WO2006061846A1 - Composition pharmaceutique visant a ameliorer la sapidite de medicaments et procede de preparation de ladite composition - Google Patents

Composition pharmaceutique visant a ameliorer la sapidite de medicaments et procede de preparation de ladite composition Download PDF

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Publication number
WO2006061846A1
WO2006061846A1 PCT/IN2004/000379 IN2004000379W WO2006061846A1 WO 2006061846 A1 WO2006061846 A1 WO 2006061846A1 IN 2004000379 W IN2004000379 W IN 2004000379W WO 2006061846 A1 WO2006061846 A1 WO 2006061846A1
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Prior art keywords
polymer
drug
lipid
composition
group
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PCT/IN2004/000379
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English (en)
Inventor
Anupa Ramesh Menjoge
Mohan Gopalkrishna Kulkarni
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Council Of Scientific And Industrial Research
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Priority to NZ551113A priority Critical patent/NZ551113A/en
Priority to CNB2004800430930A priority patent/CN100548270C/zh
Priority to BRPI0419125-0A priority patent/BRPI0419125A/pt
Priority to EP04806762A priority patent/EP1845937A1/fr
Priority to JP2007522124A priority patent/JP4629730B2/ja
Priority to AU2004325469A priority patent/AU2004325469B2/en
Priority to PCT/IN2004/000379 priority patent/WO2006061846A1/fr
Publication of WO2006061846A1 publication Critical patent/WO2006061846A1/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
    • 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
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present invention provides a pharmaceutical composition for improving palatability of (drugs. More particularly the present invention relates to bitterness inhibition of drugs by dispersing the drug in a lipid-polymer matrix.
  • the pharmaceutical compositions of the present invention release substantial amount of the drug immediately at the gastric pH.
  • the present invention also relates to the process for the preparation of these compositions. 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 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 taste buds and this 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.
  • the disagreeable taste of drugs causes difficulties in swallowing or causes patients to avoid their medication thereby resulting in low compliance of patients.
  • taste masking techniques such as use of sweeteners, amino acids, flavoring agents are often unsuccessful in masking the taste of the highly bitter drugs like quinine, barberin, etoricoxib, antibiotics like levofloxacin, ofloxacin, sparfloxacin, ciprofloxacin, cefuroxime axetil, erythromycin and clarithromycin.
  • taste masking is a major problem when the drugs are extremely unpleasant and bitter and this problem is not restricted to the liquid oral compositions like solutions, dry syrups and suspensions but may also be encountered during the formulation of chewable tablets or dispersible tablets wherein these dosage forms usually lead to perceptible exposure of active ingredient to taste buds.
  • US Patent 4,797,288 discloses a novel drug delivery system based on the hydrophobic matrix coating the core, such that the coating delays the hydration of the core.
  • the delivery system comprises of dry drug particles designed either for chewing or swallowing.
  • the hydrophobic matrix coating delaying the hydration of core comprised of about 200 - 400 % by weight of the drug.
  • the hydrophobic material had a melting point in the range of 25- 100 0 C .
  • the delivery system comprised of 61 - 95 % by weight of fatty acid
  • GB Patent 1323161 discloses coating of acetoxymethyl benzylpenicillinate using lipids having a melting point of not more than 95°C.
  • the coating of the lipid is achieved by spray congealing method.
  • the coated powder is reconstituted at a pH of 6.5.
  • the composition protects penicillin from moisture and also masks the bitter taste.
  • the use of lipids alone tends to delay the release of the drug owing to the hydrophobic nature of the lipids.
  • GB Patent 2081092 discloses use of waxy materials and high molecular weight water swellable materials.
  • the water swellable material is added to improve dissolution, which helps in increasing the absorption of the drug.
  • water swelling materials along with lipids in compositions is of limited use since these compositions would tend to leach the drugs in the aqueous media used for reconstitution of dry syrups or also in suspensions.
  • US Patent 5,405,617 discloses a solvent-less method for preparation of the taste-masked composition involving spray congealing of molten stearyl stearate and admixing an active pharmaceutical therewith.
  • US Patent .4,865,851 discloses a method for taste masking highly bitter 1 acetoxy ethyl ester of cefuroxime in particulate form, by coating with an integral coating of lipid or a mixture of lipids to mask the taste. Coated particles are incorporated in aqueous suspensions. The lipids used are insoluble in water but are dispersed or dissolved in gastro-intestinal fluid.
  • the lipids used in the composition for taste masking are in the range of 95-10% and cefuroxime axetil is in the range of 5-90%.
  • the preferred range of lipid is 90-70% and cefuroxime axetil is 10- 30%.
  • the examples disclosed in the patent show a drug to lipid ratio of 1 : 4 and above.
  • Robson et al. H. J. Robson, D. Q. M. Craig, D. Deutsch, International Journal of Pharmaceutics, 190, 1999, 183-192 have studied the dissolution of stearic acid coated cefuroxime axetil microspheres in distilled water and Sorensen modified buffer pH 5.9, 7 and pH 8.
  • 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.
  • formulations of drugs like cefuroxime axetil should be such that they release the drug in the upper gastric region rather than at the intestinal pH.
  • 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 composition has a high polymer consisting of polyvinylacetal diethylaminoacetate, aminoalkylmethacrylate copolymer Eudragit E soluble in the stomach and a monoglyceride: glyceryl monostearate used for taste masking.
  • Such coating compositions would be of use for drugs such as cefuroxime axetil, which are better absorbed from the upper gastric region.
  • cefuroxime axetil shows negative interaction with a polymer based on aminoalkylmethacrylate copolymer like Eudragit E. Alonso et al (M.J.Alonso, M.L.Lorenzo-Lamosa, M.Cuna, J.L.
  • the lipid medicament mixture is agitated continuously at a temperature at which the wax like material melts and the medicament powder sinks into the molten surfaces of the waxy material. Coated granules were obtained by cooling molten mass followed by sizing.
  • Wax like materials disclosed include glyceryl monostearate, hydrogenated fat and waxy aliphatic alcohol.
  • US Patent 6,589,955 discloses a taste masked pediatric formulation of gatifloxacin. The taste masked co-precipitate of gatifloxacin is formed with fatty acids like stearic acid or palmitic acid, the ratio of gatifloxacin to fatty acid being in a range of 1:1.8 to 1:2.3. The preferred ratio is 1:2.1.
  • US Patent 6,156,339 discloses a process for preparation of a taste masked, solid oral rapidly disintegrating dosage form comprising water dispersible carrier, filler, pharmaceutical active and a lipid such that the pharmaceutical active is in association with the lipid.
  • Weight ratio of pharmaceutically active substance to lipid is in the range of 1:1 to 1 :10.
  • Japanese Patent Application 2002138034 discloses a chewable tablet containing a bitter anitihistaminic drug, Chlorpheniramine maleate and fatty acid viz; stearic acid to mask the taste.
  • the composition contains fatty acid in the range of 0.5 pts. wt. to less than 3 pts. wt. of fatty acid per 1 pt. wt. of the drug.
  • a chewable tablet with a medicament coated by lipid material is disclosed in French Patent 2784895.
  • Lipid materials melting in a range of 37-75°C are used.
  • the patent discloses 10 %, preferably 2-5 % of lipid being used for coating of the drug.
  • the lipid materials used in formulations like the crunchable / chewable tablets or granules for taste masking applications lead to the rapid release of the drug on fracturing of the lipid coat during the mastication, however this would lead to the perception of bitter taste.
  • US Patent 6,485,742 discloses coating of hydrophilic core material comprising vitamins, by drop wise addition of the molten lipid on a fluidized core material such that the molten lipid solidifies and forms a coat on the core material.
  • Coating by lipid material masks the unpleasant flavor of the vitamin.
  • the coating material is used in the range of 0.1 to 30 % w/w of the total coated material.
  • PCT International Application WO 00/61119 discloses a process for microencapsulation of a medicament by mixing the medicament with a coating agent, which is melted and kept under stirring. The melted material is cooled under stirring to yield the microcapsules.
  • US Patent 4,837,381 discloses a slow release microsphere preparation of a wax or fat containing the biologically active protein or peptide.
  • the invention discloses the use of 30- 95% w/w of the fat or wax and 2-70 % of the protein or peptide in the microsphere preparation.
  • Microspheres prepared by thermoforming of compositions containing pharmaceutical active in a range of 5-90%, 10-90 % of glyceryl monostearate, and 2-15 % of polyethylene glycol and glyceryl palmitostearate, are disclosed in the US Patent 6,1174,52.
  • Japanese Patent Application 2001288117 discloses taste masking of oral preparation of drug rebamipide with fatty acid glycerol esters optionally with easily water-soluble substances. Water soluble or swelling substances are used to enhance release of the drug from lipid matrix. The use of water-soluble substances along with lipids limits their use in liquid oral preparation.
  • Pharmaceutical compositions with improved taste are disclosed in PCT International Application WO 00/06122.
  • the drug is dispersed in fatty acid ester of glycerol base, 1.5 to 15 parts by weight based on 1 part of the drug.
  • the fatty acid coated drug particles are further coated by water-soluble, water-insoluble or gastric soluble or an enteric polymer.
  • a substantially tasteless pharmaceutical delivery system is disclosed in EP 0670716.
  • the delivery system comprises an active ingredient, a matrix of wax core material having a melting point in the range 50-200 0 C and a hydrophobic polymer.
  • the amount of hydrophobic material present in the delivery system is 3-10 % by weight of the matrix and the amount of the wax core present in the matrix is 15-85 % by weight of the matrix.
  • Grains for oral administration obtained by spray solidification, which provide excellent taste- masking of bitter drugs, are disclosed in PCT International Application WO 00/18372.
  • the grains contain a drug with unpleasant taste and a lipid carrier having melting point of 40 to 120°C along with a polymer used to mask the unpleasant taste.
  • the polymer used ' in combination with the lipid is either an enteric polymer or a gastric polymer.
  • PCT International Application WO 03/059349 discloses oral fast dispersing dosage form comprising microparticles for enhancing the bioavailability.
  • the microparticles contain the drug: Zolpidem, fatty acids as spheronization aids like monoglycerides solubility enhancer like macrogol and the polymer coat to taste mask the product.
  • US Patent Application 2004091536 discloses granules for dry reconstitutable telithromycin suspension comprising of the core of telithromycin and waxy material coated in succession by lipid and polymer coating twice and another coat containing optionally a lipid with the polymer.
  • Matrices containing the bitter drug clarithromycin, glycerol fatty acid ester or stearyl alcohol and polymer selected from hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S are disclosed in PCT International Application WO 01 /91761.
  • the matrices provide oral formulations free of the bitter taste of clarithromycin.
  • Lipids are associated with properties like water repellency, non-toxicity and freedom from objectionable odor and color and they impart a smooth texture to the compositions. These properties make the lipids are good candidates for the taste masking applications.
  • fatty acids do exhibit good film forming hence integral coatings with lipids alone need larger amount of lipids since the medicament has to be dispersed completely in the lipid matrix.
  • the techniques like the melt granulation and spray congealing also need large amount of the molten lipids since the drug is required to be dispersed within the lipid matrix.
  • Lipids are hydrophobic in nature and so the release of the medicament is greatly impaired when lipids are used in higher amounts. Many formulations disclosed above employ polymers in combination with the lipids to accelerate the release of the drug.
  • One object of the invention is to use a blend of pH dependent polymers with lipids, either alone or a blend of lipids.
  • Another object of the invention is to provide a taste masking formulation comprising a blend of a lipid(s) in combination with an acid soluble or swellable polymer, which enables delivery of substantial amount of drug immediately, while ensuring improved palatability.
  • Another object of the invention is to provide a pharmaceutical formulation wherein the drug is dissolved in the stomach, essentially by using a specially synthesized pH sensitive polymer, which solubilizes or swells at acidic pH of the stomach but is insoluble at near neutral or neutral pH.
  • Another object of the invention is to provide a lipid-polymer matrix to coat a drug so that the amount of polymer required is lowered since it is used in combination with lipids, and the amount of lipid is also lowered due to the lipid-polymer matrix synergy which inhibits the bitter taste of the drug.
  • Another object of the invention is to use a lipid-polymer solution to coat a drug in order to lower the amount of lipid required, in comparison to the amount required for dispersion of drug in molten lipid for spray congealing or melt granulation.
  • Another object of the invention is to develop compositions, which can be used for taste masking of bitter drugs in various dosage forms, while enabling rapid release of the drug on ingestion and thus not altering the availability of the drugs.
  • Yet another object of the invention is to develop taste masked particles which can be used in liquid orals like suspensions, dry syrups, and solid dosage form like chewable tablets, fast dispersible tablets and conventional tablets.
  • the present invention provides a pharmaceutical composition
  • the pH dependent polymer is selected from the group consisting of an acid soluble polymer or an acid swellable polymer, comprising of monomer methyl methacrylate, hydroxy ethyl methacrylate and vinyl pyridine in the range of
  • the lipid component is selected from fatty acids, esters of fatty acid, fatty alcohols, hydrocarbons, neutral fats and waxes.
  • the fatty acid is selected from the group of saturated or unsaturated fatty acid.
  • the saturated fatty acid comprises long chain aliphatic carboxylic acids such as lauric acid, stearic acid and palmitic acid.
  • the fatty alcohol comprises long chain aliphatic alcohols such as stearyl alcohol, palmityl alcohol and cetyl alcohol.
  • the esters of fatty acids comprises esters of glycerol with fatty acids such as glyceryl monostearate, glyceryl monopalmitate, glyceryl tripalmitate, glyceryl behenate and hydrogenated castor oil.
  • the lipid component is used as a single lipid or a blend of lipids.
  • the composition has a ratio of pH dependent polymer to lipid in the range of 1:0.5 to 1:40, preferably 1:1 to 1:35.
  • the composition has a ratio of drug to lipid in the range of 1 :0.1 to 1 : 8, preferably 1 :0.4 to 1 :6. In another embodiment of the invention, the composition has a ratio of drug to pH dependent polymer in the range of 1:0.1 to 1:1, preferably 1:0.1 to 1:0.6.
  • the drug is used as such or in the form of a pharmaceutically acceptable salt or ester or amide thereof.
  • the drug is selected from the group of macrolide antibiotics like erythromycin, azithromycin and clarithromycin, fluroquinolones like ciprofloxacin, enrofloxacin, ofloxacin, gatifloxacin, levofloxacin and norfloxacin; cephalosporins consisting of cefuroxime, cefaclor, cephalexin, cephadroxil, cepfodoxime proxetil, nonsteoroidal, and anti-inflammatory and analgesic drugs like of ibuprofen, aspirin, acetaminophen and diclofenac sodium; and COX 2 inhibitors like etoricoxib and celecoxib; antihistamic drugs like cimetidine, ranitidine, famotidine chlorpheniramine maleate, oxazolidinones like linezolid and other drugs like dextromethorphan.
  • macrolide antibiotics like erythromycin, azithromycin and
  • the composition does not release drug at pH of saliva but rapidly releases substantial amount of the drug at pH ⁇ 3 as found in the stomach.
  • the composition is in the form of particles, with the drug dispersed within a polymer lipid matrix as such or is in a pharmaceutically acceptable dosage form.
  • the pharmaceutical composition is in the form of a liquid oral such as dry syrup or suspension.
  • the pharmaceutical composition is in the form of a solid dosage form like chewable, effervescent, rapidly disintegrating or dispersible. tablets.
  • the process comprises microencapsulation using emulsification solvent evaporation method by dissolving the polymer and lipid in an organic solvent selected from chloroform and dichloromethane to form a lipid-polymer solution, and adding the drug to the solution to form an organic phase, dispersing the organic phase in distilled water containing polyvinyl alcohol in an amount of 0.1 to 1 % w/w, continuously stirring the mixture mechanically at a rate of about 500-1000 rpm and at a temperature in the range of 25-30 0 C for a period in the range of 2-3 hrs and then separating microparticles obtained by filtration and freeze drying the particles for 5-10 hrs.
  • an organic solvent selected from chloroform and dichloromethane
  • the process comprises sizing slabs cast from a solution of the polymer and lipid in dichloromethane or chloroform containing the drug in solution or dispersed form and removal of the solvent by evaporation at 25-30 0 C.
  • the polymer and the drug are dispersed in molten lipid kept at temperature 3 -5 0 C above the melting point under stirring to obtain a molten mass, which is then gradually cooled to obtain granules, which are then sized.
  • the process comprises spray drying the lipid-polymer solution containing the drug to obtain microparticles, which are then dried in the presence of a drying gas selected from the group of nitrogen, argon, carbon dioxide and air.
  • a drying gas selected from the group of nitrogen, argon, carbon dioxide and air.
  • the present invention provides oral pharmaceutical compositions, which effectively inhibit the bitter, unpleasant and otherwise undesirable taste of the active ingredient. More specifically the invention relates to the use of the lipid - polymer blend, which mask the bitter taste of the drugs and also release a substantial amount of drug upon administration without delay at the gastric pH.
  • the composition disclosed in the present application comprises essentially of the acid soluble or swellable polymer in combination with the lipids.
  • the present invention discloses the use of lipid or blend of lipids in combination with the pH dependent polymers such that the pH dependent polymer is acid soluble or swellable.
  • the composition and method of preparation of the polymer is disclosed in our patent co-pending applications PCT/IN03/00390 and PCT/IN03/00392 filed earlier.
  • Taste masked compositions making use of the synthetic acid soluble polymers and their applications in various pharmaceutical compositions providing substantial immediate release without causing any delay in the absorption of the active ingredient are disclosed in patent applications PCT/IN03/00390 and PCT/IN03/00392.
  • these polymers are effective in taste masking of the drugs to be used in the oral dosage forms like the liquid orals and the solid dosage forms like the chewable, dispersible, rapidly disintegrating tablets.
  • the advantage of these polymers is that they are insoluble at the near neutral pH and are soluble at the acidic pH so that the release of the drug in the stomach is not affected.
  • the amount of polymer required for imparting palatability will vary. Further the dose of the active ingredient will also affect the performance of the polymer coating. In some cases where the dose is higher, the amount of polymer required to provide effective coating may be more. Liquid dosage forms like dry syrups and suspensions require a more uniform and complete polymer coating to impart taste masking effect and polymer requirement is higher as compared to conventional solid dosage forms.
  • US Patent Application No. 10/971,534 discloses the use of the polymer blends comprising the acid soluble polymer in combination with other pH dependent polymer or pH independent polymers for the taste masking applications.
  • the blend of polymers is used to lower the amount of the each polymer in blend such that it is well within the safe daily allowance as prescribed by the FDA and yet the total amount of the polymer in composition is high enough to provide the taste masking effect.
  • the preferred ratio of total amount of the polymer to drug is 0.5:1 to 4:1.
  • the amount of polymer coating disclosed is essential to prevent the leaching of the drug in the saliva or the aqueous media used to reconstitute the coated granules.
  • Such compositions are of use for the drugs having a wide absorption window along the gastrointestinal tract and also for the immediate release of the drug without delay.
  • the present invention differs from the earlier art in that it further reduces the amount of polymer used for masking unpleasant taste.
  • the present invention discloses use of a lipid-polymer matrix for taste masking applications, which reduces the amount of polymer as well as lipid required.
  • the drug to polymer ratio is in the range of 1:0.1 to 1:1.
  • the compositions of the invention bring about almost immediate and rapid release of the drug. Such compositions with rapid immediate release are of use where the drug is required to be absorbed rapidly to elicit an early therapeutic effect.
  • the compositions also enhance bioavailability of a drug with narrow absorption window restricted to the upper gastric region.
  • the acid soluble or swellable polymer used in the composition comprises of monomers methyl methacrylate, hydroxy ethyl methacrylate and vinyl pyridine in the range 50-75 %, 15-35% and 5-15% w/w respectively.
  • the protective coating has to be sufficiently hydrophobic. Lipids are hydrophobic materials and are hence used extensively in such applications. However because of their hydrophobic nature the release of the drug is delayed. Further the amount of the lipids required to provide the bitterness inhibition is very high. The use of higher loading of the lipids further lowers the rate of release. This affects the bioavailability of the drugs especially in case of the drugs, which have a narrow absorption window, limited to upper gastric region.
  • the present invention discloses lipid or lipids used in combination with acid soluble or swellable polymer, which dissolves rapidly at gastric pH and facilitates quick dissolution of a drug. Incorporation of the acid soluble/swellable polymer in composition ensures immediate release of drug from the lipid-polymer matrix.
  • the pH dependent polymer of the present invention does not dissolve at pH of saliva and prevents leaching of the drug in the oral cavity.
  • Lipids used in the composition of the invention are fatty acids, esters of fatty acid, fatty alcohols, hydrocarbons, neutral fats and waxes. Lipids that are suitable for use in the composition of the invention in general have melting points higher than 40 °C. The fatty acids are either saturated or unsaturated.
  • the saturated fatty acids used in the composition are long chain (ClO- C24) aliphatic carboxylic acids like lauric acid, stearic acid and palmitic acid.
  • the lipids used comprise fatty alcohol such as stearyl alcohol, palmityl alcohol and cetyl alcohol preferably cetyl alcohol.
  • the esters of fatty acids used comprise esters of glycerol with fatty acids such as glyceryl monostearate, glyceryl monopalmitate, glyceryl tripalmitate, glyceryl behenate and hydrogenated castor oil, preferably glyceryl monostearate and hydrogenated castor oil.
  • Another feature of the invention is the use of blend of the lipids in combination with the acid soluble or swellable polymer.
  • the ratio of pH dependent polymer to lipid in the composition is in the range 1:0.5 to 1:40 preferably 1:1 to 1:35.
  • the ratio of drug to lipid is in the range 1:0.1 to 1: 8, preferably 1: 0.4 to 1:6.
  • the drug and pH dependent polymer ratio is in the range of from 1:0.1 to 1:1 preferably 1:0.1 to 1: 0.6.
  • compositions can also be made by microencapsulation of the drug in the lipid- polymer matrix.
  • the microencapsulation of the drugs is achieved by emulsification, solvent evaporation or solvent extraction or spray drying of the drug with lipid- polymer solution or dispersion of drug in lipid-polymer solution, preferably microencapsulation by solvent evaporation and spray drying technique.
  • the preferred surfactant is polyvinyl alcohol for microencapsulation by solvent evaporation.
  • the solvent is selected such that the drug, lipid and the polymer are all soluble in the solvent.
  • the pharmaceutical composition is obtained by dispersing the drug in lipid-polymer matrix either by microencapsulation by solvent evaporation, spray drying, spray congealing, melt granulation or by tray drying method.
  • the solvents chosen for the solubilization of the drug, lipid and polymer are chlorinated hydrocarbons like dichloromethane and chloroform.
  • the taste-masked microparticles of the drug can be obtained by microencapsulation by emulsification solvent evaporation technique.
  • the dispersed phase is the organic solvent containing the drug dispersed or dissolved in lipid-polymer solution and the dispersion medium is the distilled water. The lipid and polymer is dissolved in the organic solvent.
  • the drug is added to this solution and the organic phase is then added into distilled water- containing polyvinyl alcohol (0.1 to 1 % w/w).
  • a constant mechanical stirring rate of 500 - 1000 rpm and at room temperature is maintained for 2-3 hours.
  • the solvent is allowed to evaporate and the microparticles so obtained are separated by filtration and freeze dried for 5- 10 hrs.
  • particles of the composition can be obtained by spray drying.
  • Lipid and polymer are dissolved in an organic solvent.
  • the drug is either dissolved or dispersed in this solution and spray dried to obtain taste masked micro particles.
  • the drying gas can be an inert gas such as nitrogen, argon and carbon dioxide or air.
  • the preferred gas 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 35-9O 0 C, preferably 35-75°C.
  • the gas outlet temperature is similarly dependent on the solvent but may be in the range of 25-75 0 C, preferably 25-55 0 C.
  • the lipid and polymer are solubilized in dichloromethane or chloroform and the drug is either solubilized or dispersed in the lipid- polymer solution.
  • the resulting mixture is spray dried to obtain the micro particles.
  • the taste masked particles of the present invention can also be obtained by casting of slabs in the tray.
  • the lipid and polymer are dissolved in the organic solvent and the drug is either dispersed or solubilized in lipid-polymer solution.
  • the resulting solution is poured on the tray to cast the slab.
  • the solvent is allowed to evaporate at 25-30 0 C for 2-3 hrs and the residual solvent is removed by drying the slabs at 25-30 0 C under vacuum for 24 hrs.
  • the dried material is sized and passed through 40mesh sieve. Lipids do not form good films hence integral coatings with lipids alone need larger amount of lipids to disperse the medicament completely in the lipid matrix.
  • the techniques like the melt granulation and spray congealing also need large amount of the molten lipids since the drug is required to be dispersed within the lipid matrix.
  • the large amount of the lipid required to disperse the drug during melt granulation is evident from the amount of the lipid required in example 5 and example 9, in comparison to the amount of lipid used in other examples disclosed herein.
  • Another feature of the present invention is to use the lipid polymer solution in a solvent to disperse the drug in the lipid polymer matrix such that the amount of the lipid required in the compositions is reduced.
  • the taste masked particles of the invention can also be obtained by melt granulation.
  • the lipid is placed in the jacketed vessel attached to circulating water bath.
  • the temperature of the circulating water is set, such that the lipid is maintained at 3-5°C above the melting point.
  • the polymer is dispersed in the molten lipid under stirring followed by the addition of the drug.
  • the temperature of circulating water is gradually lowered to cool the molten lipid.
  • the solid mass thus obtained is sized and passed thorough 40-mesh sieve.
  • compositions containing higher loadings of lipids as exemplified in example 5 and 9 are slower in comparison to the other compositions employing lower amounts of lipids in combination with the polymer.
  • the taste masked particles and granules obtained in the present invention may be mixed with 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, chewable or dispersible tablets, dry syrups, suspensions, sachets or any other suitable oral dosage form.
  • 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, chewable or dispersible tablets, dry syrups, suspensions, sachets or any other suitable oral dosage form.
  • the taste masked particles and granules obtained in the present invention may comprise of the blend of acid soluble or swellable polymer and lipid and can be suspended using the reconstitution medium of pH > 3.5.
  • This disclosure also compares release of a drug from a dry syrup product containing cefuroxime axetil particles having integral stearic acid coating (commercially available as Ceftum manufactured by Glaxo Wellcome Operations, Harmire Road, Barnard Castle County Durham, DL 12 8DT, UK, Marketed by Glaxo India Limited) with compositions of the present invention.
  • Cefuroxime axetil is better absorbed from upper gastric region as compared to intestinal region.
  • Dantzig et al Anne H. Dantzig, Dale C. Duckworth, Linda B.
  • Cefuroxime axetil release was determined in buffer media comprising 900 ml of 0.07 N hydrochloric acid, using USP type II apparatus rotated at 100 rpm at 37 ⁇ 0.5 0 C.
  • Samples were withdrawn at 30, 60,120, 180 and 240 min. The amount withdrawn each time was replaced with fresh media to maintain the sink conditions. The amount of drug released is 40 % in 30 min, 50 % in 60 min, 64.6 % in 120 min, 69.5% in 180 min and 77.17 % in 240 min.
  • Examples 1 and 2 disclose a method of preparing acid soluble / swellable polymer.
  • the taste masked pharmaceutical compositions as exemplified in the examples 3 to 9, given below were tested for drug release with respect to time.
  • the sample was wetted in the dissolution media removed from 900 ml of media prior to the dissolution and then placed in dissolution vessel again.
  • the glass beaker used for wetting the sample was rinsed with the dissolution media removed in excess prior to dissolution and again placed in the dissolution vessel.
  • Cefuroxime axetil release from the taste masked particles was determined in 900 ml of 0.07 N hydrochloric acid maintained at 37 + 0.5 0 C, using USP type II apparatus rotated at 100 rpm.
  • the samples were withdrawn at 30, 60,120, 180 and 240 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 0.01 N hydrochloric acid buffer, at 37 ⁇ 0.5 0 C, using USP type II apparatus rotated at 100 rpm. Samples were withdrawn at 30, 60, 120, 180 and 240 min. The amount withdrawn each time was replaced with fresh media to maintain sink conditions.
  • the pharmaceutical compositions of the invention mask the bitter taste of drugs and do not release the drug at pH of saliva but release the drug with no delay at pH of stomach and are not soluble in water.
  • Example 1 The taste making compositions and the properties thereof are described herein below with reference to the following illustrative and non-limiting examples.
  • Example 1 The taste making compositions and the properties thereof are described herein below with reference to the following illustrative and non-limiting examples.
  • Acid soluble or swellable polymer was synthesized by solution polymerization.
  • a hydrophobic monomer, basic monomer and optionally a hydrophilic monomer were dissolved in dimethyl formamide solvent.
  • the polymer has a monomer composition Methyl methacrylate 65% by wt Hydroxyethyl methacrylate 24% by wt and Vinyl Pyridine 11% by wt.
  • An azo initiator, azo bis isobutyronitrile was added to the monomer solution in dimethyl formamide. Reaction mixture was purged with nitrogen gas to provide inert atmosphere. Polymerization reaction was carried out by heating the reaction mixture to 65°C for a period of 18 hours.
  • the polymer so synthesized was recovered by precipitation, in a nonsolvent (here water), and was dried at 45°C under vacuum.
  • Molecular weight of polymer synthesized was determined using Waters gel permeation chromatography and polystyrene standard (Polysciences Inc. USA) as reference using Styragel columns. The molecular weight of the polymer is 53,000.
  • Acid soluble or swellable polymer was synthesized by solution polymerization.
  • a hydrophobic monomer, basic monomer and optionally a hydrophilic monomer were dissolved in dimethyl formamide solvent.
  • the polymer has a monomer composition Methyl methacrylate 73% by wt Hydroxyethyl methacrylate 18% by wt and Vinyl Pyridine 9% by wt.
  • Azo initiator, azo bis isobutyronitrile was added to monomer solution in dimethyl formamide. Reaction mixture was purged with nitrogen gas to provide inert atmosphere. The polymerization reaction was carried out by heating reaction mixture to 65°C for a period of
  • the molecular weight of the polymer is 52,000.
  • compositions containing various lipid-polymer blends are shown in Table 1.
  • the acid soluble polymer prepared in example 1 is used in all compositions as one of the pH dependent polymers.
  • Amount of solvent used is 7 ml of chlorinated hydrocarbons like chloroform and dichloromethane.
  • Amount of lipid and polymer are shown in table 1
  • the taste masked microparticles were obtained by emulsification solvent evaporation technique.
  • Cefuroxime axetil was dissolved in lipid-polymer solution made with requisite amount of solvent.
  • the lipid-polymer solution containing the drug was added dropwise to distilled water bath under mechanical stirring.
  • Polyvinyl alcohol was added to the distilled water 0.1 % by weight, to facilitate the dispersion of the lipid-polymer solution containing the drug.
  • a constant mechanical stirring rate of 500 rpm and at room temperature was maintained for a 3-4 hours.
  • the solvent was allowed to evaporate and the microparticles so obtained were separated by filtration, and freeze dried for 7 hrs.
  • the drug release pattern of the composition prepared was monitored and the results are tabulated in Table 2
  • Taste masked compositions are made by casting slabs of lipid- polymer containing the drug.
  • the lipid- polymer solution in organic solvent is cast in a tray containing the drug in a solution form or in a dispersed form.
  • Solvent is allowed to evaporate and particles are obtained by sizing the mass through 40 mesh sieve.
  • Lipid-Polymer solution Compositions containing various lipid-polymer blends are shown in Table 3. Acid soluble polymer prepared in example 1 is used in all coating compositions as one of the pH dependent polymers. Amount of solvent used is 7 ml of chlorinated hydrocarbons like chloroform and dichloromethane. Amount of lipid and polymer are also shown in Table 3
  • Taste masked particles are prepared by sizing the mass obtained by casting of lipid — polymer slab containing drug in dispersed form. Ciprofloxacin hydrochloride was added to lipid-polymer solution in chloroform made with requisite amount of solvent. Lipid-polymer solution containing the drug was poured in a tray to cast the slab. Solvent was allowed to evaporate at 25°C for 2-3 hrs. Residual solvent was removed by placing the composition in vacuum at 25 0 C for 24 hrs. Drug release pattern of the composition prepared was monitored and results are tabulated in Table 4.
  • Example 5 Taste masked particles are obtained by melt granulation method. Lipid is placed in a jacketed vessel attached to a circulating water bath. Temperature of circulating water is set such that lipid is maintained at 3-5°C above melting point thereof. Acid soluble polymer prepared in example 2 is used in the compositions. The polymer is dispersed in molten lipid under stirring followed by addition of Ciprofloxacin Hydrochloride. Temperature of circulating water is gradually lowered to cool the molten lipid. The solid mass thus obtained is sized by passing thorough 40mesh sieve. The compositions containing various lipid- polymer blends are shown in Table 5. Drug release pattern of the composition prepared was monitored and results are tabulated in Table 6.
  • the taste masked microparticles are obtained by spray drying.
  • the lipid and polymer are dissolved in an organic solvent, the drug is either dissolved or dispersed in this solution and 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 is in the range 35-75° C.
  • the gas outlet temperature is in the range of 35-55 °C.
  • Lipid and polymer are solubilized in chloroform and cefuroxime axetil is solubilized in the lipid- polymer solution.
  • the acid soluble polymer prepared in example 1 is used in composition.
  • the resulting mixture is spray dried to obtain the micro particles.
  • the compositions containing various lipid-polymer blends are shown in the table 7. Drug release pattern of the compositions prepared was monitored and results are tabulated in Table 8. Table 7
  • the taste masked particles are obtained by the melt granulation method.
  • the lipid is placed in the jacketed vessel attached to circulating water bath.
  • the temperature of the circulating water is set such that the lipid is maintained at 3- 5°C above the melting point of, the lipid.
  • the acid soluble polymer prepared in example 2 is used in the compositions.
  • the polymer is dispersed in the molten lipid under stirring followed by addition of Cefuroxime axetil.
  • the temperature of the circulating water is gradually lowered to cool the molten lipid.
  • the solid mass thus obtained is sized by passing thorough 40-mesh sieve.
  • the compositions containing the various lipid-polymer blends are shown in the table 9.
  • the drug release pattern of the composition prepared was monitored and the results are tabulated in Table 10 Table 9
  • compositions described herein comprise reverse enteric or acid soluble polymer in combination with the lipid or blend of lipids, which facilitates the rapid release of the drug in the gastric pH and the total amount of the polymer required with respect to the drug in the compositions is lowered.
  • the fatty acids are known for the taste masking applications however for complete coating of drug large amounts are required and since they are hydrophobic, the drug release is delayed.
  • the present invention discloses the use of the pH dependent polymer, which remains collapsed at the pH of saliva and hence acts synergistically for the taste inhibition. However the polymer solubilizes at the gastric pH and releases substantial amount of the drug without any delay.
  • the present invention discloses the use of the acid soluble polymer along with the lipids wherein the polymer remains collapsed in water and also in pH > 3.5. These preparations have the advantage over the compositions using the blends of water soluble polymers and lipids the later formulations are not suitable for the liquid oral preparations.
  • the use of the acid soluble polymer together with the fatty acid helps in achieving the taste masking at lower loading of the fatty acids and the polymer.
  • the use of lipid polymer solution to disperse the drug in the lipid-polymer matrix further lowers the amount of lipid required in the compositions to taste mask the bitter drug.
  • compositions aids in releasing the drug in the acidic pH of the stomach without delay and further the polymer does not release the drug at pH of saliva. Such compositions would therefore provide immediate and also near complete release of the drug unlike the compositions using the lipids in combination with the pH independent polymers and enteric polymers.
  • the acid soluble polymer used in the present inventions does not exhibit any negative interaction with the drug cefuroxime axetil as is exhibited by the reverse enteric coating materials comprising dimethyl aminoethyl methacrylate like Eudragit E.
  • the compositions of present invention comprising the lipid-polymer matrix are suitable for the drugs, which exhibit negative interactions with Eudragit E.
  • Eudragit E exhibits swelling upto pH 5.5.
  • compositions using the acid soluble polymer in the present compositions release - the drug rapidly in comparison to the amount released from the marketed composition Ceftum based on the integral lipid coating of the drug by stearic acid alone. This is advantageous in case of the bitter drug cefuroxime axetil as it is better absorbed from the upper gastric region.

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Abstract

La présente invention concerne des compositions comprenant une matrice de polymères lipidiques visant à masquer le goût amer ou désagréable du médicament. Le lipide ou mélange de lipides est/sont utilisé(s) en association avec le polymère sensible au pH, lequel est acido-soluble ou gonflable. Cette invention décrit le procédé de préparation de compositions pharmaceutiques de médicaments amers au goût masqué, qui comprend lesdites compositions de polymères lipidiques. L’utilisation concomitante du polymère acido-soluble, dont le pH reste très faible, au niveau de celui de la salive, inhibe la libération du médicament à ce pH et contribue ainsi à inhiber l’amertume. Lesdites compositions délivrent immédiatement une quantité importante du médicament amer au pH gastrique, la sapidité étant accrue.
PCT/IN2004/000379 2004-12-10 2004-12-10 Composition pharmaceutique visant a ameliorer la sapidite de medicaments et procede de preparation de ladite composition WO2006061846A1 (fr)

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NZ551113A NZ551113A (en) 2004-12-10 2004-12-10 Pharmaceutical composition for improving palatability of drugs by dispersing drug in lipid-polymer matrix, and process for preparation thereof
CNB2004800430930A CN100548270C (zh) 2004-12-10 2004-12-10 改善药物适口性的药用组合物及其制备方法
BRPI0419125-0A BRPI0419125A (pt) 2004-12-10 2004-12-10 composição farmacêutica e processo para a preparação de uma composição farmacêutica
EP04806762A EP1845937A1 (fr) 2004-12-10 2004-12-10 Composition pharmaceutique visant a ameliorer la sapidite de medicaments et procede de preparation de ladite composition
JP2007522124A JP4629730B2 (ja) 2004-12-10 2004-12-10 薬物ののみ易さを改善するための医薬組成物及びその調製方法
AU2004325469A AU2004325469B2 (en) 2004-12-10 2004-12-10 Pharmaceutical composition for improving palatability of drugs and process for preparation thereof
PCT/IN2004/000379 WO2006061846A1 (fr) 2004-12-10 2004-12-10 Composition pharmaceutique visant a ameliorer la sapidite de medicaments et procede de preparation de ladite composition

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WO2014047001A1 (fr) * 2012-09-18 2014-03-27 Mcneil-Ppc, Inc. Particules de dérivés d'acide propionique à point de fusion bas, destinées à être utilisées dans des formes galéniques orales
US20190200659A1 (en) * 2016-08-03 2019-07-04 Temple University-Of The Commonwealth System Of Higher Education Microencapsulation of Active Agents

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CN101084881B (zh) * 2007-06-23 2012-08-29 淮北辉克药业有限公司 靶向速释泡腾制剂及其制备方法
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
CN106727337A (zh) * 2016-12-13 2017-05-31 河南后羿实业集团有限公司 一种恩诺沙星可溶性粉及其制备方法

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US6039979A (en) * 1999-01-13 2000-03-21 Laboratoires Prographarm Multiparticulate pharmaceutical form with programmed and pulsed release and process for its preparation
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FR2514261B1 (fr) * 1981-10-08 1986-08-22 Aec Chim Organ Biolog Nouvelle composition pour l'enrobage des aliments et des medicaments et granules ainsi enrobes
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US4865851A (en) * 1987-05-14 1989-09-12 Glaxo Group Limited Pharmaceutical composition comprising cefuroxime axetil
EP0781551A1 (fr) * 1995-12-29 1997-07-02 Advanced Polymer Systems, Inc. Formulations de rétinoides dans des microsphères poreuses à l'irritation réduite et stabilité améliorée
US20030220413A1 (en) * 1998-07-23 2003-11-27 Roehm Gmbh & Co. Kg Coating and binding agent for oral or dermal pharmaceutical forms
US6039979A (en) * 1999-01-13 2000-03-21 Laboratoires Prographarm Multiparticulate pharmaceutical form with programmed and pulsed release and process for its preparation

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WO2014047001A1 (fr) * 2012-09-18 2014-03-27 Mcneil-Ppc, Inc. Particules de dérivés d'acide propionique à point de fusion bas, destinées à être utilisées dans des formes galéniques orales
US20190200659A1 (en) * 2016-08-03 2019-07-04 Temple University-Of The Commonwealth System Of Higher Education Microencapsulation of Active Agents
US11896037B2 (en) * 2016-08-03 2024-02-13 Temple University-Of The Commonwealth System Of Higher Education Microencapsulation of active agents

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