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WO1994005260A1 - Compositions pharmaceutiques destinees a masquer le gout, et procedes de fabrication - Google Patents

Compositions pharmaceutiques destinees a masquer le gout, et procedes de fabrication Download PDF

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Publication number
WO1994005260A1
WO1994005260A1 PCT/US1992/007513 US9207513W WO9405260A1 WO 1994005260 A1 WO1994005260 A1 WO 1994005260A1 US 9207513 W US9207513 W US 9207513W WO 9405260 A1 WO9405260 A1 WO 9405260A1
Authority
WO
WIPO (PCT)
Prior art keywords
drug
mixture
lipid
composition
cimetidine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1992/007513
Other languages
English (en)
Inventor
Seang H. Yiv
Alex K. Tustian
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Affinity Biotech Inc
Original Assignee
Affinity Biotech Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Affinity Biotech Inc filed Critical Affinity Biotech Inc
Priority to PCT/US1992/007513 priority Critical patent/WO1994005260A1/fr
Priority to CA002143439A priority patent/CA2143439A1/fr
Priority to AU25840/92A priority patent/AU2584092A/en
Priority to EP92920050A priority patent/EP0663818A4/fr
Publication of WO1994005260A1 publication Critical patent/WO1994005260A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats

Definitions

  • This invention relates to techniques for taste- masking pharmaceutical drugs. More specifically, the invention relates to compositions comprising a drug having its taste masked by a lipid coating contained within an aqueous polymer system for oral administration which provides an improved taste for the drug.
  • a more recent and convenient means of preparing these drugs is in a granule lipid format which avoids the storing of the drug in an aqueous solution which solution could destroy the lipid coating.
  • the granules are usually suspended in an aqueous solution immediately prior to oral administration and, in this manner, the drug is not dissolved in the mouth of the patient, but rather passes on to the gastro-intestinal tract where it is dissolved by stomach fluids.
  • Lipid coatings for masking the bitter taste of certain drugs have been beneficially employed as is shown in U.S. Patent No. 4,865,851 to James et al and U.S. Patent No. 4,764,375 to Paradissis.
  • these references describe processes which require producing granules of the lipid coated drug, which processes require special processing equipment to produce the granules.
  • the James et al. reference describes the use of providing a lipid coating onto cefuroxime axetil by use of a spray drying technique. Such a technique for coating the drug requires specific spray drying equipment and is relatively an expensive and intricate process.
  • the drug used in James necessitated an integral lipid coating and storage in the granule state because the drug would gel in an aqueous carrier solution.
  • the Paradissis reference describes the use of a lipid coating to coat potassium chloride.
  • the drug is stored in the granule state which requires assorted equipment to accomplish that process.
  • the potassium chloride is highly water soluble and therefore must be kept in the granule state because the drug and integral lipid taste-masking coating break down within minutes in an aqueous state.
  • a method of producing a stable drug composition which masks the flavor of a drug in need of flavor masking is provided which is broadly defined by the following steps.
  • a drug in particulate form is mixed with a lipid at a temperature below that where significant drug degradation occurs, preferably below about 50°C.
  • an emulsifier, a polymer solution, and a dilution solution is added to form the stable taste-masked drug composition.
  • the method proceeds as follows. A mixture of a lipid and an emulsifier are heated until that mixture is brought into a molten state. The lipid and emulsifier mixture temperature is then adjusted to a temperature below that where significant drug degradation occurs, preferably below about 50 ⁇ C. To this cooled mixture is then admixed the drug, in particulate form, which thereby forms a flavor masked drug/lipid dispersion. To this drug dispersion is supplied a polymer solution to form a concentrated drug composition. Finally, a dilution solution, preferably comprising a sweetening agent, is added to form the final drug composition.
  • a dilution solution preferably comprising a sweetening agent
  • the drug is selected from the group consisting of cimetidine, ranitidine, ibuprofen, acetaminophen, and erythromycin.
  • the method of the present invention provides a stable dispersion of the drug, in a flavor masked state, which dispersion has an extended shelf life of several months.
  • the drug to lipid weight ratio ranges from about 1:0.25 to about 1:2.
  • the drug is preferably added in amount up to about 800 milligrams per 10 milliliters (10 cc) of the drug composition.
  • the polymer is supplied as a polymer solution which contains the polymer in an aqueous solution and preferably contains carboxymethylcellulose and xanthan gum.
  • the invention also provides for the drug compositions produced by the inventive methods. Detailed Description of the Invention
  • the present invention broadly relates to a novel and economical method of preparing a stable pharmaceutical composition which contains a drug, which is characterized by having an unpleasant taste, wherein the drug is provided in a flavor masked form in a dispersion system.
  • the invention provides for the effective flavor masked encapsulation of the drug in a lipid material and for the suspension of this drug/lipid component in an aqueous phase with the aid of emulsifiers and suspending agents.
  • the drug composition produced also contains an aqueous phase comprising a polymer system and additive agents such as sweeteners and flavor enhancers.
  • the final drug composition is a dispersion which is believed to be stable indefinitely.
  • the drug composition is generally stored at a temperature range of from about 4°C to about 40°C, preferably at about 15°-25°C, and most preferably at room temperature.
  • the methods by which the pharmaceutical compositions are produced are described as follows.
  • the drug which is in particulate form, is mixed by conventional methods with the lipid at a temperature below where degradation of the drug can significantly occur. This degradation is evidenced by a substantial inactivation of the drug and is readily determined.
  • the temperature is typically kept below about 50°C to avoid the degradation of the drug at higher temperatures for most drugs.
  • the lower temperature limit of the lipid is governed by the ability to thoroughly mix the drug in the lipid.
  • the lipid can be either a paste or a liquid and it is preferred that the lipid be in a liquid state to aid in the drug admixing.
  • An emulsifier, a polymer solution and a dilution solution are then mixed with the drug/lipid mixture to form a the final stable taste-masked drug composition.
  • This final drug composition contains the drug, partially coated with the lipid and effectively taste- masked by the lipid, suspended in the polymer solution. It is preferred that the emulsifier be thoroughly admixed first, followed by the addition of the polymer solution, and the final drug volume achieved by addition of the dilution solution. However, these three components can be admixed together with the drug/lipid mixture.
  • the final drug composition is in a form which can be administered to a patient orally.
  • the inventive method can also be carried out by a different method.
  • a mixture of a lipid and an emulsifier is heated and mixed by conventional methods until a molten homogenous state is reached.
  • the temperature of the molten lipid will be at least about 20°C above the melting point of the lipid and typically will be in the range of from about 50°C - 100"C.
  • the temperature of this lipid and emulsifier mixture is then adjusted to a temperature below where significant drug degradation can occur, typically below about 50 ⁇ C, in order to accept the drug without degrading the integrity of the drug.
  • a drug in need of taste masking, in particulate form, is added to the lipid and emulsifier mixture which can be in the form of a semi-solid paste or a liquid. Then, a polymer is admixed to this dispersion. Finally, a dilution solution, preferably an aqueous solution containing, for example, sweetening agents and/or flavoring agents and/or coloring agents is added to the mixture to produce the final drug composition.
  • the melting point of the lipid should be sufficiently high to prevent melting of the substantially coated particles during the short period of time they are contacted with the mouth. Such melting would release the unpleasant taste. There potentially is no upper limit to the melting point of the lipid.
  • the lipids will conveniently have a melting point of from about 30°C to about 95°C. It is preferred to select a lipid which allows for an effective amount of the drug to be released upon digestion, and most preferably to select a lipid which does not affect the bioavailability of the drug.
  • the lipids which can be employed in the practice of the present invention include triglycerides, for example a glycerol ester of a high molecular weight (C 10 .
  • the lipid may also, for example, be a high molecular weight straight chain (C 10 . 30 ) saturated or unsaturated aliphatic acid, hydrogenated and partially hydrogenated oils such as cotton seed oil, castrol oil, and coconut oil; waxes, for example, bees wax or carnauba wax; mixtures of high molecular weight fatty acids such as mixtures of stearic and palmitic acids, and mixtures of high molecular weight straight chain aliphatic alcohols.
  • a preferred lipid is a partially hydrogenated coconut oil sold by Karlshams Company under the trade name PURECO 92.
  • the emulsifiers, or surfactants, which are useful in the practice of the present invention maybe of the anionic or nonionic type.
  • the emulsifier of the present invention can be a mixture of several emulsifiers.
  • a mixture of an anionic and a nonionic emulsifier is preferred as the emulsifying agent.
  • emulsifiers include acids, for example, stearic acid, lauric acid, palmitic acid, etc. ; glyceryl behenate, and monooleates, such as sorbitan monooleate and polyoxyethylene sorbitan monooleate.
  • Preferred emulsifiers include anionic surfactant such as a diacetyl tartaric acid monoglyceride, for example, those sold under the trade name PANODAN 205 and SDK by the Grinsted Company.
  • a preferred nonionic surfactant is glycerol stearate, for example, LIPOGMS 470 manufactured by Lipo Chemical Company.
  • Drugs in need of taste masking are those drugs which have an unpleasant taste when orally administered and include cimetidine, ranitidine, ibuprofen, acetaminophen, erythromycin and the like. Cimetidine is conveniently preferred.
  • the method of the invention provides a highly convenient and economical method of taste-masking certain unpleasant tasting drugs.
  • the drug is believed to be substantially coated but not entirely coated by the lipid.
  • certain drugs such as cifuroxime axetil which tend to gel upon contact with an aqueous medium are not suitable for use in the invention.
  • the drug is supplied in particulate form, and preferably has a weight average particle size below about 300 microns, most preferably below about 200 microns in order to avoid a gritty taste upon consumption.
  • the drug preferably has a low water solubility and the pH of the composition can be adjusted to enhance this aspect of the invention.
  • the polymers which are useful in the present invention are added to keep the lipid encapsulated drug in suspension and for thickening and include cellulose derivatives such as sodium carboxymethylcellulose as well as xanthan gum.
  • cellulose derivatives such as sodium carboxymethylcellulose as well as xanthan gum.
  • sodium carboxymethylcellulose for use in the present invention is a low molecular weight AQUALON 7LF PH manufactured by the Aqualon Company. It is preferred to provide the polymer in an aqueous solution. It is also preferred to add a substance to aid in the dissolution of the polymer in the aqueous solution, such as glycerin.
  • the dilution solution is preferably an aqueous solution and functions to dilute the concentrated drug emulsion to an acceptable level for oral administration.
  • Various sweeteners, flavoring agents, and coloring agents can also be added to the dilution solution.
  • the dilution solution is a sugar solution in a concentrated form, for example, above about 50% by weight of sweetener.
  • the various sweeteners include sucrose, sodium cyclamate, sodium saccharinate, aspartame and ammonium glycyrrhizinate.
  • Typical flavoring agents include peppermint oil flavor and artificial pineapple flavor.
  • coloring agents include titanium dioxide pigments, lake colors and iron oxide pigments.
  • the pharmaceutical drug composition of the present invention can be formulated in any desired quantities.
  • a basis of 10 cc of the final stable taste-masked drug composition can be used to define weight and volume ratios.
  • Typical oral administration volumes range from about 5 cc to 15 cc.
  • the amount of the drug to be added to a 10 cc solution of the drug composition of the present invention is from about 100 to 800 milligrams of the drug.
  • the amount of lipid to be used can readily be determined. Typically, the amount of lipid ranges from 25-200% by weight of the amount of drug employed.
  • the ratio of drug to lipid is 1:1.
  • the maximum amount of lipid to be added to a 10 cc solution of the drug composition is about 800 milligrams.
  • the amount of emulsifier to be used in the present invention varies depending upon the type of emulsifier utilized. An effective amount of emulsifier is needed however to provide a drug composition which exhibits extended shelf life. In a preferred embodiment, the amount of emulsifier is generally from about 0.3-3% by weight of the drug composition.
  • the amount of polymer to be added to a 10 cc solution of the drug composition of the present invention generally ranges from about 30 milligrams to about 120 milligrams.
  • the dilution sweetening agent solution (containing also the flavoring and coloring agents) generally is added in an amount to bring the volume of the drug composition to the 10 cc quantity.
  • the method for producing the drug composition of the present invention comprises five broad steps. In the first step, the weighed amount of lipid and emulsifier are mixed together and heated into a molten solution up to about 20°C above the melting point of the lipid. It is preferred that the temperature of the molten solution be from about 85-95"C. The lipid and emulsifier are mixed until a homogenous liquid phase is formed.
  • the second step requires for the molten solution to be cooled. It is preferred that the solution be cooled to at least 50°C or below to avoid drug degradation, but such that the mixture remains a liquid or a semi-solid paste.
  • the weighed amount of the drug to be used is added to this cooled lipid phase.
  • the drug and lipid phase are mixed thoroughly using any appropriate mixing device. In this way, the drug particles are substantially coated with the lipid material whereby a flavor masking effect is obtained as at least a portion of the drug is contained within the lipid phase and has its flavor masked by the lipid phase.
  • the polymer is preferably added as polymer solution.
  • This polymer solution is an aqueous solution in which the polymer is dissolved. If a non-aqueous solution is chosen it is to be compatible with the lipid.
  • the polymer is present in the polymer solution in an amount of from about 6% to about 10% by weight.
  • This solution may also contain glycerin in an amount of about 20% by weight to aid in the dissolution of the polymer.
  • the polymer solution is thoroughly mixed into the drug/lipid phase by the aid of mechanical mixing devices.
  • a sweetening dilution mixture is slowly added to the drug composition to enhance the flavor of that composition.
  • this sweetening solution is added in a concentrated form and contains sweetening agents, flavoring agents, and coloring agents.
  • the sweetening solution is an aqueous base solution and is added to the drug composition until the final drug composition attains its desired volume.
  • sucrose solution 65%w/w sucrose, 0.05%w/v methyl parabens; 10.560g
  • a spearmint oil flavor 8.mg
  • a peppermint oil flavor lmg
  • the product so obtained was a viscous syrup with a pH of 7.7 containing 400mg of cimetidine per approximately 10ml of liquid. This product has improved taste over the non-inventive formulation.
  • sucrose solution 65%w/w sucrose; 10.75g
  • Methyl parabens 5mg
  • artificial pineapple flavor 3mg
  • color 5%w/v FD&C yellow #5; 2.5mg
  • This composition has a pH of 7.4 and contains approximately 400mg cimetidine in 10ml of liquid.
  • Pureco 92 400mg were mixed and heated to 90 degree centigrade until a homogeneous liquid was formed.
  • the other ingredients were mixed in the same amount and in the same way described in inventive example 2.
  • This composition has a pH of 7.6 and contains about 400mg cimetidine in lOmg of liquid.
  • Lipo GMS 470 200mg
  • Pureco 92 400mg
  • the other ingredients were mixed in - li ⁇ the same amount and in the same way described in inventive example 2, except that flavor and color were not added.
  • This composition has a pH of 8.1 and contains about 400mg cimetidine in lOmg of liquid.
  • This composition has a pH of 7.7 and contains approximately 266mg cimetidine in 10ml of liquid.
  • sucrose solution 65%w/w sucrose; 10.75g
  • Methyl parabens 5mg
  • citric acid solution 10%w/v; 130mg
  • artificial pineapple flavor 4mg
  • This composition has a pH of 7.1 and contains approximately 400mg cimetidine in 10ml of liquid.
  • sucrose solution 65%w/w sucrose, 0.05%w/v methyl parabens; 7.9ml
  • a peppermint oil flavor 0.7ul
  • Panodan 205 50mg
  • Lipo GMS 470 50mg
  • Pureco 92 300mg
  • the other ingredients were mixed in the same amount and in the same way described in inventive example 9, except that the amount of citric acid was 50mg and of sucrose solution was 11.05g.
  • This composition contains approximately 320mg acetaminophen in 10ml of liquid.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Procédé permettant de masquer le goût d'un médicament sous forme particulaire, et composition médicamenteuse ainsi produite. Un médicament, sous forme particulaire et d'un goût désagréable, est mélangé à un lipide. On ajoute à ce mélange médicament/lipide un agent émulsifiant, une solution polymère et une solution de dilution édulcorante afin de constituer la composition médicamenteuse stable finale.
PCT/US1992/007513 1992-09-03 1992-09-03 Compositions pharmaceutiques destinees a masquer le gout, et procedes de fabrication Ceased WO1994005260A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PCT/US1992/007513 WO1994005260A1 (fr) 1992-09-03 1992-09-03 Compositions pharmaceutiques destinees a masquer le gout, et procedes de fabrication
CA002143439A CA2143439A1 (fr) 1992-09-03 1992-09-03 Compositions pharmaceutiques masquant le gout; methode de preparation
AU25840/92A AU2584092A (en) 1992-09-03 1992-09-03 Taste-masking pharmaceutical compositions and methods for making the same
EP92920050A EP0663818A4 (fr) 1992-09-03 1992-09-03 Compositions pharmaceutiques destinees a masquer le gout, et procedes de fabrication.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/US1992/007513 WO1994005260A1 (fr) 1992-09-03 1992-09-03 Compositions pharmaceutiques destinees a masquer le gout, et procedes de fabrication
CA002143439A CA2143439A1 (fr) 1992-09-03 1992-09-03 Compositions pharmaceutiques masquant le gout; methode de preparation

Publications (1)

Publication Number Publication Date
WO1994005260A1 true WO1994005260A1 (fr) 1994-03-17

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PCT/US1992/007513 Ceased WO1994005260A1 (fr) 1992-09-03 1992-09-03 Compositions pharmaceutiques destinees a masquer le gout, et procedes de fabrication

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WO (1) WO1994005260A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006608A1 (fr) * 1994-08-30 1996-03-07 American Home Products Corporation Procede de reduction de l'odeur et du gout desagreables associes aux antagonistes de h¿2?
US6242019B1 (en) 1997-08-14 2001-06-05 Warner-Lambert Company Taste modified hard confectionery compositions containing functional ingredients
US6287592B1 (en) 1996-12-10 2001-09-11 The Boots Company Plc Aqueous drink composition comprising ibuprofen
US6794411B1 (en) 1999-04-06 2004-09-21 Laboratoire Des Produits Ethiques Ethypharm Drinkable ibuprofen pharmaceutical suspension
GB2419094A (en) * 2004-10-12 2006-04-19 Sandoz Ag Pharmaceutical composition of unpleasnt tasing active substances
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
WO2014047005A1 (fr) 2012-09-18 2014-03-27 Mcneil-Ppc, Inc. Formes pharmaceutique orales à libération prolongée comprenant des particules de dérivés d'acide propionique à bas point de fusion

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4676984A (en) * 1985-08-14 1987-06-30 American Home Products Corp. Rehydratable antacid composition
US4865851A (en) * 1987-05-14 1989-09-12 Glaxo Group Limited Pharmaceutical composition comprising cefuroxime axetil
US4894233A (en) * 1984-10-05 1990-01-16 Sharma Shri C Novel drug delivery system for decongestants

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4894233A (en) * 1984-10-05 1990-01-16 Sharma Shri C Novel drug delivery system for decongestants
US4676984A (en) * 1985-08-14 1987-06-30 American Home Products Corp. Rehydratable antacid composition
US4865851A (en) * 1987-05-14 1989-09-12 Glaxo Group Limited Pharmaceutical composition comprising cefuroxime axetil

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0663818A4 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996006608A1 (fr) * 1994-08-30 1996-03-07 American Home Products Corporation Procede de reduction de l'odeur et du gout desagreables associes aux antagonistes de h¿2?
US6287592B1 (en) 1996-12-10 2001-09-11 The Boots Company Plc Aqueous drink composition comprising ibuprofen
US6242019B1 (en) 1997-08-14 2001-06-05 Warner-Lambert Company Taste modified hard confectionery compositions containing functional ingredients
US8092826B2 (en) 1997-08-14 2012-01-10 Kraft Foods Global Brands Llc Taste modified hard confectionery compositions containing functional ingredients
US6794411B1 (en) 1999-04-06 2004-09-21 Laboratoire Des Produits Ethiques Ethypharm Drinkable ibuprofen pharmaceutical suspension
GB2419094A (en) * 2004-10-12 2006-04-19 Sandoz Ag Pharmaceutical composition of unpleasnt tasing active substances
AU2005293800B2 (en) * 2004-10-12 2009-03-26 Sandoz Ag Taste-masking pharmaceutical compositions
US7767231B2 (en) 2004-10-12 2010-08-03 Sandoz Ag Taste-masking pharmaceutical compositions
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
WO2014047005A1 (fr) 2012-09-18 2014-03-27 Mcneil-Ppc, Inc. Formes pharmaceutique orales à libération prolongée comprenant des particules de dérivés d'acide propionique à bas point de fusion

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