AP324A - Medicaments for treating inflammatory conditions or for analgiesia. - Google Patents

Medicaments for treating inflammatory conditions or for analgiesia. Download PDF

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Publication number
AP324A
AP324A APAP/P/1992/000453A AP9200453A AP324A AP 324 A AP324 A AP 324A AP 9200453 A AP9200453 A AP 9200453A AP 324 A AP324 A AP 324A
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AP
ARIPO
Prior art keywords
bismuth citrate
analgesia
inflammatory conditions
treating
steroidal anti
Prior art date
Application number
APAP/P/1992/000453A
Other versions
AP9200453A0 (en
Inventor
Roger Stables
Original Assignee
Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB919126027A external-priority patent/GB9126027D0/en
Priority claimed from GB929206083A external-priority patent/GB9206083D0/en
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of AP9200453A0 publication Critical patent/AP9200453A0/en
Application granted granted Critical
Publication of AP324A publication Critical patent/AP324A/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Abstract

The use is described of both

Description

MEDICAMENTS
FOR TREATING INFLAMMATORY CONDITIONS OR FOR ANALGESIA
The present invention relates to improvements in the treatment of inflammatory conditions and for analgesia. More particularly it relates to the coadministration of a non-steroidal anti-inflammatory drug with a salt formed between ranitidine and a complex of bismuth with a carboxylic acid.
Systemic non-steroidal anti-inflammatory drugs, such as aspirin, 5 indomethacin, ibuprofen and piroxicam, are known to give rise to undesirable side effects. In particular, they are known to be ulcerogenic and can thus, for example, give rise to gastric and/or duodenal ulceration when administered orally. This side effect may be further enhanced in combination with other factors such as stress and smoking. Since in some treatments these compounds may have to be used for an extended period, such side effects can prove a serious disadvantage.
In our UK Patent Specification No. 2220937B we describe and claim salts formed between ranitidine and a complex of bismuth with a carboxylic acid, particularly tartaric acid and, more especially, citric acid. One such salt is N-[2-[[[525 [(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N’-methyl-2-nitro-l,lethenediamine 2-hydroxy-1,2,3-propanetricarboxylate bismuth (3+) complex, also known as ranitidine bismuth citrate.
The salts disclosed in UK Patent Specification No. 2220937B possess the H23° antagonist antisecretory properties associated with ranitidine, together with antibacterial activity against Helicobacter pylori (formerly Campylobacter pylori). In addition, such salts possess cytoprotective properties and display activity against the human gastric pepsins with preferential inhibition of pepsin 1, a pepsin isozyme associated with peptic ulcer. The salts disclosed in UK Patent Specification No.
2220937B thus possess a particularly advantageous combination of properties for the treatment of gastrointestinal disorders, especially peptic ulcer disease (e.g.
AP 0 0 0 3 2 4
HA 162
- 2gastric and duodenal ulceration) and other gastroduodenal conditions, for example gastritis and non-ulcer dyspepsia.
Tests in animals and humans have now shown that mucosal lesions of the gastrointestinal tract caused by non-steroidal anti-inflammatory drugs are significantly reduced by administering ranitidine bismuth citrate. In particular, we have demonstrated in rats the ability of ranitidine bismuth citrate to prevent indomethacin induced gastric antral ulceration using a modification of the method of Satoh et al., Gastroenterology (1981), 81, 719-725. In this test ranitidine bismuth citrate was markedly more potent than both ranitidine hydrochloride and
TTUf tripotassium dicitrato bismuthate as DeNol . A recently published human clinical study (N. Hudson et al., Gut 1992, 33 supplement, s47) also demonstrates that ranitidine bismuth citrate confers substantial protection from aspirin-induced injury to the gastric mucosa.
The present invention thus provides, in one aspect, the use of (i) ranitidine bismuth citrate and (ii) a non-steroidal anti-inflammatory drug in the manufacture of medicaments for simultaneous, separate or sequential use in treating or preventing inflammatory conditions or for analgesia.
In a further, or alternative, aspect the present invention provides the use of ranitidine bismuth citrate in the manufacture of medicaments to prevent gastrointestinal damage caused by non-steroidal anti-inflammatory drugs.
Combination therapy according to the present invention may be used in the treatment of inflammatory conditions, particularly acute and chronic musculoskeletal inflammatory conditions such as rheumatoid and osteo-arthritis and ankylosing spondylitis and for analgesia in conditions such as dysmenorrhoea, especially where the use of the anti-inflammatory drug is limited by gastrointestinal side effects. As stated above, co-administration of ranitidine bismuth citrate with a systematic non-steroidal anti-inflammatory drug may also be used to prevent gastrointestinal damage caused by non-steroidal anti-inflammatory drugs. Such gastrointestinal damage includes duodenal and/or gastric ulceration, non-steroidal
V · - _______
HA162
- 3 5 anti-inflammatory drug associated gastritis and gastric erosions, and non-steroidal anti-inflammatory drug associated mucosal damage to the small intestine.
Suitable systemic non-steroidal anti-inflammatory drugs which may be employed in the invention generally also show analgesic activity and include, for 10 example, aspirin, indomethacin, ibuprofen, piroxicam, fenoprofen, ketoprofen, naproxen, mefenamic acid, diflunisal, benorylate, azapropazone, diclofenac, fenbufen, feprazone, fenclofenac, flufenamic acid, flurbiprofen, oxyphenbutazone, phenylbutazone, sulindac and tolmetin.
The ranitidine bismuth citrate and the anti-inflammatory drug are preferably co-administered in the form of separate pharmaceutical compositions for simultaneous and/or sequential use. Alternatively the ranitidine bismuth citrate and the anti-inflammatory drug may .be administered as a single pharmaceutical composition for oral use comprising effective amounts of the active ingredients.
Thus, according to a further aspect, the invention provides a product containing (i) ranitidine bismuth citrate and (ii) a non-steroidal antiinflammatory drug as a combined preparation for simultaneous, separate or sequential use in treating or preventing inflammatory conditions or for analgesia.
When the ranitidine bismuth citrate and the non-steroidal anti-inflammatory are administered as separate preparations, the anti-inflammatory may be provided in any convenient formulation, such as in the manner known in the art and/or commercially for the compound concerned. Administration of both the ranitidine bismuth citrate and the non-steroidal anti-inflammatory by the oral route is preferred, although the anti-inflammatory, where appropriate, may also be given by another route, for example parenterally (e.g. intravenously) or rectally (e.g. by suppository).
The ranitidine bismuth citrate may conveniently be formulated as tablets (including chewable tablets), capsules (of either the hard or soft type), or as a liquid preparation, as described for example in UK Patent Specification Nos. 2220937B and 2248185A. Tablets are generally preferred.
HA162
AP 0 Ο Ο 3 2 4
As stated hereinabove, ranitidine bismuth citrate and the non-steroidal antiinflammatory drug may be administered as a single pharmaceutical composition for oral use. Thus, according to a further aspect the invention provides a pharmaceutical composition, for oral use in human or veterinary medicine, comprising ranitidine bismuth citrate and a non-steroidal anti-inflammatory drug, together, where appropriate, with a pharmaceutically acceptable carrier or excipient.
Suitable additional carriers or excipients include binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). An alkaline salt of the type described in UK Patent Specification No. 2248185A may be added to improve the rate of disintegration and/or dissolution of the composition.
The compositions may be prepared according to conventional techniques well known in the pharmaceutical industry. Thus, for example, the ranitidine bismuth citrate and the non-steroidal anti-inflammatory drug may be admixed together, if desired, with suitable carriers or excipients. Tablets may be prepared, for example, by direct compression or wet granulation of such a mixture. Capsules may be prepared by filling the blend along with suitable carriers or excipients into gelatin capsules, using a suitable filling machine. Tablets may be coated by methods well known in the art. The preparations may also contain flavouring, colouring and/or sweetening agents as appropriate.
When ranitidine bismuth citrate and the non-steroidal anti-inflammatory drug are administered as a single pharmaceutical composition for oral use the composition is preferably in the form of a capsule or, more particularly, a tablet.
The compositions for use according to the invention may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredients. The pack may for example comprise metal or plastic foil, such as a blister pack. Where theT^nitidineTnsntuth citrate and the'
HA162
-5non-steroidal anti-inflammatory drug are intended for administration as separate compositions these may be presented in the form of, for example, a twin pack.
Thus, according to a further aspect the present invention provides a twincontainer pack for use in treating or preventing inflammatory conditions or for analgesia, one of the containers containing ranitidine bismuth citrate and the other containing a non-steroidal anti-inflammatory drug.
The doses at which the ranitidine bismuth citrate and the non-steroidal antiinflammatory may be administered to man (of approximately 70kg body weight) will depend on the route of administration of the anti-inflammatory and on the nature and severity of the condition being treated. It will also be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient.
A proposed dosage of ranitidine bismuth citrate for use according to the invention is 150mg to 1.5g, preferably 200 - 800mg per unit dose. The unit dose may be administered, for example, 1 to 4 times per day, preferably once or twice per day.
The non-steroidal anti-inflammatory may conveniently be administered at doses within the normal dosage range at which the compound is therapeutically effective, for example 50mg-lg of aspirin, 10 -100 mg of indomethacin, 5 - 50 mg of piroxicam, 100-500mg of ibuprofen and 200-800mg of mefenamic acid per dosage unit taken one or more times daily in accordance with the normal dosage regime for the drug in question.
In a further aspect, the present invention provides a method of treating inflammatory conditions or for analgesia in a human or animal subject, which comprises administering to said subject effective amounts of ranitidine bismuth citrate and a non-steroidal anti-inflammatory drug.
In another, or alternative, aspect the present invention provides a method of treating gastrointestinal damage caused by non-steroidal anti-inflammatory drugs in a human or animal subject, which comprises administering to said subject an effective amount of ranitidine bismuth citrate.
AP 0 0 0 3 2 4
HA162
-6References herein to treatment include prophylactic treatment as well as the alleviation of acute symptoms.
The methods of the present invention comprise administering the nonsteroidal anti-inflammatory drug and ranitidine bismuth citrate either concurrently or non-concurrently. As used herein, concurrent administration means that the agents are given within 24 hours of each other, whereas non-concurrent administration means that the agents are given more than 24 hours apart. When the agents are administered concurrently, it may be preferable to administer the agents within about 1 hour of each other or, more preferably, within about 5 minutes of each other.
For the methods of the present invention, the duration of administration of the agents during either concurrent or non-concurrent dosing will vary according to the specific condition being treated.
The following examples illustrate pharmaceutical compositions for oral use containing both ranitidine bismuth citrate and a suitable non-steroidal antiinflammatory drug.
Example 1
TABLETS mg/tablet (a) Ranitidine bismuth citrate 400.00
Ibuprofen 400.00
Lactose 200.00
Hydroxypropyl methylcellulose 5.00
Sodium starch glycollate 30.00
Magnesium stearate 10.00
Compression weight 1045.00
The ranitidine bismuth citrate and ibuprofen are sieved through a 250/xm sieve and blended with the lactose. This mix is granulated with a solution of the
>' i « ;
HA 162
-7 hydroxypropyl methylcellulose. The granules are dried, screened and blended with the sodium starch glycollate and the magnesium stearate. The lubricated granules are compressed into tablets using 15.0mm punches.
mg/tablet (b) Ranitidine bismuth citrate 400.00
Indomethacin 50.00
Microcrystalline cellulose 114.00
Anhydrous sodium carbonate 30.00
Magnesium stearate 6.00
Compression weight 600.00
The ranitidine bismuth citrate and indomethacin are blended with the microcrystalline cellulose, sodium carbonate and magnesium stearate and compressed using 12.5mm punches.
Example 2
CAPSULES
Ranitidine bismuth citrate Capsule 200.00
Ibuprofen 400.00
Starch 1500** 196.00
Magnesium stearate 4.00
Fill weight 800.00
** A form of directly compressible starch supplied by Colorcon Ltd, Orpington, Kent.
The ranitidine bismuth citrate and ibuprofen are sieved through a 250gm sieve and blended with the Starch 1500 and magnesium stearate. The resultant mix is filled into size 0 hard gelatin capsules using a suitable filling machine.
AP 0 0 0 3 2 4
HA162
-8· mg/capsule
Ranitidine bismuth citrate 200.00
Indomethacin 50.00
Starch 1500 48.50
Magnesium stearate 1.50
Fill weight 300.00
The ranitidine bismuth citrate and indomethacin are sieved through a 250um sieve and blended with the Starch 1500 and magnesium stearate. The resultant mix is filled into size 2 hard gelatin capsules using a suitable filling machine.
Example 3
INHIBITION OF INDOMETHACIN-INDUCED GASTRIC LESIONS IN THE
RAT
The ability of ranitidine bismuth citrate to prevent indomethacin-induced gastric antral ulceration was compared with that of ranitidine hydrochloride and DeNol™.
Female rats, which had been fasted for 24 hours and then re-fed, received ranitidine bismuth citrate (1 to lOOmg/kg), ranitidine hydrochloride (10 to ’T’X/f lOOmg/kg) or De-Nol1Ivl (3 to lOOmg/kg) by oral gavage. Ranitidine bismuth citrate was administered as a suspension and the other test compounds as solutions. Thirty minutes after dosing with the test compound, animals received indomethacin (60mg/kg sc) as an ulcerogenic stimulus and after a further 6 hours the animals were killed and the antral region assessed macroscopically for damage.
Results are presented in the table below. Ranitidine bismuth citrate produced a dose-related inhibition of indomethacin-induced lesions and was relatively potent, an ED^q value of 4.5mg/kg po being calculated. Ranitidine hydrochloride and DeΝοί^Μ were markedly less potent.
HA 162
-95 ΕΡ^θ Values for Inhibition of Indomethacin - Induced Antral Ulceration
Compound Ranitidine Bismuth Citrate Ranitidine Hydrochloride De-Nol™
ED50 mg/kg p.o. 4.5 23.4 43.2
95% confidence limits 0.5 - 10.7 16.0-33.0 23.6 - 93.0
AP000324

Claims (12)

  1. 5 CLAIMS
    1. The use of (i) ranitidine bismuth citrate and (ii) a non-steroidal anti-inflammatory drug in the manufacture of medicaments for simultaneous, separate or sequential use in treating or 10 preventing inflammatory conditions or for analgesia.
  2. 2. The use of ranitidine bismuth citrate in the manufacture of medicaments to prevent gastrointestinal damage caused by non-steroidal anti-inflammatory drugs.
  3. 3. The use according to Claim 1 in which the compounds (i) and (ii) are presented as separate compositions for said use.
  4. 4. A product containing compounds (i) and (ii) as defined in Claim 1 as a combined preparation for simultaneous, separate or sequential use in treating or preventing inflammatory conditions or for analgesia.
  5. 5. A pharmaceutical composition, for oral use, which comprises both a compound (i) and »25 a compound (ii) as defined in Claim 1, together with a pharmaceutical carrier or excipient.
  6. 6. A use, product or composition according to any preceding claim in which the non-steroidal anti-inflammatory drug is selected from aspirin, indomethacin, ibuprofen,
    3Q piroxicam, fenoprofen, ketoprofen, naproxen, mefenamic acid, diflunisal, benorylate, azapropazone, diclofenac, fenbufen, feprazone, fenclofenac, flufenamic acid, flurbiprofen, oxyphenbutazone, phenylbutazone, sulindac and tolmetin.
    35
  7. 7. A use or product according to any preceding claim in which compounds (i) and (ii) are in forms suitable for oral administration.
  8. 8. A use or product according to any preceding claim in which compound (i) is
    HA 162
    II
    5
  9. 9. A use or product according to Claim 8 in which compound (i) is administered at a dosage of 200-800mg per unit dose.
  10. 10. A twin-container pack for use in treating or preventing inflammatory conditions or for 10 analgesia, one of the containers containing (i) and the other containing (ii) as defined in the preceding claims.
  11. 11. A composition according to Claim 5 or Claim 6 or a pack according to Claim 10, in association with instructions for the use of both (i) and (ii) in treating or preventing inflammatory conditions or for analgesia.
  12. 12. A method for the preparation of a composition according to Claim 5 or Claim 6 which comprises admixing (i) and (ii) together, if desired, with suitable carriers or excipients.
APAP/P/1992/000453A 1991-12-06 1992-12-04 Medicaments for treating inflammatory conditions or for analgiesia. AP324A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB919126027A GB9126027D0 (en) 1991-12-06 1991-12-06 Medicaments
GB929206083A GB9206083D0 (en) 1992-03-20 1992-03-20 Medicaments

Publications (2)

Publication Number Publication Date
AP9200453A0 AP9200453A0 (en) 1993-01-31
AP324A true AP324A (en) 1994-03-07

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APAP/P/1992/000453A AP324A (en) 1991-12-06 1992-12-04 Medicaments for treating inflammatory conditions or for analgiesia.

Country Status (26)

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US (1) US5466436A (en)
EP (1) EP0550083B1 (en)
JP (1) JPH05246853A (en)
KR (1) KR930009605A (en)
AP (1) AP324A (en)
AT (1) AT401468B (en)
AU (1) AU664574B2 (en)
BE (1) BE1007268A3 (en)
CA (1) CA2084568A1 (en)
CH (1) CH685537A5 (en)
CZ (1) CZ358092A3 (en)
DE (1) DE69228738D1 (en)
DK (1) DK0550083T3 (en)
ES (1) ES2130152T3 (en)
FR (1) FR2684554B1 (en)
GB (1) GB2262036B (en)
GR (1) GR3030426T3 (en)
IE (1) IE922866A1 (en)
IL (1) IL103978A (en)
IT (1) IT1256697B (en)
LU (1) LU88196A1 (en)
MX (1) MX9207008A (en)
MY (1) MY108146A (en)
NO (1) NO303670B1 (en)
NZ (1) NZ245365A (en)
PH (1) PH31380A (en)

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US20080021078A1 (en) * 2006-07-18 2008-01-24 Horizon Therapeutics, Inc. Methods and medicaments for administration of ibuprofen
NZ565846A (en) * 2005-07-18 2011-12-22 Horizon Therapeutics Inc Medicaments containing famotidine and ibuprofen and administration of same
US20080020040A1 (en) * 2006-07-18 2008-01-24 Horizon Therapeutics, Inc. Unit dose form for administration of ibuprofen
US8067451B2 (en) * 2006-07-18 2011-11-29 Horizon Pharma Usa, Inc. Methods and medicaments for administration of ibuprofen
US8067033B2 (en) * 2007-11-30 2011-11-29 Horizon Pharma Usa, Inc. Stable compositions of famotidine and ibuprofen
WO2008027963A2 (en) * 2006-08-31 2008-03-06 Horizon Therapeutics, Inc. Nsaid dose unit formulations with h2-receptor antagonists and methods of use
JP2012502015A (en) 2008-09-09 2012-01-26 アストラゼネカ・アクチエボラーグ Method for delivering a pharmaceutical composition to a patient in need thereof
EA201290026A1 (en) 2009-06-25 2012-07-30 Астразенека Аб A METHOD FOR TREATING A PATIENT THAT HAS A RISK OF DEVELOPMENT OF ANALISM ASSOCIATED WITH THE RECEPTION OF NONSTEROID ANTI-INFLAMMATORY MEDIA
WO2013101897A2 (en) 2011-12-28 2013-07-04 Pozen Inc. Improved compositions and methods for delivery of omeprazole plus acetylsalicylic acid
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GB2105139A (en) * 1981-07-06 1983-03-16 Rca Corp Method and apparatus for operating a microprocessor in synchronism with a video signal
EP0426479A1 (en) * 1989-11-02 1991-05-08 McNEIL-PPC, INC. Use of a composition for the manufacture of a medicament for curing the symptoms of overindulgence

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AT401468B (en) 1996-09-25
DK0550083T3 (en) 1999-10-11
CA2084568A1 (en) 1993-06-07
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AU2986392A (en) 1993-06-10
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NO924704L (en) 1993-06-07
CZ358092A3 (en) 1993-10-13
AP9200453A0 (en) 1993-01-31
ATA240692A (en) 1996-02-15
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ITRM920869A0 (en) 1992-12-04
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AU664574B2 (en) 1995-11-23
EP0550083B1 (en) 1999-03-24
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IL103978A0 (en) 1993-05-13
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ES2130152T3 (en) 1999-07-01
ITRM920869A1 (en) 1994-06-04
EP0550083A1 (en) 1993-07-07
NO924704D0 (en) 1992-12-04
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GR3030426T3 (en) 1999-09-30
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FR2684554A1 (en) 1993-06-11
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DE69228738D1 (en) 1999-04-29

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