CA2169159C - Pharmaceutical composition containing a drug/.beta.-cyclodextrin complex in combination with an acid-base couple - Google Patents
Pharmaceutical composition containing a drug/.beta.-cyclodextrin complex in combination with an acid-base couple Download PDFInfo
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- CA2169159C CA2169159C CA002169159A CA2169159A CA2169159C CA 2169159 C CA2169159 C CA 2169159C CA 002169159 A CA002169159 A CA 002169159A CA 2169159 A CA2169159 A CA 2169159A CA 2169159 C CA2169159 C CA 2169159C
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
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- 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]
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Abstract
The present invention provides a pharmaceutical composition for oral consumption in aqueous solution comprising a drug/ .beta.-cyclodextrin complex, characterised in that the composition further comprises a pharmaceutically acceptable acid-base couple, preferably an effervescent acid-base couple, in a quantity sufficient to cause the drug/.beta.-cyclodextrin complex to dissolve when the composition is mixed with cold water and provide a solution with acid or neutral pH. The preferre d acid-base couple is an effervescent couple which contains citric and/or tartaric acid and sodium bicarbonate and/or carbonate. The preferred drugs for use in the composition include lipophilic NSAID's e.g. ibuprofen, naproxen and ketoprofen.
Description
PHARMACEUTICAL COMPOSITION CONTAINING A DRUG/BETA-CYCLODEXTRIN COMPLEX IN
COMBINATION WITH AN ACID-BASE COUPLE
This invention relates to a pharmaceutical composition containing a drug which is lipophilic and has poor water solubility in the fornl of a clathrate complex, a process for its preparation, and a palatable formulation thereof suitable for oral consumption. In particular, the invention relates to a composition containing a non-steroidal anti-inflammatory (NSAID) drug as a cyclodextrin clathrate complex suitable for oral consumption in aqueous solution.
The group of non-steroidal antiinflammatory agents (NSAIDs) includes drugs such as ibuprofen, naproxen and ketoprofen which have utility in providing relief from pain and inflammation associated with a wide range of disorders including for example chronic disease states such as arthritis. Ibuprofen is also widely indicated for the treatment of symptoms associated with the common cold and flu. Formulation of these and other poorly water-soluble drugs into preparations suitable for oral administration, in particular into water-soluble forms suitable for liquid dosing, is often complicated by the physical characteristics of the drugs which include poor water solubility, irritating odour and unpleasant taste. It is an object of the present invention to provide a palatable pharmaceutical composition containing a lipophilic, poorly water-soluble drug, for example an NSA1D such as ibuprofen, naproxen or ketoprofen, formulated for oral dosing as an aqueous solution.
The ability of drug-cyclodextrin complexes to enhance water solubility and to mask unpleasant taste and odour has been known for many years. In this respect, NSA1D's such as ibuprofen have proved to be very suitable as candidates for complexation with cyclodextrins.
Japanese patent publication, JP 56-46837 (Kowa Yakuhin Kogyo) discloses a method for the preparation of an ibuprofen-Li-cyclodextrin clathrate complex involving the combination of ibuprofen with (3-cyclodextrin in water at elevated temperature and isolation of the clathrate by spray-drying. This method is reported to yield a product containing a high percentage of ibuprofen with a molar ratio of ibuprofen to 13-cyclodextrin in excess of 0.7. The increase in water solubility of the drug is considerable, being raised more than 8-fold from 10.44mg per 100m1 to 89.38mg per 100m1 at 27°C.
The water solubility achieved by complexation with (3-cyclodextrin, although significant, is not considered sufficient to permit formulation of ibuprofen as a soluble dosage form for oral administration in liquid form wherein ibuprofen is present at a therapeutic dosage level (200-600mg) in a suitable volume of water (SO-250m1).
WO 95/04528 ~ ~ ~ PCT/EP94/02515 European patent publication 274 444 (Bristol Myers) describes the preparation of ibuprofen-cyclodextrin complexes using a-cyclodextrin, 7-cyclodextrin or a methylated (3-cyclodextrin in place of Li-cyclodextrin. The water solubility of the ibuprofen-cyclodextrin complex is further enhanced to levels of practical utility using these forms of cyclodextrin, but the high cost of these materials, reflected in the cost of medicinal products containing them, is unlikely to promote their widespread use in analgesic products, more particularly in products available for self medication for the treatment of minor aches and pains and the symptomatic relief of colds and flu.
United Kingdom patent publication GB 2,189,994 (Zambon) discloses an effervescent water-soluble ibuprofen formulation comprising ibuprofen plus arginine or a mixture of arginine and lysine and an effervescent couple in the form of sodium or potassium bicarbonate and sodium bitarnate.
US Patent No 4,762,702 (Gergely) discloses a pharmaceutical preparation in which ibuprofen particles are enveloped by a coating of a hydro-colloid and fumaric acid which is intended to reduce the irritant effects of orally ingested ibuprofen. An effervescent formulation incorporating citric acid and calcium carbonate into the preparation is also described.
United Kingdom patent publication GB 2,219,585 (Reckitt & Colman) discloses a complex of 13-cyclodextrin with the sodium, potassium, ammonium, magnesium, calcium, arginine, glycine or lysine salt of ibuprofen, having a molar ratio of ibuprofen to 13-cyclodextrin in the range 1:0.2 to 1:0.75. The complexes may be formulated with a buffer system or an effervescent couple incorporating a pharmaceutically acceptable acid salt to provide a pH in the range 6 to 8 on reconstitution with water.
European patent publication 0 490 193 (Medics Chem-Pharm) discloses complexes of the active enantiomer of ibuprofen and/or its physiologically tolerated salts with a cyclodextrin and /or a cyclodextrin derivative. Although there is disclosed an ibuprofen effervescent tablet formulation, it is not soluble in the volume of water needed to form a therapeutically acceptable composition.
International Patent Application PCT/GB93/00702 (SmithKline Beecham) overcomes the problem of poor solubility of ibuprofen by reconstituting an ibuprofen/a-cyclodextrin complex in hot water to provide a pleasant tasting soluble liquid presentation. It was found that an approximately 30-fold increase in solubility could be achieved by dosing an ibuprofen-13-cyclodextrin complex in aqueous solution at elevated temperatures and thereby achieve therapeutic dosage levels of ibuprofen in solution in a single-dose liquid formulation.
The present invention provides a further drug-cyclodextrin complex formulation which is suitable for administration as an aqueous solution, and which is palatable and inexpensive to manufacture. The formulation according to the present invention provides a therapeutically active dose of the drug as a complex with ~i-cyclodextrin. The formulation is suitable for reconstitution with cold water and provides a pleasant tasting solution at acid or neutral pH.
It has been found that when formulated in the presence of an acid-base couple, preferably an effervescent acid-base couple, a drug/(3-cyclodextrin complex, which in isolation is soluble in water only at elevated temperatures, has enhanced solubility and dissolves in cold water to provide a therapeutic drug dose as a single-dose, liquid formulation.
According to the present invention there is provided a pharmaceutical composition for oral consumption in aqueous solution comprising a drug/&
cyclodextrin complex, characterised in that the composition further comprises a pharmaceutically acceptable acid-base couple, preferably an effervescent acid-base couple, in a quantity sufficient to cause the drug/f3-cyclodextrin complex to dissolve when the composition is mixed with cold water and provide a solution with acid or neutral pH.
Suitable non-effervescent acid-base couples for use in the invention are those commonly known in the art, for example a combination of a water soluble acid and a conjugate base in the form of a sodium or potassium salt. Suitable effervesent couples are also commonly known in the art, for example a combination of one or more water soluble acidic substances with one or more basic compounds which liberate carbon dioxide on neutralisation with acid.
Examples of suitable acids for use in the invention include, tartaric acid, citric acid, ascorbic acid and other edible organic acids. Suitable salts of organic acids include mono- di- and tri-basic salts, for example monosodium citrate, trisodium citrate, monosodium tarnate, trisodium tarnate and other salts of edible organic acids.
Inorganic acidic substances such as monosodium phosphate are also suitable components of acid-base couples. Examples of suitable bases for use in the invention include sodium carbonate, percarbonate and bicarbonate, and other alkali metal and alkali earth metal carbonates, percarbonates and bicarbonates, and mixed carbonate salts, such as sodium glycine carbonate and potasium glycine carbonate.
The preferred acid-base couple for this invention is an effervescent couple which contains citric and/or tartaric acid and sodium bicarbonate and/or carbonate.
The amount of couple required to solubilise the drug/f3-cyclodextrin complex will depend on the amount and type of drug used. However a minimum level of couple considered acceptable in a composition of the invention is an amount such that the weight of couple is greater than about 1 % of the weight of water in which it is designed to be reconstituted or is greater than 1 % of the weight of water in which it is to be dissolved, ie the final concentration of the couple on reconstitution in water (not WO 95/04528 ~ ~ PCT/EP94/02515 allowing for loss of carbon dioxide for effervescent couples) should be greater than about 1 % by weight. Levels below this amount are generally considered unsuitable since, on reconstitution with water, incomplete dissolution of the drug/Li-cyclodextrin occurs. The maximum level of couple considered acceptable in a composition of the invention is 15% of the weight of water in which it is to be reconstituted.
For effervescent compositions, levels in excess of this amount tend to lead to excessive effervescence, resulting in overflow of liquid from the glass or beaker and loss of some of the formulation. In addition high levels of acid-base couple tend to impart a salty taste to the palate. Compositions of the present invention are suitably 1o administered as pleasant tasting solutions in the pH range 4.0 to 7Ø
The constituents of acid-base couples suitable for use in compositions of the invention and their relative amounts may be selected using principles well known in the art of pharmaceutical drug formulation. An acid-base couple for use in compositions of the invention may be designed so that the final pH of the formulation 15 following reconstitution with water is in the range of 4.0 - 7.0 and preferably in the range of 5.0 - 6.5. The pH of solutions resulting from reconstitution of the couple in water may be adjusted by altering the ratio of the alkali and acid components of the couple. If the couple is designed so that the final pH of the formulation following reconstitution with water falls below the specified range there may be a tendency for 2o the drug/f3-cyclodextrin clathrate to precipitate, which detracts from the appearance and palatibility of the product. If the couple is designed to so that the final pH
following reconstitution is above the specified range then the solution will impart an alkaline /soapy taste.
Preferred drugs for use in the compositions of the present invention include 25 lipophilic NSAID's, for example propionic acid derivatives such as ibuprofen, naproxen and ketoprofen.
Accordingly, drug/(3-cyclodextrin clathrates which are suitable for use in this invention include ibuprofen /13-cyclodextrin clathrates, naproxen / (3-cyclodextrin clathrates, ketoprofen /(3-cyclodextrin clathrates and clathlerates of (3-cyclodextrin 30 with other propionic acid type NSAID's. In addition, the invention may use clathrates of f3-cyclodextrin with salts of ibuprofen, naproxen and other propionic acid type NSAID's, for example metal salts, such as sodium, potassium, magnesium, and calcium, or amino-acid salts such as arginine, ornithine or lysine.
The drugs according to this invention may be as either the racemate or 35 enantiomers. Any reference to the drug is intended to cover all active forms and may be either in the R or S enantiomer or racemate form.
The molar ratio of 13-cyclodextrin to drug (or drug salt) may be in the range 0.8:1 to 10:1, suitably in the range 1:1 to 10:1, more suitably in the range 1:1 to 5:1 and preferably in the range l: l to 3:1. If the ratio falls below this range, an ~~.a~~9 insufficient amount of the drug will be complexed which will lead to a deterioration in taste properties of the final product, and undissolved drug following reconstitution with water. If the amount of cyclodextrin is excessive then, for effervescent formulations, there is a tendency for excessive foam formation on mixing the formulation with water which may lead to loss of some of the formulation.
Furthermore, it is for economic reasons considered desirable to minimise the amount of cyclodextrin used in the composition.
The invention also provides a process for the preparation of a pharmacetical composition of the invention which process comprises the admixture of a drug/B-cyclodextrin clathrate complex and an acid-base couple.
A drug/B-cyclodextrin complex may be prepared by heating the drug and B-cyclodextrin in water or in a buffered aqueous solution, suitably to a temperature of 100°C, followed by crystallisation of the drug/B-cyclodextrin complex from the solution thus formed, suitably by maintaining the solution in the temperature range -5 to 20°C. Alternatively a drug/B-cyclodextrin complex may be made by any other method known in the art, for example by a co-precipitation or kneading method or by spray-drying a solution of the drug and B-cyclodextrin.
The acid-base couple may be prepared by any method known in the art, for example by dry mixing the components of the couple in a suitable mixer, or by granulation using a rotary granulator, fluid-bed granulator or other suitable granulator, followed by drying to remove residual moisture. If granulation is the chosen method of preparation, other components of the formulation may be included into the granulation step, for example part, or all of the drug/B-cyclodextrin clathrate, flavours, sweeteners and colours.
A composition of the invention may be formulated in any convenient form, for example as a tablet for solution, or alternatively in powder or granular form for reconstitution with water or as a ready-to-drink preparation.
Compositions of the invention may be formulated with any appropriate carrier or adjuvant appropriate to the chosen dosage form. Thus, compositions of the invention may include for example preservatives, suspending agents, wetting agents, flavouring agents, bulking agents, binders, adhesives, lubricants, disintegrants, colouring agents, sweetening agents, adsorbents, thickeners and diluents, appropriate to their form.
Compositions of the invention containing a drug/B-cyclodextrin complex and an acid-base couple may in addition include additional pharmaceutical agents suitable for administration therewith which are not complexed with B-cyclodextrin, including for example analgesics, antiinflammatories and antipyretics and also expectorants, antihistamines, decongestants and antitussive agents, such as for example WO 95/04528 ~ ~ PCTIEP94I02515 phenypropanolamine, phenylephrine, pseudoephedrine, dextromethorphan, caffeine, codeine and ascorbic acid.
The following Examples (1 to 18) are illustrative of the invention. Examples (A to G) are outside the scope of the invention but are included to further demonstrate aspects of the invention.
In the Examples, unless otherwise stated, the abbreviation BCD refers to B-cyclodextrin undecahydrate (B-cyclodextrin. 11 H20).
COMBINATION WITH AN ACID-BASE COUPLE
This invention relates to a pharmaceutical composition containing a drug which is lipophilic and has poor water solubility in the fornl of a clathrate complex, a process for its preparation, and a palatable formulation thereof suitable for oral consumption. In particular, the invention relates to a composition containing a non-steroidal anti-inflammatory (NSAID) drug as a cyclodextrin clathrate complex suitable for oral consumption in aqueous solution.
The group of non-steroidal antiinflammatory agents (NSAIDs) includes drugs such as ibuprofen, naproxen and ketoprofen which have utility in providing relief from pain and inflammation associated with a wide range of disorders including for example chronic disease states such as arthritis. Ibuprofen is also widely indicated for the treatment of symptoms associated with the common cold and flu. Formulation of these and other poorly water-soluble drugs into preparations suitable for oral administration, in particular into water-soluble forms suitable for liquid dosing, is often complicated by the physical characteristics of the drugs which include poor water solubility, irritating odour and unpleasant taste. It is an object of the present invention to provide a palatable pharmaceutical composition containing a lipophilic, poorly water-soluble drug, for example an NSA1D such as ibuprofen, naproxen or ketoprofen, formulated for oral dosing as an aqueous solution.
The ability of drug-cyclodextrin complexes to enhance water solubility and to mask unpleasant taste and odour has been known for many years. In this respect, NSA1D's such as ibuprofen have proved to be very suitable as candidates for complexation with cyclodextrins.
Japanese patent publication, JP 56-46837 (Kowa Yakuhin Kogyo) discloses a method for the preparation of an ibuprofen-Li-cyclodextrin clathrate complex involving the combination of ibuprofen with (3-cyclodextrin in water at elevated temperature and isolation of the clathrate by spray-drying. This method is reported to yield a product containing a high percentage of ibuprofen with a molar ratio of ibuprofen to 13-cyclodextrin in excess of 0.7. The increase in water solubility of the drug is considerable, being raised more than 8-fold from 10.44mg per 100m1 to 89.38mg per 100m1 at 27°C.
The water solubility achieved by complexation with (3-cyclodextrin, although significant, is not considered sufficient to permit formulation of ibuprofen as a soluble dosage form for oral administration in liquid form wherein ibuprofen is present at a therapeutic dosage level (200-600mg) in a suitable volume of water (SO-250m1).
WO 95/04528 ~ ~ ~ PCT/EP94/02515 European patent publication 274 444 (Bristol Myers) describes the preparation of ibuprofen-cyclodextrin complexes using a-cyclodextrin, 7-cyclodextrin or a methylated (3-cyclodextrin in place of Li-cyclodextrin. The water solubility of the ibuprofen-cyclodextrin complex is further enhanced to levels of practical utility using these forms of cyclodextrin, but the high cost of these materials, reflected in the cost of medicinal products containing them, is unlikely to promote their widespread use in analgesic products, more particularly in products available for self medication for the treatment of minor aches and pains and the symptomatic relief of colds and flu.
United Kingdom patent publication GB 2,189,994 (Zambon) discloses an effervescent water-soluble ibuprofen formulation comprising ibuprofen plus arginine or a mixture of arginine and lysine and an effervescent couple in the form of sodium or potassium bicarbonate and sodium bitarnate.
US Patent No 4,762,702 (Gergely) discloses a pharmaceutical preparation in which ibuprofen particles are enveloped by a coating of a hydro-colloid and fumaric acid which is intended to reduce the irritant effects of orally ingested ibuprofen. An effervescent formulation incorporating citric acid and calcium carbonate into the preparation is also described.
United Kingdom patent publication GB 2,219,585 (Reckitt & Colman) discloses a complex of 13-cyclodextrin with the sodium, potassium, ammonium, magnesium, calcium, arginine, glycine or lysine salt of ibuprofen, having a molar ratio of ibuprofen to 13-cyclodextrin in the range 1:0.2 to 1:0.75. The complexes may be formulated with a buffer system or an effervescent couple incorporating a pharmaceutically acceptable acid salt to provide a pH in the range 6 to 8 on reconstitution with water.
European patent publication 0 490 193 (Medics Chem-Pharm) discloses complexes of the active enantiomer of ibuprofen and/or its physiologically tolerated salts with a cyclodextrin and /or a cyclodextrin derivative. Although there is disclosed an ibuprofen effervescent tablet formulation, it is not soluble in the volume of water needed to form a therapeutically acceptable composition.
International Patent Application PCT/GB93/00702 (SmithKline Beecham) overcomes the problem of poor solubility of ibuprofen by reconstituting an ibuprofen/a-cyclodextrin complex in hot water to provide a pleasant tasting soluble liquid presentation. It was found that an approximately 30-fold increase in solubility could be achieved by dosing an ibuprofen-13-cyclodextrin complex in aqueous solution at elevated temperatures and thereby achieve therapeutic dosage levels of ibuprofen in solution in a single-dose liquid formulation.
The present invention provides a further drug-cyclodextrin complex formulation which is suitable for administration as an aqueous solution, and which is palatable and inexpensive to manufacture. The formulation according to the present invention provides a therapeutically active dose of the drug as a complex with ~i-cyclodextrin. The formulation is suitable for reconstitution with cold water and provides a pleasant tasting solution at acid or neutral pH.
It has been found that when formulated in the presence of an acid-base couple, preferably an effervescent acid-base couple, a drug/(3-cyclodextrin complex, which in isolation is soluble in water only at elevated temperatures, has enhanced solubility and dissolves in cold water to provide a therapeutic drug dose as a single-dose, liquid formulation.
According to the present invention there is provided a pharmaceutical composition for oral consumption in aqueous solution comprising a drug/&
cyclodextrin complex, characterised in that the composition further comprises a pharmaceutically acceptable acid-base couple, preferably an effervescent acid-base couple, in a quantity sufficient to cause the drug/f3-cyclodextrin complex to dissolve when the composition is mixed with cold water and provide a solution with acid or neutral pH.
Suitable non-effervescent acid-base couples for use in the invention are those commonly known in the art, for example a combination of a water soluble acid and a conjugate base in the form of a sodium or potassium salt. Suitable effervesent couples are also commonly known in the art, for example a combination of one or more water soluble acidic substances with one or more basic compounds which liberate carbon dioxide on neutralisation with acid.
Examples of suitable acids for use in the invention include, tartaric acid, citric acid, ascorbic acid and other edible organic acids. Suitable salts of organic acids include mono- di- and tri-basic salts, for example monosodium citrate, trisodium citrate, monosodium tarnate, trisodium tarnate and other salts of edible organic acids.
Inorganic acidic substances such as monosodium phosphate are also suitable components of acid-base couples. Examples of suitable bases for use in the invention include sodium carbonate, percarbonate and bicarbonate, and other alkali metal and alkali earth metal carbonates, percarbonates and bicarbonates, and mixed carbonate salts, such as sodium glycine carbonate and potasium glycine carbonate.
The preferred acid-base couple for this invention is an effervescent couple which contains citric and/or tartaric acid and sodium bicarbonate and/or carbonate.
The amount of couple required to solubilise the drug/f3-cyclodextrin complex will depend on the amount and type of drug used. However a minimum level of couple considered acceptable in a composition of the invention is an amount such that the weight of couple is greater than about 1 % of the weight of water in which it is designed to be reconstituted or is greater than 1 % of the weight of water in which it is to be dissolved, ie the final concentration of the couple on reconstitution in water (not WO 95/04528 ~ ~ PCT/EP94/02515 allowing for loss of carbon dioxide for effervescent couples) should be greater than about 1 % by weight. Levels below this amount are generally considered unsuitable since, on reconstitution with water, incomplete dissolution of the drug/Li-cyclodextrin occurs. The maximum level of couple considered acceptable in a composition of the invention is 15% of the weight of water in which it is to be reconstituted.
For effervescent compositions, levels in excess of this amount tend to lead to excessive effervescence, resulting in overflow of liquid from the glass or beaker and loss of some of the formulation. In addition high levels of acid-base couple tend to impart a salty taste to the palate. Compositions of the present invention are suitably 1o administered as pleasant tasting solutions in the pH range 4.0 to 7Ø
The constituents of acid-base couples suitable for use in compositions of the invention and their relative amounts may be selected using principles well known in the art of pharmaceutical drug formulation. An acid-base couple for use in compositions of the invention may be designed so that the final pH of the formulation 15 following reconstitution with water is in the range of 4.0 - 7.0 and preferably in the range of 5.0 - 6.5. The pH of solutions resulting from reconstitution of the couple in water may be adjusted by altering the ratio of the alkali and acid components of the couple. If the couple is designed so that the final pH of the formulation following reconstitution with water falls below the specified range there may be a tendency for 2o the drug/f3-cyclodextrin clathrate to precipitate, which detracts from the appearance and palatibility of the product. If the couple is designed to so that the final pH
following reconstitution is above the specified range then the solution will impart an alkaline /soapy taste.
Preferred drugs for use in the compositions of the present invention include 25 lipophilic NSAID's, for example propionic acid derivatives such as ibuprofen, naproxen and ketoprofen.
Accordingly, drug/(3-cyclodextrin clathrates which are suitable for use in this invention include ibuprofen /13-cyclodextrin clathrates, naproxen / (3-cyclodextrin clathrates, ketoprofen /(3-cyclodextrin clathrates and clathlerates of (3-cyclodextrin 30 with other propionic acid type NSAID's. In addition, the invention may use clathrates of f3-cyclodextrin with salts of ibuprofen, naproxen and other propionic acid type NSAID's, for example metal salts, such as sodium, potassium, magnesium, and calcium, or amino-acid salts such as arginine, ornithine or lysine.
The drugs according to this invention may be as either the racemate or 35 enantiomers. Any reference to the drug is intended to cover all active forms and may be either in the R or S enantiomer or racemate form.
The molar ratio of 13-cyclodextrin to drug (or drug salt) may be in the range 0.8:1 to 10:1, suitably in the range 1:1 to 10:1, more suitably in the range 1:1 to 5:1 and preferably in the range l: l to 3:1. If the ratio falls below this range, an ~~.a~~9 insufficient amount of the drug will be complexed which will lead to a deterioration in taste properties of the final product, and undissolved drug following reconstitution with water. If the amount of cyclodextrin is excessive then, for effervescent formulations, there is a tendency for excessive foam formation on mixing the formulation with water which may lead to loss of some of the formulation.
Furthermore, it is for economic reasons considered desirable to minimise the amount of cyclodextrin used in the composition.
The invention also provides a process for the preparation of a pharmacetical composition of the invention which process comprises the admixture of a drug/B-cyclodextrin clathrate complex and an acid-base couple.
A drug/B-cyclodextrin complex may be prepared by heating the drug and B-cyclodextrin in water or in a buffered aqueous solution, suitably to a temperature of 100°C, followed by crystallisation of the drug/B-cyclodextrin complex from the solution thus formed, suitably by maintaining the solution in the temperature range -5 to 20°C. Alternatively a drug/B-cyclodextrin complex may be made by any other method known in the art, for example by a co-precipitation or kneading method or by spray-drying a solution of the drug and B-cyclodextrin.
The acid-base couple may be prepared by any method known in the art, for example by dry mixing the components of the couple in a suitable mixer, or by granulation using a rotary granulator, fluid-bed granulator or other suitable granulator, followed by drying to remove residual moisture. If granulation is the chosen method of preparation, other components of the formulation may be included into the granulation step, for example part, or all of the drug/B-cyclodextrin clathrate, flavours, sweeteners and colours.
A composition of the invention may be formulated in any convenient form, for example as a tablet for solution, or alternatively in powder or granular form for reconstitution with water or as a ready-to-drink preparation.
Compositions of the invention may be formulated with any appropriate carrier or adjuvant appropriate to the chosen dosage form. Thus, compositions of the invention may include for example preservatives, suspending agents, wetting agents, flavouring agents, bulking agents, binders, adhesives, lubricants, disintegrants, colouring agents, sweetening agents, adsorbents, thickeners and diluents, appropriate to their form.
Compositions of the invention containing a drug/B-cyclodextrin complex and an acid-base couple may in addition include additional pharmaceutical agents suitable for administration therewith which are not complexed with B-cyclodextrin, including for example analgesics, antiinflammatories and antipyretics and also expectorants, antihistamines, decongestants and antitussive agents, such as for example WO 95/04528 ~ ~ PCTIEP94I02515 phenypropanolamine, phenylephrine, pseudoephedrine, dextromethorphan, caffeine, codeine and ascorbic acid.
The following Examples (1 to 18) are illustrative of the invention. Examples (A to G) are outside the scope of the invention but are included to further demonstrate aspects of the invention.
In the Examples, unless otherwise stated, the abbreviation BCD refers to B-cyclodextrin undecahydrate (B-cyclodextrin. 11 H20).
WO 95/04528 pCT/EP94/02515 Example 1 Preparation of I3CD/Ibuprofen Clathrate (1.1:1) BCD (146.6g, 110mM) was dissolved in water (1000m1) at 100°C.
Ibuprofen (20.68, 100mM) was added and the resulting solution was cooled to 1 °C
to give a white crystalling precipitate which was washed with cold water and dried at 50°C for 4 hours in a convection oven. The product, a white solid, was sieved through a 500p.m screen to yield 125g of BCD/ibuprofen clathrate, containing about 14%
ibuprofen.
(400mg ibuprofen per 2857mg of clathrate).
Example 2 Preparation of an effervesent pharmaceutical composition containing Ibuprofen/I3CD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a 500pm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a SOOpm screen mixed for 5 minutes with ingredient 1 and then filled into sachets, (target fill weight 10.85g) with each sachet containing the equivalent of 400mg ibuprofen.
1. Ibuprofen/BCD clathrate from example 1 57.14g 2. Sodium bicarbonate lpp.ppg 3. Citric acid (anhydrous) 60.OOg The powder from one of the sachets was added to 200m1 of cold water (15°C) to give an effervescent, pleasant tasting, clear solution, which contained 400mg ibuprofen / 200 ml of water at a pH of approximately 6.3.
Example 3 Preparation of an effervesent pharmaceutical composition containing Ibuprofen/fiCD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a SOOpm screen mixed for 5 minutes with ingredients 1 and 4 and then filled into sachets, (target fill weight 6.428g) with each sachet containing the equivalent of 200mg ibuprofen.
1. Ibuprofen/BCD clathrate from example 1 71.4g 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) 25.Og WO 95/04528 ~ ~ ~ PCT/EP94/02515 The powder from one of the sachets was added to 150m1 cold water (16°C) to i give an effervescent, pleasant tasting, clear solution, which contained 200mg ibuprofen / 150 ml of water at a pH of approximately 6Ø
Example 4 Preparation of 13CD/Naproxen Clathrate (1.8:1) Li-cyclodextrin (120.3g, 90mM) was dissolved in water (500m1) at 100°C.
Naproxen (11.5 g SOmM) was added and the resulting solution was cooled to 1°C to give a white precipitate, which was dried at 60°C in a convection oven for 16 hours.
1o The product, a white solid, was sieved through a SOOpm screen to yield 110g of (3CD/naproxen clathrate, containing about 9.4% naproxen.
Example 5 Preparation of (iCD/Naproxen Clathrate (1.1:1) a-cyclodextrin (2948, 220mM) was dissolved in water (1500m1) at 100°C.
Naproxen (46g 200mM) was added and the resulting mixture was stirred for 1 hour at 95°C and then cooled, with stirring, to 1°C to give a white precipitate, which was dried at 60°C in a convection oven for 16 hours. The product, a white solid, was sieved through a 250pM screen, to yield 250g of 13CD/naproxen clathrate, containing about 15.3% naproxen.
Example 6 Preparation of an effervescent pharmaceutical composition containing Naproxen/lZCD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a 500pm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel ways and dried for 2 hours at 60°C. The resulting granule was sieved through a 500pm screen, mixed for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target fill weight 7.38g) with each sachet containing the equivalent of 200mg naproxen 1. Naproxen/LiCD clathrate from example 4 106.Og 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) 25.Og The powder from one of the sachets was added to 150m1s cold water (15°C) _ to give an effervescent, pleasant tasting, clear solution, which contained 200mg naproxen/ 150 ml of water at a pH of approximately 6Ø
_g_ l~xample 7 Preparation of an effervescent pharmaceutical composition containing Naproxen/(3CD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a 500pm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a SOOpm screen, mixed for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target fill weight 6.307g) with each sachet containing the equivalent of 200mg naproxen.
1. Naproxen/LiCD clathrate from example 5 65.Sg 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) 25.Og The powder from one of the sachets was added to 150m1s cold water (15°C) to give an effervescent, pleasant tasting, clear solution, which contained 200mg naproxen/ 150 ml of water at a pH of approximately 6Ø
Example 8 ' Preparation of an effervescent pharmaceutical composition containing Naproxen/13CD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a SOOpm screen, mixed for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target fill weight 7.614g) with each sachet containing the equivalent of 400mg naproxen.
1. Naproxen/BCD clathrate from example 5 130.7g 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) 25.Og The powder from one of the sachets was added to 200m1s cold water (15°C) to give an effervescent, pleasant tasting, clear solution, which contained 400mg naproxen/ 200 ml of water at a pH of approximately 6Ø
Example 9 Preparation of BCD/Naproxen sodium Clathrate (1.1:1) 13-cyclodextrin (147g, 110mM) was dissolved in water (SOOmI) at 100°C.
Naproxen sodium (25.2 g 100mM) was added and the resulting solution was stirred for 1 hour at 95°C and then poured onto trays and evaporated to dryness in a WO 95/04528 ~ ~ ~ ~ PCT/EP94/02515 convection oven at 60°C. The product, a white amorphous solid, was sieved through a 250um screen, to yield 1238 of aCD/naproxen clathrate, containing about 15.156 naproxen.
Example 10 Preparation of an effervescent pharmaceutical composition containing Naproxen sodium/IiCD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a 500pm screen, mixed for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target fill weight 6.325g) with each sachet containing the equivalent of 200mg naproxen 1. Naproxen sodium/f3CD clathrate from example 9 66.38 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) 25.Og The powder from one of the sachets was added to 150m1s cold water (15°C) to give an effervescent, pleasant tasting, clear solution, which contained 200mg naproxen/ 150 ml of water at a pH of approximately 6Ø
Example 11 Preparation of a non-effervescent pharmaceutical composition containing Naproxen/(3CD clathrate for reconstitution with cold water Ingredients 2 and 3 were mixed together in a suitable mixer for 5 minutes and the resulting powder was filled into sachets, (target weight 5510mg), with each sachet containing the equivalent of 200mg naproxen.
1. Naproxen/(3CD clathrate l3.lg 2. Tri-sodium citrate 40.Og 3. Citric acid (anhydrous) 2.Og The powder from one of the sachets was added to 250m1 of cold water ( 15°C) and stirred for 1 minute to give a non-effervescent, clear solution, which contained 200mg naproxen/ 150m1 water at a pH of approximately 6.2.
Example 12 Preparation of IZCD / Ketoprofen Clathrate (5:1) Li-cyclodextrin (53.3g, 40mM) was dissolved in water (200m1) at 100°C.
Ketoprofen (2.05g, 8mM) was added and the resulting mixture was stirred for 1 hour at 95°C and then cooled, with stirring, to 1°C to give a white precipitate, which was dried at 60°C
Ibuprofen (20.68, 100mM) was added and the resulting solution was cooled to 1 °C
to give a white crystalling precipitate which was washed with cold water and dried at 50°C for 4 hours in a convection oven. The product, a white solid, was sieved through a 500p.m screen to yield 125g of BCD/ibuprofen clathrate, containing about 14%
ibuprofen.
(400mg ibuprofen per 2857mg of clathrate).
Example 2 Preparation of an effervesent pharmaceutical composition containing Ibuprofen/I3CD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a 500pm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a SOOpm screen mixed for 5 minutes with ingredient 1 and then filled into sachets, (target fill weight 10.85g) with each sachet containing the equivalent of 400mg ibuprofen.
1. Ibuprofen/BCD clathrate from example 1 57.14g 2. Sodium bicarbonate lpp.ppg 3. Citric acid (anhydrous) 60.OOg The powder from one of the sachets was added to 200m1 of cold water (15°C) to give an effervescent, pleasant tasting, clear solution, which contained 400mg ibuprofen / 200 ml of water at a pH of approximately 6.3.
Example 3 Preparation of an effervesent pharmaceutical composition containing Ibuprofen/fiCD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a SOOpm screen mixed for 5 minutes with ingredients 1 and 4 and then filled into sachets, (target fill weight 6.428g) with each sachet containing the equivalent of 200mg ibuprofen.
1. Ibuprofen/BCD clathrate from example 1 71.4g 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) 25.Og WO 95/04528 ~ ~ ~ PCT/EP94/02515 The powder from one of the sachets was added to 150m1 cold water (16°C) to i give an effervescent, pleasant tasting, clear solution, which contained 200mg ibuprofen / 150 ml of water at a pH of approximately 6Ø
Example 4 Preparation of 13CD/Naproxen Clathrate (1.8:1) Li-cyclodextrin (120.3g, 90mM) was dissolved in water (500m1) at 100°C.
Naproxen (11.5 g SOmM) was added and the resulting solution was cooled to 1°C to give a white precipitate, which was dried at 60°C in a convection oven for 16 hours.
1o The product, a white solid, was sieved through a SOOpm screen to yield 110g of (3CD/naproxen clathrate, containing about 9.4% naproxen.
Example 5 Preparation of (iCD/Naproxen Clathrate (1.1:1) a-cyclodextrin (2948, 220mM) was dissolved in water (1500m1) at 100°C.
Naproxen (46g 200mM) was added and the resulting mixture was stirred for 1 hour at 95°C and then cooled, with stirring, to 1°C to give a white precipitate, which was dried at 60°C in a convection oven for 16 hours. The product, a white solid, was sieved through a 250pM screen, to yield 250g of 13CD/naproxen clathrate, containing about 15.3% naproxen.
Example 6 Preparation of an effervescent pharmaceutical composition containing Naproxen/lZCD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a 500pm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel ways and dried for 2 hours at 60°C. The resulting granule was sieved through a 500pm screen, mixed for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target fill weight 7.38g) with each sachet containing the equivalent of 200mg naproxen 1. Naproxen/LiCD clathrate from example 4 106.Og 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) 25.Og The powder from one of the sachets was added to 150m1s cold water (15°C) _ to give an effervescent, pleasant tasting, clear solution, which contained 200mg naproxen/ 150 ml of water at a pH of approximately 6Ø
_g_ l~xample 7 Preparation of an effervescent pharmaceutical composition containing Naproxen/(3CD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a 500pm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a SOOpm screen, mixed for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target fill weight 6.307g) with each sachet containing the equivalent of 200mg naproxen.
1. Naproxen/LiCD clathrate from example 5 65.Sg 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) 25.Og The powder from one of the sachets was added to 150m1s cold water (15°C) to give an effervescent, pleasant tasting, clear solution, which contained 200mg naproxen/ 150 ml of water at a pH of approximately 6Ø
Example 8 ' Preparation of an effervescent pharmaceutical composition containing Naproxen/13CD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a SOOpm screen, mixed for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target fill weight 7.614g) with each sachet containing the equivalent of 400mg naproxen.
1. Naproxen/BCD clathrate from example 5 130.7g 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) 25.Og The powder from one of the sachets was added to 200m1s cold water (15°C) to give an effervescent, pleasant tasting, clear solution, which contained 400mg naproxen/ 200 ml of water at a pH of approximately 6Ø
Example 9 Preparation of BCD/Naproxen sodium Clathrate (1.1:1) 13-cyclodextrin (147g, 110mM) was dissolved in water (SOOmI) at 100°C.
Naproxen sodium (25.2 g 100mM) was added and the resulting solution was stirred for 1 hour at 95°C and then poured onto trays and evaporated to dryness in a WO 95/04528 ~ ~ ~ ~ PCT/EP94/02515 convection oven at 60°C. The product, a white amorphous solid, was sieved through a 250um screen, to yield 1238 of aCD/naproxen clathrate, containing about 15.156 naproxen.
Example 10 Preparation of an effervescent pharmaceutical composition containing Naproxen sodium/IiCD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a 500pm screen, mixed for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target fill weight 6.325g) with each sachet containing the equivalent of 200mg naproxen 1. Naproxen sodium/f3CD clathrate from example 9 66.38 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) 25.Og The powder from one of the sachets was added to 150m1s cold water (15°C) to give an effervescent, pleasant tasting, clear solution, which contained 200mg naproxen/ 150 ml of water at a pH of approximately 6Ø
Example 11 Preparation of a non-effervescent pharmaceutical composition containing Naproxen/(3CD clathrate for reconstitution with cold water Ingredients 2 and 3 were mixed together in a suitable mixer for 5 minutes and the resulting powder was filled into sachets, (target weight 5510mg), with each sachet containing the equivalent of 200mg naproxen.
1. Naproxen/(3CD clathrate l3.lg 2. Tri-sodium citrate 40.Og 3. Citric acid (anhydrous) 2.Og The powder from one of the sachets was added to 250m1 of cold water ( 15°C) and stirred for 1 minute to give a non-effervescent, clear solution, which contained 200mg naproxen/ 150m1 water at a pH of approximately 6.2.
Example 12 Preparation of IZCD / Ketoprofen Clathrate (5:1) Li-cyclodextrin (53.3g, 40mM) was dissolved in water (200m1) at 100°C.
Ketoprofen (2.05g, 8mM) was added and the resulting mixture was stirred for 1 hour at 95°C and then cooled, with stirring, to 1°C to give a white precipitate, which was dried at 60°C
~~ ~~9 in a convection oven for 16 hours. The product, a white solid, was sieved through a 250uM screen to yield 50.4g of f3CD / ketoprofen clathrate, containing about 3.8%
ketoprofen.
Example 13 ' Preparation of an effervescent pharmaceutical composition containing Ketoprofen/~3CD clathrate for reconstitution with cold water Ingredients 2 and 3 were sieved through a SOOpm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further S minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a 500pm screen, mixed for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target fill weight 6.316g) with each sachet containing the equivalent of SOmg ketoprofen t5 1. Ketoprofen/~3CD clathrate from example 12 26.3g 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) ~ 25.Og The powder from one of the sachets was added to 150m1s cold water (15°C) to give an effervescent, pleasant tasting, clear solution, which contained SOmg ketoprofen/
150 ml of water at a pH of approximately 6Ø
Example 14 Preparation of a ready made effervescent pharmaceutical composition containing ~i-cyclodextrin / naproxen clathrate (1.1:1) 1. (3-cyclodextrin / naproxen clathrate 13.3g 2. Trisodium citrate 29.Og 3. Sodium carbonate 3.Og 4. Methyl paraben sodium 3.Og 5. Deionised water to 200 ml Ingredients 1, 2, 3 and 4 were dissolved in item 5. 20 ml volumes of the solution were dispensed into 250m1 bottles containing 130 ml carbonated water, mixed and then fitted with air tight closures. Each bottle contained the equivalent to approximately 200mg naproxen in a solution of pH approximately 6Ø
ketoprofen.
Example 13 ' Preparation of an effervescent pharmaceutical composition containing Ketoprofen/~3CD clathrate for reconstitution with cold water Ingredients 2 and 3 were sieved through a SOOpm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further S minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a 500pm screen, mixed for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target fill weight 6.316g) with each sachet containing the equivalent of SOmg ketoprofen t5 1. Ketoprofen/~3CD clathrate from example 12 26.3g 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) ~ 25.Og The powder from one of the sachets was added to 150m1s cold water (15°C) to give an effervescent, pleasant tasting, clear solution, which contained SOmg ketoprofen/
150 ml of water at a pH of approximately 6Ø
Example 14 Preparation of a ready made effervescent pharmaceutical composition containing ~i-cyclodextrin / naproxen clathrate (1.1:1) 1. (3-cyclodextrin / naproxen clathrate 13.3g 2. Trisodium citrate 29.Og 3. Sodium carbonate 3.Og 4. Methyl paraben sodium 3.Og 5. Deionised water to 200 ml Ingredients 1, 2, 3 and 4 were dissolved in item 5. 20 ml volumes of the solution were dispensed into 250m1 bottles containing 130 ml carbonated water, mixed and then fitted with air tight closures. Each bottle contained the equivalent to approximately 200mg naproxen in a solution of pH approximately 6Ø
WO 95/04528 ~ .~ PCT/EP94/02515 Example 15 Preparation of (3CD / Naproxen Clathrate (0.9:1) ~-cyclodextrin (48.Og, 36 mmoles) and naproxen (9.2g, 40 mmoles) were added to 300 ml deionised water. The mixture was stirred for 1 hour at 95-100°C
and then cooled to 1 °C to give a white precipitate, which was dried at 60°C in a convection oven for 16 hours. The product, a white solid, was sieved through a 500 ltm screen, to yield 37.6g of (3CD / naproxen clathrate, containing about 19% naproxen.
Example 16 Preparation of a ready made effervescent pharmaceutical composition containing (3-cyclodextrin / naproxen clathrate (0.9:1) 1. ~i-cyclodextrin / naproxen clathrate 10.52g 2. Trisodium citrate 29.Og 3. Sodium carbonate 3.Og 4. Methyl paraben sodium 3.Og 5. Deionised water to 200 ml Ingredients 1, 2 ,3 and 4 were dissolved in item 5.20 ml volumes of the solution were dispensed into 250 ml bottles containing 130 ml carbonated water, mixed and_then fitted with air tight closures. Each bottle contained the equivalent to_approximately 200 mg naproxen in a solution of pH approximately 6Ø
Example 17 Preparation of an effervescent pharmaceutical composition containing (3 cyclodextrin / naproxen clathrate (1.1:1) without precomplexation 1. (3-cyclodextrin 12.8g 2. Naproxen 2.Og 3. Trisodium citrate 29.Og 4. Sodium carbonate 3.Og 5. Methyl paraben sodium 3.Og 6. Deionised water to 200 ml Ingredients 1, 2, 3, 4 and 5 were dissolved in item 6.20 ml volumes of the solution were dispensed into 250 ml bottles containing 130 ml carbonated water, mixed and then fitted with air tight closures. Each bottle contained the equivalent to approximately 200 mg naproxen in a solution of pH approximately 6Ø
and then cooled to 1 °C to give a white precipitate, which was dried at 60°C in a convection oven for 16 hours. The product, a white solid, was sieved through a 500 ltm screen, to yield 37.6g of (3CD / naproxen clathrate, containing about 19% naproxen.
Example 16 Preparation of a ready made effervescent pharmaceutical composition containing (3-cyclodextrin / naproxen clathrate (0.9:1) 1. ~i-cyclodextrin / naproxen clathrate 10.52g 2. Trisodium citrate 29.Og 3. Sodium carbonate 3.Og 4. Methyl paraben sodium 3.Og 5. Deionised water to 200 ml Ingredients 1, 2 ,3 and 4 were dissolved in item 5.20 ml volumes of the solution were dispensed into 250 ml bottles containing 130 ml carbonated water, mixed and_then fitted with air tight closures. Each bottle contained the equivalent to_approximately 200 mg naproxen in a solution of pH approximately 6Ø
Example 17 Preparation of an effervescent pharmaceutical composition containing (3 cyclodextrin / naproxen clathrate (1.1:1) without precomplexation 1. (3-cyclodextrin 12.8g 2. Naproxen 2.Og 3. Trisodium citrate 29.Og 4. Sodium carbonate 3.Og 5. Methyl paraben sodium 3.Og 6. Deionised water to 200 ml Ingredients 1, 2, 3, 4 and 5 were dissolved in item 6.20 ml volumes of the solution were dispensed into 250 ml bottles containing 130 ml carbonated water, mixed and then fitted with air tight closures. Each bottle contained the equivalent to approximately 200 mg naproxen in a solution of pH approximately 6Ø
~~ ~~~ ~9 ~xamp~e tai Preparation of a ready made effervescent pharmaceutical composition containing ~i-cyclodextrin / naproxen clathrate (0.9:1) without precomplexation 1. (3-cyclodextrin 10.4g ' 2. Naproxen 2.Og 3. Trisodium citrate 29.Og 4. Sodium carbonate 3.Og 5. Methyl paraben sodium 3.Og 6. Deionised water to 200 ml Ingredients 1, 2, 3, 4 and 5 were dissolved in item 6.20 ml volumes of the solution were dispersed into 250 ml bottles containing 130 ml carbonated water, mixed and then fitted with air tight closures. Each bottle contained the equivalent to approximately 200 mg naproxen in a solution of pH approximately 6Ø
Example A
Reconstitution in water of a commercially available Ibuprofen tablet A Nurofen Soluble (trade mark) tablet containing ibuprofen (200mg) was added to 150m1 of cold water. The tablet failed to completely dissolve, resulting in a white suspension.
Example B
Reconstitution in water of a commercially available dispersible Naproxen powder The contents of a Naproxsyn (trade mark) sachet containing naproxen (500mg) was added to 150m1 of cold water. The powder failed to completely dissolve, resulting in a white suspension.
Example C
Preparation of an effervescent pharmaceutical composition containing Ibuprofen/(iCD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a SOOpm screen mixed for 5 minutes with ingredients 1 and 4 and then filled into sachets, (target fill weight 1.928g) with each sachet containing the equivalent of 200mg ibuprofen.
1. Ibuprofen/~iCD clathrate from example 1 171.4g WO 95/04528 ~ PCT/EP94/02515 2. Sodium bicarbonate 11.68 3. Citric acid (anhydrous) 10.9g 4. Sodium carbonate (anhydrous) 2.Sg The powder from one of the sachets was added to 150m1 cold water ( 16°C) to give a suspension in which some of the ibuprofen/(3-cyclodextrin clathrate remained undissolved.
Example D
Preparation of an effervescent pharmaceutical composition containing Naproxen/13CD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a SOOpm screen, mixed for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target fill weight 2.62g) with each sachet containing the equivalent of 200mg naproxen 1. Naproxen/13CD clathrate from example 4 106.Og 2. Sodium bicarbonate 11.6g 3. Citric acid (anhydrous) 10.9g 4. Sodium carbonate (anhydrous) 2.Sg The powder from one of the sachets was added to 150m1 cold water (16°C) to give a suspension in which some of the naproxen/f3-cyclodextrin clathrate remained undissolved.
Example E
The granulation and blending process described in Example 8 was repeated, except that the naproxen 13-cyclodextrin was replaced with an equimolal quantity of naproxen sodium ( 10.95g). The resulting powder was filled into sachets (target weight 5.219g), with each sachet containing naproxen.(200mg). The powder from one of the sachets was added to 150m1s cold water (16°C) to give a suspension in which some of the drug remained undissolved.
Example F
The granulation and blending process described in Example 8 was repeated, except that the ibuprofen 13-cyclodextrin was replaced with an equimolal quantity of ibuprofen sodium (ll.lg). The resulting powder was filled into sachets (target weight 5.221g), with each sachet containing ibuprofen (200mg).
Example A
Reconstitution in water of a commercially available Ibuprofen tablet A Nurofen Soluble (trade mark) tablet containing ibuprofen (200mg) was added to 150m1 of cold water. The tablet failed to completely dissolve, resulting in a white suspension.
Example B
Reconstitution in water of a commercially available dispersible Naproxen powder The contents of a Naproxsyn (trade mark) sachet containing naproxen (500mg) was added to 150m1 of cold water. The powder failed to completely dissolve, resulting in a white suspension.
Example C
Preparation of an effervescent pharmaceutical composition containing Ibuprofen/(iCD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a SOOpm screen mixed for 5 minutes with ingredients 1 and 4 and then filled into sachets, (target fill weight 1.928g) with each sachet containing the equivalent of 200mg ibuprofen.
1. Ibuprofen/~iCD clathrate from example 1 171.4g WO 95/04528 ~ PCT/EP94/02515 2. Sodium bicarbonate 11.68 3. Citric acid (anhydrous) 10.9g 4. Sodium carbonate (anhydrous) 2.Sg The powder from one of the sachets was added to 150m1 cold water ( 16°C) to give a suspension in which some of the ibuprofen/(3-cyclodextrin clathrate remained undissolved.
Example D
Preparation of an effervescent pharmaceutical composition containing Naproxen/13CD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a SOOpm screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was sieved through a SOOpm screen, mixed for 5 minutes with ingredients 1 and 4, and then filled into sachets, (target fill weight 2.62g) with each sachet containing the equivalent of 200mg naproxen 1. Naproxen/13CD clathrate from example 4 106.Og 2. Sodium bicarbonate 11.6g 3. Citric acid (anhydrous) 10.9g 4. Sodium carbonate (anhydrous) 2.Sg The powder from one of the sachets was added to 150m1 cold water (16°C) to give a suspension in which some of the naproxen/f3-cyclodextrin clathrate remained undissolved.
Example E
The granulation and blending process described in Example 8 was repeated, except that the naproxen 13-cyclodextrin was replaced with an equimolal quantity of naproxen sodium ( 10.95g). The resulting powder was filled into sachets (target weight 5.219g), with each sachet containing naproxen.(200mg). The powder from one of the sachets was added to 150m1s cold water (16°C) to give a suspension in which some of the drug remained undissolved.
Example F
The granulation and blending process described in Example 8 was repeated, except that the ibuprofen 13-cyclodextrin was replaced with an equimolal quantity of ibuprofen sodium (ll.lg). The resulting powder was filled into sachets (target weight 5.221g), with each sachet containing ibuprofen (200mg).
The powder from one of the sachets was added to 150m1 cold water (16°C) to give a solution which initially had oily droplets floating on the surface. On standing, the droplets formed a white vitreous solid, containing undissolved ibuprofen.
Example G
Preparation of an effervescent pharmaceutical composition containing Ibuprofen/(3CD clathrate for reconstitution with cold water Ibuprofen sodium B-cyclodextrin complex (1: 0.37) was prepared as described ih GB 2,219,585 (Reckitt & Colman) Example 1. Ingredients 2 and 3 were seived through a SOOp.m screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was seived through a 500p.m screen, mixed for 5 minutes with ingredients 1 and and then filled into sachets (target fill weight 5.6g) with each sachet containing the equivalent of 200mg ibuprofen.
1. Ibuprofen/BCD clathrate ( 1:0.347) 30.Og 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) 25.Og The powder from one of the sachets was added to 150m1 cold water ( 16°C) to give a solution which initially had oily droplets floating on the surface. On standing, the droplets formed a white viscous solid containing undissolved ibuprofen.
The pH
of the mixture was approximately 6.1.
Example G
Preparation of an effervescent pharmaceutical composition containing Ibuprofen/(3CD clathrate for reconstitution with cold water Ibuprofen sodium B-cyclodextrin complex (1: 0.37) was prepared as described ih GB 2,219,585 (Reckitt & Colman) Example 1. Ingredients 2 and 3 were seived through a SOOp.m screen and mixed in a suitable mixer for 5 minutes. A small aliquot of water was added and the product was mixed for a further 5 minutes and then placed on stainless steel trays and dried for 2 hours at 60°C. The resulting granule was seived through a 500p.m screen, mixed for 5 minutes with ingredients 1 and and then filled into sachets (target fill weight 5.6g) with each sachet containing the equivalent of 200mg ibuprofen.
1. Ibuprofen/BCD clathrate ( 1:0.347) 30.Og 2. Sodium bicarbonate 116.Og 3. Citric acid (anhydrous) 109.Og 4. Sodium carbonate (anhydrous) 25.Og The powder from one of the sachets was added to 150m1 cold water ( 16°C) to give a solution which initially had oily droplets floating on the surface. On standing, the droplets formed a white viscous solid containing undissolved ibuprofen.
The pH
of the mixture was approximately 6.1.
Claims (13)
1. A pharmaceutical composition for oral consumption in aqueous solution comprising a lipophilic NSAID/.alpha.-cyclodextrin clathrate complex, wherein the composition further comprises a pharmaceutically acceptable acid-base couple, in a quantity sufficient to cause the lipophilic NSAID/.beta.-cyclodextrin clathrate complex to dissolve when the composition is mixed with cold water and provide a solution with acid or neutral pH, wherein the weight of the couple in the composition is greater than 1 % of the weight of water in which it is to be reconstituted or dissolved and wherein the ratio of .beta.-cyclodextrin to lipophilic NSAID is 0.8:1 to 10:1.
2. A pharmaceutical composition according to claim 1, wherein the lipophilic NSAID
is ibuprofen, naproxen or ketoprofen.
is ibuprofen, naproxen or ketoprofen.
3. A pharmaceutical composition according to claim 1 or claim 2, wherein the acid-base couple is an effervescent couple.
4. A pharmaceutical composition according to claim 3 wherein the effervescent couple comprises a combination of one or more water soluble acidic substances with one or more basic compounds which liberate carbon dioxide on neutralisation with acid.
5. A pharmaceutical composition according to claim 4, wherein the water soluble acidic substance is tartaric acid, citric acid or ascorbic acid.
6. A pharmaceutical composition according to any one of claims 1-5, wherein the base is selected from alkali metal and alkaline earth metal carbonates, percarbonates and bicarbonates and mixed carbonate salts.
7. A pharmaceutical composition according to any one of claims 1-6 wherein the acid-base couple is an effervescent couple which contains citric or tartaric acid and sodium bicarbonate or carbonate.
8. A pharmaceutical composition according to claim 1 wherein the acid-base couple is a non effervescent couple which is a combination of a water soluble acid and a conjugate base in the form of a sodium or potassium salt.
9. A pharmaceutical composition according to any one of claims 1-8 wherein said acid-base couple is present in a quantity sufficient to provide a solution having a pH of 4.0 to 7Ø
10. A pharmaceutical composition according to any one of claims 1-9, wherein the ratio of .beta.-cyclodextrin to lipophilic NSAID is 1:1 to 5:1.
11. A pharmaceutical composition according to any one of claims 1-10, formulated as a tablet for solution, in powder or granular form for reconstruction with water or as a ready-to-drink preparation.
12. A process for the preparation of a pharmaceutical composition as claimed in claim 1, which process comprises the admixture of a lipophilic NSAID/.beta.-cyclodextrin clathrate complex, wherein the ratio of the .beta.-cyclodextrin to lipophilic NSAID is 0.8:1 to 10:1, and an acid-base couple, wherein the acid-base couple is in a quantity sufficient to cause the lipophilic NSAID/.beta.-cyclodextrin clathrate complex to dissolve when the composition is mixed with cold water and provide a solution with acid or neutral pH and wherein the weight of the couple in the composition is greater than 1 % of the weight of water in which it is to be reconstituted or dissolved.
13. Use of a pharmaceutical composition according to claim 1 for oral dosing, wherein the composition provides a therapeutically active dose of the lipophilic NSAID
as a complex with .beta.-cyclodextrin.
as a complex with .beta.-cyclodextrin.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB939316580A GB9316580D0 (en) | 1993-08-10 | 1993-08-10 | Pharmaceutical composition |
| GB9316580.1 | 1993-08-10 | ||
| PCT/EP1994/002515 WO1995004528A2 (en) | 1993-08-10 | 1994-07-29 | PHARMACEUTICAL COMPOSITION CONTAINING A DRUG/β-CYCLODEXTRIN COMPLEX IN COMBINATION WITH AN ACID-BASE COUPLE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2169159A1 CA2169159A1 (en) | 1995-02-16 |
| CA2169159C true CA2169159C (en) | 2005-01-25 |
Family
ID=10740244
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002169159A Expired - Fee Related CA2169159C (en) | 1993-08-10 | 1994-07-29 | Pharmaceutical composition containing a drug/.beta.-cyclodextrin complex in combination with an acid-base couple |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0720476A1 (en) |
| JP (1) | JPH09501421A (en) |
| CN (1) | CN1112180C (en) |
| AU (1) | AU688789B2 (en) |
| CA (1) | CA2169159C (en) |
| GB (1) | GB9316580D0 (en) |
| TW (1) | TW354256B (en) |
| WO (1) | WO1995004528A2 (en) |
| ZA (1) | ZA945930B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA959469B (en) * | 1994-11-15 | 1996-05-15 | South African Druggists Ltd | Pharmaceutical composition |
| ES2171110B1 (en) * | 2000-03-03 | 2003-06-16 | Aplicaciones Farmacodinamicas | PHARMACEUTICAL COMPOSITION BASED ON IBUPROFEN AND PROCEDURE FOR PREPARATION. |
| ES2189682B1 (en) * | 2001-12-11 | 2004-04-01 | Laboratorios Del Dr. Esteve, S.A. | DRINKABLE PREPARATION UNDERSTANDING KETOPROPHEN AND ITS EMPLOYMENT IN THE PROCESSING OF PROCESSES PROCESSING WITH FEVER, INFLAMMATION AND / OR PAIN, IN AN ANIMAL COLLECTIVE, SIMULTANEOUSLY. |
| CZ295151B6 (en) * | 2004-02-20 | 2005-06-15 | I. Q. A., A. S. | Stable, taste-acceptable syrups containing ibuprofen and process of their preparation |
| JP5242543B2 (en) | 2006-03-16 | 2013-07-24 | ノバルティス アーゲー | Solid dosage form containing a taste masked active agent |
| KR20150050595A (en) | 2006-03-28 | 2015-05-08 | 자블린 파머슈티칼스 인코포레이티드 | Formulations of low dose diclofenac and beta-cyclodextrin |
| JP5977672B2 (en) * | 2009-04-27 | 2016-08-24 | ラボラトリオ デ アプリカシオネス ファルマコディナミカス，エセ．アー．Ｌａｂｏｒａｔｏｒｉｏ Ｄｅ Ａｐｌｉｃａｃｉｏｎｅｓ Ｆａｒｍａｃｏｄｉｎａｍｉｃａｓ，Ｓ．Ａ． | Suspension for oral administration of ibuprofen ricinate |
| HUE029953T2 (en) * | 2009-04-27 | 2017-04-28 | Laboratorio De Aplicaciones Farm S A | Ibuprofen lysinate oral suspension |
| JP5853430B2 (en) * | 2010-06-21 | 2016-02-09 | 大正製薬株式会社 | Oral solution |
| CN101987089B (en) * | 2010-11-10 | 2012-07-04 | 天大药业（珠海）有限公司 | Effervescent medicinal preparation |
| GB201021267D0 (en) * | 2010-12-15 | 2011-01-26 | Reckitt Benckiser Healthcare Int Ltd | Novel pharmaceutical formulation |
| KR20150023059A (en) * | 2012-06-28 | 2015-03-04 | 맥네일-피피씨, 인코포레이티드 | Racecadotril liquid compositions |
| US9114171B2 (en) * | 2012-06-28 | 2015-08-25 | Mcneil-Ppc, Inc. | Racecadotril liquid compositions |
| AU2013318360A1 (en) * | 2012-09-18 | 2015-03-26 | Mcneil-Ppc, Inc. | Sustained release oral dosage forms comprising low melting propionic acid derivative particles |
| CN111116794A (en) * | 2019-12-20 | 2020-05-08 | 蚌埠市鑫晟新材料科技有限公司 | Preparation method of neutral polymeric material for papermaking |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5920230A (en) * | 1982-07-19 | 1984-02-01 | チバ−ガイギ−・アクチエンゲゼルシヤフト | Drug containing piruprophen |
| DE3440288A1 (en) * | 1984-11-05 | 1986-05-07 | Gergely, Gerhard, Dr.-Ing., Wien | PHARMACEUTICAL PREPARATION WITH A CONTENT OF AT LEAST ONE Mucous-irritating SUBSTANCE OR THE LIKE, PARTICULARLY PROFESSIONALS, AND METHOD FOR THE PRODUCTION THEREOF |
| CA1298290C (en) * | 1987-01-09 | 1992-03-31 | Herand M. Markarian | Solution ibuprofen complexes, compositions and processes for preparing the same |
| GB8724763D0 (en) * | 1987-10-22 | 1987-11-25 | Aps Research Ltd | Sustained-release formulations |
| GB8813682D0 (en) * | 1988-06-09 | 1988-07-13 | Reckitt & Colmann Prod Ltd | Pharmaceutical compositions |
| CH677606A5 (en) * | 1988-07-12 | 1991-06-14 | Aesculapius Pharma Sa | |
| DE3838431A1 (en) * | 1988-11-12 | 1990-05-17 | Bayer Ag | IBUPROFEN SHOWER PREPARATIONS |
| IT1227626B (en) * | 1988-11-28 | 1991-04-23 | Vectorpharma Int | SUPPORTED DRUGS WITH INCREASED DISSOLUTION SPEED AND PROCEDURE FOR THEIR PREPARATION |
| US5019663A (en) * | 1989-04-03 | 1991-05-28 | Mobil Oil Corp. | Heat balanced paraffin upgrading with co-fed oxygenate |
| JPH02279631A (en) * | 1989-04-18 | 1990-11-15 | Yamanouchi Pharmaceut Co Ltd | Cyclodextrin clathrate for medicine and its production |
| CA2009326C (en) * | 1989-05-09 | 1998-01-27 | Lawrence J. Daher | Aqueous granulation solution and a method of tablet granulation |
| CA2021548A1 (en) * | 1989-09-01 | 1991-03-02 | Ronald Nash Duvall | Effervescent cold or sinus allergy medicine composition having reduced sodium content |
| US5024997A (en) * | 1990-06-22 | 1991-06-18 | American Home Products Corporation | Palatable ibuprofen solutions |
| DE4027927A1 (en) * | 1990-09-04 | 1992-03-05 | Bayer Ag | SHOWER COMPONENT AND METHOD FOR THEIR PRODUCTION |
| DE4038314A1 (en) * | 1990-11-30 | 1992-06-04 | Puetter Medice Chem Pharm | COMPLEXES OF THE ACTIVE ENANTIOMER OF THE IBUPROFEN WITH CYCLODEXTRIN |
| JP2579251B2 (en) * | 1991-03-12 | 1997-02-05 | ロシェ・コンシューマー・ヘルス・（ワールドワイド）・リミテッド | Non-effervescent ibuprofen composition |
-
1993
- 1993-08-10 GB GB939316580A patent/GB9316580D0/en active Pending
-
1994
- 1994-07-29 WO PCT/EP1994/002515 patent/WO1995004528A2/en not_active Application Discontinuation
- 1994-07-29 CA CA002169159A patent/CA2169159C/en not_active Expired - Fee Related
- 1994-07-29 CN CN94193729A patent/CN1112180C/en not_active Expired - Fee Related
- 1994-07-29 AU AU76099/94A patent/AU688789B2/en not_active Ceased
- 1994-07-29 EP EP94926129A patent/EP0720476A1/en not_active Withdrawn
- 1994-07-29 JP JP7506202A patent/JPH09501421A/en active Pending
- 1994-08-08 ZA ZA945930A patent/ZA945930B/en unknown
- 1994-08-11 TW TW083107332A patent/TW354256B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| GB9316580D0 (en) | 1993-09-29 |
| JPH09501421A (en) | 1997-02-10 |
| AU7609994A (en) | 1995-02-28 |
| CN1133006A (en) | 1996-10-09 |
| ZA945930B (en) | 1995-04-05 |
| WO1995004528A2 (en) | 1995-02-16 |
| AU688789B2 (en) | 1998-03-19 |
| CA2169159A1 (en) | 1995-02-16 |
| CN1112180C (en) | 2003-06-25 |
| EP0720476A1 (en) | 1996-07-10 |
| WO1995004528A3 (en) | 1995-03-16 |
| TW354256B (en) | 1999-03-11 |
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