CA2143439A1 - Taste-masking pharmaceutical compostiions and methods for making the same - Google Patents
Taste-masking pharmaceutical compostiions and methods for making the sameInfo
- Publication number
- CA2143439A1 CA2143439A1 CA002143439A CA2143439A CA2143439A1 CA 2143439 A1 CA2143439 A1 CA 2143439A1 CA 002143439 A CA002143439 A CA 002143439A CA 2143439 A CA2143439 A CA 2143439A CA 2143439 A1 CA2143439 A1 CA 2143439A1
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- Prior art keywords
- drug
- lipid
- mixture
- composition
- cimetidine
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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
- A61K9/0087—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
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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
A method of masking the flavor of a drug which is present in particulate form and the drug composition produced there-from is provided. A drug, in particulate form, which has an unpalatable taste is mixed with a lipid. To this drug/lipid mixture is added an emulsifying agent, a polymer solution and a sweetening dilution solution to provide the final stable drug composition.
Description
.
TA8T~-MA8RING PHARMAC~UTICAh CO~PO8ITION8 AND
METHOD~ FOR MA~lN~ T~E 8AME
Field of the Invention This invention relates to techniques for taste-masking pharmaceutical drugs. More specifically, theinvention 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.
Backqround of th~ Invention It is well known that many medicaments intended for oral administration are highly unpalatable because of their bitter taste. Sweeteners have been added to these medicaments in order to mask the unpleasant taste, however, sweeteners alone are insufficient to entirely mask the bitter taste of many drugs.
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. By storing the drug within an integral coating of a lipid a granule format, the drug can be maintained in its flavor masked form for at least 14 days and maybe longer.
Lipid coatings for masking the bitter taste of ~343~ 2 -- 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. However, 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 tec-hnique. 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. Again, 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 need therefore exists to provide a drug composition and a method for preparing the same in which a drug which has an unpalatable taste is presented in a taste-masked form wherein the drug composition is in a readied state for oral administration, can be stored in such a stable state, and does not require additional formulation immediately prior to oral administration.
8umm~rY of the Invention 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 50C. To this drug and lipid mixture is added an emulsifier, a polymer solution, and a ~ W094/05260 2 1 ~ 3 ~ 3 9 PCT/US92/07513 dilution solution to form the stable taste-masked drug composition.
In an alternative embodiment, 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.
Preferably, 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.
Certain preferred particular embodiments of the invention are also disclosed. The drug to lipid weight ratio ranges from about 1:0.25 to about 1:2. Also, the drug is preferably added in amount up to about 800 milligrams per 10 milliliters (10 cc) of the drug composition. In another preferred embodiment of the invention, 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.
W094/05260 PCT/US92/075~3 ~
2143~39 - ~ -~De~ailed 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 en~capsulation 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 ~nhAnç~r5. The final drug composition is a dispersion which is believed to be stable indefinitely. Stability has been demonstrated from as short as a day up to as long as 3 months in its flavor masked state. 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. In one embodiment, 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 50C 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 W094/05~60 PCT/US92/07~13 21~3~3~
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. First, a mixture of a lipid and an emulsifier is heated and mixed by conventional methods until a molten homoge~ous state is reached. Preferably, the temperature of the molten lipid will be at least about 20C
above the melting point of the lipid and typically will be in the range of from about 50C - 100C. The temperature of this lipid and emulsifier mixture is then adjusted to a temperature below where significant drug degradation can occur, typically below about 50C, 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.
In order to produce the taste-masking pharmaceutical compositions suitable for oral administration, 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 30C to about 95C. 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.
W O 94/05260 PC~r/US92/07~13 2~43~3~ - 6 -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 (C1030) aliphatic acid; fatty acids or monohydric alcohols thereof, fixed oils, fats, waxes, sterols, phospholipids and glycolipids. The lipid may also, for example, be a high molecular weight straight chain (C1030) 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. Examples of 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 PANOD~N 205 and SDK by the Grinsted Company. Also, a preferred nonionic surfactant is glycerol stearate, for example, LIPOGMS 470 manufactured by Lipo Chemical Co~rAny.
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. However, the drug is believed to be substantially coated but not entirely coated by the lipid. Thus certain W094/05260 2 1 ~ 3 4 ~ 9 PCT/US92/07513 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 ~hAnse 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. One particular 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. Basically, 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. Examples of coloring agents include titanium dioxide pigments, lake colors and iron oxide pigments.
Other suitable additives are included within the scope of the invention, such as an antacid to a cimetidine preparation.
The pharmaceutical drug composition of the present invention can be formulated in any desired quantities. In order to more fully describe the present invention, a basis W094/05260 PCT/US92/07513 ~
2~43~39 - 8 -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 ~he drug composition of the present invention is from about 100 to 800 milligrams of the drug. Once the amount of drug to be added has been determined, the amount of lipid to be used can readily be determined. Typically, the amount of lipid ranges from 25-200% by weight of the amou~t of drug employed. In a preferred embodiment, the ratio of drug to lipid is 1:1.
However, 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.
In a more detailed embodiment of the invention, 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 20OC 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.
~ W094/05260 2 1 ~ 3 4 3 ~ PCT/US92/07513 _ 9 _ In the next step, 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 5 coated with the lipid material whereby a flavor masking effect r is obt~; ne~ as at least a portion of the drug is contained within the lipid phase and has its flavor masked by the lipid phase.
To this drug/lipid phase is added an appropriate lO amount of the polymer, i.e. an amount of polymer sufficient to suspend the lipid coated particles and provide the desired thickness. 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 15 chosen it is to be compatible with the lipid. Preferably, 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 20 thoroughly mixed into the drug/lipid phase by the aid of mechanical mixing devices.
In the last step, a sweetening dilution mixture is slowly added to the drug composition to enhance the flavor of that composition. Preferably, this sweetening solution is 25 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.
lNV~.~ ' V~ EXANPLE 1 70mg of Panodan 205, 50mg of Lipo GMS 470, and 400mg of Pureco 92 were weighed into the same vessel, and heated to about 90 degree centigrade until clear homogeneous liquid phase was formed. This lipid phase was allowed to cool to room temperature at which point it becomes a semisolid paste.
To this lipid phase was added cimetidine (400mg). This W094/05260 PCT/US92/07513 ~~
?.~43~39 - lo mixture was mixed until homogeneous. To this drug-lipid mixture was added polymer solution (8%w/v 7LF PH, 20%w/v Glycerin, 788 mg). This mixture so obtained was mixed until homogeneous. To this mixture was added the sucrose solution (65%w/w sucrose, 0.05%w/v methyl parabens; 10.560g), a spearmint oil flavor (2.8mg), a peppermint oil flavor (lmg), and the mixture was mixed until homogeneous. The product so obtained was a viscous syrup with a pH of 7.7 containing 400mg of cimetidine per approximately lOml of liquid. This product has improved taste over the non-inventive formulation.
IN~ENTIV~ BXA~PLE 2 Panodan 205 (9Omg) and Pureco 92 (400mg) were mixed and heated to about 90 degree centigrade until a homogeneous liquid was formed. This lipid phase was allowed to cool to room temperature. Cimetidine (400mg) was added to this lipid phase. The mixture so obtained was mixed until homogeneous.
To this drug-lipid mixture was added polymer solution (8%w/v CMC 7LF PH, 20%w/v Glycerin; 788mg). The mixture so obtained was mixed until homogeneous. To this mixture was added the sucrose solution (65%w/w sucrose; 10.75g), Methyl parabens (5mg), artificial pineapple flavor (3mg) and color (5%w/v FD&C
yellow #5; 2.Smg). This composition has a pH of 7.4 and contains approximately 400mg cimetidine in lOml of liquid.
l~.V~ V~ ~XANPLE 3 Lipo GMS 470 (lOOmg), stearic acid (lOOmg) and 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.
lN V~I. ~ l V ~ BXAMPLE
Lipo GMS 470 (20Omg) and Pureco 92 (40Omg) were mixed and heated to 90 degree centigrade until a homogeneous liquid phase was formed. The other ingredients were mixed in 21~343~
W094/05260 PCT/~S92/07513 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.
IN~_.. lv~ E~ANPLB 5 Panodan 205 (47mg), Lipo GMS 470 (33mg) and Pureco 92 (267mg) were mixed and heated to about 90 degree centigrade until a homogeneous liquid was formed. This lipid phase was allowed to cool to room temperature. Cimetidine (267mg) was added to this lipid phase. The mixture so obtained was mixed until homogeneous. To this drug-lipid mixture was added a CMC
solution (8%w/v CMC 7LF PH, 20%w/v Glycerin; 788mg) and a Xanthan Gum solution (Keltrol from Kelco 2%w/v, Glycerin 20%w/v; 150mg). The mixture so obtA~ was mixed until homogeneous. To this mixture was added the sucrose solution (65%w/w sucrose; 11.07g), Methyl parabens (5mg). This composition has a pH of 7.7 and contains approximately 266mg cimetidine in lOml of liquid.
l~.V~ V~ ~XAMPLB 6 Lipo G~S 470 (150mg), Cottonseed oil (338mg) and glycerol behenate (112mg) were mixed and heated to about 90 degree centigrade until a homogeneous liquid was formed. This lipid phase was allowed to cool to room temperature.
Cimetidine (400mg) was added to this lipid phase. This mixture so obtained was mixed until homogeneous. To this drug-lipid mixture was added a CMC solution (8%w/v CMC 7LF PH, %w/v Glycerin; 788mg). The mixture so obtained was mixed until homogeneous. To this mixture was added the sucrose solution (65%w/w sucrose; 10.75g), Methyl parabens (5mg), citric acid solution (10%w/v; 130mg), and artificial pineapple flavor (4mg). This composition has a pH of 7.1 and contains approximately 400mg cimetidine in lOml of liquid.
lNV~N-llV~ EXAMPLE 7 lOOul of Panodan SDK, 600ul of Nestle Choco-bake were mixed and heated to about 90 degree centigrade until a W O 94/05260 PC~r/US92/07513 ~
~3~3~
clear homogeneous liquid phase was formed. This lipid phase was allowed to cool to room temperature at which point it becomes a semisolid paste. To this lipid phase was added cimetidine (400mg). This mixture was mixed until homogeneous.
To this drug-lipid mixture was added a polymer solution (4%w/v 7LF PH, 10%w/v Glycerin; lOOOul). The mixture so obtained was mixed until homogeneous. To this mixture was added the sucrose solution (65%w/w sucrose, 0.05%w/v methyl parabens;
7.9ml) and a peppermint oil flavor (0.7ul), and the mixture was mixed until homogeneous. The product so obtained was a viscous syrup containing 400mg of cimetidine per approximately lOml of liquid.
50ul of Panodan SDK, 50ul of stearic acid and 600ul of Nestle Choco-bake were mixed and heated to about 90 degree centigrade until a clear homogeneous liquid phase was formed.
The other ingredients were mixed in the same amount and in the same way described in inventive example 7. The product so obtained was a viscous syrup containing 400mg of cimetidine per approximately lOml of liquid.
l~.V~. ~ lV~ EXAMPLB 9 Panodan 205 (32mg), Lipo GMS 470 (32mg) and Pureco 92 (200mg) were mixed and heated to about 90 degree centigrade until a homogeneous liquid was formed. This lipid phase was allowed to cool to room temperature. Acetaminophen (320mg) was added to this lipid phase. The mixture so obtained was mixed until homogeneous. To this drug-lipid mixture was added polymer solution (8%w/v CMC 7LF PH, 20~w/v Glycerin; 788mg).
The mixture so obtained was mixed until homogeneous. To this mixture was added the sucrose solution (65%w/w sucrose;
11.26g). Sodium benzoate (lOmg) and citric acid (40mg). This composition has a pH of 3.8 containing approximately 320mg acetaminophen in lOml of liquid.
~ W094/05260 2 1 ~ 3 4 3 9 PCT/US92/07S13 INVENTIVB ~XANPLE lo Panodan 205 (50mg), Lipo GMS 470 (50mg) and Pureco 92 (300mg) were mixed and heated to about so 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 9, except that the amount of citric acid was 50mg and of sucrose solution was 11.05g. This composition contains approximately 320mg acetaminophen in lOml of liquid.
TA8T~-MA8RING PHARMAC~UTICAh CO~PO8ITION8 AND
METHOD~ FOR MA~lN~ T~E 8AME
Field of the Invention This invention relates to techniques for taste-masking pharmaceutical drugs. More specifically, theinvention 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.
Backqround of th~ Invention It is well known that many medicaments intended for oral administration are highly unpalatable because of their bitter taste. Sweeteners have been added to these medicaments in order to mask the unpleasant taste, however, sweeteners alone are insufficient to entirely mask the bitter taste of many drugs.
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. By storing the drug within an integral coating of a lipid a granule format, the drug can be maintained in its flavor masked form for at least 14 days and maybe longer.
Lipid coatings for masking the bitter taste of ~343~ 2 -- 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. However, 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 tec-hnique. 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. Again, 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 need therefore exists to provide a drug composition and a method for preparing the same in which a drug which has an unpalatable taste is presented in a taste-masked form wherein the drug composition is in a readied state for oral administration, can be stored in such a stable state, and does not require additional formulation immediately prior to oral administration.
8umm~rY of the Invention 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 50C. To this drug and lipid mixture is added an emulsifier, a polymer solution, and a ~ W094/05260 2 1 ~ 3 ~ 3 9 PCT/US92/07513 dilution solution to form the stable taste-masked drug composition.
In an alternative embodiment, 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.
Preferably, 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.
Certain preferred particular embodiments of the invention are also disclosed. The drug to lipid weight ratio ranges from about 1:0.25 to about 1:2. Also, the drug is preferably added in amount up to about 800 milligrams per 10 milliliters (10 cc) of the drug composition. In another preferred embodiment of the invention, 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.
W094/05260 PCT/US92/075~3 ~
2143~39 - ~ -~De~ailed 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 en~capsulation 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 ~nhAnç~r5. The final drug composition is a dispersion which is believed to be stable indefinitely. Stability has been demonstrated from as short as a day up to as long as 3 months in its flavor masked state. 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. In one embodiment, 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 50C 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 W094/05~60 PCT/US92/07~13 21~3~3~
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. First, a mixture of a lipid and an emulsifier is heated and mixed by conventional methods until a molten homoge~ous state is reached. Preferably, the temperature of the molten lipid will be at least about 20C
above the melting point of the lipid and typically will be in the range of from about 50C - 100C. The temperature of this lipid and emulsifier mixture is then adjusted to a temperature below where significant drug degradation can occur, typically below about 50C, 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.
In order to produce the taste-masking pharmaceutical compositions suitable for oral administration, 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 30C to about 95C. 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.
W O 94/05260 PC~r/US92/07~13 2~43~3~ - 6 -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 (C1030) aliphatic acid; fatty acids or monohydric alcohols thereof, fixed oils, fats, waxes, sterols, phospholipids and glycolipids. The lipid may also, for example, be a high molecular weight straight chain (C1030) 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. Examples of 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 PANOD~N 205 and SDK by the Grinsted Company. Also, a preferred nonionic surfactant is glycerol stearate, for example, LIPOGMS 470 manufactured by Lipo Chemical Co~rAny.
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. However, the drug is believed to be substantially coated but not entirely coated by the lipid. Thus certain W094/05260 2 1 ~ 3 4 ~ 9 PCT/US92/07513 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 ~hAnse 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. One particular 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. Basically, 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. Examples of coloring agents include titanium dioxide pigments, lake colors and iron oxide pigments.
Other suitable additives are included within the scope of the invention, such as an antacid to a cimetidine preparation.
The pharmaceutical drug composition of the present invention can be formulated in any desired quantities. In order to more fully describe the present invention, a basis W094/05260 PCT/US92/07513 ~
2~43~39 - 8 -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 ~he drug composition of the present invention is from about 100 to 800 milligrams of the drug. Once the amount of drug to be added has been determined, the amount of lipid to be used can readily be determined. Typically, the amount of lipid ranges from 25-200% by weight of the amou~t of drug employed. In a preferred embodiment, the ratio of drug to lipid is 1:1.
However, 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.
In a more detailed embodiment of the invention, 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 20OC 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.
~ W094/05260 2 1 ~ 3 4 3 ~ PCT/US92/07513 _ 9 _ In the next step, 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 5 coated with the lipid material whereby a flavor masking effect r is obt~; ne~ as at least a portion of the drug is contained within the lipid phase and has its flavor masked by the lipid phase.
To this drug/lipid phase is added an appropriate lO amount of the polymer, i.e. an amount of polymer sufficient to suspend the lipid coated particles and provide the desired thickness. 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 15 chosen it is to be compatible with the lipid. Preferably, 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 20 thoroughly mixed into the drug/lipid phase by the aid of mechanical mixing devices.
In the last step, a sweetening dilution mixture is slowly added to the drug composition to enhance the flavor of that composition. Preferably, this sweetening solution is 25 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.
lNV~.~ ' V~ EXANPLE 1 70mg of Panodan 205, 50mg of Lipo GMS 470, and 400mg of Pureco 92 were weighed into the same vessel, and heated to about 90 degree centigrade until clear homogeneous liquid phase was formed. This lipid phase was allowed to cool to room temperature at which point it becomes a semisolid paste.
To this lipid phase was added cimetidine (400mg). This W094/05260 PCT/US92/07513 ~~
?.~43~39 - lo mixture was mixed until homogeneous. To this drug-lipid mixture was added polymer solution (8%w/v 7LF PH, 20%w/v Glycerin, 788 mg). This mixture so obtained was mixed until homogeneous. To this mixture was added the sucrose solution (65%w/w sucrose, 0.05%w/v methyl parabens; 10.560g), a spearmint oil flavor (2.8mg), a peppermint oil flavor (lmg), and the mixture was mixed until homogeneous. The product so obtained was a viscous syrup with a pH of 7.7 containing 400mg of cimetidine per approximately lOml of liquid. This product has improved taste over the non-inventive formulation.
IN~ENTIV~ BXA~PLE 2 Panodan 205 (9Omg) and Pureco 92 (400mg) were mixed and heated to about 90 degree centigrade until a homogeneous liquid was formed. This lipid phase was allowed to cool to room temperature. Cimetidine (400mg) was added to this lipid phase. The mixture so obtained was mixed until homogeneous.
To this drug-lipid mixture was added polymer solution (8%w/v CMC 7LF PH, 20%w/v Glycerin; 788mg). The mixture so obtained was mixed until homogeneous. To this mixture was added the sucrose solution (65%w/w sucrose; 10.75g), Methyl parabens (5mg), artificial pineapple flavor (3mg) and color (5%w/v FD&C
yellow #5; 2.Smg). This composition has a pH of 7.4 and contains approximately 400mg cimetidine in lOml of liquid.
l~.V~ V~ ~XANPLE 3 Lipo GMS 470 (lOOmg), stearic acid (lOOmg) and 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.
lN V~I. ~ l V ~ BXAMPLE
Lipo GMS 470 (20Omg) and Pureco 92 (40Omg) were mixed and heated to 90 degree centigrade until a homogeneous liquid phase was formed. The other ingredients were mixed in 21~343~
W094/05260 PCT/~S92/07513 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.
IN~_.. lv~ E~ANPLB 5 Panodan 205 (47mg), Lipo GMS 470 (33mg) and Pureco 92 (267mg) were mixed and heated to about 90 degree centigrade until a homogeneous liquid was formed. This lipid phase was allowed to cool to room temperature. Cimetidine (267mg) was added to this lipid phase. The mixture so obtained was mixed until homogeneous. To this drug-lipid mixture was added a CMC
solution (8%w/v CMC 7LF PH, 20%w/v Glycerin; 788mg) and a Xanthan Gum solution (Keltrol from Kelco 2%w/v, Glycerin 20%w/v; 150mg). The mixture so obtA~ was mixed until homogeneous. To this mixture was added the sucrose solution (65%w/w sucrose; 11.07g), Methyl parabens (5mg). This composition has a pH of 7.7 and contains approximately 266mg cimetidine in lOml of liquid.
l~.V~ V~ ~XAMPLB 6 Lipo G~S 470 (150mg), Cottonseed oil (338mg) and glycerol behenate (112mg) were mixed and heated to about 90 degree centigrade until a homogeneous liquid was formed. This lipid phase was allowed to cool to room temperature.
Cimetidine (400mg) was added to this lipid phase. This mixture so obtained was mixed until homogeneous. To this drug-lipid mixture was added a CMC solution (8%w/v CMC 7LF PH, %w/v Glycerin; 788mg). The mixture so obtained was mixed until homogeneous. To this mixture was added the sucrose solution (65%w/w sucrose; 10.75g), Methyl parabens (5mg), citric acid solution (10%w/v; 130mg), and artificial pineapple flavor (4mg). This composition has a pH of 7.1 and contains approximately 400mg cimetidine in lOml of liquid.
lNV~N-llV~ EXAMPLE 7 lOOul of Panodan SDK, 600ul of Nestle Choco-bake were mixed and heated to about 90 degree centigrade until a W O 94/05260 PC~r/US92/07513 ~
~3~3~
clear homogeneous liquid phase was formed. This lipid phase was allowed to cool to room temperature at which point it becomes a semisolid paste. To this lipid phase was added cimetidine (400mg). This mixture was mixed until homogeneous.
To this drug-lipid mixture was added a polymer solution (4%w/v 7LF PH, 10%w/v Glycerin; lOOOul). The mixture so obtained was mixed until homogeneous. To this mixture was added the sucrose solution (65%w/w sucrose, 0.05%w/v methyl parabens;
7.9ml) and a peppermint oil flavor (0.7ul), and the mixture was mixed until homogeneous. The product so obtained was a viscous syrup containing 400mg of cimetidine per approximately lOml of liquid.
50ul of Panodan SDK, 50ul of stearic acid and 600ul of Nestle Choco-bake were mixed and heated to about 90 degree centigrade until a clear homogeneous liquid phase was formed.
The other ingredients were mixed in the same amount and in the same way described in inventive example 7. The product so obtained was a viscous syrup containing 400mg of cimetidine per approximately lOml of liquid.
l~.V~. ~ lV~ EXAMPLB 9 Panodan 205 (32mg), Lipo GMS 470 (32mg) and Pureco 92 (200mg) were mixed and heated to about 90 degree centigrade until a homogeneous liquid was formed. This lipid phase was allowed to cool to room temperature. Acetaminophen (320mg) was added to this lipid phase. The mixture so obtained was mixed until homogeneous. To this drug-lipid mixture was added polymer solution (8%w/v CMC 7LF PH, 20~w/v Glycerin; 788mg).
The mixture so obtained was mixed until homogeneous. To this mixture was added the sucrose solution (65%w/w sucrose;
11.26g). Sodium benzoate (lOmg) and citric acid (40mg). This composition has a pH of 3.8 containing approximately 320mg acetaminophen in lOml of liquid.
~ W094/05260 2 1 ~ 3 4 3 9 PCT/US92/07S13 INVENTIVB ~XANPLE lo Panodan 205 (50mg), Lipo GMS 470 (50mg) and Pureco 92 (300mg) were mixed and heated to about so 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 9, except that the amount of citric acid was 50mg and of sucrose solution was 11.05g. This composition contains approximately 320mg acetaminophen in lOml of liquid.
Claims (20)
1. A method of producing an aqueous stable drug composition which masks the flavor of a drug in need of taste-masking, consisting essentially of the steps of:
(a) mixing the drug in particulate form into a lipid at a temperature below where significant drug degradation occurs; and (b) adding an emulsifier, a polymer and an aqueous dilution solution to the mixture of step (a) to form the aqueous stable taste-masked drug composition.
(a) mixing the drug in particulate form into a lipid at a temperature below where significant drug degradation occurs; and (b) adding an emulsifier, a polymer and an aqueous dilution solution to the mixture of step (a) to form the aqueous stable taste-masked drug composition.
2. A method of producing an aqueous stable drug composition which masks the flavor of a drug in need of taste-masking, consisting essentially of the steps of:
(a) heating a mixture of a lipid and an emulsifier until the mixture is in a molten state;
(b) adjusting the temperature of the mixture below where significant drug degradation occurs;
(c) admixing to the mixture the drug in particulate form;
(d) adding a polymer to the mixture of step (c) to form a concentrated drug composition; and (e) diluting the concentrated composition with an aqueous dilution solution to produce the stable taste-masked drug composition.
(a) heating a mixture of a lipid and an emulsifier until the mixture is in a molten state;
(b) adjusting the temperature of the mixture below where significant drug degradation occurs;
(c) admixing to the mixture the drug in particulate form;
(d) adding a polymer to the mixture of step (c) to form a concentrated drug composition; and (e) diluting the concentrated composition with an aqueous dilution solution to produce the stable taste-masked drug composition.
3. The method of claims 1 or 2 wherein the drug is selected from the group consisting of cimetidine, ranitidine, ibuprofen, acetaminophen, and erythromycin.
4. The method of claim 3 wherein the drug to lipid weight ratio is from about 1:0.25 to about 1:2.
5. The method according to claim 3 wherein the drug is present in a concentration of less than 800 mg per 10 cc of the drug composition.
6. The method according to claim 3 wherein the emulsifier is present in an amount of from 0.3 to 3% by weight of the drug composition.
7. The method according to claim 3 wherein the polymer is added in the form of an aqueous solution and comprises a cellulose derivative or xanthan gum.
8. The method according to claim 7 wherein the aqueous polymer solution is added after the emulsifier is thoroughly mixed with the lipid and drug mixture.
9. The method of claim 2 wherein the temperature of step (a) is in the range from 50-100°C and the temperature of step (b) is adjusted to about 50°C or below.
10. A method of producing a stable cimetidine drug composition which masks the flavor of cimetidine, consisting essentially of the steps of:
(a) heating a mixture of a lipid and an emulsifier until the mixture is in a molten state;
(b) adjusting the temperature of the mixture to about 50°C or below;
(c) admixing to the mixture cimetidine in particulate form;
(d) adding a polymer solution to the mixture of step (c) to form a concentrated drug composition; and (e) diluting the concentrated composition with an aqueous dilution solution to produce the stable taste-masked drug composition.
(a) heating a mixture of a lipid and an emulsifier until the mixture is in a molten state;
(b) adjusting the temperature of the mixture to about 50°C or below;
(c) admixing to the mixture cimetidine in particulate form;
(d) adding a polymer solution to the mixture of step (c) to form a concentrated drug composition; and (e) diluting the concentrated composition with an aqueous dilution solution to produce the stable taste-masked drug composition.
11. The method according to claim 10 wherein the temperature of step (a) is in the range from about 50-100°C.
12. The method according to claim 10 wherein the cimetidine to lipid weight ratio is from about 1:0.25 to about 1:2.
13. The method according to claim 10 wherein the cimetidine is present in a concentration of less than 800 mg per 10 cc of the drug composition.
14. The method according to claim 10 wherein the cimetidine drug composition, on a 10 cc volume basis, the cimetidine is present in an amount of from 400-800 mg, the lipid is present in an amount of from 200-800 mg, the emulsifier is present in an amount of from 0.3 to 3% by weight of the cimetidine composition, and the polymer is present in an amount of from 30-120 mg.
15. The method according to claim 10 wherein the polymer comprises a mixture of carboxymethylcellulose and xanthan gum.
16. The method according to claim 12 wherein the lipid and emulsifier are heated to a temperature of about 85-95°C.
17. A stable drug composition produced by the process of any of the proceeding claims.
18. An aqueous stable drug composition which masks the flavor of a drug in need of taste-masking, comprising, on a 10 ml basis, about 100 to about 800 mg of a drug selected from the group consisting of cimetidine, ranitidine, ibuprofen, acetaminophen, and erythromycin; from about 25 to about 800 mg of a lipid; from about 30 to about 120 mg of a polymer; and wherein the composition further comprises from about 0.3-3% wt.
of a surfactant.
of a surfactant.
19. The aqueous drug composition of claim 18 wherein the drug comprises cimetidine.
20. The aqueous composition of claims 18 or 19 wherein the polymer comprises a cellulose derivative or xanthan gum.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP92920050A EP0663818A4 (en) | 1992-09-03 | 1992-09-03 | Taste-masking pharmaceutical compositions and methods for making the same. |
| PCT/US1992/007513 WO1994005260A1 (en) | 1992-09-03 | 1992-09-03 | Taste-masking pharmaceutical compositions and methods for making the same |
| CA002143439A CA2143439A1 (en) | 1992-09-03 | 1992-09-03 | Taste-masking pharmaceutical compostiions and methods for making the same |
| AU25840/92A AU2584092A (en) | 1992-09-03 | 1992-09-03 | Taste-masking pharmaceutical compositions and methods for making the same |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US1992/007513 WO1994005260A1 (en) | 1992-09-03 | 1992-09-03 | Taste-masking pharmaceutical compositions and methods for making the same |
| CA002143439A CA2143439A1 (en) | 1992-09-03 | 1992-09-03 | Taste-masking pharmaceutical compostiions and methods for making the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2143439A1 true CA2143439A1 (en) | 1994-03-17 |
Family
ID=25677809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002143439A Abandoned CA2143439A1 (en) | 1992-09-03 | 1992-09-03 | Taste-masking pharmaceutical compostiions and methods for making the same |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA2143439A1 (en) |
| WO (1) | WO1994005260A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5576344A (en) * | 1994-08-30 | 1996-11-19 | American Home Products Corporation | Process for reducing the adverse taste and malodor associated with H2 -antagonists |
| GB9625589D0 (en) | 1996-12-10 | 1997-01-29 | Boots Co Plc | Therapeutic agents |
| US6242019B1 (en) | 1997-08-14 | 2001-06-05 | Warner-Lambert Company | Taste modified hard confectionery compositions containing functional ingredients |
| BR0009557A (en) | 1999-04-06 | 2002-05-28 | Ethypharm Lab Prod Ethiques | Pharmaceutical suspension for ibuprofen drinking |
| GB2419094A (en) * | 2004-10-12 | 2006-04-19 | Sandoz Ag | Pharmaceutical composition of unpleasnt tasing active substances |
| CA2884119A1 (en) | 2012-09-18 | 2014-03-27 | Mcneil-Ppc, Inc. | Low melting propionic acid derivative particles for use in oral dosage forms |
| AU2013318360A1 (en) | 2012-09-18 | 2015-03-26 | Mcneil-Ppc, Inc. | Sustained release oral dosage forms comprising low melting propionic acid derivative particles |
Family Cites Families (3)
| 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 |
| NL193682C (en) * | 1987-05-14 | 2000-07-04 | Glaxo Group Ltd | Coated Cefuroxime Maxetil Composition. |
-
1992
- 1992-09-03 WO PCT/US1992/007513 patent/WO1994005260A1/en not_active Application Discontinuation
- 1992-09-03 CA CA002143439A patent/CA2143439A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO1994005260A1 (en) | 1994-03-17 |
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