United States Patent [19J
`Lukacsko et al.
`
`[11] Patent Number:
`
`4,757,060
`[45] Date of Patent:
`Jul. 12, 1988
`
`[54] NON-STEROIDAL ANTI-INFLAMMATORY
`COMPOSmONS PROTECI'ED AGAINST
`GASTROINTESTINAL INJURY WITH A
`COMBINATION OF CERTAIN HI AND H2,
`RECEPTOR BLOCKERS
`
`[52] U.S. CI ..................................... 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 al ..................... 514/162
`
`OTHER PUBLICATIONS
`& 94 (1981)-24923V.
`Chern. Abst 93 (1980)-19117K
`Primary Examiner-Stanley J. Friedman
`
`Agent, or Firm- Morton S. Simon
`Attorney,
`[57]
`ABSTRACf
`
`[75] Inventors:
`Alison B. Lukacsko, Robbinsville;
`Randy J. Koslo, East Windsor;
`Joseph J. Piala, Metuchen, all of N.J.
`
`[73] Assignee: Bristol-Myers
`Company, New York,
`N.Y.
`
`[21] Appl. No.: 867,882
`
`[22] Filed: Apr. 29, 1986
`
`Data
`Related U.S. Application
`[63] Continuation-in-part
`
`abandoned.
`
`A pharmaceutical composition and process for adminis­
`
`
`
`tering non-steroidal drugs which are protected against
`of Ser. No. 836,264, Mar. 4, 1986,
`
`
`injury to the gastrointestinal tract by a combination of
`certain HI and H2 receptor blockers.
`
`[51] Int. Cl.4 ..........A61K 3 1/60; A61K 31/62;
`...........
`A61K /615
`
`17 Claims, No Drawings
`
`

`
`1
`
`4,757,060
`
`NON-STEROIDAL ANTI-INFLAMMATORY
`COMPOSmONS PROTECTED AGAINST
`GASTROINTESTINAL INJURY WITH A
`COMBINATION OF CERTAIN Ht AND H2,
`RECEPTOR BLOCKERS
`
`2
`
`the present invention. Moreover, the cyproheptadine
`
`
`
`was administered by intraperitoneal injection prior to
`
`
`the intra gastric administration of the aspirin. In contrast
`
`
`to this the compositions of the present invention lend
`5 themselves
`
`to oral administration at which time the
`
`NSAID and the combination H 1 and H2 receptor block­
`ers are coadministered.
`CONTINUING APPLICATION
`As will be pointed out in more detail below it has
`
`been found that by employing certain combinations of
`
`in part of Ser. No. This application is a continuation
`
`836,264, filed Mar. 4, 1986 and now abandoned. 10 Ht and H2 histamine
`receptor blockers as further de­
`fmed herein that these two
`
`act synergistically in their
`
`This invention relates to non-steroidal anti-inflamma­
`
`
`protective effect against NSAID-induced gastrointesti­
`tory drug (hereinafter referred to as NSAID) composi­
`
`
`
`nal injury. This was an unexpected result and would not
`tions containing protectants against NSAID-induced
`
`
`have been anticipated on the basis of the present state of
`gastrointestinal injury and to processes for administer­
`
`
`15 the art.
`ing such composition. More particularly, it concerns
`
`
`compositions and processes of the aforesaid type that
`
`
`
`A number of Ht and H2 receptor blockers are known
`
`employ certain combinations of histamine receptor
`in the prior art which are useful for the purposes of the
`
`
`blockers as the protectants. The compositions of this
`
`present invention. However, not all of the Ht receptors
`
`
`
`invention are useful in treating conditions and symp­
`
`
`blockers are equally effective in practicing this inven­
`
`toms that are classically treated by the administration of 20
`
`tion. Those that are useful should also exhibit anticho­
`
`NSAIDs e.g. headache pain, pain and inflamm ation
`
`linergic properties.
`
`
`associated with arthritis and other systemic diseases,
`
`By way of illustrating the Ht receptor blockers that
`
`elevated body temperatures etc.
`may be employed herein mention may be made of the
`Aspirin and other NSAIDs have long been the most
`
`
`
`following: ethanolamines (e.g. diphenhydramine or its
`popular drugs for the management of pain, inflamm a-25
`
`
`hydrochloride salt; carbinoxamine or its maleate salt);
`
`tion and fever. However, one of the drawbacks in their
`
`
`ethylenediamines (e.g. tripelennamine or its hydrochlo­
`
`use is the gastrointestinal injury and/or bleeding that
`
`
`
`ride or citrate salts); alkylamines (e.g. chlorpheniramine
`
`
`sometimes accompanies their administration to individ­
`
`or its maleate salt, brompheniramine or its maleate salt);
`uals. This becomes a problem where large and sustained
`
`
`
`piperazines (e.g. hydroxyzine or its hydrochloride or
`doses of NSAIDs must be given to control the symp-30
`
`
`pamoate salts, cyclizine or its hydrochloride or lactate
`toms, as for example, in the case of the management of
`salts, etc. To exemplify the H2 receptor blockers that
`arthritis.
`
`may be advantageously used in the practice of this in­
`
`It has now been found that NSAID-induced gastroin­
`
`vention the following are given: cimetidene, ranitidine,
`
`
`testinal injury can be significantly reduced when a com­
`
`35 famotidine, etc.
`bination of histamine receptor blockers and particularly
`
`
`Generally any combination of Ht. and H2 receptor
`
`
`a combination of Ht and H2 receptor blockers are ad­
`blockers as outlined above are useful for the purpose of
`
`
`ministered concurrently with the NSAID.
`
`
`
`this invention. Nevertheless certain combinations of Ht
`
`As pointed out in U.S. Pat. No. 4,996,571 Ht and H2
`
`and H2 receptor blockers have been found to be particu­
`receptor blockers form two well-known classes of phar­
`
`
`larly efficacious. Thus the combination of chlorphenira­
`macologically active drugs that serve as blocking 40
`
`
`
`mine plus ranitidine, diphenhydramine plus ranitidine,
`agents for histamine at Ht and H2 histamine receptor
`
`
`
`
`chlorpheniramine plus cimetidine, and diphenhydra­
`
`sites, respectively. Histamine receptor sites have been
`
`
`mine plus cimetidine are the combinations of choice in
`
`differentiated on the basis of the classes of antihista­
`the present invention.
`mines that can serve to block these sites. The fact that a
`
`The Ht and H2 receptors blockers may be used in the
`
`
`drug is identified as an antihistamine does not necessar-45
`form of their bases or in the form of their pharmaceuti­
`ily mean that it will be effective in blocking all the
`
`
`cally acceptable salts. When employed as salts these will
`
`known histamine receptor sites but may in fact be selec­
`usually be acid addition salts wherein the acid portion
`tive so that it will act at one site e.g. Ht site but not at
`
`
`may be hydrochloric, maleic, ascorbic, citric, pamoic,
`another e.g. H2 site.
`
`
`lactic, tartaric, etc.
`It has been reported in prior art that H2 receptor 50
`The NSAIDs form a well-known class of drugs that
`
`blocking agents or antagonists protect against aspirin­
`
`are antiinflamm atory analgesics. These have the com­
`
`
`induced lesions in certain laboratory animals. One such
`
`mon property of inhibiting the formation of prostagla-
`
`study is a report in Gastroenterology Vol. 88, No. 5 part
`
`dins which have a protective affect on the gastrointesti­
`2. p. 1344. It has also been reported that cyproheptadine
`nal mucosa. See Goodman and Gilman "The Pharma­
`
`has been evaluated as a protectant against aspirin in-55
`
`
`
`cological Basis for Therapeutics" 7th Edition, p. 678. It
`
`duced gastrointestinal injury (Indian J. Med. Res. 1980,
`
`is because of this inhibiting effect that the oral adminis­
`
`71, p. 926-32). Although the cyproheptadine may have
`tration of drugs of this class tend to result in gastrointes­
`
`
`
`some Ht-receptor antagonist properties, it does not act
`tinal injury and/or bleeding and is at least part of the
`
`exclusively at the Ht receptor sites but rather acts pre-
`
`problem that the present invention seeks to reduce or
`
`
`dominantly at the serotonin receptor sites.
`60
`eliminate.
`
`Aside from the above the present invention has fur­
`A number of NSAIDs are known in the prior art to
`
`
`ther significant distinctions from the teachings in the
`
`
`which the present invention has application. The most
`
`Indian Journal. For one thing in this reference the aspi­
`
`commonly known group are the salicylates of which
`
`
`rin and the cyproheptadine are not coadministered as
`
`would be the case in the present invention. Furthermore 65
`aspirin is the prime example. A further group of
`
`
`
`the treatment in this reference with cyproheptadine is
`
`
`NSAIDs that have utility in connection with the instant
`
`reported as not modifying the gastric acidity. This is
`
`
`
`invention are the proprionic acid derivatives. Included
`
`
`contrary to the observations made in connection with
`
`in this group are ibuprofen, naproxen. A further group
`
`

`
`4,757,060
`
` ·
`1.
`
`Aspirin
`
`Ranitidine hydrochloride
`
`Chlorpheniramine maleate
`
`325 mg
`3.33 mg
`3.33 mg
`
`4
`3
`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-inflammatory agents,
`salt. Also belonging to the class NSAIDs with which 5 antipyretics,
`antirheumatics,
`vasodilators,
`anti-oxidants,
`
`
`the present invention fs 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
`
`the present 10 forms. As indicated
`that in the practice of
`It is contemplated
`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 Ht 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 15 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 fo� of the product,
`envelopes.
`e�c.
`powders, suspenstons e.g. tablets, �apsules,
`
`
`The following Examples are given to further illus-
`The quanttty of H receptor blocker that wdl be con-
`.
`.
`.
`· .
`. .
`
`trate the present mventton. It ts to be understood, ow-
`h
`tame m t e compost 10n o ts mven ton may vary 20
`·t·
`f th' ·
`t'
`· d · h
`.
`somewhat. All that is required is that an effective ever, that this mventton ts not tmtte t ereto.
` d h
`amount be present so that the Ht receptor blocker can
`EXAMPLE 1
`
`
`make its contribution as a protectant against NSAID
`
`induced gastrointestinal injury.
`
`Similarly the quantity of H2 receptor blocker in the 25
`
`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
`The above ingredients are mixed in powdered or
`
`part as protectant.
`The NSAID will be contained in the composition of 30 granular form and loaded into gelatin capsules.
`
`
`
`
`this invention at levels at which it is generally found in
`EXAMPLE 2
`therapeutic NSAID compositions intended for oral
`
`
`
`administration. This will usually be a pharmaceutically
`
`
`
`acceptable analgesic/ anti-inflammatory dose.
`
`
`of the NSAID and the 35 The quantitative relationship
`Ht 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 40
`
`the following table:
`
`Aspirin
`
`Cimetidine hydrochloride
`
`Chlorpheniramine maleate
`
`325 mg
`1 6.67 mg
`3.33 mg
`
`
`
`Prepared as described in Example 1.
`
`EXAMPLE 3
`
`325 mg
`Aspirin
`
`Cimetidine hydrochloride
`3.33 mg
`1 6.67 mg
`
`Diphenhyramine hydrochloride
`
`Ingredient
`General Range
`
`
`
`Preferred Range
`
`NSAID
`
`about 1 0/mg/kg/day
`about 1 5 mg/kg/day to
`about 75 mg/kg/day 45
`to about
`!�u7rs���day about 1 00 ug/kg/day to
`about so mglkg/day
`
`Prepared as described in Example 1.
`
`H1 Receptor
`
`
`The following experiments were carried out to test
`to about
`Blocker
`
`
`the effectiveness of the combination ofHt and H2recep-
`500 mglkg/day
`H2 Receptor
`about 1 0 uglkg/day about 0.010 mg/kg/day to
`
`tor blockers in protecting the stomach against NSAID-
`about 1 0 mglkg/day 50
`to about
`Blocker
`
`induced gastrointestinal injury and to compare any
`1 g/kg/day
`
`____ .....;...:;:;..;;;:;;.::::::..____________
`
`
`protection afforded by the individual Ht and H2 recep-
`
`tor blockers. In these studies the Ht and H2 receptor
`The unit dosage forms for the present products will
`
`blockers are used in the form of the following acid salts:
`
`
`
`be formulated for convenient oral administration. Each
`
`
`ranitidine HCl, diphenhydramine HCl, chlorophenira­
`contain from about 200 mg to 55
`such unit will generally
`
`mine maleate, cimetidine HCI. A standard dose of 975
`about 600 mg of NSAID, from about 0.1 mg to about 70
`
`mg of aspirin is administered orally to dogs along with,
`
`
`mg ofHt receptor blocker and from 0.5 mg to about 350
`
`respectively, treatment (a) through (h) as indicated
`
`
`mg of H2 receptor blocker. In formulating these prod­
`below. The stomach lining of the dogs are examined
`
`
`ucts pharmaceutically acceptable doses·of the aforesaid
`
`endoscopically and rated as to the degree of injury. The
`
`ingredients within the ranges set out above will be em-60
`
`results are given in the table following the description
`ployed.
`of the methodology.
`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
`chlor­
`
`particular dosage form. Thus, for example, when ad-65
`treat·
`ranitidine
`cimetidine
`diphenhydramine
`pheniramine
`
`
`ministered as a tablet the products of this invention may
`ment
`50mg
`1 0mg
`50mg
`1 0mg
`
`
`also contain lubricants, excipients, binding agents, disin­
`
`
`tegrating agents, flavoring agents, etc. In addition these
`
`a
`b
`
`X
`
`X
`
`

`
`5
`-continued
`
`4,757,060
`
`6
`The results of these tests with respect to the two hour
`
`
`
`
`injury daa are summarized in the following table below:
`
`chior-
`diphenhydramine pheniramine
`treat-cimetidine ranitidine
`1 0mg
`50mg
`IOmg
`ment 50mg
`
`X
`
`X
`
`5
`
`c
`d
`e
`f
`g
`
`2 Hr. Score
`Injury pH
`
`5.6 3.I
`3.5 5.3
`
`4.0 4.4
`
`2.4 5.6
`
`4.0 3.6
`0.6 5.4
`
`1 .6 4.7
`1 .0 7.0
`
`X
`
`X
`
`X
`
`X
`X
`
`X
`
`Test Composition
`
`45
`
`50
`
`aspirin (975 mg)
`aspirin (975 mg) +
`
`ranitidine HCI (10 mg)
`10
`aspirin (975 mg) +
`All test formulations are prepared on the day of the
`
`
`chiorpheniramine maleate (IO mg)
`
`
`tests. The capsules are placed in the back of the dog's
`aspirin (975 mg) +
`
`
`
`throat. A stomach catheter with attached funnel is posi­
`
`cimetidine HCI (50 mg)
`tioned in the dog's stomach and 50 ml. of deionized
`aspirin (975 mg) +
`
`diphenhydramine HCI (50 mg)
`water is administered.
`15
`aspirin (975 mg) +
`Healthy adult beagle dogs of either sex are selected
`
`ranitidine HCI (10 mg) +
`
`
`for testing. Dogs are housed individually in stainless
`
`diphenhydramine HCI (SO mg)
`
`steel cages with grid floors to allow excreta to pass
`
`aspirin (975 mg) + ranitidine HCI
`
`(I 0 mg) + chiorpheniramine maleate ( 10 mg)
`
`
`
`through. Room temperature in the holding rooms and
`
`aspirin (975 mg) + cimetidine HCI
`
`
`test laboratories is maintained between 65• F. and ss• F. 20
`
`(50 mg) + diphenhydramine HCI (50 mg)
`
`
`and relative humidity between 30% and 80%. Room
`
`lights remain on from 6:00 AM to 4:00 PM.
`An examination of these data shows that singificantly
`
`
`
`Each dog is trained to stand in a stanchion with sling
`
`
`
`more, synergistic protection is obtained when a combi­
`
`support and to accept a bit tied in its mouth. A gastro­
`
`
`nation of an HI and H2 receptor blocker is employed
`scope is then passed through the bit into the dog's stom-25
`ach. This training
`
`
`together with aspirin as compared with the cases in
`
`requires ten days to two weeks in
`most dogs.
`
`
`
`which HI or H2 receptor blocker, respectively, is issued
`To determine whether a dog is suitable for test pur­
`
`
`alone.
`
`poses, its stomach is examined for a normal mucosa. and
`We claim:
`
`
`
`its gastric responsiveness to NSAID is evaluated (as 30
`1. A NSAID composition having reduced potential
`
`An acceptable
`under Test procedure).
`
`gastric irritation
`
`for NSAID induced gastrointestinal injury comprising
`
`score in the antrum must be 5 or greater, 2 hours after
`
`
`(a) an analgesic or antiinflammatory amount of a
`dosage.
`
`
`NSAID selected from the group consisting of aspi­
`Food is withheld from test dogs for 24 hrs. before the
`
`
`
`rin and pharmaceutically acceptable salts of aspi­
`
`test and during the test and water is allowed ad lib. The 35
`rin; and
`dogs are moved into a holding area away from the
`(b) a protective amount of:
`
`
`
`kennel. Fasted dogs of either sex are examined gastro­
`(i) an H1 receptor blocker selected from the group
`
`
`
`
`
`scopically to ensure that their stomachs have normal
`
`
`consisting of diphenhydramine and pharmaceuti­
`
`
`
`healthy mucosal linings. The dogs are dosed orally with
`
`
`cally acceptable salts of diphenhydramine; and
`
`test formulations, which are flushed into their stomachs
`40
`
`
`
`(ii) an H2 receptor blocker selected from the group
`with 5 ml. of deionized
`water. They are then re-exam­
`
`
`
`
`consisting of cimetidine, ranitidine, famotidine and
`
`
`ined two and four hours later for gastric petechiae and
`
`
`pharmaceutically acceptable salts thereof; said
`
`
`
`signs of bleeding according to the following scale:
`
`
`NSAID being present in the composition in an
`O=uniform, pale to dark pink mucosa
`amount of from about 10 mg to about 100 mg per
`
`1 =darker pink or blotchy mucosa
`
`kg per day, based on the weight of a subject to
`
`
`2=petechias and/or light red streaks
`
`
`whom the composition is being administered; said
`3=few small lesions
`
`
`
`HI receptor blocker being present in the composi­
`
`
`4=many or connected small lesions (striations)
`tion in an amount of from about 2.5 g to about 500
`5=few large lesions
`mg per kg per day, based on the weight of a subject
`6=many large lesions
`
`to whom the composition is being administered;
`
`
`7=massive hemorrhagic damage
`
`
`and said H2 receptor being present in the composi­
`
`
`Severity of injury for each treatment and at each time is
`tion in an amount of from about 10 g to about I g
`
`
`
`calculated as the mean gastric irritation score.
`
`per kg per day, based on the weight of a subject to
`
`
`
`In addition to the endoscopic observation of the gas­
`
`whom the composition is being administered.
`
`
`tric mucosa of each dog a qualitative description of 55
`
`
`2. The composition according to claim 1, wherein the
`
`
`
`gastric fluid is recorded and a pH measurement is made
`
`
`
`H2 receptor blocker is ranitidine or a pharmaceutically
`
`of the gastric fluid. All of these are done 2 hours after
`
`acceptable salt of ranitidine.
`
`administration of the test product.
`
`
`3. The composition according to claim 1, wherein the
`
`
`A base line is established by . measuring the various
`
`
`
`H2 receptor blocker is cimetidine or a pharmaceutically
`60
`
`
`parameters after the administration of 975 mg of aspirin
`
`acceptable salt of cimetidine.
`
`
`
`by itself. The resting stomach has an irritation score of
`
`
`· 4. The composition according to claim 1, wherein the
`
`
`0 and a pH of 5 to 5.5. Aspirin alone produces injury
`
`
`
`H2 receptor blocker is famotidine or a pharmaceutically
`
`which scores at approximately 5.6 after 2 hours and the
`
`acceptable salt of famotidine.
`
`gastric pH at this time is about 3.1. After 4 hours these
`
`
`5. The composition according to claim 1, wherein the
`
`values are 4.0 for the irritation factor and the pH is 65
`
`
`about 4.7. This indicates that a certain amount of heal­
`
`NSAID is present in an amount of from abut 200 mg to
`ing takes place between the 2nd and 4th hour after
`
`
`about 600 mg; the HI receptor blocker is present in an
`administration.
`amount of from about 0.1 mg to about 70 mg; and the
`
`

`
`4,757,060
`
`8
`7
`10. The process according to claim 9, wherein the
`H2 receptor blocker is present in an amount of from
`
`NSAID, the H1 receptor blocker, and the H2 receptor
`about 0.5 mg to about 350 mg.
`
`blocker are administered concomitantly.
`
`6. The composition according to claim 2, wherein the
`
`11. The process according to claim 8, wherein the Hz
`NSAID is 975 mg of aspirin,
`the Ht receptor blocker is
`
`
`receptor blocker is ranitidine or a pharmaceutically
`5
`50 mg of diphenhydramine
`HCl, and the Hz receptor
`
`acceptable salt of ranitidine.
`blocker is 10 mg of ranitidine
`HCI.
`
`12. The process according to claim 8, wherein the Hz
`
`7. The composition according to claim 3, wherein the
`
`
`receptor blocker is cimetidine or a pharmaceutically
`NSAID is 97S mg of aspirin, the
`
`acceptale salt of cimetidine.
`Ht receptor blocker is
`13. The process according to claim 8, wherein the Hz
`HCl and the Hz receptor 10
`SO mg of diphenhydramine
`
`
`receptor blocker is famotidine or a pharmaceutically
`blocker is SO mg of cimetidine
`HCI.
`
`acceptable salt of famotidine.
`8. A process for reducing the potential
`of aspirin or of
`14. The process according to claim 8, wherein the
`
`
`
`a pharmaceutically acceptable salt of aspirin, to induce
`NSAID and the H 1 and Hz receptor blockers are admin­
`
`gastrointestinal injury in a subject which comprises 15
`from about 200
`istered in a unit dosage form containing
`
`
`administering to said subject, based on the weight of the
`mg to about 600 mg of NSAID, from about 0.1 mg to
`about 70 mg of Ht receptor blocker and from about O.S
`subject,
`mg to about 3SO mg of Hz receptor blocker.
`(a) from about 10 mg to about 100 mg per kg per day
`15. The process according to claim 8, wherein the
`of an NSAID selected
`
`from the group consisting of
`NSAID and the Ht and H2receptor
`blockers are admin­
`
`aspirin and pharmaceutically acceptable salts of 20
`
`istered to a subject in a daily average done based on the
`aspirin;
`of from about 10 mg per kg per
`weight of the subject,
`(b) from about 2.S p.g to about SOO mg per kg per day
`day to about 100 mg per kg per day of NSAID, from
`
`of an Ht receptor blocker selected from the group
`about 2.S g per kg per day to about SOO mg per kg per
`
`
`consisting of diphenydramine and pharmaceuti-
`and from about 10 g per keg
`day of Ht receptor blocker,
`25
`per day to about 1 gm per kg per day of Hz receptor
`
`
`cally acceptable salts of diphenydramine; and
`blocker.
`(c) from about 10 p.g to about 1 g per kg per day of an
`16. The process according to claim 11, wherein 97S
`
`Hz receptor binder selected from the group consist­
`
`SO mg of diphenhydramine HCl and 10
`mg of aspirin,
`
`
`
`ing of cimetidine, ranitidine, famotidine, and phar-
`
`mg of ranitidine HCI are administered.
`30
`
`
`maceutically acceptable salts thereof.
`17. The process according to claim 12, wherein 97S
`9. The process according to claim 8, wherein the
`
`SO mg of diphenhydramine HCI and SO
`mg of aspirin,
`NSAID, the Ht receptor blocker and the Hz receptor
`
`mg of cimetidine HCl are administered.
`* * * * *
`blocker are administered orally.
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65.
`
`

`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`CERTIFICATE OF CORRECTION
`
`PATENT NO.
`DATED
`
`4,757,060
`
`July 12, 1988
`
`Alison B. Luka csko, Randy J . Kosl o, J oseph J. Fiala
`INVENTOR(S)
`
`It is certified
`that error appears
`in the above-identified
`patent
`and that said Letters Patent
`is hereby corrected as shown b elow:
`
`In Column 6, at line 48, change "2.5 g" to --2.5 _u....g-- and,
`at line 52, change "10 g" to --10�--.
`
`In Column 8, at line 24, change "2.5 g" to --2.5 ,v.-g-- and,
`at line 25, change 1110 g" to --10 ;W"g-- and, on the same line,
`change "keg11 to --kg--.
`
`Signed and Sealed this
`
`
`
`Fifth Day of �lay, 1992
`
`DOUGLAS B. COMER
`
`
`
`
`
`Acting Commissioner of Patents and Trademarks
`
`Attest:
`
`
`
`Attesting Officer