United States Patent [191
`Goldman et a1.
`
`[54] PHARMACEUTICAL COMPOSITIONS AND
`METHODS FOR TREATING THE
`SYMPTOMS OF OVERINDULGENCE
`[75] Inventors: William J. Goldman, Ambler;
`Thomas N. Gates, Doylestown, both
`of Pa.
`[73] Assignee: McNeil-PFC, Inc., Milltown, NJ.
`[21] Appl. No.: 876,824
`[22] Filed:
`Apr. 29, 1992
`
`[63]
`
`Related US. Application Data
`Continuation of Ser. No. 430,837, Nov. 2, 1989, aban
`doned.
`
`[51] Int. Cl.5 ....................... .. A61K 9/08; A61K 9/10;
`A61K 9/14
`[52] US. Cl. .................................. .. 424/489; 424/455;
`514/183; 514/359; 514/420; 514/810; 514/811;
`514/816; 514/926; 514/927; 514/937
`[58] Field of Search ............. .. 514/937, 810, 811, 926,
`514/927; 424/441, 489, 455
`References Cited
`U.S. PATENT DOCUMENTS
`
`[56]
`
`4,554,276 11/1985 LaMattina ......................... .. 514/272
`4,676,984 6/1987 Wu et a1.
`.... .. 424/157
`
`4,704,728 11/1987 Wu ct a1. . . . . . . . .
`
`. . . . .. 424/157
`
`4,757,060 7/1988 Lukacsko et a]. .
`4,766,117 8/1988 Crawford et a]. .
`
`4,786,505 11/1988 Lovgren et al. 5,037,815 8/1991 Lukacsko et a].
`
`514/160
`.. 514/219
`
`.. 424/475
`514/557
`
`FOREIGN PATENT DOCUMENTS
`
`woss/o3443 8/1985 PCT 1nt'1 App]. .
`21051931». 9/1982 United Kingdom.
`
`OTHER PUBLICATIONS
`Friedman, L. S., and K. J. Isselbacher: Indigestion in
`Harrison’s Principles of Internal Medicine, 11th Edition,
`1986, McGraw Hill Book Company, N.Y., p. 171-175.
`Glass, G. B. J. L. Slomiany and A. S1omiany,: Biochem
`ical and Pathological Derangements of the Gastrointes
`tinal Tract following Acute and Chronic Ingestion of
`
`Illlllllllllllllllllllllllllll!!!)llll?llllllllllllllllllllllllllllllllll
`
`52041 18A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,204,118
`Apr. 20, 1993
`
`Ethanol in Biochemistry and Pharmacology of Ethanol,
`1979, Plenum Press, N.Y., vol. 1, pp. 551-586.
`Ritchie, J. M.: The Aliphatic Alcohols in Goodman and
`Gilman, The Pharmacological Basis of Therapeutics, 7th
`Edition, 1985, MacMillan Publishing Co, N.Y., pp.
`375-386.
`Lorber, S. H., and V. P. Dimoso, Jr.: Diseases of the
`Gastrointestinal Tract in The Biology of Alcoholism, vol.
`3: Clinical Pathology, 1974 Plenum Press, N.Y., pp.
`339-357.
`Adams, R. D. and J. B. Martin: Headache in Harrison’s
`Principles of Internal Medicine, 11th Edition, 1986,
`McGraw Hill Book Company, N.Y., pp. 26-33.
`Seegers, A. J. M. L. P. Jager, and J. Van Noordwijk:
`Effects of Phenacetin Parcetamol and Caffeine on the
`Erosive Activity of Acetylsalicyclic Acid in the Rat
`Stomach: Dose-Response Relationships, Time Course
`of Erosion Development and Effects of Acid Secretion,
`J. Pharm, Pharmacol 31:840-848, 1979.
`Stem, A. 1., D. L. Hogan, L. H. Kahn, and J. I. Isen
`berg: Protective Effect of Acetaminophen ‘Against As
`pirin-and Ethanol-Induced Damage to the Human
`Gastric Mucosa. Gastroenterology 86:728-733, 1984.
`Deykin, D., P. Janson, and L. McMahon: Ethanol Po
`tentiation of Aspirin-Induced Prolongation of the
`Bleeding Time. NEJM 306:852-854, 1982.
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-James M. Spear
`
`ABSTRACT
`[57]
`This invention relates to a pharmaceutical composition
`for treating the symptoms of overidulgence comprising
`an analgesic effective amount of acetaminophen or a
`non-steroidal anti-in?ammatory drug and a gastric acid
`inhibiting effective amount of an H1 or H; blocker,
`proton pump inhibitor or a combination thereof and
`methods of treating the symptoms of overindulgence
`comprising administering such pharmaceutical compo
`smons.
`
`14 Claims, No Drawings
`
`Lupin Exh. 1014
`
`

`
`1
`
`5,204,118
`
`PHARMACEUTICAL COMPOSITIONS AND
`METHODS FOR TREATING THE SYMPTOMS OF
`OVERINDULGENCE
`
`This is a continuation of application Ser. No.
`07/430,837, ?led Nov. 2, 1989 now abandoned.
`
`FIELD OF THE INVENTION
`This invention relates to pharmaceutical composi
`tions for treating the symptoms of overindulgence.
`More particularly, the invention comprises treating the
`symptoms of overindulgence with a combination of
`non-steroidal anti-in?ammatory drug or acetaminophen
`and a histamine receptor blocker and/or a proton pump
`inhibitor composition.
`BACKGROUND OF THE INVENTION
`Non-steroidal anti-in?ammatory drugs (hereinafter
`referred to as “NSAID(S)”) and acetaminophen (here
`inafter referred to as “APAP”) are known to be effec
`tive analgesics for the treatment of mild to moderate
`pain. Histamine receptor blockers (referred to generi
`cally herein as H1 or H; blockers) are effective inhibi
`tors of gastric acid production. Proton pump inhibitors
`have been recently introduced as effective gastric acid
`inhibitors.
`The symptoms of overindulgence due to excessive or
`inappropriate intake of food and/or alcoholic beverage
`are well known and include headache as well as indiges
`tion, upper abdominal discomfort, bloating, heartburn
`or pyrosis. These latter symptoms collectively are
`sometimes referred to as acid indigestion or sour stom
`ach. Indigestion has been variously described and will
`be de?ned herein as encompassing one or more of the
`following symptoms: abdominal pain and/or pressure,
`heartburn, a sense of abdominal fullness or bloating,
`excessive belching or ?atulence and a vague feeling that
`digestion has not proceeded naturally (See Friedman,
`L. S., and K. J. Isselbacher, “Indigestion”, Harrison’s
`of Internal Medicine, llth Edition, McGraw
`Hill Book Company, N.Y., p 171-175, 1986).
`The pathophysiology of indigestion is generally be
`lieved to be related to increased intraluminal acidity.
`The effects of alcohol and/or food on the gastrointesti
`nal tract are in?uenced by a number of factors, includ
`ing the mental state of the patient, the amount and type
`of food concurrently ingested, the individual subject’s
`tolerance for alcohol and the presence or absence of
`disease. Gastric secretions stimulated by alcohol are
`rich in acid and normal in pepsin content. Stimulation of
`the antral mucosa by alcohol also leads to increased
`gastric secretion. Histamine has also been shown to be
`released in response to the alcohol-gastrin inter-rela
`tionship. (See Glass, G. B. J., B. L. Slomiany and A.
`Slomiany, “Biochemical and Pathological Derange
`ments of the Gastrointestinal Tract following Acute
`and Chronic Ingestion of Ethanol”, Biochemistry and
`Pharmacology of Ethanol. Vol 1, Plenum
`
`

`
`5,204,118
`
`3
`SUMMARY OF THE INVENTION
`The foregoing object of ful?lling a long felt need for
`pharmaceutical compositions which can relieve the
`symptoms of overindulgence de?ned herein as head
`ache and acid indigestion has now
`
`

`
`EXAMPLES
`The invention will now be illustrated by examples.
`The examples are not intended to be limiting of the
`scope of the present invention but read in conjunction
`with the detailed and general description above, pro
`vide further understanding of the present invention and
`an outline of a process for preparing the compositions of
`the invention. Example l-lO disclose various formula
`tions for preparing tablets or caplets in accordance with
`the invention. Various conventional techniques for pre
`paring medicament tablets or caplets can
`
`5,204,118
`5
`6
`mine receptor is called an H2 receptor with the inhibi
`Other ingredients both active and inactive can be
`added to the combination pharmaceutical compositions
`tors of this site being called the H2 receptor blocker, the
`of the invention. For example, flavoring compositions
`histamine H1 receptor site blockers comprise another
`are desirably added to chewable and liquid dosage
`class of antihistamine drugs. The combination of H1 and
`forms. Further, antidiarrheal, anti?atulent, antispas
`H; blockers can synergistically protect the gastrointesti
`modic and/or anticholinergic compositions may be
`nal mucosa from the effects of chemically induced dam
`added to the compositions of the invention to reduce
`age such as occurs in alcohol and food related overin
`dulgence.
`and relieve gastrointestinal distress, which may be asso
`ciated with acid indigestion. Examples of antidiarrheals
`The composition of the present invention shall prefer
`include loperamide, atta'pulgite, bismuth subsalicylate,
`ably contain a combination of the following composi
`diphenoxylate HCl, polycarbophil, calcium polycarbo
`tions or their pharmaceutically acceptable salts either
`phil and mixtures thereof. An example of an anti?atu
`acetaminophen from 500 to 1000 mg per dose or one of
`lent is simethicone. Examples of antispasmodics include
`several NSAIDs from the group of: propionic acid
`phenobarbital dicyclomine HCl, belladonna alkaloids,
`derivatives including ibuprofen (the term ibuprofen is
`and atropine.
`meant to include administration of both racemic
`mixture of R- and S-enantiomers and the substantially
`pure S-enantiomer which is the analgesic active form of
`ibuprofen) from 200 to 400 mg per dose; naproxen from
`200 to 500 mg per dose; fenoprofen from 200 to 600 mg
`per dose; ketoprofen from 50 to 300 mg per dose, me
`clofenamate from 50 to 400 mg per dose, mefenamic
`acid from 250 to 500 mg per dose; piroxicam from 10 to
`20 mg per dose; indomethacin from 25 to 200 mg per
`dose, sulindac from 150 to 400 mg per dose, tolmetin
`from 200 to 1200 mg per dose; in combination with the
`H2 receptor blocking drugs including cimetidine from
`150 to 800 mg per dose; ranitidine from 50 to 300 mg per
`dose; famotidine from 5 to 40 mg per dose; or in combi
`nation with the..proton pump inhibitor drugs including
`omeprazole from 60 to 500 mg per dose; and/or an H1
`receptor blocking drug from the group ethanolamines
`including diphenhydramine 25 to 200 mg per dose;
`dimenhydrinate from 50 to 400 mg per dose, carbinoxa
`mine from 4 to 8 mg per dose; from the group
`ethylenediamines including tripelennamine from 25 to
`300 mg per dose; pyrilamine from 25 to 100 mg per
`dose; from the group alkylamines including chlorphen
`iramine from 2 to 24 mg per dose, from the group piper
`azines including hydroxyzine from 25 to 100 mg per
`dose, cyclizine from 50 to 300 mg per dose, meclizine
`from 8 to 400 mg per dose; and from the group pheno
`thiazines including promethazine from 12.5 to 50 mg
`per dose.
`-
`The dosage ranges described above are preferred
`adult doses and may vary depending upon the age and
`weight of the patient as would be known by those
`skilled in the Pharmaceutical arts. Further, if a combi
`nation of, for example an H1 and H2 blocker is used, the
`dosage for each may be reduced.
`'
`
`To establish the **********************cy of the composition of this
`invention in humans, patients suffering from the symp
`toms of overindulgence which will include any of the
`constellation of signs of indigestion, upper abdominal
`discomfort, bloating, heartburn or pyrosis and headache
`can be administered acetaminophen or a non-steroidal
`anti-in?ammatory drug with and without histamine
`receptor blockers (H1 and/or H2 blocking agents). To
`determine efficacy, patients are asked to subjectively
`estimate onset of relief, duration of relief and time to
`maximum relief. Appropriate statistical methods are
`used to show that on the average, acetaminophen or
`non-steroidal anti-in?ammatory agents with H1 hista
`mine and/or H2 histamine receptor blocking drugs are
`65
`more efficacious.
`‘
`Since appropriate animal models for the evaluation of
`overindulgence are not available, studies will not be
`conducted involving laboratory animals.
`
`5
`
`45
`
`

`
`7
`other auxiliary agents and coloring agents.
`
`EXAMPLE 7
`A tablet consisting of:
`500 mg of acetaminophen;
`150 mg of cimetidine;
`25 mg of diphenhydramine; and
`other auxiliary agents and coloring agents.
`
`EXAMPLE 8
`A tablet consisting of:
`200 mg of ibuprofen;
`150 mg of cimetidine;
`25 mg of diphenhydramine; and
`other auxiliary agents and coloring agents.
`EXAMPLE 9
`A tablet consisting of:
`500 mg of acetaminophen;
`50 mg of ranitidine;
`25 mg of diphenhydramine; and
`other auxiliary agents and coloring agents.
`
`EXAMPLE 10
`A tablet consisting of:
`200 mg of ibuprofen;
`50 mg of ranitidine;
`25 mg of diphenhydramine; and
`other auxiliary agents and coloring agents.
`
`EXAMPLE 1 l
`A tablet consisting of:
`500 mg of acetaminphen;
`60 mg of omeprazole; and
`other auxiliary agents and coloring agents.
`
`EXAMPLE 12
`A tablet consisting of:
`200 mg ibuprofen;
`60 mg omeprazole; and
`other auxiliary agents and coloring agents.
`
`EXAMPLE 13
`A tablet consisting of:
`500 mg acetaminophen;
`60 mg omeprazole;
`25 mg diphenhydramine; and
`other auxiliary agents and coloring agents.
`
`EXAMPLE 14
`A tablet consisting of:
`200 mg ibuprofen;
`60 mg omeprazole;
`25 mg diphenhydrarnine; and
`other auxiliary agents and coloring agents.
`Various other dosage forms can be applied herein
`such as a ?lled gelatin capsule, liquid emulsion/suspen
`sion or chewable tablet form employing the dosage
`actives provided above or other dosage amounts in
`accordance with the present invention. A liquid suspen
`sion of ibuprofen to which cimetidine, diphenhydra
`mine, ranitidine or combinations thereof in the amounts
`provided above can be added to the ibuprofen suspen
`sion disclosed in co-pending US. patent application Ser.
`65
`No. 372,734, now abandoned, the entire disclosure of
`this patent application is hereby incorporated herein by
`reference.
`
`55
`
`60
`
`5,204,118
`
`15
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`METHOD OF TREATING PATIENTS FOR THE
`SYMPTOMS OF OVERINDULGENCE
`A patient exhibiting the symptoms or suffering from
`the symptoms of overindulgence
`administration of one tablet of the pharmaceutical com
`position in accordance with any of Examples l-lO.
`The scope of the present invention is not limited by
`the description, examples and suggested uses herein and
`modi?cations can be made without departing from the
`spirit of the invention. For example, the pharmaceutical
`compositions of the invention may be provided in a
`sustained release formulation for prolonged and/or
`nightime treatment of the symptoms of overindulgence.
`Application of the compositions and methods of the
`present invention for medical and pharmaceutical uses
`can be accomplished by any clinical, medical and phar
`maceutical methods and techniques as are presently or
`prospectively known to those skilled in the art. Thus it
`is intended that the presently claimed invention cover
`the modi?cations and variations of this invention pro
`vided that they come within the scope of the appended
`claims and their equivalents.
`What is claimed is:
`1. A pharmaceutical composition for treating the
`symptoms of overindulgence due to the excessive or
`inappropriate intake of food and/ or alcoholic beverages
`comprising a therapeutically effective amount of an
`analgesic and a gastric acid inhibiting effective amount
`of a proton pump inhibitor wherein the therapeutically
`effective amount of the analgesic is selected from the
`group consisting of acetaminophen from 500 to 1000 mg
`per dose, ibuprofen from 200 to 400 mg per dose, na
`proxen from 200 to 500 mg per dose, fenoprofen from
`200 to 600 mg per dose, ketoprofen from 50 to 300 mg
`per dose, meclofenamate from 50 to 400 mg per dose,
`mefenamic acid from 250 to 500 mg per dose, piroxicam
`from 10 to 20 mg per dose, indomethacin from 25 to 200
`mg per dose, sulindac from 150 to 400 mg per dose,
`tolmetin from 200 to 1200 mg per dose and phar
`maceutically acceptable salts; in combination with an
`effective amount of the proton pump inhibitor ome
`prazole of from 60 to 500 mg per dose and its pharma
`ceutically acceptable salts.
`2. A pharmaceutical composition in accordance with
`claim 1 comprising a combination of ibuprofen and
`omeprazole.
`3. A pharmaceutical composition in accordance with
`claim 1 comprising acetaminophen and omeprazole.
`4. A pharmaceutical composition in accordance with
`claim 1 comprising a racemic mixture of R- and S-ibu
`profen, substantially pure S-ibuprofen or naproxen and
`omeprazole.
`5. A pharmaceutical composition in accordance with
`claim 1 wherein additionally there is present a therapeu
`tically effective amount of an H1 on H2 receptor blocker
`selected from the group consisting of cimetidine from
`150 to 800 mg per dose, ranitidine from 50 to 300 mg per
`dose, famotidine from 5 to 40 mg per dose, diphenhy
`dramine 25 to 200 mg per dose, dimenhydrinate from 50
`to 400 mg per dose, carbinoxamine from 4 to 8 mg per
`dose, tripelennamine from 25 to 300 mg per dose, pyrila
`mine from 25 to 100 mg per dose, chlorpheniramine
`from 2 to 24 mg per dose, hydroxyzine from 25 to 100
`mg per dose, cyclizine from 50 to 300 mg per dose,
`meclizine from 8 to 400 mg per dose and promethazine
`from 12.5 to 50 mg per dose.
`
`

`
`5,204,118
`9
`6. A pharmaceutical composition in accordance with
`claim 1 comprising naproxen and omeprazole.
`7. A pharmaceutical composition in accordance with
`claim 1 wherein the pharmaceutical composition is in
`liquid dosage form.
`8. A method of treating the symptoms of overindul
`gence due to the excessive or inappropriate intake of
`food and/or alcoholic beverages comprising adminis
`tering to a patient suffering from the symptoms of over
`indulgence a combination pharmaceutical composition
`comprising a therapeutically effective amount of an
`analgesic and a gastric acid inhibiting effective amount
`of a proton pump inhibitor wherein the therapeutically
`effective amount of analgesic is selected from the group
`consisting of acetaminophen from 500 to 1000 mg per
`dose, ibuprofen from 200 to 400 mg per dose, naproxen
`from 200 to 500 mg per dose, fenoprofen from 200 to
`600 mg per dose, ketoprofen from 50 to 300 mg per
`dose, meclofenamate from 50 to 400 mg per dose, mefe
`namic acid from 250 to 500 mg per dose, piroxicam
`from 10 to 20 mg per dose, indomethacin from 25 to 200
`mg per dose, sulindac from 150 to 400 mg per dose,
`tolmetin from 200 to 1200 mg per dose and their phar-v
`maceutically acceptable salts; in combination with an
`effective amount of a proton pump inhibitor selected
`from the group consisting of omeprazole from 60 to 500
`mg per dose, and its pharmaceutically acceptable salts.
`9. The method of claim 8 wherein the pharmaceutical
`composition comprises acetaminophen, omeprazole and
`additionally an H2 receptor blocker selected from the
`
`15
`
`20
`
`25
`
`10
`group consisting of cimetidine, ranitidine, famotidine
`and pharmaceutically acceptable salts thereof.
`10. The method of claim 8 wherein the pharmaceuti
`cal composition comprises acetaminophen, omeprazole
`and additionally H1 receptor blocker selected from the
`group consisting of diphenhydramine, dimenhydrinate,
`carbinoxamine, tripelennamine, pyrilamine, chlorphen
`iramine, hydroxyzine, cyclizine, meclizine, prometha
`zine, and pharmaceutically acceptable salts thereof.
`11. The method of claim 8 wherein the pharmaceuti
`cal composition comprises ibuprofen or naproxen, ome
`prazole and additionally an H1 receptor blocker se
`lected from the group consisting of cimetidine, raniti
`dine, famotidine and pharmaceutically acceptable salts
`thereof.
`12. The method of claim 8 wherein the pharmaceuti
`cal composition comprises ibuprofen or naproxen, ome
`prazole and additionally an H1 receptor blocker se
`lected from the group consisting of diphenhydramine,
`dimenhydrinate, carbinoxamine, tripelennamine, pyrila
`mine, chlorpheniramine, hydroxyzine, cyclinzine, mec
`lizine, promethazine, and pharmaceutically acceptable
`salts thereof.
`13. The method of claim 8 wherein the pharmaceuti
`cal composition comprises a combination of ibuprofen
`and omeprazole.
`14. The method of claim 8 wherein the pharmaceuti
`cal composition comprises naproxen and omeprazole.
`
`I
`
`* # i 0
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65