WO1994025006A1

WO1994025006A1 - Taste-masking pharmaceutical compositions and methods for making the same

Info

Publication number: WO1994025006A1
Application number: PCT/US1994/004569
Authority: WO
Inventors: Seang H. Yiv; Alex K. Tustian
Original assignee: Affinity Biotech, Inc.
Priority date: 1993-04-26
Filing date: 1994-04-26
Publication date: 1994-11-10
Also published as: AU6774694A

Abstract

A method of masking the flavor of a drug which is present in particulate form and the drug composition produced therefrom 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

TASTE-MASKING PHARMACEUTICAL COMPOSITIONS AND METHODS FOR MAKING THE SAME

This is a continuation-in-part of U.S. Serial No. 753,099 filed August 30, 1991.

Field of the Invention

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 thus providing an improved taste for the drug.

Background of the 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 in 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 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 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. 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.

Summary 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 50*C. To this drug and lipid mixture is added an emulsifier or surfactant, a polymer solution, and a 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^βC. 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.

A further embodiment of the present invention is a method for preparing a taste-masked drug composition in which the tendency of the drug to aggregate is inhibited by the incorporation of a surfactant with the particulate drug. In this method the particulate drug is combined with the molten surfactant and the resultant mixture is then solidified and reduced to a powder form. This powder is then admixed into a molten or semi-solid lipid, followed by the admixture of the polymer, suspension agent, and aqueous solution. As with the other methods of the present invention, the lipid and drug mixture does not require resolidification or the formation of individual particles prior to being blended with the aqueous solution.

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, and the compositions produced therefrom, which compositions contain 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 stability of the drug composition 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^β-25^βC, and most preferably at room temperature. Stability is dependent upon various factors such as the type and structure of the drug, and the sequence of addition of the constituents during the manufacturing process.

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 90'C, more preferably 75*C, most preferably 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 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. First, a mixture of a lipid and an emulsifier is heated and mixed by conventional methods until a molten homogenous state is reached. Preferably, 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^βC - 100^βC. 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^βC, 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 30°C to about 95^PC. 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 (C₁₀.₃₀) 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 (C₁₀.₃₀) 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. 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 surfactants such as a diacetyl tartaric acid monoglyceride, for example, those sold under the trade name PANODAN 205, FDP and SDK by the Grinsted Company. Also, 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. Cimetidine can be obtained in various polymorphic forms such as polymorph A, B, C, D, and E. It is preferred to use the polymorphic form B in the formulation methods because some of the other forms, such as A, convert to form B over time and this conversion may adversely affect the viscosity of the composition. 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 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. 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 40% by weight, more preferably above about 50% by weight of sweetener. The preferred amount of sweetener in the aqueous solution is from about 50 to about 85 w/v percent. 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 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. 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 amount 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.

The pharmaceutical drug composition of the present invention preferably contains from about 1.5 to about 8 wt. percent of the drug; from about 0.8 to about 8, more preferably about 1.5 to about 8 wt. percent of the lipid; from about 0.2 to about 4, more preferably from about 0.2 to about 3 wt. percent emulsifier or surfactant; from about 0.1 to about 2, preferably from about 0.2 to about 1.2 wt. percent of the polymer suspension agent; and about 80 to about 95 wt. percent of the aqueous dilution solution which itself contains from about 40 to about 65 wt. percent sweetener. Although it is preferred to add the sweetener as part of the aqueous solution, it need not be, and the amount of sweetener in the drug composition is from about 30 to about 65 wt. percent. 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 20°C above the melting point of the lipid. It is preferred that the temperature of the molten solution be from about 85-95^βC. 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^βC or below to avoid drug degradation, but such that the mixture remains a liquid or a semi-solid paste. - lo ¬

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 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.

To this drug/lipid phase is added an appropriate 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 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 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 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. In a preferred embodiment of the present invention a taste masked drug composition is prepared having a less gritty feel upon oral administration. It has surprisingly been found that when a small amount of a surfactant, preferably an anionic surfactant, is incorporated into the drug particles prior to their formulation with the lipid material, the resulting composition has a less gritty feel in the mouth upon oral administration. The resulting formulation also has an acceptable viscosity which does not increase adversely with time during storage. It is believed that the anionic surfactant acts to reduce any drug particle agglomeration during the formulation and storage of the composition. A further preferred embodiment of the methods is to incorporate at least 70 wt. percent, preferably at least 90 wt. percent, and more preferably the entire amount of the surfactants and emulsifiers into the drug matrix prior to blending the drug with the lipid. The incorporation of the anionic surfactant with the drug particles is accomplished by bringing the surfactant into the molten state. The anionic surfactant is preferably selected to have a melting point below about 110"C, more preferably below about 95"C. The particulate drug is then admixed to the molten surfactant and blended to obtain a homogeneous mixture. This mixture is then solidified, preferably by cooling to below about 25^βC, more preferably to below about 10°C, and ground using conventional means to a desired particle size. This process of heating, mixing, cooling, and grinding can be repeated a plurality of times to increase the incorporation of the surfactant into the drug particle matrix. The drug particles containing the surfactant are then admixed with the lipid or lipid mixture which is either in a molten or semi-solid state. The polymer, suspension agent, and aqueous solution are admixed with the lipid and drug mixture while the lipid is either in a molten or semi-solid state.

The present inventive methods are advantageous over the prior processes in that the lipid and drug mixture does not require solidification prior to admixture with the aqueous solution or either the polymer and emulsifier. Preferably, the aqueous solution is blended with the lipid and drug mixture at a temperature above the melting point of the lipid. As those of skill in the art know, the lipid or mixture of lipids may have a melting point range rather than a distinct melting point temperature. Thus, the aqueous solution is preferably blended with the drug and lipid mixture at a temperature at which the entire lipid composition is molten, however the aqueous solution can also be blended while at least a portion of the lipid is in the molten state, and the lipid is generally referred to as a semi-solid at this state.

EXAMPLE 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 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 10ml of liquid. This product has improved taste over the non-inventive formulation.

EXAMPLE 2 Panodan 205 (90mg) 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; 2.5mg). This composition has a pH of 7.4 and contains approximately 400mg cimetidine in 10ml of liquid. EXAMPLE 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.

EXAMPLE 4

Lipo GMS 470 (200mg) and Pureco 92 (400mg) were mixed and heated to 90 degree centigrade until a homogeneous liquid phase was formed. The other ingredients were mixed in 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 lO g of liquid.

EXAMPLE 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 obtained' 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 10ml of liquid.

EXAMPLE 6

Lipo GMS 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 10ml of liquid.

EXAMPLE 7 lOOul of Panodan SDK, 600ul of Nestle Choco-bake were mixed and heated to about 90 degree centigrade until a 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 10ml of liquid.

EXAMPLE 8

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 ^f same way described in inventive example 7. The product so obtained was a viscous syrup containing 400mg of cimetidine per approximately 10ml of liquid. EXAMPLE 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 10ml of liquid.

EXAMPLE 10 Panodan 205 (50mg) , Lipo GMS 470 (50mg) and Pureco

92 (300mg) were mixed and heated to about 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 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.

EXAMPLE 11 The following example was made in which an anionic surfactant was incorporated into the drug matrix prior to admixing the drug with the lipid.

Panodan FDP, a modified monoglyceride anionic surfactant (Grinsted Co.), (2.33 g) , Lipo GMS-470 (1.67 g) , and cimetidine polymorph B (13.33 g) were mixed as dry powders, then heated to 90°C for 15-20 minutes with blending ^" and then cooled to about 25°C. The solidified mass was then ground into a powder. This blending process was repeated twice more by heating the ground powder to about 90°C, blending, cooling, solidifying the mass, and grounding it into a powder. The resulting powder was then admixed with Pureco 92, purified coconut oil (13.33 g, m.p. 34'C) at about 70°C. The mixture obtained was then cooled to about 45-50"C and blended with an aqueous sucrose solution (558 g; 65% w/w sucrose, preserved with methylparaben) , an aqueous xanthan gum solution (2.5 g; 7.5% w/v Keltrol xanthan gum from Kelco Co., 2% w/v glycerin) . After blending, this mixture was cooled to about 25^βC. The drug composition obtained was a smooth suspension containing 267 mg of cimetidine per 10 ml of liquid and had a ncn-gritty feel upon oral administration.

Claims

What is claimed;

1. A method of producing an aqueous stable drug composition which masks the taste of a drug in need of taste- masking, comprising the steps of: (a) mixing a drug in particulate form into a molten surfactant;

(b) solidifying the mixture of step (a) and reducing the solidified mixture into a powder;

(c) admixing the powder of step (b) with a lipid in a molten or semi-solid state to form lipid coated particles; and

(d) blending an aqueous solution with the lipid coated particles.

2. The method of claim 1 wherein the aqueous solution is blended with the lipid coated particles while the lipid is in a molten or semi-solid state.

3. The method of claim 2 wherein the surfactant comprises an anionic surfactant.

4. The method of claim 3 wherein the aqueous solution further comprises a sweetener.

5. The method of claim 4 wherein the aqueous solution is present in an amount of from about 80 to about 95 weight percent of the composition and the^' aqueous solution comprises from about 40 to about 65 wt. percent sweetener.

6. The method of claim 5 wherein the drug is present in an amount of from about 1.5 to about 8 wt.%, and the lipid is present in an amount of from about 0.8 to about 8 wt.%, of the drug composition.

7. The method of claim 6 further comprising a polymer suspension agent in an amount of from about 0.1 to about 2 wt.%, and wherein the surfactant is present in an amount of from about 0.2 to about 4 wt.%, of the drug composition.

8. The method of claim 7 wherein the drug is selected from the group consisting of cimetidine, ranitidine, ibuprofen, acetaminophen, and erythromycin.

9. The method of claim 7 wherein the drug is cimetidine.

10. The method of claim 8 wherein at least 70 wt% of the surfactant is added to the drug composition in step (a).

11. The method of claim 2 wherein the aqueous solution is blended with the lipid coated particles while the lipid is in a molten state.

12. The method of claim 11 wherein the surfactant comprises an anionic surfactant, and wherein the drug is present in an amount of from about 1.5 to about 8 wt.%, the lipid is present in an amount of from about 0.8 to about 8 wt.%, the surfactant is present in an amount of from about 0.2 to about 4 wt.%, the aqueous solution is present in an amount of from about 80 to about 95 wt.% and further comprises from about 40 to about 65 wt.% sweetener, and wherein the drug composition further comprises from about 0.2 to about 1.2 wt.% of a polymer suspension agent.

13. An aqueous stable drug composition which masks the flavor of a drug in need of taste-masking, comprising from about 1.5 to about 8 wt.% of a drug selected from the group consisting of cimetidine, ranitidine, ibuprofen, acetaminophen, and erythromycin; from about 0.8 to about 8 wt.% of a lipid; from about 0.2 to about 4 wt.% of a surfactant; from about 80 to about 95 wt.% of an aqueous solution comprising from about 40 to about 65 wt.% sweetener; and from about 0.2 to about 1.2 wt.% of a polymer suspension agent.

14. The drug composition of claim 13 wherein the surfactant comprises an anionic surfactant.

15. The drug composition of claim 14 wherein the drug comprises cimetidine.

16. A method of producing an aqueous stable drug composition which masks the flavor of a drug in need of taste- masking, comprising the steps of:

(a) mixing a drug selected from the group consisting of cimetidine, ranitidine, ibuprofen, acetaminophen, and erythromycin in particulate form into a molten or semi-solid lipid; and

(b) adding an emulsifier, a polymer and an aqueous solution to the mixture of step (a) to form the stable aqueous taste-masked drug composition.

17. The method according to claim 16 wherein the aqueous solution comprises a sweetening agent.

18. The method of claim 17 wherein the drug is cimetidine.

19. The method of claim 17 wherein the aqueous solution comprises above about 50% by weight sweetener.

20. A method of producing a stable drug composition which masks the flavor of a drug in need of taste-masking, comprising the steps of:

(a) providing a mixture of a lipid comprising an emulsifier, the lipid being in a molten or semi- solid state;

(b) admixing to the lipid mixture of step (a) a drug selected from the group consisting of cimetidine, ranitidine, ibuprofen, acetaminophen, and erythromycin in particulate form;

(c) adding a polymer solution to the mixture of step (b) to form a concentrated drug composition; and

(d) diluting the concentrated composition with an aqueous solution while the lipid is in a molten or semi-solid state to produce the stable taste-masked drug composition.

21. The method of claim 20 wherein the aqueous solution further comprises a sweetener.

22. The method of claim 21 wherein the drug is cimetidine.

23. The method of claim 21 wherein the aqueous solution comprises above about 50% by weight sweetener.