WO1995004528A2 - PHARMACEUTICAL COMPOSITION CONTAINING A DRUG/β-CYCLODEXTRIN COMPLEX IN COMBINATION WITH AN ACID-BASE COUPLE - Google Patents

PHARMACEUTICAL COMPOSITION CONTAINING A DRUG/β-CYCLODEXTRIN COMPLEX IN COMBINATION WITH AN ACID-BASE COUPLE Download PDF

Info

Publication number
WO1995004528A2
WO1995004528A2 PCT/EP1994/002515 EP9402515W WO9504528A2 WO 1995004528 A2 WO1995004528 A2 WO 1995004528A2 EP 9402515 W EP9402515 W EP 9402515W WO 9504528 A2 WO9504528 A2 WO 9504528A2
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
acid
drug
cyclodextrin
composition according
Prior art date
Application number
PCT/EP1994/002515
Other languages
French (fr)
Other versions
WO1995004528A3 (en
Inventor
Timothy James Grattan
Original Assignee
Smithkline Beecham Plc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Plc filed Critical Smithkline Beecham Plc
Priority to JP7506202A priority Critical patent/JPH09501421A/en
Priority to AU76099/94A priority patent/AU688789B2/en
Priority to EP94926129A priority patent/EP0720476A1/en
Priority to CA002169159A priority patent/CA2169159C/en
Publication of WO1995004528A2 publication Critical patent/WO1995004528A2/en
Publication of WO1995004528A3 publication Critical patent/WO1995004528A3/en

Links

Classifications

    • 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
    • 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
    • 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
    • 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
    • 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]

Definitions

  • This invention relates to a pharmaceutical composition containing a drug 5 which is lipophilic and has poor water solubility in the form of a clathrate complex, a process for its preparation, and a palatable formulation thereof suitable for oral consumption.
  • 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.
  • NSAID non- steroidal anti-inflammatory
  • NSAIDs non-steroidal antiinflammatory agents
  • 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.
  • NSAID such as ibuprofen, naproxen or ketoprofen
  • NSAID's such as ibuprofen have proved to be very suitable as candidates for
  • JP 56-46837 discloses a method for the preparation of an ibuprofen- ⁇ -cyclodextrin clathrate complex involving the combination of ibuprofen with ⁇ -cyclodextrin in water at elevated temperature and isolation of the clathrate by spray-drying. This method is reported to
  • US Patent No 4,762,702 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 discloses a complex of ⁇ -cyclodextrin with the sodium, potassium, ammonium, magnesium, calcium, arginine, glycine or lysine salt of ibuprofen, having a molar ratio of ibuprofen to ⁇ -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 0490 193 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.
  • 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 ⁇ - 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/ ⁇ -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.
  • a pharmaceutical composition for oral consumption in aqueous solution comprising a drug/ ⁇ - cyclodextrin complex
  • the composition further comprises a pharmaceutically acceptable acid-base couple, preferably an effervescent acid-base couple, in a quantity sufficient to cause the drug/ ⁇ -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.
  • 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 tartrate, trisodium tartrate and other salts of edible organic acids.
  • Inorganic acidic substances such as monosodium phosphate are also suitable components of acid-base couples.
  • 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/ ⁇ -cyclodextrin complex will depend on the amount and type of drug used.
  • 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 allowing for loss of carbon dioxide for effervescent couples) should be greater than about 1% by weight.
  • compositions of the present invention are suitably administered as pleasant tasting solutions in the pH range 4.0 to 7.0.
  • 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 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 the drug/ ⁇ -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 lipophilic NSAID's, for example propionic acid derivatives such as ibuprofen, naproxen and ketoprofen.
  • drug/ ⁇ -cyclodextrin clathrates which are suitable for use in this invention include ibuprofen / ⁇ -cyclodextrin clathrates, naproxen / ⁇ -cyclodextrin clathrates, ketoprofen / ⁇ -cyclodextrin clathrates and clathlerates of ⁇ -cyclodextrin with other propionic acid type NSAID's.
  • the invention may use clathrates of ⁇ -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.
  • metal salts such as sodium, potassium, magnesium, and calcium
  • amino-acid salts such as arginine, ornithine or lysine.
  • the drugs according to this invention may be as either the racemate or 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 ⁇ -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 1:1 to 3:1. If the ratio falls below this range, an 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.
  • the invention also provides a process for the preparation of a pharmacetical composition of the invention which process comprises the admixture of a drug/ ⁇ - cyclodextrin clathrate complex and an acid-base couple.
  • a drug/ ⁇ -cyclodextrin complex may be prepared by heating the drug and ⁇ - cyclodextrin in water or in a buffered aqueous solution, suitably to a temperature of 100°C, followed by crystallisation of the drug/ ⁇ -cyclodextrin complex from the solution thus formed, suitably by maintaining the solution in the temperature range -5 to 20°C.
  • a drug/ ⁇ -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 ⁇ -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/ ⁇ -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.
  • 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/ ⁇ -cyclodextrin complex and an acid-base couple may in addition include additional pharmaceutical agents suitable for administration therewith which are not complexed with ⁇ -cyclodextrin, including for example analgesics, antiinflammatories and antipyretics and also expectorants, antihistamines, decongestants and antitussive agents, such as for example phenypropanolamine, phenylephrine, pseudoephedrine, dextromethorphan, caffeine, codeine and ascorbic acid.
  • additional pharmaceutical agents suitable for administration therewith which are not complexed with ⁇ -cyclodextrin, including for example analgesics, antiinflammatories and antipyretics and also expectorants, antihistamines, decongestants and antitussive agents, such as for example phenypropanolamine, phenylephrine, pseudoephedrine, dextromethorphan, caffeine, codeine
  • 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.
  • abbreviation BCD refers to ⁇ - cyclodextrin undecahydrate ( ⁇ -cyclodextrin. I IH2O).
  • the powder from one of the sachets was added to 200ml 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.
  • Ibuprofen/BCD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a 500 ⁇ 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 sieved through a 500 ⁇ m 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.
  • ⁇ CD/Naproxen Clathrate (1.8:1) ⁇ -cyclodextrin (120.3g, 90mM) was dissolved in water (500ml) at 100°C. Naproxen (11.5 g 50mM) 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. The product, a white solid, was sieved through a 500 ⁇ m screen to yield 1 lOg of ⁇ CD/naproxen clathrate, containing about 9.4% naproxen.
  • Naproxen/ ⁇ CD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a 500 ⁇ 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 sieved through a 500 ⁇ m 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
  • the powder from one of the sachets was added to 150mls 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 6.0.
  • Ingredients 2 and 3 were seived through a 500 ⁇ 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 sieved through a 500 ⁇ m 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.
  • the powder from one of the sachets was added to 200mls 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 6.0.
  • ⁇ CD/Naproxen sodium Clathrate 1.1:1
  • ⁇ -cyclodextrin 147g, 1 lOmM
  • Naproxen sodium 25.2 g lOOmM
  • the product was sieved through a 250 ⁇ m screen, to yield 123g of BCD/naproxen clathrate, containing about 15.1% naproxen.
  • the powder from one of the sachets was added to 150mls 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 6.0.
  • Naproxen/ ⁇ CD 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.
  • Tri-sodium citrate 40.0g 3.
  • Citric acid (anhydrous) 2.0g
  • the powder from one of the sachets was added to 250ml of cold water (15°C) and stirred for 1 minute to give a non-effervescent, clear solution, which contained 200mg naproxen/ 150ml water at a pH of approximately 6.2.
  • the powder from one of the sachets was added to 150mls cold water (15°C) to give an effervescent, pleasant tasting, clear solution, which contained 50mg ketoprofen/ 150 ml of water at a pH of approximately 6.0.
  • Example 14 Preparation of a ready made effervescent pharmaceutical composition containing ⁇ -cyclodextrin / naproxen clathrate (1.1:1)
  • Example 16 Preparation of a ready made effervescent pharmaceutical composition containing ⁇ -cyclodextrin / naproxen clathrate (0.9:1)
  • Example 17 Preparation of an effervescent pharmaceutical composition containing ⁇ - cyclodextrin / naproxen clathrate (1.1:1) without precomplexation
  • a Nurofen Soluble (trade mark) tablet containing ibuprofen (200mg) was added to 150ml of cold water. The tablet failed to completely dissolve, resulting in a white suspension.
  • the powder from one of the sachets was added to 150ml cold water (16°C) to give a suspension in which some of the ibuprofen/ ⁇ -cyclodextrin clathrate remained undissolved.
  • Ingredients 2 and 3 were seived through a 500 ⁇ 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 sieved through a 500 ⁇ m 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.
  • the powder from one of the sachets was added to 150ml cold water (16°C) to give a suspension in which some of the naproxen/ ⁇ -cyclodextrin clathrate remained undissolved.
  • Example 8 The granulation and blending process described in Example 8 was repeated, except that the naproxen ⁇ -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 150mls cold water (16°C) to give a suspension in which some of the drug remained undissolved.
  • Example 8 The granulation and blending process described in Example 8 was repeated, except that the ibuprofen ⁇ -cyclodextrin was replaced with an equimolal quantity of ibuprofen sodium (1 l.lg).
  • the resulting powder was filled into sachets (target weight 5.22 lg), with each sachet containing ibuprofen (200mg).
  • the powder from one of the sachets was added to 150ml 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.
  • Ibuprofen sodium ⁇ -cyclodextrin complex (1: 0.37) was prepared as described i GB 2,219,585 (Reckitt & Colman) Example 1. Ingredients 2 and 3 were seived through a 500 ⁇ 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 500 ⁇ m screen, mixed for 5 minutes with ingredients 1 and 4 and then filled into sachets (target fill weight 5.6g) with each sachet containing the equivalent of 200mg ibuprofen.
  • sachets target fill weight 5.6g

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Nanotechnology (AREA)
  • Biophysics (AREA)
  • Rheumatology (AREA)
  • General Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Medical Informatics (AREA)
  • Pain & Pain Management (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention provides a pharmaceutical composition for oral consumption in aqueous solution comprising a drug/β-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/β-cyclodextrin complex to dissolve when the composition is mixed with cold water and provide a solution with acid or neutral pH. The preferred 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 5 which is lipophilic and has poor water solubility in the form 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.
10 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
15 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,
20 poorly water-soluble drug, for example an NSAID 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, NSAID's such as ibuprofen have proved to be very suitable as candidates for
25 complexation with cyclodextrins.
Japanese patent publication, JP 56-46837 (Kowa Yakuhin Kogyo) discloses a method for the preparation of an ibuprofen-β-cyclodextrin clathrate complex involving the combination of ibuprofen with β-cyclodextrin in water at elevated temperature and isolation of the clathrate by spray-drying. This method is reported to
30 yield a product containing a high percentage of ibuprofen with a molar ratio of ibuprofen to β-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 100ml to 89.38mg per 100ml at 27°C.
The water solubility achieved by complexation with β-cyclodextrin, although
35 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 (50- 250ml). European patent publication 274 444 (Bristol Myers) describes the preparation of ibuprofen-cyclodextrin complexes using α-cyclodextrin, γ- cyclodextrin or a methylated β-cyclodextrin in place of β-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 bitartrate.
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 β-cyclodextrin with the sodium, potassium, ammonium, magnesium, calcium, arginine, glycine or lysine salt of ibuprofen, having a molar ratio of ibuprofen to β-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 0490 193 (Medica 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/β-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-β-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 β- 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/β-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/β- 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/β-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 tartrate, trisodium tartrate 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/β-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 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/β-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 administered as pleasant tasting solutions in the pH range 4.0 to 7.0.
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 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 the drug/β-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 lipophilic NSAID's, for example propionic acid derivatives such as ibuprofen, naproxen and ketoprofen.
Accordingly, drug/β-cyclodextrin clathrates which are suitable for use in this invention include ibuprofen /β-cyclodextrin clathrates, naproxen / β-cyclodextrin clathrates, ketoprofen /β-cyclodextrin clathrates and clathlerates of β-cyclodextrin with other propionic acid type NSAID's. In addition, the invention may use clathrates of β-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 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 β-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 1:1 to 3:1. If the ratio falls below this range, an 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/β- cyclodextrin clathrate complex and an acid-base couple.
A drug/β-cyclodextrin complex may be prepared by heating the drug and β- cyclodextrin in water or in a buffered aqueous solution, suitably to a temperature of 100°C, followed by crystallisation of the drug/β-cyclodextrin complex from the solution thus formed, suitably by maintaining the solution in the temperature range -5 to 20°C. Alternatively a drug/β-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 β-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/β-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/β-cyclodextrin complex and an acid-base couple may in addition include additional pharmaceutical agents suitable for administration therewith which are not complexed with β-cyclodextrin, including for example analgesics, antiinflammatories and antipyretics and also expectorants, antihistamines, decongestants and antitussive agents, such as for example 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 β- cyclodextrin undecahydrate (β-cyclodextrin. I IH2O).
Example 1
Preparation of βCD/Ibuprofen Clathrate (1.1:1)
BCD (146.6g, 1 lOmM) was dissolved in water (1000ml) at 100°C. Ibuprofen (20.6g, lOOmM) 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 500μm screen to yield 125g of βCD/ibuprofen clathrate, containing about 14% ibuprofen. (400mg ibuprofen per 2857mg of clathrate).
Example 2
Preparation of an effervesent pharmaceutical composition containing
Ibuprofen/βCD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a 500μm 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 500μm 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/βCD clathrate from example 1 57J4g
2. Sodium bicarbonate lOO.OOg
3. Citric acid (anhydrous) 60.00g
The powder from one of the sachets was added to 200ml 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/BCD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a 500μm 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 500μm 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/βCD clathrate from example 1 71.4g
2. Sodium bicarbonate 116.0g
3. Citric acid (anhydrous) 109.0g
4. Sodium carbonate (anhydrous) 25.0g The powder from one of the sachets was added to 150ml cold water (16°C) to give an effervescent, pleasant tasting, clear solution, which contained 200mg ibuprofen / 150 ml of water at a pH of approximately 6.0.
Example 4
Preparation of βCD/Naproxen Clathrate (1.8:1) β-cyclodextrin (120.3g, 90mM) was dissolved in water (500ml) at 100°C. Naproxen (11.5 g 50mM) 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. The product, a white solid, was sieved through a 500μm screen to yield 1 lOg of βCD/naproxen clathrate, containing about 9.4% naproxen.
Example 5
Preparation of βCD/Naproxen Clathrate (1.1:1) β-cyclodextrin (294g, 220mM) was dissolved in water (1500ml) 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 250μM screen, to yield 250g of BCD/naproxen clathrate, containing about 15.3% naproxen.
Example 6
Preparation of an effervescent pharmaceutical composition containing
Naproxen/βCD clathrate for reconstitution with cold water Ingredients 2 and 3 were seived through a 500μm 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 500μm 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/βCD clathrate from example 4 106.0g
2. Sodium bicarbonate llό.Og
3. Citric acid (anhydrous) 109.0g
4. Sodium carbonate (anhydrous) 25.0g The powder from one of the sachets was added to 150mls 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 6.0. Example 7
Preparation of an effervescent pharmaceutical composition containing
Naproxen/βCD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a 500μm 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 500μm 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/βCD clathrate from example 5 65.5g
2. Sodium bicarbonate 116.0g
3. Citric acid (anhydrous) 109.0g
4. Sodium carbonate (anhydrous) 25.0g
The powder from one of the sachets was added to 150mls 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 6.0.
Example 8
Preparation of an effervescent pharmaceutical composition containing Naproxen/βCD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a 500μm 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 500μm 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/βCD clathrate from example 5 130.7g
2. Sodium bicarbonate llό.Og
3. Citric acid (anhydrous) 109.0g 4. Sodium carbonate (anhydrous) 25.0g
The powder from one of the sachets was added to 200mls 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 6.0.
Example 9
Preparation of βCD/Naproxen sodium Clathrate (1.1:1) β-cyclodextrin (147g, 1 lOmM) was dissolved in water (500ml) at 100°C. Naproxen sodium (25.2 g lOOmM) 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 convection oven at 60°C. The product, a white amorphous solid, was sieved through a 250μm screen, to yield 123g of BCD/naproxen clathrate, containing about 15.1% naproxen.
Example 10
Preparation of an effervescent pharmaceutical composition containing Naproxen sodium βCD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a 500μm 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 500μm 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/BCD clathrate from example 9 66.3g 2. Sodium bicarbonate l lό.Og
3. Citric acid (anhydrous) 109.0g
4. Sodium carbonate (anhydrous) 25.0g
The powder from one of the sachets was added to 150mls 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 6.0.
Example 11
Preparation of a non-effervescent pharmaceutical composition containing
Naproxen/βCD 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/βCD clathrate 13Jg
2. Tri-sodium citrate 40.0g 3. Citric acid (anhydrous) 2.0g
The powder from one of the sachets was added to 250ml of cold water (15°C) and stirred for 1 minute to give a non-effervescent, clear solution, which contained 200mg naproxen/ 150ml water at a pH of approximately 6.2.
Example 12
Preparation of βCD / Ketoprofen Clathrate (5:1) β-cyclodextrin (53.3g, 40mM) was dissolved in water (200ml) at 100 C. Ketoprofen
(2.05g, 8mM) was added and the resulting mixture was stirred for 1 hour at 95 C and
O 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 250μM screen to yield 50.4g of BCD / ketoprofen clathrate, containing about 3.8% ketoprofen.
Example 13
Preparation of an effervescent pharmaceutical composition containing Ketoprofen/βCD clathrate for reconstitution with cold water
Ingredients 2 and 3 were sieved through a 500μm 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 500μm 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 50mg ketoprofen
1. Ketoprofen/βCD clathrate from example 12 26.3g
2. Sodium bicarbonate 116.0g
3. Citric acid (anhydrous) 109.0g
4. Sodium carbonate (anhydrous) 25.0g
The powder from one of the sachets was added to 150mls cold water (15°C) to give an effervescent, pleasant tasting, clear solution, which contained 50mg ketoprofen/ 150 ml of water at a pH of approximately 6.0.
Example 14 Preparation of a ready made effervescent pharmaceutical composition containing β-cyclodextrin / naproxen clathrate (1.1:1)
1. β-cyclodextrin / naproxen clathrate 13.3g
2. Trisodium citrate 29.0g 3. Sodium carbonate 3.0g
4. Methyl paraben sodium 3.0g
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 250ml 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 6.0. Example 15
Preparation of βCD / Naproxen Clathrate (0.9:1) β-cyclodextrin (48.0g, 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 μm screen, to yield 37.6g of βCD / naproxen clathrate, containing about 19% naproxen.
Example 16 Preparation of a ready made effervescent pharmaceutical composition containing β-cyclodextrin / naproxen clathrate (0.9:1)
1. β-cyclodextrin / naproxen clathrate 10.52g
2. Trisodium citrate 29.0g 3. Sodium carbonate 3.0g
4. Methyl paraben sodium 3.0g
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 6.0.
Example 17 Preparation of an effervescent pharmaceutical composition containing β- cyclodextrin / naproxen clathrate (1.1:1) without precomplexation
1. β-cyclodextrin 12.8g
2. Naproxen 2.0g 3. Trisodium citrate 29.0g
4. Sodium carbonate 3.0g
5. Methyl paraben sodium 3.0g
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 6.0. example 18
Preparation of a ready made effervescent pharmaceutical composition containing β-cyclodextrin / naproxen clathrate (0.9:1) without precomplexation
1. β-cyclodextrin 10.4g
2. Naproxen 2.0g
3. Trisodium citrate 29.0g
4. Sodium carbonate 3.0g
5. Methyl paraben sodium 3.0g 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 6.0.
Example A
Reconstitution in water of a commercially available Ibuprofen tablet
A Nurofen Soluble (trade mark) tablet containing ibuprofen (200mg) was added to 150ml 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 150ml of cold water. The powder failed to completely dissolve, resulting in a white suspension.
Example C
Preparation of an effervescent pharmaceutical composition containing Ibuprofen/βCD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a 500μm 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 500μm 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/βCD clathrate from example 1 171.4g 2. Sodium bicarbonate 11.6g
3. Citric acid (anhydrous) 10.9g
4. Sodium carbonate (anhydrous) 2.5g
The powder from one of the sachets was added to 150ml cold water (16°C) to give a suspension in which some of the ibuprofen/β-cyclodextrin clathrate remained undissolved.
Example D
Preparation of an effervescent pharmaceutical composition containing Naproxen/βCD clathrate for reconstitution with cold water
Ingredients 2 and 3 were seived through a 500μm 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 500μm 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/BCD clathrate from example 4 106.0g
2. Sodium bicarbonate 11.6g
3. Citric acid (anhydrous) 10.9g 4. Sodium carbonate (anhydrous) 2.5g
The powder from one of the sachets was added to 150ml cold water (16°C) to give a suspension in which some of the naproxen/β-cyclodextrin clathrate remained undissolved.
Example E
The granulation and blending process described in Example 8 was repeated, except that the naproxen β-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 150mls 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 β-cyclodextrin was replaced with an equimolal quantity of ibuprofen sodium (1 l.lg). The resulting powder was filled into sachets (target weight 5.22 lg), with each sachet containing ibuprofen (200mg). The powder from one of the sachets was added to 150ml 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/βCD clathrate for reconstitution with cold water
Ibuprofen sodium β-cyclodextrin complex (1: 0.37) was prepared as described i GB 2,219,585 (Reckitt & Colman) Example 1. Ingredients 2 and 3 were seived through a 500μm 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 500μm screen, mixed for 5 minutes with ingredients 1 and 4 and then filled into sachets (target fill weight 5.6g) with each sachet containing the equivalent of 200mg ibuprofen.
1. Ibuprofen/βCD clathrate (1:0.347) 30.0g
2. Sodium bicarbonate l lό.Og
3. Citric acid (anhydrous) 109.0g
4. Sodium carbonate (anhydrous) 25.0g The powder from one of the sachets was added to 150ml 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 6J.

Claims

Claims
1. A pharmaceutical composition for oral consumption in aqueous solution comprising a drug/β-cyclodextrin complex, characterised in that the composition further comprises a pharmaceutically acceptable acid-base couple, in a quantity sufficient to cause the drug/β-cyclodextrin complex to dissolve when the composition is mixed with cold water and provide a solution with acid or neutral pH.
2. A pharmaceutical composition according to claim 1 wherein the drug is a lipophilic NSAID.
3. A pharmaceutical composition according to claim 2, wherein the drug is ibuprofen, naproxen or ketoprofen.
4. A pharmaceutical composition according to claims 1 to 3, wherein the acid- base couple is an effervescent couple and may be 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, ascorbic acid or other edible or *gea- nic acids.
6. A pharmaceutical composition according to claim 5, wherein the organic acids are mono-di- and tri-basic salts.
7. A pharmaceutical composition according to any one of the above claims, wherein the base includes alkali metal and alkaline earth metal carbonates, percarbonates and bicarbonates and mixed carbonate salts.
8. A pharmaceutical composition according to any one of the above claims wherein the acid-base couple is an effervescent couple which contains citric and/or tartaric acid and sodium bicarbonate and/or carbonate.
9. A pharmaceutical composition according to claim 1 wherein the acid-base couple is a non effervescent couple and is a combination of a water soluble acid and a conjugate base in the form of a sodium or potassium salt.
10. A pharmaceutical composition according to any one of claims 1 to 9 wherein the weight of couple in the composition is greater than 1% of the weight of water in which it is to be reconstituted or dissolved.
11. A pharmaceutical composition according to claim 10 which is administered as a solution in the pH range 4.0 to 7.0.
12. A pharmaceutical composition according to any one of claims 1 to 11, wherein the ratio of β-cyclodextrin to drug is 0.8:1 to 10:1.
13. A pharmaceutical composition according to claim 12, wherein the ratio of β- cyclodextrin to drug is 1:1 to 5:1.
14. A pharmaceutical composition according to any one of the above claims, formulated as a tablet for solution, in powder or granular form for reconstruction with water or as a ready-to-drink preparation.
15. A process for the preparation of a pharmaceutical composition as claimed in claim 1 , which process comprises the admixture of a drug/β-cyclodextrin clathrate complex and an acid-base couple.
16. A method for oral dosing of a pharmaceutical composition according to claim 1, wherein the composition provides a therapeutically active dose of the drug as a complex with β-cyclodextrin.
PCT/EP1994/002515 1993-08-10 1994-07-29 PHARMACEUTICAL COMPOSITION CONTAINING A DRUG/β-CYCLODEXTRIN COMPLEX IN COMBINATION WITH AN ACID-BASE COUPLE WO1995004528A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP7506202A JPH09501421A (en) 1993-08-10 1994-07-29 Pharmaceutical composition containing a drug / β-cyclodextrin complex in combination with an acid-base couple
AU76099/94A AU688789B2 (en) 1993-08-10 1994-07-29 Pharmaceutical composition containing a drug/beta -cyclodextrin complex in combination with an acid-base couple
EP94926129A EP0720476A1 (en) 1993-08-10 1994-07-29 PHARMACEUTICAL COMPOSITION CONTAINING A DRUG/$g(b)-CYCLODEXTRIN COMPLEX IN COMBINATION WITH AN ACID-BASE COUPLE
CA002169159A CA2169159C (en) 1993-08-10 1994-07-29 Pharmaceutical composition containing a drug/.beta.-cyclodextrin complex in combination with an acid-base couple

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB939316580A GB9316580D0 (en) 1993-08-10 1993-08-10 Pharmaceutical composition
GB9316580.1 1993-08-10

Publications (2)

Publication Number Publication Date
WO1995004528A2 true WO1995004528A2 (en) 1995-02-16
WO1995004528A3 WO1995004528A3 (en) 1995-03-16

Family

ID=10740244

Family Applications (1)

Application Number Title Priority Date Filing Date
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

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)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996014839A1 (en) * 1994-11-15 1996-05-23 Farmarc Nederland Bv Pharmaceutical composition comprising non-steroidal anti-inflammatory drugs
EP1129709A2 (en) * 2000-03-03 2001-09-05 Laboratorio de Aplicaciones Farmacodinamicas, S.A. Pharmaceutical composition based on ibuprofen and a procedure for the preparation thereof
ES2189682A1 (en) * 2001-12-11 2003-07-01 Esteve Labor Dr Drinkable preparation comprising ketoprofen and use thereof in the simultaneous treatment of a group of animals of respiratory diseases
WO2005079858A1 (en) * 2004-02-20 2005-09-01 I.Q.A., A.S. Stable, palatable syrup containing ibuprofen and method of its preparation
WO2010125212A1 (en) * 2009-04-27 2010-11-04 Laboratorio De Aplicaciones Farmacodinamicas, S.A. Oral ibuprofen lysinate suspension
EP2253329A1 (en) * 2009-04-27 2010-11-24 Laboratorio de Aplicaciones Farmacodinamicas, S.A. Ibuprofen lysinate oral suspension
GB2486567A (en) * 2010-12-15 2012-06-20 Reckitt Benckiser Healthcare Int Ltd Solutions of an NSAID and one or more cyclodextrins
US8580954B2 (en) 2006-03-28 2013-11-12 Hospira, Inc. Formulations of low dose diclofenac and beta-cyclodextrin
US20140005261A1 (en) * 2012-06-28 2014-01-02 Mcneil-Ppc, Inc. Racecadotril liquid compositions
US20140271831A1 (en) * 2013-03-15 2014-09-18 Mcneil-Ppc, Inc. Racecadotril liquid compositions
US8986735B2 (en) 2006-03-16 2015-03-24 Novartis Ag Solid dosage form containing a taste masked active agent
GR1010732B (en) * 2023-06-02 2024-07-25 Ιουλια Κλεωνος Τσετη Pharmaceutical composition of ibuprophen and paracetamol for oral administration

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
CN115919792A (en) * 2022-12-09 2023-04-07 华夏国药(菏泽)制药有限公司 Vitamin C effervescent tablet and preparation method thereof

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4762702A (en) * 1984-11-05 1988-08-09 Gerhard Gergely Pharmaceutical preparation containing ibuprofen and a process for its preparation
EP0313328A1 (en) * 1987-10-22 1989-04-26 Biosat Limited Sustained-release formulations
EP0346006A1 (en) * 1988-06-09 1989-12-13 Reckitt And Colman Products Limited Pharmaceutical compositions containing ibuprofen-cyclodextrin complexes
EP0369228A1 (en) * 1988-11-12 1990-05-23 Bayer Ag Effervescent Ibuprofen compositions
US5024997A (en) * 1990-06-22 1991-06-18 American Home Products Corporation Palatable ibuprofen solutions
WO1992009308A1 (en) * 1990-11-30 1992-06-11 Medice Chem.-Pharm. Fabrik Pütter Gmbh & Co. Kg Complexes of the active enantiomer of ibuprofene with cyclodextrin

Family Cites Families (10)

* Cited by examiner, † Cited by third party
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
CA1298290C (en) * 1987-01-09 1992-03-31 Herand M. Markarian Solution ibuprofen complexes, compositions and processes for preparing the same
CH677606A5 (en) * 1988-07-12 1991-06-14 Aesculapius Pharma Sa
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
DE4027927A1 (en) * 1990-09-04 1992-03-05 Bayer Ag SHOWER COMPONENT AND METHOD FOR THEIR PRODUCTION
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

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4762702A (en) * 1984-11-05 1988-08-09 Gerhard Gergely Pharmaceutical preparation containing ibuprofen and a process for its preparation
EP0313328A1 (en) * 1987-10-22 1989-04-26 Biosat Limited Sustained-release formulations
EP0346006A1 (en) * 1988-06-09 1989-12-13 Reckitt And Colman Products Limited Pharmaceutical compositions containing ibuprofen-cyclodextrin complexes
EP0369228A1 (en) * 1988-11-12 1990-05-23 Bayer Ag Effervescent Ibuprofen compositions
US5024997A (en) * 1990-06-22 1991-06-18 American Home Products Corporation Palatable ibuprofen solutions
WO1992009308A1 (en) * 1990-11-30 1992-06-11 Medice Chem.-Pharm. Fabrik Pütter Gmbh & Co. Kg Complexes of the active enantiomer of ibuprofene with cyclodextrin

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996014839A1 (en) * 1994-11-15 1996-05-23 Farmarc Nederland Bv Pharmaceutical composition comprising non-steroidal anti-inflammatory drugs
US5854226A (en) * 1994-11-15 1998-12-29 Farmarc Nederland Bv Pharmaceutical composition
EP1129709A2 (en) * 2000-03-03 2001-09-05 Laboratorio de Aplicaciones Farmacodinamicas, S.A. Pharmaceutical composition based on ibuprofen and a procedure for the preparation thereof
EP1129709A3 (en) * 2000-03-03 2001-11-14 Laboratorio de Aplicaciones Farmacodinamicas, S.A. Pharmaceutical composition based on ibuprofen and a procedure for the preparation thereof
ES2171110A1 (en) * 2000-03-03 2002-08-16 Aplicaciones Farmacodinamicas Pharmaceutical composition based on ibuprofen and a procedure for the preparation thereof
ES2189682A1 (en) * 2001-12-11 2003-07-01 Esteve Labor Dr Drinkable preparation comprising ketoprofen and use thereof in the simultaneous treatment of a group of animals of respiratory diseases
WO2005079858A1 (en) * 2004-02-20 2005-09-01 I.Q.A., A.S. Stable, palatable syrup containing ibuprofen and method of its preparation
US8986735B2 (en) 2006-03-16 2015-03-24 Novartis Ag Solid dosage form containing a taste masked active agent
US8580954B2 (en) 2006-03-28 2013-11-12 Hospira, Inc. Formulations of low dose diclofenac and beta-cyclodextrin
CN102448499A (en) * 2009-04-27 2012-05-09 药效学应用实验室股份有限公司 Oral ibuprofen lysinate suspension
EP2253329A1 (en) * 2009-04-27 2010-11-24 Laboratorio de Aplicaciones Farmacodinamicas, S.A. Ibuprofen lysinate oral suspension
WO2010125212A1 (en) * 2009-04-27 2010-11-04 Laboratorio De Aplicaciones Farmacodinamicas, S.A. Oral ibuprofen lysinate suspension
GB2486567A (en) * 2010-12-15 2012-06-20 Reckitt Benckiser Healthcare Int Ltd Solutions of an NSAID and one or more cyclodextrins
WO2012080718A1 (en) * 2010-12-15 2012-06-21 Reckitt Benckiser Healthcare International Limited Novel pharmaceutical formulation comprising nsaid and cyclodextrin
US10363316B2 (en) 2010-12-15 2019-07-30 Reckitt Benckiser Healthcare (Uk) Limited Pharmaceutical formulation comprising NSAID and cyclodextrin
GB2486567B (en) * 2010-12-15 2014-09-10 Reckitt Benckiser Healthcare Int Ltd Pharmaceutical formulation
RU2607592C2 (en) * 2010-12-15 2017-01-10 Рекитт Бенкизер Хелскэа Интернэшнл Лимитед New pharmaceutical composition containing nsaid and cyclodextrin
US9138482B2 (en) 2010-12-15 2015-09-22 Reckitt Benckiser Healthcare International Limited Pharmaceutical formulation comprising NSAID and cyclodextrin
US9084721B2 (en) * 2012-06-28 2015-07-21 Mcneil-Ppc, Inc. Racecadotril liquid compositions
US9114171B2 (en) * 2012-06-28 2015-08-25 Mcneil-Ppc, Inc. Racecadotril liquid compositions
US20140274948A1 (en) * 2012-06-28 2014-09-18 Mcneil-Ppc, Inc. Racecadotril liquid compositions
US20140005261A1 (en) * 2012-06-28 2014-01-02 Mcneil-Ppc, Inc. Racecadotril liquid compositions
US20140271831A1 (en) * 2013-03-15 2014-09-18 Mcneil-Ppc, Inc. Racecadotril liquid compositions
GR1010732B (en) * 2023-06-02 2024-07-25 Ιουλια Κλεωνος Τσετη Pharmaceutical composition of ibuprophen and paracetamol for oral administration

Also Published As

Publication number Publication date
EP0720476A1 (en) 1996-07-10
GB9316580D0 (en) 1993-09-29
TW354256B (en) 1999-03-11
AU7609994A (en) 1995-02-28
CN1112180C (en) 2003-06-25
CA2169159A1 (en) 1995-02-16
AU688789B2 (en) 1998-03-19
WO1995004528A3 (en) 1995-03-16
CA2169159C (en) 2005-01-25
JPH09501421A (en) 1997-02-10
ZA945930B (en) 1995-04-05
CN1133006A (en) 1996-10-09

Similar Documents

Publication Publication Date Title
US5866162A (en) Pharmaceutical composition containing a drug/β-cyclodextrin complex in combination with an acid-base couple
US5616621A (en) Taste masking liquids
US7078053B2 (en) Ibuprofen composition
US20200323776A1 (en) Diclofenac formulations and methods of use
CA2169159C (en) Pharmaceutical composition containing a drug/.beta.-cyclodextrin complex in combination with an acid-base couple
CA1320192C (en) Pharmaceutical compositions
US5262179A (en) Non-effervescent ibuprofen compositions
US5597583A (en) Pharmaceutical composition
NZ235276A (en) Non-effervescent water-soluble pharmaceutical composition comprising a water-soluble ibuprophen salt and a taste masking compound
TW505525B (en) Pharmaceutical compositions based on diclofenac
JP2004067682A (en) Pharmaceutical composition having antibiotic activity
EP0717637A1 (en) Inclusion complexes of beta-cyclodextrin with flurbiprofen, ketoprofen and naproxen
JPH04295422A (en) Noneffervescent ibuprofen composition

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 94193729.1

Country of ref document: CN

AK Designated states

Kind code of ref document: A2

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK ES FI GB GE HU JP KE KG KP KR KZ LK LT LU LV MD MG MN MW NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): KE MW SD AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

AK Designated states

Kind code of ref document: A3

Designated state(s): AM AT AU BB BG BR BY CA CH CN CZ DE DK ES FI GB GE HU JP KE KG KP KR KZ LK LT LU LV MD MG MN MW NL NO NZ PL PT RO RU SD SE SI SK TJ TT UA US UZ VN

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): KE MW SD AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1994926129

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2169159

Country of ref document: CA

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1994926129

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 1996 591513

Country of ref document: US

Date of ref document: 19960913

Kind code of ref document: A

WWW Wipo information: withdrawn in national office

Ref document number: 1994926129

Country of ref document: EP