions of the present invention lend
`themselves to oral administration at which time the
`NSAID and the combination H1 and H2 receptor block
`ers are coadministered.
`As will be pointed out in more detail below it has
`been found that by employing certain combinations of
`H1 and H2 histamine receptor blockers as further de
`?ned herein that these two act synergistically in their
`protective effect against NSAID-induced gastrointesti
`nal injury. This was an unexpected result and would not
`have been anticipated on the basis of the present state of
`the art.
`A number of H1 and H2 receptor blockers are known
`in the prior art which are useful for the purposes of the
`present invention. However, not all of the H1 receptors
`blockers are equally effective in practicing this inven
`tion. Those that are useful should also exhibit anticho
`linergic properties.
`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 hydrochlo
`ride or citrate salts); alkylamines (e.g. chlorpheniramine
`or its maleate salt, brompheniramine or its maleate salt);
`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 in
`vention the following are given: cimetidene, ranitidine,
`famotidine, etc.
`Generally any combination of H1, and H2 receptor
`blockers as outlined above are useful for the purpose of
`this invention. Nevertheless certain combinations of H1
`and H2 receptor blockers have been found to be particu
`larly ef?cacious. Thus the combination of chlorphenira
`mine plus ranitidine, diphenhydramine plus ranitidine,
`chlorpheniramine plus cimetidine, and diphenhydra
`mine plus cimetidine are the combinations of choice in
`the present invention.
`The H] and H2 receptors blockers may be used in the
`form of their bases or in the form of their pharmaceuti
`cally 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 NSAIDs form a well-known class of drugs that
`are antiinflammatory analgesics. These have the com
`mon property of inhibiting the formation of prostagla
`dins which have a protective affect on the gastrointesti
`nal mucosa. See Goodman and Gilman “The Pharma
`cological Basis for Therapeutics” 7th Edition, p. 678. It
`is because of this inhibiting effect that the oral adminis
`tration of drugs of this class tend to result in gastrointes
`tinal 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
`aspirin 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, naproxen. A further group
`
`40
`
`CONTINUING APPLICATION
`This application is a continuation in part of Ser. No.
`836,264, ?led Mar. 4, 1986 and now abandoned.
`This invention relates to non-steroidal anti-in?amma
`tory drug (hereinafter referred to as NSAID) composi
`tions containing protectants against NSAID-induced
`gastrointestinal injury and to processes for administer
`ing such composition. More particularly, it concerns
`compositions and processes of the aforesaid type that
`employ certain combinations of histamine receptor
`blockers as the protectants. The compositions of this
`invention are useful in treating conditions and symp
`20
`toms that are classically treated by the administration of
`NSAIDs e.g. headache pain, pain and in?ammation
`associated with arthritis and other systemic diseases,
`elevated body temperatures etc.
`Aspirin and other NSAIDs have long been the most
`popular drugs for the management of pain, inflamma
`tion and fever. However, one of the drawbacks in their
`use is the gastrointestinal injury and/or bleeding that
`sometimes accompanies their administration to individ
`uals. This becomes a problem where large and sustained
`30
`doses of NSAIDs must be given to control the symp
`toms, as for example, in the case of the management of
`arthritis.
`It has now been found that NSAID-induced gastroin
`testinal injury can be signi?cantly reduced when a com
`bination of histamine receptor blockers and particularly
`a combination of H1 and H2 receptor blockers are ad
`ministered concurrently with the NSAID.
`As pointed out in US. Pat. No. 4,996,571 H1 and H2
`receptor blockers form two well-known classes of phar
`macologically active drugs that serve as blocking
`agents for histamine at H1 and H2 histamine receptor
`sites, respectively. Histamine receptor sites have been
`differentiated on the basis of the classes of antihista
`mines that can serve to block these sites. The fact that a
`drug is identi?ed as an antihistamine does not necessar
`ily mean that it will be effective in blocking all the
`known histamine receptor sites but may in fact be selec
`tive so that it will act at one site e.g. H1 site but not at
`another e.g. H2 site.
`It has been reported in prior art that H2 receptor
`blocking agents or antagonists protect against aspirin
`induced lesions in certain laboratory animals. One such
`study is a report 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 in
`duced gastrointestinal injury (Indian J. Med. Res. 1980,
`71, p. 926-32). Although the cyproheptadine may have
`some Hl-receptor antagonist properties, it does not act
`exclusively at the H1 receptor sites but rather acts pre
`dominantly at the serotonin receptor sites.
`Aside from the above the present invention has fur
`ther signi?cant distinctions from the teachings in the
`Indian Journal. For one thing in this reference the aspi
`rin 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. This is
`contrary to the observations made in connection with
`
`45
`
`55
`
`65
`
`

`

`20
`
`EXAMPLE 1
`
`Aspirin
`Ranitidine hydrochloride
`Chlorpheniramine maleate
`
`325 mg
`3.33 mg
`3.33 mg
`
`The above ingredients are mixed in powdered or
`granular form and loaded into gelatin capsules.
`
`EXAMPLE 2
`
`4,757,060
`3
`4
`of NSAIDs, employable herein are the fenamates and
`products may also contain other pharmaceutically ac
`compounds closely related to them structurally. These
`‘ tive ingredients such as: decongestants, analgesic adju~
`may be illustrated by such compounds as mefenamic
`vants, antihistamines, expectorants, antitussives, diuret
`acid, meclofenamate sodium, diclofenac and its sodium
`ics, other analgesics, other anti-in?ammatory agents,
`salt. Also belonging to the class NSAIDs with which
`antipyretics, antirheumatics, anti-oxidants, vasodilators,
`the present invention is concerned are the indole deriva
`smooth muscle relaxants, skeletal muscle relaxants,
`tives (e. g. indomethacin); pyrrole alkanoic acid deriva
`bronchodilators, vitamins, trace minerals, amino acids
`tives (e.g. tolmetin); pyrazalone derivatives (e.g. phen
`and biological peptides.
`ylbutazone); oxicams (e.g. piroxicam), etc.
`The products of this invention may take a variety of
`It is contemplated that in the practice of the present
`forms. As indicated above they may assume the form of
`invention the NSAID and the histamine receptor block
`tablets. However, the NSAID and the H1 and H2 recep
`ers will be administered concurrently in a convenient
`tor blockers may also be in powdered or granular form
`product form. The essential ingredients of such prod
`contained in edible capsules such as gelatin capsules.
`ucts will be the H1 and H2 receptor blockers and the
`The present products may also take the form of suspen
`NSAID. Over and above this these products may also
`sions or solutions of the above ingredients in a suitable
`contain other ingredients which will to a large extent
`liquid medium or as powders packaged in suitable paper
`depend upon the particular dosage form of the product,
`envelopes.
`eg tablets, capsules, powders, suspensions etc.
`The following Examples are given to further illus
`The quantity of H receptor blocker that will be con
`trate the present invention. It is to be understood, how
`tained in the composition of this invention may vary
`ever, that this invention is not limited thereto.
`somewhat. All that is required is that an effective
`amount be present so that the H1 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 quan
`tity which will enable the H2 receptor blocker to play its
`part as protectant.
`The NSAID will be contained in the composition of
`30
`this invention at levels at which it is generally found in
`therapeutic NSAID compositions intended for oral
`administration. This will usually be a pharmaceutically
`acceptable analgesic/ amt-inflammatory dose.
`The quantitative relationship of the NSAID and the
`H1 and H2 receptor blockers contained in the present
`products may be expressed on the basis of the daily
`average dose of the ingredient, e.g mg/kg. of body
`weight/day. In this case the average daily dose for the
`ingredients will have the values in the range set forth in
`the following table:
`
`Aspirin
`cimetidine hydrochloride
`Chlorpheniramine maleate
`
`325 mg
`16.67 mg
`3.33 mg
`
`Prepared as described in Example 1.
`
`EXAMPLE 3
`
`Ingredient
`NSAID
`
`General Range
`about IO/mg/kg/day
`to about
`100 mg/kg/ day
`H1 Receptor about 2.5 ug/kg/day
`Blocker
`to about
`500 mg/kg/day
`H2 Receptor about 10 ug/kg/day
`Blocker
`to about
`l g/kg/day
`
`Preferred Range
`about 15 mg/kg/day to
`about 75 mg/kg/day
`
`about 100 ug/kg/day to
`about 50 mg/kg/day
`
`45
`
`about 0.010 mg/kg/day to
`about 10 mg/kg/day
`
`50
`
`The unit dosage forms for the present products will
`be formulated for convenient oral administration. Each
`such unit will generally contain from about 200 mg to
`55
`about 600 mg of NSAID, from about 0.1 mg to about 70
`mg of H1 receptor blocker and from 0.5 mg to about 350
`mg of H2 receptor blocker. In formulating these prod
`ucts pharmaceutically acceptable doses'of the aforesaid
`ingredients within the ranges set out above will be em
`ployed.
`Depending upon the dosage form employed the prod
`ucts of this invention may also contain other adjuvants
`that may be useful in formulating or administering the
`particular dosage form. Thus, for example, when ad
`65
`ministered as a tablet the products of this invention may
`also contain lubricants, excipients, binding agents, disin
`tegrating agents, ?avoring agents, etc. In addition these
`
`60
`
`Aspirin
`cimetidine hydrochloride
`Diphenhyramine hydrochloride
`
`325 mg
`3.33 mg
`16.67 mg
`
`Prepared as described in Example 1.
`The following experiments were carried out to test
`the effectiveness of the combination of H1 and H2 recep
`tor blockers in protecting the stomach against NSAID
`induced gastrointestinal injury and to compare any
`protection afforded by the individual H1 and H2 recep
`tor blockers. In these studies the H1 and H2 receptor
`blockers are used in the form of the following acid salts:
`ranitidine HCl, diphenhydramine HCl, chlorophenira
`mine maleate, cimetidine HCl. A standard dose of 975
`mg of aspirin is administered orally to dogs along with,
`respectively, treatment (a) through (h) as indicated
`below. The stomach lining of the dogs are examined
`endoscopically and rated as to the degree of injury. The
`results are given in the table following the description
`of the methodology.
`
`treat-
`ment
`
`cimetidine ranitidine diphenhydramine
`50 mg
`10 mg
`50 mg
`
`chlor
`pheniramine
`10 mg
`
`a
`b
`
`x
`
`x
`
`

`

`-continued
`
`treat-
`ment
`
`cimetidine ranitidine diphenhydramine
`50 mg
`10 mg
`50 mg
`
`4,757,060
`6
`The results of these tests with respect to the two hour
`injury daa are summarized in the following table below:
`
`chlor
`pheniramine
`10 mg
`
`c
`d
`e
`f
`g
`
`x
`
`x
`
`x
`
`x
`
`x
`x
`
`x
`
`x
`
`Test Composition
`aspirin (975 mg)
`aspirin (975 mg) +
`ranitidine HCl (10 mg)
`aspirin (975 mg) +
`chlorpheniramine maleate (10 mg)
`aspirin (975 mg) +
`cimetidine HCl (50 mg)
`aspirin (975 mg) +
`diphenhydramine HCl (50 mg)
`aspirin (975 mg) +
`ranitidine HCl (10 mg) +
`diphenhydramine HCl (50 mg)
`aspirin (975 mg) + ranitidine HCl
`(10 mg) + chlorpheniramine maleate (10 mg)
`aspirin (975 mg) + cimetidine HCl
`(50 mg) + diphenhydramine HCl (50 mg)
`
`15
`
`2 Hr. Score
`Injury
`pH
`5.6
`3.1
`3.5
`5.3
`
`4.0
`
`2.4
`
`4.0
`
`0.6
`
`1.6
`
`1.0
`
`4.4
`
`5.6
`
`3.6
`
`5.4
`
`4.7
`
`7.0
`
`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 attached funnel is posi
`tioned 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 ?oors to allow excreta to pass
`through. Room temperature in the holding rooms and
`test laboratories is maintained between 65° F. and 85° 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 gastro
`scope is then passed through the bit into the dog’s stom
`ach. This training requires ten days to two weeks in
`most dogs.
`To determine whether a dog is suitable for test pur
`poses, its stomach is examined for a normal mucosa, and
`its gastric responsiveness to NSAID is evaluated (as
`under Test procedure). An acceptable gastric irritation
`score in the antrum must be 5 or greater, 2 hours after
`dosage.
`Food is withheld from test dogs for 24 hrs. 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 gastro
`scopically to ensure that their stomachs have normal
`healthy mucosal linings. The dogs are dosed orally with
`test formulations, which are ?ushed into their stomachs
`with 5 ml. of deionized water. They are then re-exam
`ined two and four hours later for gastric petechiae and
`signs of bleeding according to the following scale:
`0=uniform, pale to dark pink mucosa
`l=darker pink or blotchy mucosa
`2=petechias 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 gas
`tric mucosa of each dog a qualitative description of
`gastric fluid is recorded and a pH measurement is made
`of the gastric ?uid. All of these are done 2 hours after
`administration of the test product.
`A base line is established byvmeasuring the various
`parameters after the administration of 975 mg of aspirin
`by itself. The resting stomach has an irritation score of
`O and a pH of 5 to 5.5. Aspirin alone produces injury
`which scores at approximately 5.6 after 2 hours and the
`gastric pH at this time is about 3.1. After 4 hours these
`values are 4.0 for the irritation factor and the pH is
`about 4.7. This indicates that a certain amount of heal
`ing takes place between the 2nd and 4th hour after
`administration.
`
`25
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`An examination of these data shows that singi?cantly
`more, synergistic protection is obtained when a combi
`nation of an H1 and H2 receptor blocker is employed
`together with aspirin as compared with the cases in
`which H1 or H2 receptor blocker, respectively, is issued
`alone.
`We claim:
`1. A NSAID composition having reduced potential
`for NSAID induced gastrointestinal injury comprising
`(a) an analgesic or antiin?ammatory amount of a
`NSAID selected from the group consisting of aspi
`rin and pharmaceutically acceptable salts of aspi
`rin; and
`(b) a protective amount of:
`(i) an H1 receptor blocker selected from the group
`consisting of diphenhydramine and pharmaceuti
`cally acceptable salts of diphenhydramine; and
`(ii) an H2 receptor blocker selected from the group
`consisting of cimetidine, ranitidine, famotidine and
`pharmaceutically acceptable salts thereof; said
`NSAID being present in the composition in an
`amount of from about 10 mg to about 100 mg per
`kg per day, based on the weight of a subject to
`whom the composition is being administered; said
`H1 receptor blocker being present in the composi
`tion in an amount of from about 2.5 g to about 500
`mg per kg per day, based on the weight of a subject
`to whom the composition is being administered;
`and said H2 receptor being present in the composi
`tion in an amount of from about 10 g to about 1 g
`per kg per day, based on the weight of a subject to
`' whom the composition is being administered.
`2. The composition according to claim 1, wherein the
`H2 receptor blocker is ranitidine or a pharmaceutically
`acceptable salt of ranitidine.
`3. The composition according to claim 1, wherein the
`H2 receptor blocker is cimetidine or a pharmaceutically
`acceptable salt of cimetidine.
`~ 4. The composition according to claim 1, wherein the
`H2 receptor blocker is famotidine or a pharmaceutically
`acceptable salt of famotidine.
`5. The composition according to claim 1, wherein the
`NSAID is present in an amount of from abut 200 mg to
`about 600 mg; the H1 receptor blocker is present in an
`amount of from about 0.1 mg to about 70 mg; and the
`
`

`

`0
`
`7
`H2 receptor blocker is present in an amount of from
`about 0.5 mg to about 350 mg.
`6. The composition according to claim 2, wherein the
`NSAID is 975 mg of aspirin, the H1 receptor blocker is
`50 mg of diphenhydramine HCl, and the H2 receptor
`blocker is 10 mg of ranitidine HCl.
`7. The composition according to claim 3, wherein the
`NSAID is 975 mg of aspirin, the H1 receptor blocker is
`50 mg of diphenhydramine HCl and the H2 receptor
`blocker is 50 mg of cimetidine HCl.
`8. A process for reducing the potential of aspirin or of
`a pharmaceutically acceptable salt of aspirin, to induce
`gastrointestinal injury in a subject which comprises
`administering to said subject, based on the weight of the
`subject,
`(a) from about 10 mg to about 100 mg per kg per day
`of an NSAID selected from the group consisting of
`20
`aspirin and pharmaceutically acceptable salts of
`aspirin;
`(b) from about 2.5 pg to about 500 mg per kg per day
`of an H1 receptor blocker selected from the group
`consisting of diphenydramine and pharmaceuti
`cally acceptable salts of diphenydramine; and
`(c) from about 10 pg to about 1 g per kg per day of an
`H2 receptor binder selected from the group consist»
`ing of cimetidine, ranitidine, famotidine, and phar
`maceutically acceptable salts thereof.
`9. The process according to claim 8, wherein the
`NSAID, the H1 receptor blocker and the H2 receptor
`blocker are administered orally.
`
`4,757,060
`8
`10. The process according to claim 9, wherein the
`NSAID, the H1 receptor blocker, and the H2 receptor
`blocker are administered concomitantly.
`11. The process according to claim 8, wherein the H2
`receptor blocker is ranitidine or a pharmaceutically
`acceptable salt of ranitidine.
`12. The process according to claim 8, wherein the H2
`receptor blocker is cimetidine or a pharmaceutically
`acceptale salt of cimetidine.
`13. The process according to claim 8, wherein the H2
`receptor blocker is famotidine or a pharmaceutically
`acceptable salt of famotidine.
`14. The process according to claim 8, wherein the
`NSAID and the H1 and H2 receptor blockers are admin
`istered in a unit dosage form containing from about 200
`mg to about 600 mg of NSAID, from about 0.1 mg to
`about 70 mg of H1 receptor blocker and from about 0.5
`mg to about 350 mg of H2 receptor blocker.
`15. The process according to claim 8, wherein the
`NSAID and the H1 and H2 receptor blockers are admin
`istered to a subject in a daily average done based on the
`weight of the subject, of from about 10 mg per kg per
`day to about 100 mg per kg per day of NSAID, from
`about 2.5 g per kg per day to about 500 mg per kg per
`day of H1 receptor blocker, and from about 10 g per keg
`per day to about 1 gm per kg per day of H2 receptor
`blocker.
`16. The process according to claim 11, wherein 975
`mg of aspirin, 50 mg of diphenhydramine HCl and 10
`mg of ranitidine HCl are administered.
`17. The process according to claim 12, wherein 975
`mg of aspirin, 50 mg of diphenhydramine HCl and 50
`mg of cimetidine HCl are administered.
`Ill
`Ill
`1*
`1k
`10‘
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65.
`
`

`

`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`PATENT NO. 1 4,757,060
`
`DATED
`
`3 July 12 , 1988
`
`|NVENT0R(5) ; Alison B . Lukacsko , Randy J . Koslo , Joseph J. Piala
`
`it is certified that error appears in the above-identified patent and that said Letters Patent
`is hereby corrected as shown below:
`
`In Column 6 , at line 48 , change "2 . 5 g" to ——2 . 5 1~g—— and ,
`at line 52 , change "10 g" to ——lO Mg—- .
`
`In Column 8 , at line 24 , change "2 . 5 g" to ——2 . 5 ,o-g—— and ,
`at line 25 , change "10 g" to —-l0 ,u/g-—— and , on the same line ,
`change "keg" to ——kg——.
`
`Signed and Sealed this
`Fifth Day of May, 1992
`
`: Arrest:
`
`Arresting O?‘icer
`
`Acting Commissioner of Patents and Trademarks
`
`DOUGLAS B. COMER
`
`