United States Patent [191
`Goldman et al.
`
`11111111111111111111111111111111111111111111111 IIIII 11111111111111111111111
`
`
`
`
`
`
`
`
`
`
`
`US005204 118A
`[II] Patent Number: 5,204,118
`[45) Date of Patent: Apr. 20, 1993
`
`[54] PHARMACEUTICAL COMPOSITIONS AND
`METHODS FOR TREATING THE
`SYMPTOMS OF OVERINDULGENCE
`
`[21] Appl. No.: 876,824
`
`[22] Filed: Apr. 29, 1992
`
`
`
`Related U.S. Application Data
`
`of Ser. No. 430,837, Nov. 2, 1989, aban­
`[63]
`Continuation
`doned.
`
`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
`William J. Goldman, Ambler;
`
`The Pharmacological Basis of Therapeutics, 7th
`Gilman,
`[75] Inventors:
`
`
`
`Edition, 1985, MacMillan Publishing Co, N.Y., pp.
`
`Thomas N. Gates, Doylestown, both
`375-386.
`ofPa.
`Lorber, S. H., and V. P. Dimoso, Jr.: Diseases of the
`[73] Assignee:
`
`McNeil-PPC, Inc., Milltown, N.J.
`
`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
`Acid in the Rat
`Int. CJ.s .............
`
`Erosive Activity of Acetylsalicyclic
`
`............ A61K 9/08; A61K 9/10;
`[51]
`
`
`
`Stomach: Dose-Response Relationships, Time Course
`A61K 9/14
`U.S. CI . ...........
`
`
`of Erosion Development and Effects of Acid Secretion,
`
`......................... 424/489; 424/455;
`[52]
`
`
`J. Pharm, Pharmacol 31:840-848, 1979.
`
`
`
`514/183; 514/359; 514/420; 514/810; 514/811;
`
`
`
`514/816; 514/926; 514/927; 514/937
`Stern, A. I., D. L. Hogan, L. H. Kahn, and J. I. Isen­
`
`
`Field of Search ............... 514/937, 810, 811, 926,
`
`
`
`berg: Protective Effect of Acetaminophen Against As­
`[58)
`
`514/927; 424/441,489,455
`
`
`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.
`4,554,276 11/1985 LaMattina ........................... 514/272
`
`4,676,984 6/1987 Wu et al. ............................. 424/157
`Primary Examiner-Thurman K. Page
`
`4,704,728 11/1987 Wu et al. ............................. 424/157
`
`4,757,060 7/1988 Lukacsko et al. .................. 514/160
`Assistant Examiner-James
`M. Spear
`
`4,766,117 8/1988 Crawford et al. .................. 514/219
`
`4,786,505 11/1988 Lovgren et al. .................... 424/475
`[57]
`
`5,037,815 8/1991 Lukacsko et al. .................. 514/557
`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-inflammatory drug and a gastric acid
`
`
`inhibiting effective amount of an H1 or H2 blocker,
`
`
`
`proton pump inhibitor or a combination thereof and
`
`
`
`Friedman, L. S., and K. J. Isselbacher: Indigestion in
`
`methods of treating the symptoms of overindulgence
`
`
`
`Harrison's Principles of Internal Medicine, 11th Edition,
`
`
`
`comprising administering such pharmaceutical compo­
`1986, McGraw Hill Book Company, N.Y., p. 171-175.
`sitions.
`
`
`
`Glass, G. B. J. L. Slomiany and A. Slomiany,: Biochem­
`
`
`ical and Pathological Derangements of the Gastrointes­
`
`
`tinal Tract following Acute and Chronic Ingestion of
`
`[56]
`
`
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`FOREIGN PATENT DOCUMENTS
`
`WO 85/03443 8/1985 PCT lnt'l Appl. .
`2105193A 9/1982 United Kingdom .
`
`OTHER PUBLICATIONS
`
`ABSTRACT
`
`14 Claims, No Drawings
`
`

`
`1
`
`5,204,118
`
`PHARMACEUTICAL COMPOSITIONS AND
`METHODS FOR TREATING THE SYMPTOMS OF
`OVERINDULGENCE
`
`2
`1985). The irritation produced by alcohol stimulates
`
`
`
`sensitized visceral afferent nerves which accompany
`
`the abdominal sympathetic pathway and is responsible
`
`for the symptom of abdominal discomfort which ac-
`5 companies overindulgence. Inflammation
`also generally
`This is a continuation of application Ser. No.
`
`
`
`
`
`lowers the threshold for pain from visceral distention or
`
`07/430,837, filed Nov. 2, 1989 now abandoned.
`
`exaggerated muscular contraction (See Lorber, S. H.,
`and V. P. Dimoso, Jr., "Diseases of the Gastrointestinal
`FIELD OF THE INVENTION
`
`
`Tract", The Biology of Alcoholism, Vol 3, Clinical Pa-
`lO thology, Plenum
`This invention relates to pharm aceutical composi­
`
`
`Press, N.Y., p 339-357, 1974).
`is frequently
`
`tions for treating the symptoms of overindulgence.
`Heartburn or pyrosis
`
`associated with
`and is the result of reflux of acidic
`
`
`
`
`More particularly, the invention comprises treating the
`overindulgence
`gas­
`
`
`symptoms of overindulgence with a combination of
`
`tric content into the lower esophagus after a large meal
`
`
`non-steroidal anti-inflammatory drug or acetaminophen
`
`
`
`or excessive alcohol intake. Heartburn is described as a
`15 sensation of warmth or burning located substernally or
`
`
`and a histamine receptor blocker and/or a proton pump
`inhibitor composition.
`
`
`
`high in the epigastrum with occasional radiation into
`
`the neck and occasionally to the arms.
`BACKGROUND OF THE INVENTION
`Treatment of the gastric mucosal irritation and heart-
`
`
`
`has
`
`
`
`
`Non-steroidal anti-inflammatory drugs (hereinafter burn assoc iated with overindulgence due to alcohol
`(here-20 traditionally
`
`
`referred to as "NSAID(S)") and acetaminophen
`been directed toward reducing gastric
`
`
`
`
`Recent introduction oral antacids. with various inafter referred to as "APAP") are known to be effec- acidity
`
`
`
`
`tive analgesics for the treatment of mild to moderate of H2 receptor blocking agents has added another di-
`
`
`regimen and has only lately pain. Histamine receptor blockers (referred to generi-mension to the treatment
`
`
`
`
`
`mucosal for gastric as a routine therapy cally herein as Ht or H2 blockers) are effective inhibi-been considered
`
`
`
`
`
`
`
`
`tors of gastric acid production. Proton pump inhibitors 25 irritation due to a variety of causes. Histamine is known
`
`
`
`
`
`
`is acid. Evidence of gastric the release have been recently introduced as effective gastric acid to stimulate
`
`
`available
`that blocking the histamine
`inhibitors.
`gastric
`response is
`
`
`
`
`The symptoms of overindulgence due to excessive or possible with agents which selectively block the Ht
`
`
`
`
`
`inappropriate intake of food and/or alcoholic beverage receptor. Similarly, combinations of Hand H2 receptor
`30 blocking agents have been shown to have a synergistic
`
`
`are well known and include headache as well as indiges-
`
`
`
`
`
`An appropriate the gastric mucosa. tion, upper abdominal discomfort, bloating, heartburn effect on protecting
`
`
`
`
`
`
`
`or pyrosis. These latter symptoms collectively are treatment of heartburn or pyrosis could encompass a
`
`
`
`
`
`
`sometimes referred to as acid indigestion or sour stom-composition containing an Hreceptor blocking agent,
`
`
`
`
`
`
`ach. Indigestion has been variously described and will an H2 receptor blocking agent or a combination of the
`one or more of the 35 two depending
`be defined herein as encompassing
`
`
`
`upon the desired result or severity of the
`
`
`following symptoms: abdominal pain and/or pressure, condition.
`heartburn, a sense of abdominal fullness or bloating, Headache due to excessive food or alcohol ingestion
`
`
`
`
`
`
`
`
`
`
`
`
`
`excessive belching or flatulence and a vague feeling that is a much more obscure subject. While the etiology of
`
`
`
`
`digestion has not proceeded naturally (See Friedman, the common headache due to overindulgence may be
`40 related
`Harrison's
`
`L. S., and K. J. Isselbacher, "Indigestion",
`
`
`
`to the essential oils, metabolic by-products of
`
`Principles of Internal Medicine, lith Edition,
`
`
`
`
`McGraw ethyl alcohol metabolism or osmotic changes induced
`
`
`
`by the anhydrous nature of the alcohol itself, specific
`
`
`Hill Book Company, N.Y., p 171-175, 1986).
`
`
`
`
`are difficult to determine. of the mechanism The pathophysiology of indigestion is generally be- details
`
`
`
`
`
`
`
`Iieved to be related to increased intraluminal acidity. Should etiologies and mechanisms of headache produc-
`
`
`
`
`The effects of alcohol and/or food on the gastrointesti-45 tion be more precisely known, therapy can be more
`
`
`
`
`nal tract are influenced by a number of factors, includ-specifically oriented. Meanwhile, treatment has been
`
`
`
`
`
`therapy with and symptomatic at avoidance ing the mental state of the patient, the amount and type directed
`
`
`
`of food concurrently ingested, the individual subject's
`
`
`
`analgesic compositions, e.g. aspirin or APAP (See
`Ha"ison's
`
`
`
`
`tolerance for alcohol and the presence or absence of Adams, R. D. and J. B. Martin, "Headache",
`are 50 Principles of Internal Medicine, 11th Edition,
`McGraw
`
`
`
`
`disease. Gastric secretions stimulated by alcohol
`
`
`
`rich in acid and normal in pepsin content. Stimulation of Hill Book Company, N.Y., p 26-33, 1986).
`
`
`
`the antral mucosa by alcohol also leads to increased The treatment of the symptoms of overindulgence
`
`
`
`
`
`
`gastric secretion. Histamine has also been shown to be often requires the co-administration of an analgesic to
`
`
`
`released in response to the alcohol-gastrin inter-rela-
`
`
`relieve the headache along with an agent to reduce
`and A. 55 gastric
`(See Glass, G. B. J., B. L. Slomiany
`tionship.
`
`
`acidity which is generally believed to cause the
`
`
`
`
`
`Slomiany, "Biochemical and Pathological Derange-indigestion and heartburn. For example, effervescent
`
`
`
`with products comprising aspirin or AP AP combined
`
`ments of the Gastrointestinal Tract following Acute
`
`
`
`Biochemistry and an antacid such as sodium or calcium carbonates have
`
`and Chronic Ingestion of Ethanol",
`
`
`
`Pharmacology of Ethanol. Vol 1, Plenum Press, N.Y., p been commercially available as treatments for the symp-
`60 toms of overindulgence.
`
`551-586, 1979.)
`
`
`
`Alcohol in concentrations of about 10% in the stom- The concept of combining an agent to reduce or
`
`
`
`
`ach results in an acid rich secretion. Alcoholic drinks of inhibit the production of gastric acid with an analgesic
`
`
`
`
`
`been heretofore has, however, composition 40% concentration and over are quite irritating to the in a single
`
`
`
`gastric mucosa and cause congestive hyperemia and
`
`
`overlooked as a method of treating overindulgence.
`mucosa and can produce 65 Such a combination
`
`inflammation of the gastric
`
`would be a significant advance and
`
`
`
`
`
`erosive gastritis (See Ritchie, J. M., "The Aliphatic meet a long felt need for treating the symptoms of over-
`
`
`
`Basis of Therapeutics, indulgence, permitting a single composition to more
`The Pharmacological
`Alcohols",
`
`
`
`
`
`7th Edition, MacMillan Publishing Co, N.Y., p 372-386, effectively treat all the symptoms concurrently.
`
`

`
`fs
`tt
`
`3
`
`5,204,118
`
`4
`proven analgesic
`and
`clinically
`APAP, a well-known
`SUMMARY OF THE INVENTION
`the pain
`by elevating
`analgesia
`produces
`antipyretic,
`as an analgesic
`for both
`AP AP is indicated
`a long felt need for threshold.
`of fulfilling
`object
`The foregoing
`arthritic
`including
`pain conditions,
`the acute and chronic
`which can relieve
`compositions
`pharmaceutical
`defined herein as head-5 and rheumatic
`conditions
`involving
`musculoskeletal
`of overindulgence
`symptoms
`and neuralgias.
`myalgias
`dysmenorrhea,
`in pain, headache,
`has now been accomplished
`ache and acid indigestion
`producing
`rarely
`safe analgesic,
`and methods of the APAP is an extremely
`with the compositions
`accordance
`by aspirin-
`well tolerated
`and is especially
`side-effects
`invention.
`present
`and J.
`A. J. M., L. P. Jager,
`(Seegers,
`patients.
`as sensitive
`with the purposes of the invention,
`In accordance
`10 Van Noordwijk, "Effects of Phenacetin
`Parcetamol and
`the invention
`embodied and fully described herein,
`of Acetylsalicylic
`Activity
`and methods Caffeine on the Erosive
`compositions
`pharmaceutical
`comprises
`Dose-Response Relation-
`compris-Acid in the Rat Stomach:
`of overindulgence
`the symptoms
`for treating
`Development
`and Ef-
`Time Course of Erosion
`amount of an NSAID or ships,
`effective
`ing an analgesic
`J. Pharmacal 31:840-848,
`amount of fects of Acid Secretion",
`effective
`acid inhibiting
`APAP and a gastric
`or a 15 1979), have shown that APAP decreases the gastric
`an HI or H2 blocker or, a proton pump inhibitor
`ulcerogenic NSAID.
`of a strongly
`activity
`erosive
`thereof.
`combination
`the NSAID is selected (Stem, A. I., D. L. Hogan, L. H. Kahn, and J. I. !sen-
`embodiments
`In preferred
`Against
`Effect of Acetaminophen
`ber�, . "Protective
`acid derivatives
`of propionic
`from the grou consisting
`p
`Damage to the Human
`Ethanol-Induced
`Aspmn-and
`fi
`fi fi
`�� '
`·
`d k
`an eto-
`mcludmg 1bupro en, enopro en, naproxen
`. M , G
`as troe �ero �-I
`.
`.
`20
`astnc
`l 86 728 733 1984)
`APAP
`
`G
`meclofena-
`including
`acid derivatives,
`fenamic
`profen;
`mg � ose
`dd"
`o dam
`pirox-ave a Jtu:�n .fiY s 0
`h
`wn t a
`h
` a
`including
`acid; oxicams,
`mate and mefenamic
`. . 1 d" .
`.
`.
`.
`d h . 1. prevents
`cosal
`-
`a s1gru Jean amoun o gastnc mu
`t
`me u mg m omet acm, su m-
`ac1ds,
`Jearn; mdole acetJc
`·
`· d al h 1 F rth APAP
`. II
`d b both
`bl sal age cause y asp1nn an co o . u er,
`·
`y accepta e ts .
`and pharmaceutJca
`dac, tolmetm;
`rt" 1 1 II "t d
`· h"b" IS pa 1cu ar y we sm e as an an ges1c m pa 1en
`· t" ts
`al ·
`fi H H
`The pre erred 1 or 2 or prot_o� pump m 1 J-25 with hemostatic
`thereof.
`0� the H2 upper gastrointestinal
`disturbances
`as well as in patients
`with
`from the g�oup_ �onsJstm� .
`tors are selecte?
`gastri-
`ulcers,
`including
`disorders
`ramt1dme
`and t" d h" t h
`drugs cJmetJdme,
`blocking
`receptor
`·
`.
`1 IS an 1a us erma.
`. .
`h"b" d
`the proton pum� m 1 Uor rug omeprazo
`e; Aspirin
`famotJdme;
`and the � 1 rec�ptor _block!ng drugs, fr?m th� group the treatment
`used for
`are commonly
`and other NSAIDs
`et�anolamme� mclu?mg dJphenhydr
`amme, dJmen�y-30 etiologies.
`of a variety
`of
`of pain and inflammation
`of action of this class of
`The mechanism
`oxa�me, fro� the g�oup_ ethylenedJa-
`dr�m ate,_ carbJ
`of the enzyme of prostaglandin
`drugs is by inhibition
` tn�elenn�mme, pynla�me,
`rom the synthetase,
`mmes, mcludm
`The periph-
`and peripherally.
`both centrally
`�me, fro'!l era! prostaglandin
`. mcl�dmg �hlorphemra
`group alkyla�mes •
`t�e group_ �nperazmes,
`activity
`of aspi-
`inhibiting
`synthetase
`mcludmg hydr�x�zme,_ cych-rin and other NSAIDs is responsible
`for the anti-inflam-
`�s, mclud-35 matory and analgesic
`zme, mechzme: from the group phenothJazm
`ing promet�azme. In more prefe�red em� J�ents t_he varied
`activity
`as well as for many of the
`is specifically
`Aspirin
`of these drugs.
`side-effects
`are used m. combmat1on
`With excluded
`APAP or Ibuprofen
`by itself,
`since aspirin,
`from this invention
`cimetidine.
`In the
`mucosa.
`of the gastric
`inflammation
`severe
`. . causes
`.
`.
`herem,
`he m- presence
`and br?adly descnbed
`As embod1ed
`c?mpnses a metho�. for tre�t�ng �he 40 Similarly,
`is enhanced.
`of aspirin
`this effect
`of alcohol,
`further
`vention
`prolongation
`of bleeding
`time induced
`by
`(See
`compnsmg admm1stenng
`of ovenndulgence
`symptoms
`in the presence of alcohol
`is enhanced
`aspirin,
`to a patient
`composition
`pharmaceutical
`a combination
`D., P. Janson and L. McMahon, "Ethanol
`Deykin,
`amount of APAP or Potentiation
`effective
`an analgesic
`comprising
`ert:ect�v
`Prolongation
`of the
`of Aspirin-Induced
`acid inhibiting
` Bleeding
`an NSAID and a gastric
`Time", New England Journal of Medicine.
`or, a proton pump mh1b1-45 306:852-854, 1982). For these reasons
`is not a
`amount of an H1 or H2 blocker
`aspirin
`above. rational
`as is described
`thereof
`tor or a combination
`alone or in combination
`with
`choice either
`acid indigestion
`in gen­
`for treating
`other compositions
`OF PREFERRED
`DETAILED DESCRIPTION
`While other
`to overindulgence.
`eral and as it relates
`EMBODIMENTS OF THE INVENTION
`stomach
`lead to increased
`NSAIDs can by themselves
`so
`to preferred
`will now be made in detail
`Reference
`this effect is not as severe with the combinations
`upset,
`of which are
`examples
`of the invention,
`embodiments
`gastric acid inhibiting
`which combine
`of the invention
`section.
`examples
`in the following
`illustrated
`of an H 1 or H2 blocker or a proton pump inhibi­
`amounts
`of providing
`a
`of the invention
`the object
`To achieve
`with such NSAIDs as with
`thereof
`tor or a combination
`the symp­
`the symptoms
`for treating
`composition
`pharmaceutical
`in treating
`and they are thus useful
`aspirin,
`amount of 55
`effective
`an analgesic
`of overindulgence
`with the combi­
`in accordance
`toms of overindulgence
`with a gastric acid
`APAP or an NSAID is combined
`of the invention.
`composition
`nation
`amount of an H1 or H2 blocker or a
`effective
`inhibiting
`and histamine
`acetylcholine
`of gastrin,
`The presence
`thereof.
`or a combination
`proton pump inhibitor
`receptor
`with the histamine
`interacting
`in the stomach
`in accordance
`with
`of overindulgence
`The treatment
`cell results in the increased secretion of
`on the parietal
`defmed for the 60
`and as hereinafter
`the present invention
`of gastrin and acetyl­
`acid. The activity
`hydrochloric
`to the symptom­
`is directed
`purposes of this invention
`by histamine.
`Inhi­
`to be influenced
`are believed
`choline
`of acid indigestion
`and
`of the complaints
`atic relief
`the attachment
`prevents
`receptor
`of the histamine
`bition
`cell and subsequently
`inhib­
`to the parietal
`of histamine
`the use of an agent which
`This requires
`headache.
`a proton pump inhibitor,
`Omeprazole,
`its acid secretion.
`discomfort
`and
`abdominal
`would treat the headache,
`65
`for acid
`the enzyme responsible
`inhibits
`irreversibly
`Since no single
`acidity.
`gastric
`reduce the intraluminal
`production.
`the multi­
`of treating
`agent has been found to be capable
`are differentiated
`by the
`receptors
`The histamine
`a composition
`such as
`of overindulgence,
`ple symptoms
`hista-
`so that while the acid secreting
`class of inhibitor
`is recommended.
`in this invention
`is described
`
`f.
` -
`:d
`
`.e
`
`_f
`
`_t
`
`_n
`
`_g
`
`

`
`5,204,118
`
`30
`
`5
`6
`mine receptor is called an H2 receptor with the inhibi­
`
`
`Other ingredients both active and inactive can be
`
`
`
`
`
`tors of this site being called the H2 receptor blocker, the
`
`
`added to the combination pharmaceutical compositions
`
`
`
`of the invention. For example, flavoring compositions
`
`
`
`histamine H1 receptor site blockers comprise another
`
`
`are desirably added to chewable and liquid dosage
`
`
`of H 1 and class of antihistamine drugs. The combination
`5
`
`
`
`forms. Further, antidiarrheal, antiflatulent, antispas­
`
`
`
`H2 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
`which may be asso ­
`
`
`and relieve gastrointestinal distress,
`dulgence.
`
`
`
`ciated with acid indigestion. Examples of antidiarrheals
`
`
`
`The composition of the present invention shall prefer­
`10 include
`
`
`loperamide, attapulgite, bismuth subsalicylate,
`ably contain a combination of the following composi­
`
`
`
`
`
`
`diphenoxylate HCI, polycarbophil, calcium polycarbo­
`
`tions or their pharmaceutically acceptable salts either
`
`from SOO to 1000 mg per dose or one of
`
`phil and mixtures thereof. An example of an antiflatu­
`acetaminophen
`
`
`
`lent is simethicone. Examples of antispasmodics include
`
`several NSAIDs from the group of: propionic acid
`
`
`
`phenobarbital dicyclomine HCI, belladonna alkaloids,
`
`derivatives including ibuprofen (the term ibuprofen is
`
`
`
`15
`and atropine.
`
`
`meant to include administration of both the racemic
`
`
`mixture of R-and S-enantiomers and the substantially
`EXAMPLES
`
`
`
`pure S-enantiomer which is the analgesic active form of
`from 200 to 400 mg per dose; naproxen
`The invention will now be illustrated by examples.
`
`
`ibuprofen)
`from
`from 200 to 600 mg
`
`
`
`The examples are not intended to be limiting of the
`from 50 to 300 mg per dose, me-20
`200 to 500 mg per dose; fenoprofen
`
`scope of the present invention but read in conjunction
`per dose; ketoprofen
`from 50 to 400 mg per dose, mefenamic
`
`
`
`with the detailed and general description above, pro­
`clofenamate
`
`
`
`vide further understanding of the present invention and
`
`acid from 250 to 500 mg per dose; piroxicam from 10 to
`
`
`
`an outline of a process for preparing the compositions of
`
`20 mg per dose; indomethacin from 25 to 200 mg per
`from 150 to 400 mg per dose, tolmetin
`
`the invention. Example 1-10 disclose various formula­
`25
`dose, sulindac
`
`
`
`
`tions for preparing tablets or caplets in accordance with
`
`from 200 to 1200 mg per dose; in combination with the
`
`
`
`the invention. Various conventional techniques for pre­
`
`
`
`
`H2 receptor blocking drugs including cimetidine from
`
`
`
`paring medicament tablets or caplets can be employed
`in the art as is dis­
`
`150 to 800 mg per dose; ranitidine from 50 to 300 mg per
`as would be known to those skilled
`
`dose; famotidine from 5 to 40 mg per dose; or in combi­
`closed for example by Remington's Pharmaceutical
`
`Co., Chapter 90, "Oral Solid
`
`nation with the .. proton pump inhibitor drugs including
`
`Sciences. Mack Publishing
`
`omeprazole from 60 to 500 mg per dose; and/or an H1
`
`Dosage Forms", pp. 1603-1632 (1985). The disclosure
`
`
`receptor blocking drug from the group ethanolamines
`
`
`of this reference is hereby incorporated herein by refer­
`
`
`including diphenhydramine 25 to 200 mg per dose;
`ence.
`from 50 to 400 mg per dose, carbinoxa­
`dimenhydrinate
`mine from 4 to 8 mg per dose; from the group 35
`
`EXAMPLE 1
`
`EXAMPLE 2
`
`ethylenediamines including tripelennamine from 25 to
`
`
`
`A tablet consisting of:
`
`
`
`300 mg per dose; pyrilamine from 25 to 100 mg per
`500 mg of acetaminophen;
`
`
`dose; from the group alkylamines including chlorphen­
`
`150 mg of cimetidine; and
`
`iramine from 2 to 24 mg per dose, from the group piper­
`
`
`other auxiliary agents and coloring agents.
`from 25 to 100 mg per 40
`
`azines including hydroxyzine
`
`dose, cyclizine from 50 to 300 mg per dose, meclizine
`from 8 to 400 mg per dose; and from the group pheno­
`A tablet consisting of:
`
`
`
`
`
`thiazines including promethazine from 12.5 to 50 mg
`500 mg of acetaminophen;
`per dose.
`
`25 mg of diphenhydramine; and
`45
`The dosage ranges described above are preferred
`
`
`
`other auxiliary agents and coloring agents.
`
`adult doses and may vary depending upon the age and
`EXAMPLE3
`weight of the patient as would be known by those
`
`
`
`
`skilled in the Pharmaceutical arts. Further, if a combi­
`
`
`A tablet consisting of:
`
`
`nation of, for example an H1 and H2 blocker is used, the
`200 mg of ibuprofen;
`so
`dosage for each may be reduced.
`
`150 mg of cimetidine; and
`
`
`To establish the efficacy of the composition of this
`
`
`other auxiliary agents and coloring agents.
`invention in humans, patients suffering from the symp­
`
`
`
`EXAMPLE4
`
`
`toms of overindulgence which will include any of the
`
`
`constellation of signs of indigestion, upper abdominal
`
`
`A tablet consisting of:
`55
`
`
`
`
`discomfort, bloating, heartburn or pyrosis and headache
`200 mg of ibuprofen;
`
`
`can be administered acetaminophen or a non-steroidal
`
`50 mg of ranitidine; and
`
`anti-inflammatory drug with and without histamine
`
`
`other auxiliary agents and coloring agents.
`
`
`receptor blockers (H1 and/or H2 blocking agents). To
`EXAMPLES
`
`
`determine efficacy, patients are asked to subjectively
`and time to 60
`
`
`
`estimate onset of relief, duration of relief
`
`
`A tablet consisting of:
`
`
`
`maximum relief. Appropriate statistical methods are
`200 mg of ibuprofen;
`
`25 mg of diphenhydramine; and
`
`used to show that on the average, acetaminophen or
`
`
`
`non-steroidal anti-inflammatory agents with H1 hista­
`
`
`other auxiliary agents and coloring agents.
`
`
`mine and/or H2 histamine receptor blocking drugs are
`65
`EXAMPLE6
`more efficacious.
`
`
`A tablet consisting of:
`
`
`Since appropriate animal models for the evaluation of
`500 mg of acetaminophen;
`
`
`
`overindulgence are not available, studies will not be
`
`50 mg of ranitidine; and
`
`
`
`conducted involving laboratory animals.
`
`

`
`7
`
`other auxiliary agents and coloring agents.
`
`EXAMPLE7
`
`A t ablet consisting of:
`500 mg of acetaminophen;
`150 mg of cimetidine;
`
`25 mg of diphenhydramine; and
`
`other auxiliary agents and coloring agents.
`
`EXAMPLE 8
`
`5,204,118
`
`8
`
`METHOD OF TREATING PATIENTS FOR THE
`SYMPTOMS OF OVERINDULGENCE
`A patient exhibiting t he symptoms or suffering from
`5 t he symptoms of overindulgence
`is t reated by t he oral
`administration of one t ablet of t he pharmaceutical com­
`
`position in accordance with any of Examples 1-10.
`The scope of t he present invention is not limited by
`t he description, examples and suggested uses herein and
`
`10 modifications can be made without departing from t he
`
`A t ablet consisting of:
`200 mg of ibuprofen;
`150 mg of cimetidine;
`
`25 mg of diphenhydramine; and
`
`other auxiliary agents and coloring agents.
`
`spirit of t he invention. For example, t he pharmaceutical
`compositions of t he invention may be provided in a
`sustained release formulation for prolonged and/or
`
`nightime t reatment of t he symptoms of overindulgence.
`
`15 Application of t he compositions and methods of t he
`
`EXAMPLE9
`
`A t ablet consisting of:
`500 mg of acetaminophen;
`50 mg of ranitidine;
`25 mg of diphenhydramine; and
`
`
`other auxiliary agents and coloring agents.
`
`EXAMPLE 10
`
`A t ablet consisting of:
`200 mg of ibuprofen;
`50 mg of ranitidine;
`25 mg of diphenhydramine; and
`
`
`other auxiliary agents and coloring agents.
`EXAMPLE II
`A t ablet consisting of:
`500 mg of acetaminphen;
`60 mg of omeprazole;
`and
`
`
`
`other auxiliary agents and coloring agents.
`
`EXAMPLE 12
`
`A t ablet consisting of:
`200 mg ibuprofen;
`60 mg omeprazole;
`and
`
`
`
`other auxiliary agents and coloring agents.
`
`EXAMPLE 13
`
`A t ablet consisting of:
`500 mg acetaminophen;
`60 mg omeprazole;
`
`25 mg diphenhydramine; and
`
`other auxiliary agents and coloring agents.
`
`EXAMPLE 14
`
`present invention for medical and pharmaceutical uses
`
`
`can be accomplished by any clinical, medical and phar­
`maceutical methods and t echniques as are presently or
`prospectively known t o t hose skilled in t he art. Thus it
`20 is intended t hat t he presently claimed invention cover
`
`30 analgesic
`
`t he modifications and variations of t his invention pro­
`vided t hat t hey come within t he scope of t he appended
`
`claims and t heir equivalents.
`25 What is claimed is:
`1. A pharmaceutical composition for t reating t he
`
`
`symptoms of overindulgence due t o t he excessive or
`
`
`inappropriate intake of food and/or alcoholic beverages
`
`comprising a t herapeutically effective amount of an
`and a gastric acid inhibiting effective amount
`of a proton pump inhibitor wherein t he t herapeutically
`
`effective amount of t he analgesic is selected from t he
`group consisting of acetaminophen from 500 t o 1000 mg
`from 200 t o 400 mg per dose, na-
`per dose, ibuprofen
`35 proxen from 200 t o 500 mg per dose, fenoprofen
`from
`200 t o 600 mg per dose, ketoprofen from 50 t o 300 mg
`e from 50 t o 400 mg per dose,
`per dose, meclofenamat
`mefenamic acid from 250 t o 500 mg per dose, piroxicam
`from 10 t o 20 mg per dose, indomethacin from 25 t o 200
`40 mg per dose, sulindac from 150 t o 400 mg per dose,
`t olmetin from 200 t o 1200 mg per dose and t heir phar­
`maceutically acceptable salts; in combination with an
`effective amount of t he proton pump inhibitor ome­
`prazole of from 60 t o 500 mg per dose and its pharma-
`45 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
`50 claim 1 comprising
`acetaminophen and omeprazole.
`4. A pharmaceutical composition in accordance with
`claim 1 comprising
`a racemic mixture of R- and S-ibu­
`A t ablet consisting of:
`
`profen, substantially pure S-ibuprofen or naproxen and
`200 mg ibuprofen;
`60 mg omeprazole;
`omeprazole.
`5. A pharmaceutical composition in accordance
`55
`with
`
`25 mg diphenhydramine; and
`claim 1 wherein additionally t here is present a t herapeu­
`
`other auxiliary agents and coloring agents.
`t ically effective amount of an H1 on H2 receptor blocker
`Various other dosage forms can be applied herein
`selected from t he group consisting of cimetidine from
`such as a filled gelatin capsule, liquid emulsion/suspen­
`
`150 io 800 mg per dose, ranitidine from 50 t o 300 mg per
`sion or chewable t ablet form employing t he dosage
`actives provided above or other dosage amounts in 60
`dose, famotidine from 5 t o 40 mg per dose, diphenhy­
`dramine 25 t o 200 mg per dose, dimenhydrinate from 50
`
`accordance with t he present invention. A liquid suspen­
`t o 400 mg per dose, carbinoxamine
`from 4 t o 8 mg per
`sion of ibuprofen t o which cimetidine, diphenhydra­
`
`dose, t ripelennamine from 25 t o 300 mg per dose, pyrila­
`mine, ranitidine or combinations t hereof in t he amounts
`mine from 25 t o 100 mg per dose, chlorpheniramine
`
`provided above can be added t o t he ibuprofen suspen­
`U.S. patent application Ser. 65
`
`from 2 t o 24 mg per dose, hydroxyzine from 25 t o 100
`
`sion disclosed in co-pending
`
`mg per dose, cyclizine from 50 t o 300 mg per dose,
`
`No. 372,734, now abandoned, t he entire disclosure of
`from 8 t o 400 mg per dose and promethazine
`meclizine
`
`t his patent application is hereby incorporated herein by
`from 12.5 t o 50 mg per dose.
`reference.
`
`

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