WO2005055987A1 - Compositions pharmaceutiques au gout masque comportant une medicament amer et un polymere sensible au ph - Google Patents

Compositions pharmaceutiques au gout masque comportant une medicament amer et un polymere sensible au ph Download PDF

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Publication number
WO2005055987A1
WO2005055987A1 PCT/IN2003/000392 IN0300392W WO2005055987A1 WO 2005055987 A1 WO2005055987 A1 WO 2005055987A1 IN 0300392 W IN0300392 W IN 0300392W WO 2005055987 A1 WO2005055987 A1 WO 2005055987A1
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Prior art keywords
methacrylate
drag
composition
polymer
acrylate
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PCT/IN2003/000392
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English (en)
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Mohan Gopalkrishna Kulkarni
Anupa Ramesh Menjoge
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Council Of Scientific & Industrial Research
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Priority to CA002549572A priority Critical patent/CA2549572A1/fr
Priority to JP2005511660A priority patent/JP2007518670A/ja
Priority to AU2003292509A priority patent/AU2003292509B2/en
Priority to PCT/IN2003/000392 priority patent/WO2005055987A1/fr
Priority to CN200380110830XA priority patent/CN1878539B/zh
Priority to EP03768091A priority patent/EP1694302A1/fr
Publication of WO2005055987A1 publication Critical patent/WO2005055987A1/fr

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to taste masked compositions comprising a bitter drug and a pH sensitive polymer and methods for preparing the same.
  • the present invention also relates to a process for the preparation of a taste masked pharmaceutical composition comprising bitter drug and a pH sensitive polymer.
  • Background of invention Although a variety of delivery systems are being developed for different routes of administration like the oral, parenteral, nasal and transdermal, the oral route remains attractive for drug delivery because this mode of administration is an easy, convenient, noninvasive and familiar method of drug delivery.
  • the majority of prescribed drugs are designed for oral application since they can be self-administered by the patient without hospitalization.
  • Oral dosage forms are designed according to the nature of the drug, the nature of application and the need for any special effects.
  • the common oral dosage forms include: liquid mixtures like solutions, suspensions, solid dosage forms like tablets and capsules and liquid filled capsules etc.
  • the solid dosage forms are further modified depending on the therapeutic action desired, like controlled, extended or delayed release.
  • patients at the extremes of age, such as children and the elderly often experience difficulty in swallowing solid oral dosages forms.
  • the drugs are mostly provided in liquid dosage forms such as solutions, emulsions and suspensions.
  • These dosage forms usually lead to perceptible exposure of the active drug ingredient to the taste buds, which is a very serious problem when the drug has an extremely unpleasant or bitter taste.
  • the bitter taste of the drugs, which are orally administered, is disadvantageous in several aspects. Taste is an important parameter governing the compliance.
  • Patent Application WO 03/13470 discloses the use of ammonium glycyrrhyzinate to taste-mask the formulation comprising of a dry blend of paroxetine and a glycyrrhyzinate formulated as a dispersible powder or moulded into a dispersible or chewable tablet.
  • Patent Application WO 03/11227 discloses a taste masked composition for the delivery of ibuprofen which causes a throat catch in the form of chewable ibuprofen tablets with the polymer, carbomer 934.
  • European Patent EP 1219291 discloses chewable tablets and texture masked particles of the active ingredient, acetaminophen which is coated by a taste masking polymer ethyl cellulose and a film forming polymer and a texture masking coating solution of hydroxypropyl methyl cellulose and polyethylene glycol 800 and acesulfame potassium.
  • JP 2002363066 the taste masked pharmaceutical or food composition is disclosed which is suitable for formulation as granule, tablet or a chewable tablet.
  • the taste masked fine granule is obtained by using polymers such as ethyl cellulose, hydroxy propyl cellulose.
  • European patent EP 1166777 discloses yet another chewable tablet made from taste masked particles.
  • the active ingredient ibuprofen was coated by the enteric polymer HPMCP and an insoluble film forming agent cellulose acetate and chewable tablets with no throat burn were prepared from the coated particles by blending with aspartame, acesulfame potassium, citric acid, granular mannitol, fumaric acid, microcrystalline cellulose, and flavor.
  • Taste masking techniques are extended to the dispersible dosage forms and rapidly disintegrating tablets, too.
  • Patent Application WO 01/58449 discloses the water dispersible powder and tablets of paroxetine for the immediate release of the drug and a taste- masking agent comprising of the methacrylic acid copolymer.
  • the taste-masked composition was obtained by spray drying of parox:etine and the polymer.
  • Patent Application WO 02/64119 discloses quickly disintegrating tablets in the oral cavity providing masking of the unpleasant taste and the fast absorption of the active from the tablets in the digestive tract.
  • the disclosure is limited to the drug, which is hardly soluble in water under neutral or alkaline conditions but highly soluble in water under acidic conditions giving an unpleasant taste.
  • the physicochemical properties of different drug molecules are different and so such systems would not be suitable for the drugs, which are water soluble.
  • Patent Application WO 01/52848 discloses a taste masked oral formulation of linezolid which can be formulated as a suspension, a fast-disintegrating, effervescent or chewable tablet, by microencapsulating the antibiotic by solvent coacervation of ethyl cellulose with an optional seal coat of shellac and further coating the particles by functional polymer Eudragit L30 D.
  • the formulated microcapsules can be suspended in an aqueous medium prior to oral administration to pediatric and geriatric patients, who are unwilling and / or find it difficult to swallow the tablets, else, fast-disintegrating tablets can be formulated which rapidly disperse into taste masked granules in the mouth.
  • the film is composed of an ion exchange resin, amberlite and a water soluble polymer pullulan as taste masking agent for the bitter drug, dextromethorphan.
  • the film adheres to the oral cavity and dissolves to deliver the active ingredient.
  • the use of the water soluble polymer in the formulation would restrict the use of such delivery system if the taste masking was desired for liquid oral preparation. Further such delivery systems may not be well accepted in case of pediatric and geriatric preparations where patient compliance is very important.
  • US Patent 6,001,392 discloses a controlled, release syrup suspension for the oral administration containing dextromethorphan adsorbed on to a polystyrene sulfonate ion exchange resin.
  • the drug polymer complex is coated by a mixture of ethyl cellulose or ethyl cellulose latexes with plasticizers and water dispersible polymers such as SURELEASE.
  • plasticizers and water dispersible polymers such as SURELEASE.
  • SURELEASE water dispersible polymers
  • US Patent 4,808,411 discloses a taste masked composition comprising 75-95 % of erythromycin and about 5 to 75 % of carbomer where the drug and carbomer are held together by ionic interactions between erythromycin and carbomer.
  • the complex is further coated with a functional polymer, hydroxy propyl methylcellulose phthalate to make the preparation palatable. Erythromycin is released slowly from the complex to avoid a significant perception of bitterness in the mouth. It is clear that slow release, not fast release of bitter medicament is critical as disclosed in the patent. But complexing alone is not sufficient enough to mask taste. Coating with functional polymers is required to attain desired palatability and further proper selection of complexing agent is vital since drag release should not be compromised.
  • Coating of drags is another method but this alone may prove effective, only for moderately bitter drugs or in products where coated particles are formulated as aqueous preparations just before administration or are formulated in non-aqueous medium.
  • Patent Application WO 02/092106 discloses a taste-masked composition comprising polycarbophil and a macrolide antibiotic, clarithromycin. The complex is further coated with an acid resistant polymer Eudragit L100 55, releasing the drug in the intestine.
  • enteric coating may alter the bioavailability.
  • European Patent Application EP 0409254 discloses an oral particulate preparation with unpleasant taste being masked using ethyl cellulose and a water swelling agent where the active is released rapidly from the said formulation.
  • US Patent 5,635,200 discloses a taste-masked preparation of bitter drug ranitidine by a lipid coating and dispersion of these coated particles in the non- aqueous medium.
  • US Patent Application 2003-028025 discloses taste-masked composition of gatifloxacin suitable for use in oral dosage forms, particularly for pediatric formulations.
  • a crystalline co-precipitate of gatifloxacin and one or both of stearic acid and palmitic acid is used to effectively mask the bitter taste of gatifloxacin in the mouth and in aqueous suspension through a full dosage cycle of fourteen days.
  • Patent Application WO 02/72111 discloses a taste masked pharmaceutical suspension of telithromycin.
  • Four different coating agents Novata AB, Eudragit El 00, glycerol monostearate and talc M10 are employed and at least three successive layers of coating are essential to taste mask telithromycin.
  • the coated granules as disclosed could further be formulated as dry syrup, which is reconstituted as a suspension.
  • US Patent 4,865,851 discloses yet another method for taste masking highly bitter 1 acetoxy ethyl ester of cefuroxime in particulate form being coated with an integral coating of lipid or a mixture of lipids, which serves to mask the taste.
  • the taste masking coatings, using lipids requires that the melting point of the lipid should be sufficiently high to prevent melting in the mouth and should not be so high that active ingredient itself melts or is chemically degraded.
  • Cefuroxime axetil in a substantially amorphous form with maximum bioavailability has a low melting point of about 70 degree C and the difference in the melting of the lipid and drag is very marginal and also the temperature at which the mixture is atomized is higher than the melting point of the lipid.
  • the lipid based microencapsulation requires a highly sophisticated hot melt granulation process for producing fine particles without adversely affecting the drug molecule.
  • British Patent 2081092 also discloses a lipid coating for the purpose of taste masking. It was however found that wax coating resulted in poor dissolution of the active ingredients in the alimentary tract. Further the Patent discloses a technique to overcome this problem by mixing the waxes with a water swellable polymer. Again the use of the water swellable polymer referred to in the patent makes it less appropriate for the liquid orals like suspensions and dry syrup.
  • Patent 5,286,489 describes a porous drag polymer matrix formed by admixing a bitter tasting active ingredient and a methacrylic ester copolymer in at least a 1 : 1 weight ratio of active ingredient to copolymer, effective to mask the taste of the drug. None of the examples described in the patent disclose the effect of these polymers on the release of the drug from the matrix. It is observed that the drag release is retarded from the matrix described herein.
  • Patent Application WO 00/56266 discloses the use of a high viscosity swellable polymer carbomer, in combination with film forming polymethacrylates and channelising agents for taste masking of bitter drugs.
  • a taste masking composition using a combination of two enteric polymers comprising methacrylic acid copolymer and a phthalate polymer is disclosed.
  • the patent discloses the use of the channelising agents which comprise the water soluble or water swellable materials to aid the release of the active ingredient .
  • the enteric polymers as disclosed in the patent are known to release the active ingredient in the alkaline pH where the polymers are soluble. Release of active ingredient will be delayed due to the use of the enteric polymers and in case of the medicaments having a narrow absorption window restricted to upper gastrointestinal tract; such system would be of limited use.
  • Microencapsulation of highly bitter drag cefuroxime axetil for taste masking is disclosed by M.Cuna et.al (M. Cuna, M.L. Lorenzo, J.L. Vila Jato, D. Torres, M.J. Alonso, Acta Technologiae et Legis Medicamenti. volume VII, N.3, 1996) using different polymeric materials like cellulose acetate trimellitate, HPMCP-50, HPMCP-55 with the final aim to mask the taste and assuring its release in the intestinal cavity.
  • Alonso M. J. Alonso, M.L Lorenzo-Lamosa, M.Cuna, J. L. Vila- Jato and D.
  • Cefuroxime axetil is hydrolyzed to cefuroxime in the intestinal lumen by the esterases reducing the cefuroxime axetil concentration in the lumen and resulting in reduced absorption, leading to low bioavailability of Cefuroxime axetil in humans.
  • Cefuroxime axetil already has a low bioavailability of 32-50 % and hence further reduction in the bioavailability due to the formulation aspects should be minimized.
  • the taste masking formulations should be so designed that the bioavailability of the drugs is not compromised and the use of certain polymers like the enteric coatings should not affect the time to peak. Further the drag should be sufficiently absorbed to ensure effective therapeutic concentration in the plasma.
  • Vogelman et al B. Nogelman, William A. Craig Journal of Pediatric 1986, 108 (5, pt2) 835-40, & B. Nogelman, William A. Craig, S. Ebert, S. Gudmundsson, J. Leggett, Journal of Infectious Diseases 1988,158(4), 831-47) have established that bactericidal killing is rapid, intensive and increases proportionately to the concentration. In the presence of high concentration of the drug, the killing is complete and almost instantaneous.
  • cefuroxime axetil a second generation cephalosporin antibiotic and celecoxib, from the class of COX 2 inhibitors. Both celecoxib and cefuroxime have relatively high dose requirement further increasing the difficulty in administering the therapeutically effective dose.
  • Cefuroxime axetil exhibits the tendency to gel in contact with the aqueous media, necessitating that the dosage form disintegrates into particles rapidly and releases the drag at a faster rate before the gelling occurs in vivo.
  • Another problem associated with cefuroxime relates to extremely bitter taste of the drug making it necessary to formulate cefuroxime in a coated delivery system to make it palatable.
  • Celecoxib has an extremely low aqueous solubility and is not readily dissolved and dispersed for rapid absorption in the gastrointestinal tract further the amorphous form of celecoxib which is known to increase its dissolution and also its bioavailability tends to crystallize in contact with the aqueous medium.
  • Etoricoxib another molecule from the COX 2 inhibitor family is also associated with extremely bitter taste.
  • Patent Application WO 02/43707 discloses oral pharmaceutical formulations for cefuroxime axetil in tablet form such that the cefuroxime axetil is contained in the tablet core, coated with double layered film coat of hydroxypropyl Methyl cellulose and shellac.
  • the first film coat as disclosed, serves to mask bitter taste of cefuroxime axetil and second film coat serves to delay the rupture time beyond 40 seconds.
  • US Patent 548,436 discloses chewable tablets made from a coated medicament where the coating is designed to be soluble at the lower pH of the stomach but relatively water insoluble at the higher pH of the mouth.
  • the coatings comprise a polymer blend of dimethylaminoethyl methacrylate and neutral methacrylic acid ester and a cellulose ester.
  • the above mentioned "reverse enteric" coating method of taste masking oral formulation is disclosed in connection with chewable tablets.
  • Patent Application WO 02/096392 discloses taste masking of highly water soluble drug cetrizine hydrochloride.
  • the polymers like hydroxy propyl methyl cellulose, polyvinyl pyrrolidone, ethyl cellulose are used which effectively mask the taste of cetrizine in tablet form and release the drug immediately under the acidic conditions prevalent in stomach. It is evident from the above disclosures, that taste masking can be achieved by various methods. Many natural and synthetic polymers, resins and waxes alone or in combination have been employed for taste masking.
  • the enteric polymers like eudragit L are used for taste masking but the pH of saliva is near 5.8 and these polymers solubilize at pH beyond 5.5 so there is a possibility of drag being partially leached.
  • Obj ects of the invention It is the object of the present invention to provide an oral taste masked composition which can deliver a substantial amount of the bitter active immediately with improved palatability by using the specially synthesized pH sensitive polymers which solubilize or swell in the acidic conditions of the stomach and are insoluble or de-swell in the neutral or near neutral media and which can be applied in various pharmaceutical oral dosage forms.
  • oral dosage form as used herein means any pharmaceutical composition intended to be administered to an individual by delivering said composition to the gastro intestinal tract of an individual via mouth.
  • Oral dosage forms include tablets like chewable tablets, dispersible tablets, coated tablets; liquids such as dry syrups and suspensions.
  • the object of the present invention is to provide taste-masking compositions, consisting of a pH sensitive polymer and further a method for the synthesis of these polymers and also the method of preparation of pharmaceutical composition containing these polymers.
  • the other object of the present invention is to synthesize polymers, which effectively mask the unpleasant taste of the drug but do not compromise the dissolution rate and bioavailability of drag and further rapidly release the drag in the gastric cavity.
  • Yet another object of the present invention is to develop a pH sensitive polymer suitable for taste masking the liquid orals like suspensions, dry syrups, and solid dosage form like chewable tablets, fast dispersible tablets and conventional tablets.
  • Yet another object of the present invention is to prevent the leaching of the drag at the pH of saliva and in the reconstitution medium, from the liquid and solid dosage forms.
  • the hydrophobic monomer (A) is a acrylic or a methacrylic acid ester selected from the group consisting of cyclohexyl acrylate, dodecyl acrylate, 2 ethyl hexyl acrylate, octyl acrylate, tertiary butyl acrylate, phenyl acrylate, butyl acrylate, methyl methacrylate, benzyl methacrylate, cyclohexyl methacrylate, phenyl methacrylate, tertiary butyl methacrylate, butyl methacrylate, 2 ethyl hexyl methacrylate, propyl methacrylate preferably butyl acrylate, methyl methacrylate and butyl methacrylate.
  • the basic monomer (B) is selected from the group consisting of amino alkyl acrylic acid and methacrylic acid esters selected from the group consisting of dimethyl amino ethyl methacrylate, dimethyl amino ethyl acrylate, diethyl amino ethyl methacrylate, diethyl amino ethyl acrylate, piperidine ethyl methacrylate, 2 tert- butyl amino ethyl methacrylate, preferably dimethyl amino ethyl methacrylate and diethyl amino ethyl acrylate
  • the basic monomer (B) is an alkenyl pyridine selected from the group consisting of 2-vinyl pyridine, 3- vinyl pyridine, 4-vinyl pyridine and 5- vinyl 2 picoline, 2-vinyl 4 picoline, 2 isopropenyl pyridine, iso propenyl pyridine, preferably 4- vinyl pyridine.
  • the basic monomer (B) is selected from vinyl quinolines, aminoalkyl vinyl ethers, amino ethyl styrenes and allylic amines, preferably ally lie amines.
  • the hydrophilic monomer (C) is an acrylic or methacrylic acid ester selected from the group consisting of hydroxy ethyl methacrylate, hydroxy propyl methacrylate, hydroxy ethyl ethyl methacrylate, hydroxy ethyl acrylate, hydroxy propyl acrylate, hydroxy ethyl ethyl acrylate preferably hydroxy ethyl methacrylate and hydroxy ethyl ethyl methacrylate.
  • the drag comprises a macrolide antibiotic selected from the group consisting of erythromycin, azithromycin and clarithromycin, fluroquinolones selected from the group consisting of ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin and norfloxacin, cephalosporins selected from the group consisting of cefuroxime, cephalexin, cephadroxil, cepfodoxime proxetil, nonsteoroidal, and anti- inflammatory and analgesic drags selected from the group consisting of ibuprofen and diclofenac sodium and COX 2 inhibitors selected from the group consisting of etoricoxib and celecoxib, antihistamic drags selected from the group consisting of chlorpheniramine maleate, oxazolidinones selected from the group consisting of linezolid and other drag like dextromethorphan.
  • a macrolide antibiotic selected from the group consist
  • the pH sensitive polymer solubilizes or swells in the acidic pH ⁇ 3 as found in stomach and remains insoluble or de swelled in the pH > 3.5.
  • the drag itself or its pharmaceutically acceptable salt or ester or amide is used.
  • the drug is in the form of microparticles dispersed within or coated with the polymer matrix.
  • the pharmaceutical dosage forms which could be prepared using the composition of the present invention may be liquid orals; such as dry syrup or suspension and chewable or dispersible tablets.
  • the pharmaceutical composition comprising the microparticles by themselves or in a pharmaceutically acceptable dosage form, release a minimal amount of drug at pH of saliva from the oral dosage form but rapidly release substantial amount of the drug immediately at pH ⁇ 3 found in the stomach.
  • the microparticles are formulated as aqueous suspension or are reconstituted in liquid medium for a normal storage period.
  • the pharmaceutical composition is obtained by dispersion or coating of the bitter drag in the matrix of pH sensitive polymer by any of the known techniques, preferably by microencapsulation, spray drying, fluid bed processing, co precipitation in a non solvent or by tray drying method.
  • the taste masked drug polymer matrix in particulate form is suspended using the reconstitution medium of pH 4.5 comprising of sucrose, tutti- frutti flavor, citric acid and polyvinyl pyrrolidone.
  • the hydrophobic monomer (A) is a acrylic or a methacrylic acid ester selected from the group consisting of cyclohexyl acrylate, dodecyl acrylate, 2 ethyl hexyl acrylate, octyl acrylate, tertiary butyl acrylate, phenyl acrylate, butyl acrylate, methyl methacrylate, benzyl methacrylate, cyclohexyl methacrylate, phenyl methacrylate, tertiary butyl methacrylate, butyl methacrylate, 2 ethyl hexyl methacrylate, propyl methacrylate preferably butyl acrylate, methyl methacrylate and butyl methacrylate.
  • the basic monomer (B) is selected from the group consisting of amino alkyl acrylic acid and methacrylic acid esters selected from the group consisting of dimethyl amino ethyl methacrylate, dimethyl amino ethyl acrylate, diethyl amino ethyl methacrylate, diethyl amino ethyl acrylate, piperidine ethyl methacrylate, 2 tert- butyl amino ethyl methacrylate, preferably dimethyl amino ethyl methacrylate and diethyl amino ethyl acrylate
  • the basic monomer (B) is an alkenyl pyridine selected from the group consisting of 2-vinyl pyridine, 3- vinyl pyridine, 4-vinyl pyridine and 5- vinyl 2 picoline, 2-vinyl 4 picoline, 2 isopropenyl pyridine, iso propenyl pyridine, preferably 4- vinyl pyridine.
  • the basic monomer (B) is selected from vinyl quinolines, aminoalkyl vinyl ethers, amino ethyl styrenes and allylic amines, preferably allylic amines.
  • the hydrophilic monomer (C) is an acrylic or methacrylic acid ester selected from the group consisting of hydroxy ethyl methacrylate, hydroxy propyl methacrylate, hydroxy ethyl ethyl methacrylate, hydroxy ethyl acrylate, hydroxy propyl acrylate, hydroxy ethyl ethyl acrylate preferably hydroxy ethyl methacrylate and hydroxy ethyl ethyl methacrylate.
  • the drug comprises a macrolide antibiotic selected from the group consisting of erythromycin, azithromycin and clarithromycin, fluroquinolones selected from the group consisting of ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin and norfloxacin, cephalosporins selected from the group consisting of cefuroxime, cephalexin, cephadroxil, cepfodoxime proxetil, nonsteoroidal, and anti- inflammatory and analgesic drags selected from the group consisting of ibuprofen and diclofenac sodium and COX 2 inhibitors selected from the group consisting of etoricoxib and celecoxib, antihistamic drugs selected from the group consisting of chlorpheniramine maleate, oxazolidinones selected from the group consisting of linezolid and other drag like dextromethorphan.
  • a macrolide antibiotic selected from the group consisting
  • the drag itself or its pharmaceutically acceptable salt or ester or amide is used.
  • the total polymer to drug ratio for optimal taste masking bitter drag in the range 30:1 to 0.2: 1 by weight. More preferably the ratio of the polymer to drag is 5: 1 to 0.4: 1 by weight.
  • the pH sensitive polymer solubilizes or swells in the acidic pH ⁇ 3 as found in stomach and remains insoluble or de swelled in the pH > 3.5.
  • the drag is in the form of microparticles dispersed within or coated with the polymer matrix.
  • the present invention provides oral pharmaceutical compositions, which effectively mask the bitter, unpleasant and otherwise undesirable taste of the active ingredient. More specifically the invention relates to the synthesis of the pH sensitive polymers which can be used in various pharmaceutical compositions providing taste masking and substantial immediate release and absorption of the bitter active ingredient, which is generally desirable in case of solid and liquid dosage forms like tablets; chewable or dispersible and suspensions or dry syrups. It also relates to the process for preparing such a composition.
  • composition of the present invention is in the form of a taste masked formulation providing a substantial immediate release of the bitter active compound due to the solubilization or swelling of the reverse enteric polymer in acidic pH of ⁇ 3 and the prevention of release of the drag in the pH range of > 3.5 as found in saliva and reconstitution media over the complete period of storage of up to 14 days.
  • the pH sensitive polymer is synthesized comprising of essentially of a hydrophobic monomer, a basic monomer and optionally a hydrophilic monomer.
  • An important feature of the present invention is that it provides taste-masked microcapsules of bitter drugs, suitable for oral administration as a suspension, a fast- disintegrating, effervescent or chewable tablet, and more specifically relates to such oral dosage forms in which the bitter taste of drugs is masked by a functional membrane coating on said microcapsules by pH sensitive polymer.
  • a taste-masked microcapsule composition for taste masking an orally effective bitter drag in accordance with the present invention comprises microcapsules of the drug in a polymeric coating matrix prepared by emulsification, solvent evaporation or solvent extraction or by the spray drying technique. More specifically the present invention relates to the taste masked liquid oral formulation like the dry syrups intended for the pediatric use.
  • taste-masked compositions of the invention are further advantageous in that the reconstituted liquid preparations made from them are stable over the normal therapeutic dosage schedule, typically up to fourteen days.
  • taste masking of bitter drug is achieved by using a pH sensitive polymeric coating on the bitter drag, wherein the polymer essentially solubilizes or swells in the acidic condition of the stomach and remains insoluble or de-swelled at neutral or near neutral pH.
  • the pH sensitive polymer when applied to the pharmaceutical dosage forms like, the liquid orals such as dry syrup or suspension and tablets; chewable or dispersible, releases the active ingredient in the acidic pH of the stomach but maintains the taste palatable, by preventing the leaching of the drug in pH of saliva or suspending media or in the near neutral aqueous environment.
  • the said pH sensitive polymers are synthesized using monomers essentially from the class of hydrophobic monomer and basic monomers and optionally a hydrophilic monomer.
  • Another aspect of the present invention is to formulate a coated bitter drag in the form of suspensions and prevent leaching of the drag in suspending media during reconstitution period of up to 14 days, and also ensure substantial release of active drag in the simulated gastric fluid without compromising on bioavailability.
  • pH sensitive polymers of the present invention inhibit the release of the active agent in the aqueous media of pH >3.5 such that the leaching of bitter drug in the saliva and also in the reconstitution media, in case of liquid orals is inhibited and release the drag rapidly in the pH range of ⁇ 3 as found in the stomach.
  • the present invention also provides for the taste masking of bitter drugs like macrolide antibiotics such as erythromycin, azithromycin and clarithromycin, fluroquinolones such as ciprofloxacin, enrofloxacin, ofioxacin, gatifloxacin, levofloxacin and norfloxacin, cephalosporins such as cefuroxime, cephalexin, cephadroxil, cepfodoxime proxetil, nonsteoroidal and anti-inflammatory and analgesic drugs such as ibuprofen, diclofenac sodium and COX 2 inhibitors like etoricoxib and celecoxib, antihistamic drags like chlorpheniramine maleate, oxazolidinones like linezolid and other drug like dextromethorphan.
  • macrolide antibiotics such as erythromycin, azithromycin and clarithromycin
  • fluroquinolones such as ciprofloxacin,
  • the drug itself or its pharmaceutically acceptable salt or ester or amide may be used in the present invention.
  • the drugs preferred for the practice of present invention can be chosen from a wide range comprising cefuroxime axetil, ciprofloxacin, celecoxib and clarithromycin.
  • the pharmaceutical composition described herein has the total polymer to drag ratio for optimal taste masking bitter drag in the range 30:1 to 0.2:1 by weight. More preferably the ratio of the polymer to drug is 5 : 1 to O.4: 1 by weight.
  • the invention comprises development of a formulation useful as a stable taste-masking liquid suspension capable of being ingested without producing the unpleasant taste associated with the active agent, while still providing immediate bioavailability upon exposure to the pH levels found in the stomach of a human.
  • taste-masked particles obtained as described in the invention are optionally blended with other pharmaceutically acceptable excipients such as flavors, sweeteners, suspending agents and / or preservatives and formulated as dry syrup or compressed into fast disintegrating, effervescent or chewable tablets.
  • Stable aqueous suspensions can be constituted from the dry syrup powder for oral administration up to 14 days for pediatric and geriatric patients who are unwilling and / or find it difficult to swallow tablets.
  • Fast disintegrating tablets rapidly disintegrate in the mouth and are therefore suitable for oral administration to patients who find it difficult to swallow tablets.
  • Such dosage forms on oral administration should release not more than 10%, most preferably not more than 5%, at pH of reconstitution media up to 14 days but rapidly release at least 40- 60% within 15 min and not less than 70 % in an hour at pH as found in the stomach.
  • the mean particle size of the microcapsules will be in the range of about 30 to 1000 microns, most preferably in the range of about 100 to 500 microns.
  • bitter, unpleasant tasting drugs examples include, but are not limited to macrolide antibiotics such as erythromycin azithromycin and clarithromycin, fluroquinolones such as ciprofloxacin enrofloxacin, ofloxacin, gatifloxacin, levofloxacin and norfloxacin, cephalosporins such as cefuroxime, cephalexin, cephadroxil, cepfodoxime proxetil nonsteoroidal and anti-inflammatory and analgesic drugs such as ibuprofen, diclofenac sodium and COX 2 inhibitors like celecoxib and etoricoxib, antihistamic drags like ' chlorpheniramine maleate, oxazolidinones like linezolid and other drag like dextromethorphan.
  • macrolide antibiotics such as erythromycin azithromycin and clarithromycin
  • fluroquinolones such as ciprofloxacin enrofloxacin
  • Alonso disclosed the release of cefuroxime axetil from the microparticles obtained using the polymeric coating of Eudragit E, Eudragit LI 00-55 and eudragit RL-100. (M. J. Alonso, M.L Lorenzo-Lamosa, M.Cuna, J. L. Vila-Jato and D. Torres, Journal of Microencapsulation, 1997, Volume 14, No.5, 607-616).
  • the release of cefuroxime axetil was almost complete from eudragit E microspheres in 0.07 N HCl in 20 -30 min..
  • the release from the eudragit E microsphere in Sorensens buffer pH 7 was found to be slow as compared to the 0.07 N HCl.
  • the release data are summarized below Media 0.07 N HCL
  • cefuroxime axetil The drag molecules like cefuroxime axetil tend to gel in presence of the aqueous media. Also if the tablets are not protected from moisture during storage, they result in poor dissolution and lower drag bioavailability. So the liquid oral preparation of cefuroxime axetil needs to protect the drug during the reconstitution period from the aqueous environment. Cefuroxime axetil has a limited absorption region in the gastrointestinal tract as the enzyme esterases, hydrolyses it to cefuroxime, which cannot be absorbed across the tract thereby reducing its bioavailability. Cefuroxime axetil is also associated with an extremely bitter taste. The pharmaceutical compositions of cefuroxime axetil are therefore required to be taste masked.
  • the bitter drugs used for taste masking include cefuroxime axetil, ciprofloxacin hydrochloride and clarithromycin.
  • cefuroxime axetil ciprofloxacin hydrochloride and clarithromycin.
  • One of the feature of the present invention is fast swelling and / or dissolution of the polymer in acidic pH, with rapid release of drug, like cefuroxime axetil which have a low bioavailability of 32-50 %, from the polymer coating and thus should not cause any delay in the absorption and alter the bioavailability.
  • the release of the drugs form the polymers used in the present invention is disclosed in the examples.
  • the pharmaceutical composition may be obtained by coating of the drag using of pH sensitive polymer either by microencapsulation, spray drying, fluid bed processing, co-precipitation in a non solvent or by tray drying method.
  • the drag is dispersed within the polymer matrix.
  • the taste masking, compositions are made by microencapsulation of the drag in the polymer matrix.
  • the microencapsulation of the bitter drugs can be obtained by emulsification, solvent evaporation or solvent extraction and spray drying of the drug polymer solution or dispersion of drag in polymer solution. If the drag is not soluble in the polymer solution then it is dispersed in the polymer solution uniformly with the help of the dispersing agents like the surfactants.
  • the preferred surfactants are the nonionic surfactants belonging to the class of SPAN and TWEEN.
  • the solvent is selected such that the drag and the polymer are both soluble in the solvent.
  • the solvents chosen for the solubilization of the drag and polymer are alcohols like methanol, ethanol, isopropanol, butanol, chlorinated hydrocarbons like dichloromethane, chloroform, ketones like methyl ethyl ketone, methyl iso-butyl ketone and acetone.
  • the solvents used to dissolve the drug and polymers are methanol, acetone and dichloromethane.
  • the preferred solvent to dissolve the drag and polymer is acetone or a mixture of methanol and dichloromethane, in the ratio 1 : 1 to 1 : 1.5.
  • the taste-masked microcapsules of the bitter drug can be obtained by microencapsulation by emulsification solvent evaporation technique.
  • the dispersed phase is the organic solvent containing the drag and polymer and the dispersion medium is the liquid paraffin.
  • the pH sensitive polymer synthesized is dissolved in the organic solvent (acetone, methanol, dichloromethane or a mixture of methanol and dichloromethane in the ratio 1:1 to 1: 1.5.)
  • the drag is added to the polymer solution resulting in a solution or a homogeneous dispersion.
  • the organic phase is then added into the light liquid paraffin-containing span 85 (0.1 to 1 % w/w). A constant mechanical stirring rate of 1000 rpm and at room temperature is maintained for a 3-4 hours. The solvent is allowed to evaporate and the microspheres so obtained are separated by filtration, washed by petroleum ether or by n hexane and dried under vacuum for up to 24 hours. The taste-masked microcapsules of the bitter drug can be further obtained by microencapsulation by emulsification solvent extraction technique.
  • the dispersed phase is the organic solvent containing the drug and polymer and the dispersion medium is the liquid paraffin.
  • the pH sensitive polymer synthesized is dissolved in the organic solvent (acetone, methanol, dichloromethane or a mixture of methanol and dichloromethane in the ratio 1 : 1 to 1: 1.5.).
  • the drug is added to the polymer solution resulting in a solution or a homogeneous dispersion.
  • the organic phase is then added into the light liquid paraffin-containing span 85 (0.1 to 1 % w/w).
  • a constant mechanical stirring rate of 500 rpm and 25 ° C is maintained for 30 min and 40 ml of n hexane or cyclohexane is added at a rate of 5 ml /min, followed by another 40 ml n hexane or cyclohexane being added rapidly.
  • the microparticles are separated by filtration and washed by petroleum ether or by n hexane and dried at 27°C under vacuum for up to 24 hours.
  • the taste masked micro particles can be obtained by spray drying.
  • the drug - polymer solution or dispersion in the organic solvent is spray dried to obtain the taste masked micro particles.
  • the drying gas can be an inert gas such as nitrogen, argon and carbon dioxide or air.
  • the preferred gas in the present invention is air.
  • the gas inlet temperature to the spray dryer depends on the choice of the solvent used but may be in the range of 35 - 150°C preferably 40 -60°C.
  • the gas outlet temperature is similarly dependant on the solvent but may be in the range of 25 to 50, preferably 25 to 40°C.
  • the polymer is solubilized in methanol or a mixture of methanol and dichloromethane 1 : 1 and the drag is either solubilized or dispersed in the polymer solution.
  • the resulting mixture is spray dried to obtain the taste masked micro particles.
  • the taste masked particles and granules obtained may be mixed with the flavoring agents such as natural or artificial flavors, citric and tartaric acids, sweeteners such as sucrose, saccharin and aspartame, and other pharmaceutically acceptable excipients to be formulated as conventional whole, chewable or dispersible tablets, dry syrups, suspensions, sachets or any other suitable oral dosage form.
  • the present invention is more directed towards the taste masking of the liquid oral compositions suitable for the pediatric patients or those, who have a difficulty in swallowing the solid dosage form.
  • the taste masked pharmaceutical composition is prepared by reconstitution of the polymer coated drag particles in a liquid vehicle comprising sucrose, flavor and citric acid and a suspending agent like cellulose derivatives or polyvinyl pyrro ⁇ done or xanthan gum etc.
  • the taste masked pharmaceutical composition of the present invention is prepared by using the reconstitution medium of pH 4.5 comprising of sucrose, tutti- fratti flavor, citric acid and polyvinyl pyrrolidone.
  • the taste masked pharmaceutical compositions as exemplified in the examples 1 to 12 given below were tested for the drug release with respect to time.
  • Cefuroxime axetil release from the taste masked particles was determined in 900 ml of 0.07 N hydrochloric acid, at 37 ⁇ 0.5 °C, using USP type II apparatus rotated at 100 rpm. The samples were withdrawn at 15, 30, 45, 60 and 90 min. The amount withdrawn each time was replaced with fresh media to maintain the sink conditions.
  • Ciprofloxacin hydrochloride release from the taste masked particles was determined in 900 ml of 0.1 N hydrochloric acid buffer, at 37 ⁇ 0.5°C, using USP type II apparatus rotated at 100 rpm. The samples were withdrawn at 15, 30, 45, and 60, min. The amount withdrawn each time was replaced with fresh media to maintain the sink conditions.
  • Clarithromycin release from the taste masked particles was determined in 900 ml of acetate buffer pH 2.8, at 37 + 0.5°C, using USP type II apparatus rotated at 100 rpm. The samples were withdrawn at 15, 30, 45 and 60 min. The amount withdrawn each time was replaced with fresh media to maintain the sink conditions.
  • Celecoxib release from taste masked particles was determined by placing composition consisting of celecoxib and polymer in 0.1 N HCl 100ml for 30 min and then addition of 900ml of 0.1 N NaOH solution, at 37 ⁇ 0.5 °C, using USP type II apparatus rotated at 100 rpm. Samples were withdrawn from 0.1 N NaOH solution at 15, 30, 45 and 60 min.
  • Example 1 Taste masked microcapsules were obtained by emulsification solvent evaporation technique. 3.50 g of ciprofloxacin was dispersed in polymer solution containing 900 mg of polymer in 45 ml of mixture of methanol and dichloromethane (1 : 1). The polymer has the monomer composition Methyl methacrylate 60 % by weight Hydroxyethyl methacrylate 25
  • Example 2 Taste-masked microcapsules of the bitter drug were obtained by microencapsulation by emulsification solvent evaporation technique. 2.35 g of ciprofloxacin was dispersed in polymer solution containing 7.0 g of polymer in 40 ml of mixture of methanol and dichloromethane (1:1). The polymer has the monomer composition Methyl methacrylate 60 % by weight Hydroxyethyl methacrylate 25 % by weight and Vinyl Pyridine 15% by weight. The microencapsulation of the ciprofloxacin with the pH sensitive polymer was achieved using the method similar as mentioned in the example 1. The drug release pattern of the composition prepared was studied and the results are tabulated in Table-2
  • Example 3 Taste masked microcapsules were obtained by microencapsulation by emulsification solvent evaporation technique. 2.0g of clarithromycin was dissolved in polymer solution containing 4.0g of polymer in 40ml of mixture of methanol and dichloromethane (1: 1). The polymer has the monomer composition Methyl methacrylate 60% by wt Hydroxyethyl methacrylate 25% by wt and Vinyl Pyridine 15% by wt. Microencapsulation of clarithromycin with pH sensitive polymer was achieved using a method similar to that of example 1. Drug release pattern of composition prepared was studied and results are tabulated in Table 3. Example 4 Taste masked microcapsules were obtained by microencapsulation by emulsification solvent evaporation technique.
  • Example 5 Taste masked microcapsules of cephalosporin antibiotic cefuroxime axetil were obtained by microencapsulation by emulsification solvent evaporation technique. 2.0g of cefuroxime axetil was dissolved in polymer solution containing 6.0g of polymer in 40ml of mixture of methanol and dichloromethane (1: 1). The polymer has the monomer composition Methyl methacrylate 43% by wt Hydroxyethyl methacrylate 42% by wt and Vinyl Pyridine 15% by wt. Microencapsulation of cefuroxime axetil with pH sensitive polymer was achieved using a method similar to that of example 1. Drug release pattern of composition prepared was studied and results are tabulated in Table-5
  • Taste masked pharmaceutical composition of microcapsules prepared in example 5 is prepared for microparticles having drug equivalent to 4 doses by using reconstitution medium of pH 4.5 comprising of sucrose 85 % w/v, tutti- fratti flavor qs., citric acid qs. and polyvinyl pyrrolidone 2%.
  • the drug release during the storage for 7 days is shown in the table 6 Table 6
  • Example 6 Taste masked microcapsules of cefuroxime axetil were obtained by microencapsulation by emulsification solvent evaporation technique. 2.0 g of cefuroxime axetil was dissolved in polymer solution containing 6.0 g of polymer in 40 ml of mixture of methanol and dichloromethane (1: 1). The polymer has the monomer composition Methyl methacrylate 60 % by weight, Hydroxyethyl methacrylate 25 % by weight and Vinyl Pyridine 15% by weight. The microencapsulation of cefuroxime axetil with the pH sensitive polymer was achieved using the method similar as mentioned in the example 1. The drug release pattern of the composition prepared was studied and the results are tabulated in Table-7
  • Taste masked pharmaceutical composition of microcapsules prepared in example 6 is prepared for microparticles having drug equivalent to 4 doses by using reconstitution medium of pH 4.5 comprising of sucrose 85 % w/v, tutti- fratti flavor qs., citric acid qs. and polyvinyl pyrrolidone 2%.
  • the drug release during the storage for 7 days is shown in the table 8 Table 8
  • Example 7 Taste masked microcapsules of the bitter cephalosporin antibiotic cefuroxime axetil were obtained by microencapsulation by emulsification solvent evaporation technique. 2.0 g of cefuroxime axetil was dissolved in polymer solution containing 6.0 g of polymer in 40 ml of mixture of methanol and dichloromethane (1: 1). The polymer has the monomer composition Methyl methacrylate 70 % by weight and Vinyl Pyridine 30% by weight. The microencapsulation of the cefuroxime axetil with the pH sensitive polymer was achieved using the method similar as mentioned in the example 1. The drag release pattern of the composition prepared was studied and the results are tabulated in Table-9
  • Taste masked pharmaceutical composition of microcapsules prepared in example 7 is prepared for microparticles having drag equivalent to 4 doses by using reconstitution medium of pH 4.5 comprising of sucrose 85 % w/v, tutti- fratti flavor qs., citric acid qs. and polyvinyl pyrrolidone 2%.
  • the drug release during the storage for 7 days is shown in the table 10 Table 10
  • Example 8 Taste masked microcapsules of the bitter cephalosporin antibiotic cefuroxime axetil were obtained by microencapsulation by emulsification solvent evaporation technique. 2.0 g of cefuroxime axetil was dissolved in polymer solution containing 6.0 g of polymer in 40 ml of mixture of methanol and dichloromethane (1: 1). The polymer has the monomer composition Methyl methacrylate 35 % by weight, Hydroxyethyl methacrylate 35 % by weight and Vinyl Pyridine 30% by weight. The microencapsulation of the cefuroxime axetil with the pH sensitive polymer was achieved using the method similar as mentioned in the example 1. The drug release pattern of the composition prepared was studied and the results are tabulated in Table- 11
  • Example 9 The cefuroxime axetil - polymer solution in the organic solvent was spray dried to obtain the taste masked micro particles.
  • the polymer has the monomer composition Methyl methacrylate 60 % by weight Hydroxyethyl methacrylate 25 % by weight and 4 Vinyl pyridine 15% by weight of polymer .
  • the drying gas was air.
  • the inlet air temperature to the spray dryer was in the range 40 - 70° C.
  • the outlet air temperature was in the range of 25 to 60 °C.
  • the polymer weighing 2.4 g was solubilized in the mixture of methanol and dichloromethane 1: 1 and cefuroxime axetil weighing 4.8 g was added in the polymer solution.
  • the atomization was in the range of 1 — 2 kg.
  • the feed rate was 20 to 85 rpm .
  • the resulting solution was spray dried to obtain the taste masked micro particles.
  • the drag release pattern of the composition prepared was studied and the results are tabulated in Table- 12
  • Taste masked pharmaceutical composition of microcapsules prepared in example 9 is prepared for microparticles having drug equivalent to 5 doses by using reconstitution medium of pH 4.5 comprising of sucrose 85 % w/v, tutti- fratti flavor qs., citric acid qs. and polyvinyl pyrrolidone 2%.
  • the drag release during the storage for 7 days is shown in the table 13 Table 13
  • Example 10 The cefuroxime axetil - polymer solution in the organic solvent was spray dried to obtain the taste masked micro particles.
  • the polymer has the monomer composition Methyl methacrylate 60 % by weight Hydroxyethyl methacrylate 25 % by weight and 4 Vinyl pyridine 15% by weight of polymer .
  • the solvent used was a mixture of methanol and dichloromethane 1: 1.
  • the drying gas was air.
  • the inlet air temperature to the spray dryer was in the range 40 - 70° C.
  • the outlet air temperature was in the range of 25 to 60 °C.
  • the polymer weighing 2.4 g was solubilized in the in the mixture of methanol and dichloromethane 1: 1 and cefuroxime axetil weighing 4.8 g was added in the polymer solution.
  • the atomization was in the range of 1 - 2 kg.
  • the feed rate was 20 to 85 rpm .
  • the resulting solution was spray dried to obtain the taste masked micro particles.
  • the drug release pattern of the composition prepared was studied and the results are tabulated in Table- 14
  • the taste masked pharmaceutical composition of the microcapsules prepared in example 10 is prepared for microparticles having the drag equivalent to 5 doses by using the reconstitution medium of pH 4.5 comprising of sucrose 85 % w/v, tutti- fratti flavor qs., citric acid qs. and polyvinyl pyrrolidone 2%.
  • the drag release during the storage for 7 days is shown in the table 15 Table 15
  • Example 11 The celecoxib - polymer solution in the organic solvent was spray dried to obtain the taste masked micro particles.
  • the polymer has the monomer composition Methyl methacrylate 60 % by weight Hydroxyethyl methacrylate 25 % by weight and 4 Vinyl pyridine 15% by weight of polymer .
  • the solvent used was a mixture of methanol and dichloromethane (1.5: 1).
  • the drying gas was air.
  • the inlet air temperature to the spray dryer was in the range 40 - 70° C.
  • the outlet air temperature was in the range of 25 to 60 °C.
  • the polymer weighing 1.5 g was solubilized in mixture of methanol and dichloromethane (1.5: 1) and celecoxib weighing 2.0 g was added in the polymer solution.
  • the atomization was in the range of 1 - 2 kg.
  • the feed rate was 20 to 85 rpm .
  • the resulting solution was spray dried to obtain the taste masked micro particles.
  • the drag release pattern of the composition prepared was studied and the results are tabulated in Table- 16
  • Example 12 The celecoxib - polymer solution in the organic solvent was spray dried to obtain the taste masked micro particles.
  • the polymer has the monomer composition Methyl methacrylate 60 % by weight Hydroxyethyl methacrylate 25 % by weight and 4 Vinyl pyridine 15% by weight of polymer .
  • the solvent used was a mixture of methanol and dichloromethane (1.5: 1).
  • the drying gas was air.
  • the inlet air temperature to the spray dryer was in the range 40 - 70° C.
  • the outlet air temperature was in the range of 25 to 60 °C.
  • the polymer weighing 0.750 g was solubilized in the mixture of methanol and dichloromethane (1.5: 1) and celecoxib weighing 2.0 g was added in the polymer solution.
  • the atomization is in the range of 1 - 2 kg.
  • the feed rate was 20 to 85 rpm .
  • the resulting solution was spray dried to obtain the taste masked micro particles.
  • the drag release pattern of the composition prepared was studied and the results are tabulated in Table- 17

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Abstract

La présente invention a trait à des compositions pharmaceutiques comportant des polymères sensible au pH utilisés pour masquer le goût de médicaments très amers. Le polymère sensible au pH agit comme un enrobage entérique inverse, qui est soluble dans la plage de pH acide comprise entre 1,0 et 3,0 présente dans l'estomac mais est insoluble dans la plage de pH comprise entre 3,5 et 7 assurant ainsi l'inhibition de la libération du médicament amer au niveau du pH de la salive et également au niveau du pH du milieu de reconstitution dans le cas des liquides buccaux.
PCT/IN2003/000392 2003-12-15 2003-12-15 Compositions pharmaceutiques au gout masque comportant une medicament amer et un polymere sensible au ph WO2005055987A1 (fr)

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CA002549572A CA2549572A1 (fr) 2003-12-15 2003-12-15 Compositions pharmaceutiques au gout masque comportant une medicament amer et un polymere sensible au ph
JP2005511660A JP2007518670A (ja) 2003-12-15 2003-12-15 苦味のある薬物、及びｐＨ感受性ポリマーを含む風味マスクされた医薬組成物
AU2003292509A AU2003292509B2 (en) 2003-12-15 2003-12-15 Taste masked pharmaceutical compositions comprising bitter drug and pH sensitive polymer
PCT/IN2003/000392 WO2005055987A1 (fr) 2003-12-15 2003-12-15 Compositions pharmaceutiques au gout masque comportant une medicament amer et un polymere sensible au ph
CN200380110830XA CN1878539B (zh) 2003-12-15 2003-12-15 含苦味药物和pH敏感性聚合物的掩味的药物组合物
EP03768091A EP1694302A1 (fr) 2003-12-15 2003-12-15 Compositions pharmaceutiques au gout masque comportant une medicament amer et un polymere sensible au ph

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JP2009035505A (ja) * 2007-08-01 2009-02-19 Takada Seiyaku Kk レボフロキサシン錠剤
CN102302472A (zh) * 2011-09-08 2012-01-04 河南迪冉生物科技有限公司 恩诺沙星微囊及其制备方法
CN103191680A (zh) * 2013-03-26 2013-07-10 厦门大学 一种pH敏感的复合中空微球及其制备方法
WO2017221268A1 (fr) * 2016-06-21 2017-12-28 Laila Nutraceuticals Formulation masquant le goût de composés naturels amers
CN109862902A (zh) * 2016-09-08 2019-06-07 莱拉营养食品有限公司 天然化合物的气味掩蔽制剂
TWI683662B (zh) * 2014-12-05 2020-02-01 美商艾瑞岡醫藥公司 抗癌症組成物（一）
US11224575B2 (en) 2014-12-05 2022-01-18 Aragon Pharmaceuticals, Inc. Anticancer compositions

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JP2007518669A (ja) * 2003-12-15 2007-07-12 カウンシル オブ サイエンティフィク アンド インダストリアル リサーチ ｐＨ感受性ポリマーを含む風味マスクされる医薬組成物
JP5563841B2 (ja) * 2010-02-05 2014-07-30 沢井製薬株式会社 薬物の不快な味をマスキングした経口医薬組成物
JP5915014B2 (ja) * 2010-07-30 2016-05-11 大正製薬株式会社 内服液剤
CN102188406B (zh) * 2011-05-12 2015-02-25 黑龙江大学 盐酸左氧氟沙星掩味微胶囊的生产方法
MX356579B (es) * 2011-06-17 2018-06-05 Evonik Roehm Gmbh Composicion farmaceutica o nutraceutica de resistencia gastrica con resistencia contra la influenza de etanol.
CN102344520B (zh) * 2011-07-12 2015-04-22 华东理工大学 两种pH敏感再生型聚合物、其制备方法和形成的再生型两水相体系及应用
CN114209661B (zh) * 2022-02-21 2022-04-29 北京罗诺强施医药技术研发中心有限公司 呈细粒形式的固体药物组合物

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JP2009035505A (ja) * 2007-08-01 2009-02-19 Takada Seiyaku Kk レボフロキサシン錠剤
CN102302472A (zh) * 2011-09-08 2012-01-04 河南迪冉生物科技有限公司 恩诺沙星微囊及其制备方法
CN102302472B (zh) * 2011-09-08 2012-08-01 河南迪冉生物科技有限公司 恩诺沙星微囊及其制备方法
CN103191680A (zh) * 2013-03-26 2013-07-10 厦门大学 一种pH敏感的复合中空微球及其制备方法
TWI683662B (zh) * 2014-12-05 2020-02-01 美商艾瑞岡醫藥公司 抗癌症組成物（一）
US11224575B2 (en) 2014-12-05 2022-01-18 Aragon Pharmaceuticals, Inc. Anticancer compositions
US20220151931A1 (en) * 2014-12-05 2022-05-19 Aragon Pharmaceuticals, Inc. Anticancer compositions
US11911511B2 (en) 2014-12-05 2024-02-27 Aragon Pharmaceuticals, Inc. Anticancer compositions
WO2017221268A1 (fr) * 2016-06-21 2017-12-28 Laila Nutraceuticals Formulation masquant le goût de composés naturels amers
AU2017282039B2 (en) * 2016-06-21 2022-01-06 Laila Nutraceuticals Taste masking formulation for bitter natural compounds
US11576941B2 (en) 2016-06-21 2023-02-14 Laila Nutraceuticals Taste masking formulation for bitter natural compounds
CN109862902A (zh) * 2016-09-08 2019-06-07 莱拉营养食品有限公司 天然化合物的气味掩蔽制剂
EP3509611A4 (fr) * 2016-09-08 2020-05-06 Laila Nutraceuticals Formulations de masquage d'odeur pour composés naturels
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