IL98034A - Pharmaceutical compositions including ibuprofen and a prostaglandin - Google Patents
Pharmaceutical compositions including ibuprofen and a prostaglandinInfo
- Publication number
- IL98034A IL98034A IL9803491A IL9803491A IL98034A IL 98034 A IL98034 A IL 98034A IL 9803491 A IL9803491 A IL 9803491A IL 9803491 A IL9803491 A IL 9803491A IL 98034 A IL98034 A IL 98034A
- Authority
- IL
- Israel
- Prior art keywords
- ibuprofen
- prostaglandin
- pharmaceutical composition
- carbon atoms
- nsaid
- Prior art date
Links
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
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
Abstract
A pharmaceutical composition includes a core of an NSAID selected from ibuprofen and ibuprofen salts, which core is surrounded by an intermediate coating impermeable to the passage of ibuprofen and a mantle coating of a prostaglandin surrounding the coated ibuprofen core.
[WO9116886A1]
Description
' T-liUDtmDl 13Ί131-.·>Κ Ο'^^Ί^Π ilinpll ^ UDil Pharmaceutical compositions including ibuprofen and a prostaglandin G. D. SEARLE & CO.
C. 83444 0357K Case No. 2610 PHARMACEUTICAL COMPOSITION CONTAINING IBUPROFEN AND A PROSTAGLANDIN Background of the Invention The invention herein is directed to a new pharmaceutical composition which consists of a generally trilayer tablet having an inner core, an intermediate barrier coating and an outer mantle coating surrounding the inner core. The inner core includes the NSAID ibuprofen or a salt of ibuprofen. The mantle coating includes a prostaglandin, described hereinafter in more detail .
Nonsteroidal anti-inflammatory drugs (NSAIDs) comprise a class of drugs which have long been recognized as having high therapeutic value especially for the treatment of inflammatory conditions such as exhibited in inflammatory diseases like osteoarthritis (OA) and rheumatoid arthritis (RA) . While the NSAIDs present a beneficial therapeutic value they also exhibit undesirable side effects. An especially undesirable side effect of the administration of NSAIDs is the ulcerogenic effects generally associated with chronic use. The chronic use of NSAIDs, the use of high dosages of NSAIDs and the use of NSAIDs by the elderly c?"- le?<3 a HtSM'j) .induced ulcers. NSAID induced ulcers in the stomach can be dangerous . Such ulcers generally exhibit little or few symptoms and may cause dangerous bleeding when undetected. In some instances, bleeding ulcers can prove fatal. The United States Food and Drug Administration requires a class warning for all NSAIDs, which states: Serious gastrointestinal toxicity such as bleeding, ulceration, and perforation can occur at any time, with or without warning symptoms, in patients treated chronically with NSAID therapy.
Certain prostaglandins have been shown to prevent NSAID induced ulcers. Acceptable prostaglandin compounds for the invention herein and their preparation are described in U.S. Patents 3,965,143, 4,060,691, 4,271,314, and 4,683,328. The prostaglandin compound commercially available under the USAN (United States Adopted Name) name misoprostol is a pharmaceutically acceptable prostaglandin which has been accepted for use in the treatment of NSAID induced ulcers in many countries, including the United States. Misoprostol is commercially available by prescription in such countries.
While prostaglandins are beneficial compounds and have found therapeutic usage, prostaglandins are generally considered highly unstable. Therefore, it is desirable to find prostaglandins with the desired anti-ulcerogenic properties and which can be stabilized or provided in stabilized formulations especially with respect to contemplated oral methods of delivery.
It would be desirable to provide a pharmaceutical composition which would exhibit the beneficial properties of an NSAID and which composition would exhibit the beneficial properties of a prostaglandin for countering (by inhibiting, reducing or preventing) the ulcerogenic side effects attendant to NSAID administration.
Summary of the Invention The invention herein is directed to a pharmaceutical composition comprising a core consisting of an NSAID selected from ibuprofen and ibuprofen salts. An intermediate barrier coating surrounds the core. Such an intermediate coating prevents contact between the NSAID and the prostaglandin to thereby inhibit any deleterious or otherwise non-beneficial interaction of the NSAID and prostaglandin such as degradation of the prostaglandin by the NSAID. A mantle coating of a prostaglandin surrounds the core and intermediate coating. The prostaglandin preferably is an orally available prostaglandin. -4- 98034/2 Acceptable prostaglandins for use herein include prostaglandins having the following structure wherein R represents hydrogen or lower alkyl having 1 to 6 carbon atoms, represents hydrogen, vinyl or lower alkyl having 1 to 4 carbon atoms and the wavy line represents R or S stereochemistry; R2, R3# and R^ are hydrogen or lower alkyl having 1 to 4 carbon atoms or R2. and 3 together with carbon Y form a cycloalkenyl having 4 to 6 carbon atoms or R3 or R^ together with carbons X and Y form a cycloalkenyl having 4 to 6 carbon atoms and wherein the X-Y bond can be saturated or unsaturated.
An especially preferred pharmaceutical composition herein has a structure wherein the core comprises the NSAID ibuprofen in a therapeutic amount such as from 300 to 800 milligrams (mg) , an intermediate coating comprising a material impervious/impermeable to the ibuprofen, and a mantle coating surrounding the core consisting of misoprostol in a therapeutic amount of 100 to 200 micrograms (meg) . An especially preferred intermediate coating can be formed from a crystalline-forming material such as a sugar, and more specifically sucrose.
The invention herein will be more fully understood with regard to the following brief description of the accompanying drawings and the following detailed description.
Brief Description of the Drawings Figure 1 is a schematic representation of a tablet comprising the pharmaceutical composition herein.
Detailed Description of the Invention The invention herein is directed to a pharmaceutical composition which is a generally trilayer tablet consisting of a core of the nonsteroidal anti-inflammatory drug (NSAID), ibuprofen and ibuprofen salts. Ibuprofen is the USAN name for (+)-2-(p-isobutylphenyl)-propionic acid. Surrounding the core is an intermediate - 6-7 - 98034/2 coating of an impervious/impermeable material to the ibuprofen. An especially preferred intermediate coating can be formed from a crystalline forming material such as a sugar, and more specifically sucrose. Surrounding the core and intermediate coating is a mantle coating which consists of a prostaglandin of the structure wherein R represents hydrogen or lower alkyl having 1 to 6 carbon atoms, R1 represents hydrogen, vinyl or lower alkyl having 1 to 4 carbon atoms and the wavy line represents R or S stereochemistry; R2, R^, and R^ are hydrogen or lower alkyl having 1 to 4 carbon atoms or R2 and ^ together with carbon Y form a cycloalkenyl having 4 to 6 carbon atoms or R^ or ^ together with carbons X and Y form a cycloalkenyl having 4 to 6 carbon atoms and wherein the X-Y bond can be saturated or unsaturated . per day in divided doses. For mild to moderate- pain the recommended dosage is 400 mg every 4 to 6 hours as necessary for relief of pain. For dysmenorrhea the recommended dosage is 400 mg every 4 hours as necessary for the relief of pain. The inner core for the pharmaceutical composition herein therefore can be in an amount to accomplish such a dosing regimen and can contain from 150 to 800 mg of ibuprofen and preferably in a dosage of 400 mg. Various excipients can also be combined with the ibuprofen as is well known in the pharmaceutical art and including the inactive ingredients listed in the PDR 44th edition for ibuprofen as sold under the brand name and trademark MOTRIN by The Upjohn Company.
If the inner core is an ibuprofen salt, the ibuprofen salt can be present in a therapeutically acceptable amount as is referred to in the above discussion with respect to the acid.
Surrounding the core 12 is a barrier or an intermediate coating 14. The intermediate coating 14 can be any suitable coating which prevents passage of the ibuprofen. Ibuprofen is a compound that exhibits sublimation. Therefore an intermediate coating material is selected from those materials which prevent the passage of such a gaseous phase. It has been found herein that 0357K crystalline forming materials are impervious to ibuprofen in a gas phase. Any material which forms a crystalline structure can be used for the intermediate coating. An especially preferred class of compounds which can be used include crystalline forming sugars and more preferably sucrose. Sucrose is especially preferred as it exhibits crystalline properties at 55 °C and it remains in the crystalline state and does not absorb any appreciable amounts of water up to a very high relative humidity value (84%). The intermediate coating 14 segregates the NSAID from the prostaglandin. The intermediate coating 14 prevents the degradation of the prostaglandin by the presence of the NSAID. Studies have shown that an admixture of misoprostol and ibuprofen is undesirably unstable for a commercially acceptable product. Solid state stability studies have shown that misoprostol is extremely unstable in the presence of ibuprofen and degrades at a rapid rate. A 10:1 mixture of ibuprofen: misoprostol stored at 55°C yields only 44% misoprostol after 4 days and only 18% after storage at 65°C for 3 days. It is, therefore, highly desirable to formulate a composition (dosage form) which would effectively separate the two active ingredients while providing a delivery system for each ingredient. 0357K Additional studies have shown that an intermediate coating of certain polymers is unacceptable due to ibuprofen bleed through of the polymer which ibuprofen then interacts with and degrades the misoprostol. The intermediate coating can be coated onto the inner core using standard coating techniques. For example, aqueous or solvent coating techniques can be used to apply the coating to the inner core.
The mantle coating 16 surrounds the inner core of the NSAID and the intermediate coating, encapsulating the intermediate coated NSAID core. The mantle coating includes of a prostaglandin and more preferably an orally available prostaglandin. The mantle coating can be applied by compression coating or solvent coating techniques such as are well known in the tableting art.
The terms "prostaglandin" and/or its accepted acronym "PG" or, as more appropriately for the E-series prostaglandins, "PGE," are used herein to refer to naturally occurring or man-made E-series prostaglandins and their analogs and derivatives.
It has been found herein that acceptable prostaglandins include the E1 prostaglandins shown by the following Formula I 0357K E, prostaglandins shown by the following Formula II and E, prostaglandins shown by the following Formula III wherein R represents hydrogen or lower alkyl having 1 to 6 carbon atoms, R1 represents hydrogen, vinyl or lower alkyl having 1 to 4 carbon atoms and the wavy line represents R or S stereochemistry; R2, R3, and 4 are hydrogen or lower alkyl having 1 to 4 carbon atoms or R2 and 3 together with carbon Y form a cycloalkenyl having 4 to 6 carbon atoms or ^ or R4 together with carbons X and Y form a cycloalkenyl having 4 to 6 carbon atoms and wherein the X-Y bond can be saturated or unsaturated. - 12 - 98034/2 By lower alkyl is meant straight or branched chain alkyl such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl or tertiary butyl, pentyl, or hexyl with the indicated limitation of the number of carbon atoms. With regard to the illustrated structures, the dashed line indicates the grouping being behind the plane of the paper and the solid, blackened triangular shape indicates that the group is in front of the plane of the paper.
It has been found herein that acceptable prostaglandins include the prostaglandin misoprostol represented by the following Formula: With regard to the illustrated structure, the dashed line indicates the grouping being behind the plane of the paper and the solid, blackened triangular shape indicates that the group is in front of the plane of the paper.
The prostaglandins useful in the composition herein can be prepared by known reaction schemes such as by the methods taught in U.S. Patents 3,965,143, 4,271,314 and 4,683,328. The individual isomers can be obtained by chromatographic separation. - 13 - 98034/2 When the prostaglandin is misoprostol, (+)methyl 11a, 16-dihydroxy-16-methyl~9-oxoprast-13E-en-l-oate, the misoprostol can be present in an amount from 50 to about 500 meg and preferably from 100 to about 200 meg.
The invention will be further understood with regard to the following examples. 0357K Example 1 A pharmaceutical composition was prepared consisting of an ibuprofen central core, a sucrose intermediate coating and a misoprostol mantle. The tablet had the following composition.
Component Unit Formula (mg) ibuprofen 400. Q0 pregelatinized cornstarch 155.00 croscarmallose sodium 43.00 stearic acid 12.30 acacia 5.00 sugar (sucrose) 29.00 misoprostol :HPMC dispersion (1:100) misoprostol 0.10 hydroxypropyl methylcelluose 9.90 colloidal silicon dioxide 4.60 calcium sulfate 77.00 starch U.S. P. 41.00 HPMC 6 cps (Pharmacoat 606) 58.50 Example 2 A pharmaceutical composition was prepared consisting of an ibuprofen central core, a sucrose intermediate coating and a misoprostol mantle. The composition had the following composition.
Component Unit Formula (mg) ibuprofen 600.00 pregelatinized cornstarch 155.00 croscarmallose sodium 43.00 stearic acid 12.30 acacia 5.00 sugar (sucrose) 29.00 misoprostol :HP C dispersion (1:100) misoprostol 0.20 hydroxy propyl methyl celluose* 20.0 colloidal silicon dioxide 4.60 calcium sulfate 77.00 starch U.S. P. 41.00 HPMC 6 cps (Pharmacoat 606) 58.50 Example 3 A pharmaceutical composition is prepared consisting of an ibuprofen central core, a sucrose intermediate coating and a misoprostol mantle. The composition has the following composition.
Component Unit Formula (mg) ibuprofen 800.00 pregelatinized cornstarch 155.00 croscarmallose sodium 43.00 stearic acid 12.30 acacia 5.00 sugar (sucrose) 29.00 misoprostol :HP C dispersion (1:100) misoprostol 0.20 hydroxy propyl methyl celluose* 20.0 colloidal silicon dioxide 4.60 calcium sulfate 77.00 starch U.S. P. 41.00 HP C 6 cps (Pharmacoat 606) 58.50 Example 4 The following polymers were evaluated as barriers to ibuprofen sublimation. The determination of their abilities to perform as a barriers was made by bromocresol green (BCG) indicator or by misoprostol degradation. The BCG was applied in the outer coating rather than misoprostol. The BCG coating initially was a bright shade of blue when applied but as it came into contact with the acidic ibuprofen a color change occurred and shades of green to yellow were observed.
Hydroxypropyl methylcellulose 6 cps (aqueous) Ethyl cellulose (aqueous) Eudragit E30D (aqueous) Eudragit E100 (ethanol) Polyvinyl alcohol (ethanol) Shellac (aqueous, ethanol) Polyvinyl acetate phthalate (aqueous) Cellulose acetate phthalate (methylene chloride-acetone) The observed stability data showed rapid and extensive misoprostol degradation for all of the polymer barriers tested.
Example 5 The following chemical barriers were evaluated to determine their efficacy as barriers to ibuprofen as the acid molecule.
Aluminum hydroxide/HP C Aluminum hydroxide/Eudragit E30D Tricalcium Phosphate/HPMC Calcium oxide/HPMC Magnesium hydroxide/HPMC Magnesium oxide/HPMC The observed stability data showed rapid and extensive misoprostol degradation for all of the chemical barriers tested.
The composition that is the. invention herein provides an ease of delivery of the NSAID ibuprofen for its therapeutic value such as the alleviation of inflammation in a system which limits the undesirable side effects of such NSAID therapy. That is, the composition herein consisting of a generally trilayer tablet provides a prostaglandin in combination with the NSAID ibuprofen whereby the prostaglandin can be administered for its beneficial therapeutic value in preventing and or inhibiting the incidence of NSAID induced ulcers.
A particularly beneficial aspect of the invention herein is that the combination of the two components in a trilayer tablet assures compliance with the therapeutic regimen of the two active components. That is, a co-administration of the active components (ibuprofen and prostaglandin) separately can be difficult to achieve and can be difficult for a patient to faithfully follow. By placing the two active components in the same tablet or composition, adherence to the therapeutic regimen is controlled as the administration of the tablet containing the NSAID assures compliance of the administration of the prostaglandin.
The composition herein is especially utile as the composition herein exhibits a stability for the prostaglandin and the ibuprofen in such a fixed combination as herein described.
Claims (8)
1. A pharmaceutical composition comprising: a. a core consisting of an NSAID selected from ibuprofen and ibuprofen salts; and b. an intermediate coating surrounding the core c a mantle coating surrounding the core consisting of a prostaglandin of the structural formula wherein R represents hydrogen or lower alkyl having 1 to 6 carbon atoms, R1 represents hydrogen, vinyl or lower alkyl having 1 to 4 carbon atoms and the wavy line represents R or S stereochemistry; R2, R^ , and 4 are hydrogen or lower alkyl having 1 to 4 carbon atoms or R2 and together with carbon Y form a cycloalkenyl having 4 to 6 carbon atoms or R3 or 4 together with carbons X and Y form a cycloalkenyl having 4 to 6 carbon atoms and wherein the X-Y bond can be saturated or unsaturated .
2. A pharmaceutical composition as recited in Claim 1 wherein the prostagladin comprises misoprostol. - 22 - 98034/2 A pharmaceutical composition as recited in Claim 1
3. wherein the NSAID comprises ibuprofen.
4. A pharmaceutical composition as recited in Claim 1 wherein the NSAID comprises an ibuprofen salt.
5. A pharmaceutical composition as recited in Claim 1 wherein the intermediate coating comprises a sucrose coating.
6. A pharmaceutical composition as recited in Claim 1 wherein the prostaglandin: mantle coating comprises a stabilized prostaglandin formulation.
7. A pharmaceutical composition as recited in Claim 1 j wherein the NSAID comprises ibuprofen from about 150 to 800 mg, the intermediate coating comprises sucrose and the mantle coating comprises a stabilized prostaglandin formulation containing about 100 to 200 meg of misoprostol .
8. A method of treating inflammation comprising administering to a non- human animal in need of such treatment, a therapeutically effective amount of a composition according to Claim 1. DR. REINHOLDVOHN AND PARTNERS
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US51836490A | 1990-05-03 | 1990-05-03 |
Publications (2)
Publication Number | Publication Date |
---|---|
IL98034A0 IL98034A0 (en) | 1992-06-21 |
IL98034A true IL98034A (en) | 1996-10-31 |
Family
ID=24063626
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IL9803491A IL98034A (en) | 1990-05-03 | 1991-05-02 | Pharmaceutical compositions including ibuprofen and a prostaglandin |
Country Status (7)
Country | Link |
---|---|
AU (1) | AU8089091A (en) |
IE (1) | IE62050B1 (en) |
IL (1) | IL98034A (en) |
NZ (1) | NZ238023A (en) |
PT (1) | PT97550B (en) |
WO (1) | WO1991016886A1 (en) |
ZA (1) | ZA913354B (en) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2241342C (en) * | 1998-06-15 | 2000-02-08 | Bernard Charles Sherman | Pharmaceutical tablets comprising an nsaid and a prostaglandin |
US6319519B2 (en) | 1998-07-07 | 2001-11-20 | Norton Healthcare Ltd. | Anti-inflammatory pharmaceutical formulations |
US6387410B1 (en) * | 1998-09-10 | 2002-05-14 | Norton Healthcare Ltd | Anti-inflammatory pharmaceutical formulations |
SE9803761D0 (en) * | 1998-11-04 | 1998-11-04 | Synphora Ab | Method to avoid increased iridial pigmentation during prostaglandin treatment |
CA2277407A1 (en) * | 1999-07-14 | 2001-01-14 | Bernard Charles Sherman | Pharmaceutical tablet comprising an nsaid and misoprostol |
EP1216030A1 (en) * | 1999-10-01 | 2002-06-26 | Norton Healthcare Limited | Anti-inflammatory pharmaceutical formulations |
US8206741B2 (en) | 2001-06-01 | 2012-06-26 | Pozen Inc. | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
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 |
EP2344139A1 (en) | 2008-09-09 | 2011-07-20 | AstraZeneca AB | Method for delivering a pharmaceutical composition to 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 |
BR112014016085A8 (en) | 2011-12-28 | 2017-07-04 | Pozen Inc | Enhanced compositions and methods for delivery of omeprazole plus acetylsalicylic acid |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4301146A (en) * | 1980-07-29 | 1981-11-17 | G. D. Searle & Co. | Stabilization of 16-oxygenated prostanoic acid derivatives |
GB2135881A (en) * | 1983-03-02 | 1984-09-12 | Erba Farmitalia | Method and pharmaceutical compositions for inhibiting or reducing gastrointestinal side effects of non-steroidal anti-inflammatory drugs |
GB8512344D0 (en) * | 1985-05-15 | 1985-06-19 | May & Baker Ltd | Compositions of matter |
EP0298666B1 (en) * | 1987-07-08 | 1993-08-11 | American Home Products Corporation | Spray dried ibuprofen compositions |
-
1991
- 1991-05-01 AU AU80890/91A patent/AU8089091A/en not_active Abandoned
- 1991-05-01 WO PCT/US1991/002984 patent/WO1991016886A1/en unknown
- 1991-05-02 NZ NZ238023A patent/NZ238023A/en unknown
- 1991-05-02 IE IE148591A patent/IE62050B1/en not_active IP Right Cessation
- 1991-05-02 PT PT97550A patent/PT97550B/en not_active IP Right Cessation
- 1991-05-02 IL IL9803491A patent/IL98034A/en active IP Right Grant
- 1991-05-03 ZA ZA913354A patent/ZA913354B/en unknown
Also Published As
Publication number | Publication date |
---|---|
IL98034A0 (en) | 1992-06-21 |
AU8089091A (en) | 1991-11-27 |
NZ238023A (en) | 1992-08-26 |
WO1991016886A1 (en) | 1991-11-14 |
IE911485A1 (en) | 1991-11-06 |
ZA913354B (en) | 1992-07-29 |
IE62050B1 (en) | 1994-12-14 |
PT97550B (en) | 1999-03-31 |
PT97550A (en) | 1992-02-28 |
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