AU2004202902A1 - Pharmaceutical composition comprising skim milk powder - Google Patents

Description

AUSTRALIA

Patents Act COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority Related Art: Name of Applicant: Alpex Pharma SA Actual Inventor(s): Federico Stroppolo, Franco Ciccarello, Rita Milani, Lorenzo Bellorini Address for Service and Correspondence: PHILLIPS ORMONDE FITZPATRICK Patent and Trade Mark Attorneys 367 Collins Street Melbourne 3000 AUSTRALIA Invention Title: PHARMACEUTICAL COMPOSITION COMPRISING SKIM MILK POWDER Our Ref 723057 POF Code: 888/468781 The following statement is a full description of this invention, including the best method of performing it known to applicant(s): -1- 6006q WO 03/053415 PCT/GB02/05825 PHARMACEUTICAL COMPOSITION COMPRISING SKIM MILK POWDER FIELD OF THE INVENTION The present invention relates to pleasant-tasting compositions made from an unpleasant-tasting therapeutic agent and a taste-masking agent, oral dosage forms of such compositions, methods of making the compositions and methods of treating therewith.

Many dosage forms of therapeutic agents are designed to be administered orally. This route of administration is convenient, economical and effective in quickly and easily placing the desired dosage of a therapeutic agent in contact with the relatively large surface membrane of the stomach which has a rich supply of capillaries for passage into the bloodstream. A common disadvantage associated with many such oral dosage forms is the presence of an objectionable or unpleasant taste.

The presence of an objectionable or unpleasant taste can affect patient compliance adversely, especially for therapeutic agents in which an extended or frequent course and/or large doses are indicated. Thus, it has been recognized that improving the taste of unpleasant-tasting therapeutic agents can affect patient compliance positively.

REPORTED DEVELOPMENTS Compositions have been developed for the purposes of improving the taste of unpleasant-tasting therapeutic agents. For example, British Patent No. 1,257,594 to the Lepetit Group (hereinafter "the '594 patent") discloses a composition comprising aluminum sodium silicate and powdered milk. The composition is prepared by suspending-aluminum sodium silicate and powdered milk in water and then drying the suspension by evaporation in vacuo either by heating the mixture under reduced pressure or by lyophilization. The composition formed in accordance with this process is disclosed as distinctly different from a composition of aluminum sodium silicate and powdered milk formed by dry blending insofar as the dry blended WO 03/053415 PCT/GB02/05825 composition is not considered to be effective in masking the unpleasant taste of aluminum sodium silicate.

U.S. Patent No. 5,785,984 to Kurihara et. al. (hereinafter "the '984 patent") discloses a taste-modifying, bitterness-masking and bitterness-decreasing agent comprising a protein-lipid complex which can be added to a food, pharmaceutical or cosmetic that has a bitter-tasting component. The compositions of the '984 patent are produced by a relatively complicated process in which the protein-lipid complex is itself created in a multi-step process and then combined with a food, pharmaceutical or cosmetic that has a bitter-tasting component.

SUMMARY OF THE INVENTION In accordance with the present invention, there is provided a pharmaceutical composition comprising therapeutic agent generally speaking an unpleasant-tasting one and skim milk powder. The agent may be any substance or mixture of substances intended for oral administration that has curative, beneficial and/or nutritional value in humans. Typically it has a substantially stable unpleasant taste.

The skim milk powder suitable for use may be any commercially available milk powder, or synthetic equivalent thereof, usually having a fat content of less than about 1.25 wt.% and a moisture content of less than about 4 The composition of the present invention, preferably in oral dosage form, may further comprise a conventional pharmaceutical excipient. The excipient can serve a number of functions, for example, further enhancing the taste of the composition and/or contributing to the physical properties of oral dosage forms made therefrom.

A further aspect of the present invention is a method of making a pharmaceutical composition comprising the step of dry blending such therapeutic agent and skim milk powder in an amount sufficient to mask the (unpleasant) taste of the therapeutic agent. The therapeutic agent and the skim milk powder are combined in a ratio sufficient to provide effective taste-masking of the therapeutic agent, 1 WO 03/053415 PCT/GB02/05825 preferably in a ratio of skim milk powder to therapeutic agent of from at least 1:1, typically from about 1:1 to about 1,000,000:1.

There are important advantages that stem from the formulation and use of the present invention. The use of skim milk powder is effective in masking the taste of many unpleasant-tasting therapeutic agents. It is also an inexpensive, pharmaceutically acceptable and readily available material that can contribute positively to the physical properties required of many oral dosage forms. Further, compositions of the present invention are able to be formed by conventional and inexpensive production techniques. Such compositions are suitable for use in the formulation of a wide variety of oral dosage forms.

DETAILED DESCRIPTION OF THE INVENTION The composition of the present invention comprises a therapeutic agent and skim milk powder.

The term "therapeutic agent" as relevant for the purposes of the present invention includes any substance or mixture of substances intended for oral administration that has curative, beneficial and/or nutritional value in humans and which has a substantially unpleasant taste, either alone or in combination with other substances. The term "unpleasant taste" is defined for present purposes as a taste which gives rise to a statistically significant rating of possessing an objectionable taste when the unmasked form of the therapeutic agent having such taste is provided in a random sampling to a group of humans having an ordinary perception of taste.

Examples of such therapeutic agents are set forth in table 1 below.

TABLE 1 Category Agent Typical Dosage Range ACE Inhibitor Enalapril 2.5 mg 20 mg Captopril 12.5 mg- 50 mg Ramipril 2.5 mg 5 mg Analgesic Acetaminophen 100 mg 500 mg_ Antidepressant Imipramine 10 mg- 50 mg WO 03/053415 WO 03/53415PCT/GBO2/05825 Citaloprarn Fluexitine 20 mg 10me-20mg Antihistaminic Astemizole 5 mg 10 mg Cetirizine 5 mg -10 mg Clemastine 1.34 mg 2.68 mg Ebastine 10 mg Fexofenadine 30 mg 180 mg 10 mg Antiulcerative Famotidine 20 mg 40 mg Cimetidine 20 mg 800 mg Omeprazole 10 rng 40 mg Anti-arrhythmic Acebutolol. 200 mg 400 mg Amiodarone 100 mg 200 mg Atenolol 25 mg 100 mg Carteolol 5 mg 20 mg Verapamil 120 mg 240 mg Beta adrenergic agonist Albuterol 2 mg 4 mg Dopexamine 50 mg Formoterol 6 mg 12 mg Calcium antagonist Diltiazem 60 mg 300 mg Lacidipine 2 mg -4 mg Nicardipine 20 mg Nifedipine 5 mg 20 mg Verapamil 20 mg 400 mg Corticosteroid Budesonide 200 mg 400 mg Dexomethasone 0.5 mg- 10 mg Prednisolone 5m g -15 mg.

COX-2 Inhibitor Rofecoxib 12.5 mg 25 mg Celecoxib 100 mg 200 mg Decongestant Phenyleprine 1.25 mg 20 mg Energy promoter Carnitine 50 mg 500 mg 2 mg 100 mg Expectorant Guaifenesin 50 mg 1200 mg Lipid regulating drug Lovastatine 10 mg -20 mg Mineral salt Boron 20 mg 200 mg Calcium 50 mg 2000 mg Chloride 20 mg 100 mg Chromium 0.02 mg 0.2 mg Copper 0.6 mg- 5 mg Iodine 20 mg 200 mg Iron 2 mg Magnesium 10 mg -I000 mg Manganese 0.6 mg 10 mg Molybdenum 20 mg 200 mg Nickel 0.5 mg Potassium 20 mg 1000 mg Phosphorus 50 mg 1500 mg I_ Selenium 5 mg 100 mg PCT/GB02/05825 WO 03/053415 Silicon Tin Vanadium Zinc 2 mg-20 mg 5 mg 100 mg 5 mg 100 mg 0.6mg- 100mg Mucolytic Natural product Narcotic Non-Steroidal Anti-Inflammatory Drug Tranquilizer non narcotic Vitamin Ambroxol Carbocisteine N-Acetylcysteine Sobrerol 30 mg -60'mg 200 mg -275 mg 50 mg 1000 mg 200 mg,- 300 mg

I

Acerola Ginseng GuaranA Lycopene 5 mg 5000mg 0.5 mg 5.000 mg 5 mg 500mg 5 mg 5000mg Fentanyl Morphine Methadone 0.05 mg 7.6 mg -75 mg 5 mg 100mg Aceclofenac Ibuprofen Ketoprofen Ketorolac Naproxen Nimesulide 50 mg 1200 mg 25 mg -200 mg 10 mg 250 mg 500 mg 50mgn- 100 mg

I

5mg- Buspirone Alprazolamn Camazepamn Clorazepamn Lorazepam Nitrazolamn 0.5 mg 3mg 10 mg 11.25 mg 50 mg I mg-2.5 mg 5 mg 8 mg- 1300mg Vitamin A Vitamin B, Vitamin B 2 Vitamin B 6 Vitamin B 12 Vitamin C Vitamin D 3 Vitamin E Vitamin K, Vitamin PP Pantothenic Acid Biotin Folic Acid 0.1 mg -4 mg 0.1 mg- 4mg 0.05 mg 4 mg 0.2 mg -4 mg 5 mg -2000 mg 0.5 Trg 20 mg 0.5 mg 0.5 mg 200 mg 1 mg-2Omg 1 mg 0.5 mg -l100mg.

30 m g- 1000 mg The invention includes within its scope the use of pharmaceutically acc eptable salts of any of the foregoing and mixtures of two or more of any of the foregoing.

WO 03/053415 PCT/GB02/05825 Preferred therapeutic agents for use in the composition of the present invention are minerals, vitamins, natural products, antihistaminics, antiuceratives, corticosteroids, antidepressants, mucolytics, expectorants, decongestants, antitussives and analgesics. Particularly preferred therapeutic agents are: calcium; vitamin D 3 acerola; vitamins BI, B 6 and PP; acerola; ginseng; guaranA; clemastine fumarate; cetirizine; famotidine; prednisolone salts, imipramine, N-acetylcysteine, guaifenesin, phenylephrine, dextromethorpan, acetaminophen, and fexofenadine.

The therapeutic agent may include two or more substances having the same or different beneficial properties may be used. For example, the therapeutic agent may comprise a combination of vitamins, minerals and other dietary supplements in relative proportions suitable for the formation of an oral dosage form that provides substantially all of a person's daily nutritional needs.

The therapeutic agent is included in the composition in an amount sufficient to impart to oral dosage forms made therefrom the desired curative, beneficial and/or nutritional effect. Such amount will vary in accordance with a number of factors including, for example, the particular species of therapeutic agent used, the presence of other ingredients, the specific type of oral dosage formulation employed, and the particular application in which the composition is intended to be used. It is believed that in most applications, the amount of therapeutic agent included in the composition will be from about 0.01 wt.% to about 50.00 In preferred form, the amount of therapeutic agent included in the composition will be from about 0.05 wt.% to about 30.00 and even more preferably from about 0.09 wt.% to about 8.33 wt.%.

The use of the present invention is particularly effective with a therapeutic agent where unpleasant taste is substantially stable over time, that is, the degree of unpleasantness does not intensify due to chemical changes in the therapeutic agent, for example, through hydrolysis, oxidization, or degradation, of one or more constituents comprising the agent. An example of a therapeutic agent with an unpleasant taste that is not substantially stable over time is acetylsalicylic acid (ASA).

WO 03/053415 PCT/GB02/05825 In the presence of moisture, ASA is known to hydrolyze into acetic and salicylic acids. The presence of acetic acid resulting from hydrolysis can increase substantially the unpleasant taste of ASA. As a consequence, an amount of skim milk powder which is effective in masking the taste of unhydrolyzed ASA may be rendered less effective or even ineffective in masking the taste of ASA which has hydrolyzed.

As set forth above, the term "skim milk powder" is defined for present purposes as the solids component of skim milk in powder form with no more than about 4 moisture content and no more than about 1.25% fat content. Skim milk powder is made commonly by spray drying liquid skim milk and comprises typically from about 34% to about 37% protein; from about 49% to about 52% carbohydrate; from about 8% to about 9% ash; minerals, for example, calcium, sodium, potassium, phosphorus, iron, magnesium and zinc; and amino acids, for, example, isoleucine, leucine, lysine, methionine and phenylalanine. It is further considered within the scope of the present invention to use in place of or in combination with the skim milk powder a synthetic mixture of some or all of the components found in skim milk powder those identified above preferably including milk protein(s)).

The skim milk powder is included in the composition in an amount at least sufficient to mask the taste of the unpleasant-tasting therapeutic agent. An amount of skim milk powder in excess of the amount required to mask the taste of the unpleasant-tasting therapeutic agent may be desired in applications in which other desired properties are sought. The amount of skim milk powder will vary in accordance with a number of factors including, for example, the particular species of therapeutic agent used, the presence of other ingredients, the specific type of the oral dosage formulation, and the particular application in which the composition is intended to be used. It is believed that for most applications, the ratio of skim milk powder to therapeutic agent will be from about 1:1 to about 1,000,000:1. In preferred form, the ratio will be from about 1:1 to about 1,000:1, and even more preferably from about 1:1 to about 100:1. (These are generally weight ratios).

WO 03/053415 PCT/GB02/05825 While not intending to be bound by any particular theory, it is believed that the proteins in the skim milk powder act to mask the taste of the therapeutic agent by blocking the taste receptors located on the tongue. This blocking action may occur either by preferential binding of the proteins to receptor sites, by formation of a film over the receptor site which acts as a physical barrier to the therapeutic agent, or by some other mechanism. The carbohydrates and sugars present in skim milk powder enhance the palatability of the compositions and contribute to the physical characteristics of the composition.

The composition of the present invention may include also conventional excipients of the type used in pharmaceutical compositions. Examples of suitable excipients include: diluents, binders, disintegrants, surfactants, hydrophilic polymers, film-coating polymers, lubricants, glidants (or anti-adherents), plasticizers, pH modifiers, preservatives, coloring, flavoring and/or aromatic substances.

There are applications in which the selected therapeutic agent is administered in small doses. In such applications, diluents are used to increase the volume occupied by a unit dose of the therapeutic agent so that the oral dosage form containing the therapeutic agent does not have inconveniently small dimensions.

Diluents are selected in such applications so as to not inhibit the bioavailability of the therapeutic agent or impair the mechanical characteristics of the oral dosage form that is used. Examples of suitable diluents include microcrystalline cellulose; lactose, sucrose, fructose, glucose, dextrose, or other sugars; dibasic calcium phosphate; calcium sulfate; cellulose; ethylcellulose; cellulose derivatives; kaolin; mannitol, lactitol, maltitol, xylitol, sorbitol, or other sugar alcohols; dry starch; dextrin, maltodextrin or other polysaccharides; inositol; or mixtures thereof.

A binder may be used in the composition of the present invention to improve the physical properties of a oral dosage forms such as tablets made therefrom. In those applications in which the therapeutic agent has low bioavailability, a relatively large quantity of the therapeutic agent is required in each unit dose. When the WO 03/053415 PCT/GBO2/05825 therapeutic agent also exhibits poor pressability (the ability to be pressed into tablet form), such compositions yield oral dosage forms which have low strength and are unacceptably friable. The addition of a binder material to such compositions imparts cohesiveness to the composition and improves its physical properties. Examples of suitable binders include starches, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, polyvinyl pyrrolidone, acacia, guar gum, hydroxyethylcellulose, agar, calcium carrageenan, sodium alginate, gelatin, saccharides (including glucose, sucrose, dextrose and lactose), molasses, extract of Irish moss, panwar gum, ghatti gum, mucilage ofisapol husk, carboxymethylcellulose, methylcellulose, veegum, larch arbolactan, polyethylene glycols, waxes and mixtures thereof.

A disintegrant may be used in the composition of the present invention to promote rapid decomposition of an oral dosage form thereof following administration.

Rapid decomposition of the oral dosage form insures that the therapeutic agent is released quickly following administration. By providing a component in an oral dosage form which is readily soluble in the oral cavity, the oral dosage form is readily disintegrated when administered. Examples of suitable disintegrants include starches, sodium starch glycolate, crospovidone, croscarmellose, microcrystalline cellulose, low substituted hydroxypropyl cellulose, pectins, potassium methacrylatedivinylbenzene copolymer, polyvinyl alcohol, thylamide, sodium bicarbonate, sodium carbonate, starch derivatives, dextrin, beta cyclodextrin, dextrin derivatives, magnesium oxide, clays, bentonite and mixtures thereof.

A surfactant may be used in the composition of the present invention to disperse the therapeutic agent at the situs of release. Examples of suitable surfactants include nonionic surfactants, for example, sorbitan sesquioleate, polyoxyethylene sorbitan monooleate, polyoxyethylene monostearate, glycerol monostearate, propylene glycol monolaurate, polyoxyethylene lauryl ether, polyoxyethylene cetyl WO 03/053415 PCT/GB02/05825 ether or polyoxyethylene hydrogenated castor oil, and ionic surfactants such as sodium dodecyl sulfate or benzalkonium chloride.

Examples of suitable hydrophilic polymers include hydroxypropylmethyl cellulose; carbomers; polyethylene oxides; hydroxypropyl cellulose; hydroxyethyl cellulose; carboxymethylcellulose; sodium carboxymethylcellulose; carboxyvinyl polymers; polyvinyl alcohol; glucans; scleroglucans; mannans; xanthans; carboxymethylcellulose and its derivatives; methylcellulose; cellulose; crosslinked polyvinylpyrrolidone; carboxymethyl starch; potassium methacrylate-divinylbenzene copolymer; hydroxypropylcyclodextrin; alpha, beta, gamma cyclodextrin or derivatives and other dextran derivatives; natural gums; seaweed extract; plant exudate; agar; agarose; algin; sodium alginate; potassium alginate; carrageenan; kappa-carrageenan; lambda-carrageenan; fucoidan, furcellaran; laminarin; hypnea; eucheuma; gum arabic; gum ghatti; gum karaya; gum tragacanth; guar gum; locust bean gum; quince psyllium; flax seed; okra gum; arabinogalactin; pectin; scleroglucan; dextran; amylose; amylopectin; dextrin; acacia; karaya; guar; a swellable mixture of agar and carboxymethyl cellulose; a swellable composition comprising methyl cellulose mixed with a sparingly cross-linked agar; a blend of sodium alginate; and locust bean gum.

Examples of suitable film-coating polymers include enteric polymer coating materials, such as, for example, cellulose acetate phthalate, cellulose acetate trimaletate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, Eudragit® poly acrylic acid and poly acrylate and methacrylate coatings, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, shellac; hydrogels and gel-forming materials, such as, for example, carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, polyvinyl alcohol, hydroxyethyl cellulose, methyl cellulose, gelatin, starch and cellulose-based cross-linked polymers, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, WO 03/053415 PCT/GB02/05825 crosslinked starch, microcrystalline cellulose, chitin, cellulose acetate, cellulose proprionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose triacetate, aminoacryl-methacrylate copolymer (Eudragit® RS-PM, Rohm Haas), pullulan, collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, carboxymethyl ethyl cellulose, swellable hydrophilic polymers, poly(hydroxyalkyl methacrylate) wt. -5k 5,000k), polyvinylpyrrolidone wt. -10k 360k), anionic and cationic hydrogels, polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin wt. -30k 300k), polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, Polyox® polyethylene oxides wt. -100k 5,000k), AquaKeep® acrylate polymers, diesters of polyglucan, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glycollate Explotab®; Edward Mandell C.

Ltd.); hydrophilic polymers such as polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, poly(ethylene terphthalate), poly(vinyl isobutyl ether), polyurethane, polyethylene oxides Polyox®, Union Carbide), methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate, ethylcellulose; cellulose butyrate, cellulose propionate, gelatin, collagen, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, copolymers of methacrylic acid or methacrylic acid Eudragit®, Rohm and Haas), other acrylic acid derivatives, ethyl acrylate-methyl methacrylate copolymer, sorbitan esters, polydimethyl siloxane, natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, gums: arabic, karaya, locust bean, tragacanth, carrageenan, guar, xanthans, scleroglucan and mixtures and blends thereof.

WO 03/053415 PCT/GB02/05825 A lubricant may be used in the composition of the present invention to facilitate manufacturing of oral dosage forms made therefrom. In applications in which the composition is tableted, a lubricant is included in the composition so that the pressed tablet will slide from the die in which it is pressed without mechanical damage to the tablet. Lubricants can also effect the manner in which individual components of a powder slide when pressed into tablets, reducing the formation of voids within a tablet, thereby reducing tablet to tablet weight variation due to void formation. Examples of suitable lubricants include stearic acid, magnesium stearate, talc, calcium stearate, hydrogenated vegetable oils, sodium benzoate, sodium chloride, leucine, magnesium lauryl sulfate, colloidal silicon dioxide, glyceryl mono stearate, waxes, hydrogenated oils, and polyethylene glycol.

Examples of suitable gliants (or anti-adherents) include colloidal silica, fumed silicon dioxide, silica hydrogels, talc, fumed silica, gypsum, kaolin, glycerol monostearate and magnesium stearate.

Suitable plasticizers include acetylated monoglycerides, butyl phthalyl butyl glycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate, ethyl phthalyl ethyl glycolate, glycerin; propylene glycol, triacetin, citrate, tripropioin, diacetin, dibutyl phthalate, acetyl monoglyceride, polyethylene glycols, castor oil, triethyl citrate, polyhydric alcohols, glycerol, acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate, tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-ethylhexyl azelate, dibutyl sebacate, glyceryl monocaprylate, glyceryl monocaprate.

Examples of suitable pH modifiers include organic acids such as citric acid, fumaric acid, tartaric acid, succinic acid, ascorbic acid, malic acid, glutaric acid, adipic acid, lactic acid, fumaric acid, salts of these acids; salts of inorganic acids and WO 03/053415 PCT/GB02/05825 magnesium hydroxide; sodium, potassium, calcium and magnesium salts of carbonate, bicarbonate, citrate and phosphate; and amino acids such as arginine, glycine and lysine.

Flavoring agents may be used in the compositions of the present invention to make oral dosage forms made therefrom more palatable than they would be in the absence of such flavoring agents. Unflavored oral dosage forms tend to be perceived as gritty or chalky in the absence of such flavoring agents. Flavoring agents play no essential part in the-performance of the skim milk powder in masking the unpleasant taste of the therapeutic agent and, in fact, are ineffective by themselves in rendering palatable therapeutic agents which have an objectionable taste in the absence of skim milk powder. Suitable flavoring agents may provide sweetness, and/or a particular flavor, and include honey flavor, banana flavor, wild berry flavor, glycyrrhiza (licorice) flavor, chocolate flavor, vanilla flavor caramel flavor, and various forms of sugar.

The excipient is included in the composition in an amount sufficient to impart or enhance the physical and/or organoleptic properties of oral dosage formulations made therefrom. The amount of excipient will vary in accordance with a number of factors including, for example, the particular species of therapeutic agent used, the amount of skim milk powder used, the presence of other ingredients, the specific type of oral dosage formulation, and the particular application in which the composition is intended to be used. It is believed that for most applications, the amount ofexcipient included in the composition will be from about 0.1 to about 99 In preferred embodiments, the amount ofexcipient included in the composition will be from about 0.2 wt.% to about 90 and even more preferably from about 0.3 wt.% to about 70 wt.%.

Flowability refers to the ability of a bulk powder to fill a mold (as for pressing into a tablet). It is expressed as the tendency of a fixed volume of a powder to spread (rather than to form a conical shaped mound) when poured onto a flat surface under WO 03/053415 PCT/GB02/05825 controlled conditions and is measured in units of degrees of angle of the conical mound with respect to the surface on which it sits. In preferred form, the composition of the present invention will have a flowability as measured by an angle of repose between about 30 to about Density is defined in the conventional sense of mass/unit volume. The bulk density of a powder composition includes the interparticulate void volume. As a result, the bulk density of a powder composition depends on both the density of the powder particles and the spatial arrangement of particles in the powder volume. In measuring the density of powders, bulk density is determined by measuring the volume of a known mass of powder that has been passed through a screen into a graduated cylinder. Tapped density is determined after a standard compacting vibration has been applied to the volumetric vessel. Lower density powders tend to be more easily pressed into cohesive tablets than high density powders, and low density powders tend to achieve cohesiveness at lower pressing pressure, and therefore generally also yield lower density tablets. In preferred form, the composition of the present invention has a bulk density of from about 0.4 to about 0.9 g/ml and a tapped density of from about 0.5 to about 1.1 g/ml.

The composition of the present invention for oral use can be in any form suitable for the oral administration of a therapeutic agent. For example, the oral .dosage formulation may be in the form of a chewable tablet, swallowable tablet, effervescent tablet, fast melt tablet, multiparticulate capsule, dry syrup, powder, sprinkle, or sachet. In preferred embodiments, the oral dosage formulation is in the form of a chewable tablet or a fast melt tablet. In such embodiments, the tablet may be uncoated or it may be coated by known techniques for a variety of purposes including, for example, protection of the composition, or improving the aesthetics of the tablet.

Tablets can be characterized by homogeneity, hardness, friability, speed of disintegration, and speed of dispersibility of the therapeutic agent contained therein.

WO 03/053415 PCT/GB02/05825 Homogeneity refers to the variability of the amount of therapeutic agent contained in random samples of the bulk powder or dosage forms. Defined in terms of stated dose, it is preferred that any one sample of an oral dosage form of the present invention contain between about 85% and about 115% of the stated dose of the therapeutic agent. A 10 unit sampling of an oral dosage form of the present invention, when.

averaged, will provide preferably between about 95% and about 105% of the stated dose of the therapeutic agent.

Tablet hardness is expressed as the amount of force that must be applied for a tablet to break. One method of measuring tablet hardness employs an apparatus known as a Schleuniger tablet hardness tester. According to this method, a force is applied perpendicular to the edge of the tablet and directed across the diameter of the tablet under test until the tablet fractures. In preferred embodiments of the present invention in which the oral dosage form is a chewable tablet, the tablet has a hardness, as measured by a Schleuniger tablet hardness tester, of from about 0.5 Kp to about Kp and more preferably from about 1 Kp to about 20 Kp. In preferred embodiments of the present invention in which the oral dosage form is a fast melt tablet, the tablet has a hardness, as measured by a Schleuniger tablet hardness tester, of from about Kp to about 10 Kp and more preferably from about 1 Kp to about 10 Kp. In preferred embodiments of the present invention in which the oral dosage form is an effervescent tablet, the tablet has a hardness, as measured by a Schleuniger tablet hardness tester, of from about 1 Kp to about 25 Kp and more preferably from about 3 Kp to about 20 Kp.

Friability is measured by tumbling a standard sampling of tablets in a standard apparatus at a standard speed for a standard time and measuring the weight loss of the tablets due to material being ablated from the tablets. In preferred embodiments of the present invention in which the oral dosage form is a tablet, the tablet has a friability of from about 0.1% to about and more preferably from about 0.2% to about 1%.

WO 03/053415 PCT/GB02/05825 Disintegration time is measured by placing the tablet in a standard gastric solution held at a given temperature with a standard amount'of agitation. The time recorded is the time elapsed from contact with the solution until the tablet falls into pieces small enough to pass through a standard screen. In preferred embodiments of the present invention in which the oral dosage form is a non-effervescent tablet, the tablet has a disintegration time of from about 10 seconds to about 30 minutes and more preferably from about 30 seconds to about 15 minutes. In preferred embodiments of the oral dosage form of the present invention in which the oral dosage form is in the form of an effervescent tablet, the tablet will have a disintegration time from about 10 seconds to about 5 minutes, and more preferably from about 30 to about 3 minutes.

The composition of the present invention can be made in any suitable way, for example by dry blending the therapeutic agent and skim milk powder and optional ingredients to homogeneity. The dry blended composition is suitable for use in forming the oral dosage formulations of the present invention and, upon ingestion, will mask effectively the unpleasant taste of the therapeutic agent.

EXAMPLES

The following compositions are illustrative of the taste-masking effect of the present invention as applied to a variety of therapeutic agents which are recognized as having an unpleasant taste. The various sugars, sweeteners, and flavoring agents employed in the compositions described below are insufficient on their own to eliminate the unpleasant taste of the therapeutic agents with which they are combined, but serve only to enhance further the taste of the resulting composition and/or the physical properties of the oral dosage forms made therefrom.

The oral dosage forms described in Example Nos. 1 to 21 set forth below were evaluated for their taste. The taste test was designed to elicit subjective evaluations of taste with respect to various flavor characteristics such as sweet, salty, sour, bitter, WO 031053415 PCT/GB02/05825 warm, cool, burning, irritating, anesthetic, and aftertaste. A group of volunteer tasters were provided a series of samples and asked to rate each sample on a scale from 1 (lowest) to 5 (highest) for each taste characteristic. The samples that were provided comprised both unmasked therapeutic agents as well as oral dosage formulations in accordance with the present invention that included such therapeutic agents in combination with skim milk powder. The data collected from the volunteers (set out in tabular form in and found to provide a statistically significant change in taste ratings when comparing the unmasked therapeutic agent to the therapeutic agent as part of oral dosage formulations made in accordance with the present invention.

For Example Nos. 1 through 11, the ingredients were blended mechanically for 15 minutes at room temperature in a cube mixer, The resulting mixtures were tableted by a single punch tableting machine using a plane punch of 18 mm in diameter.

Example No. 1 In this example, the unpleasant chalky taste associated with calcium phosphate dibasic has been is eliminated effectively by the inclusion of skim milk powder in the tablet described below.

calcium phosphate dibasic 3.90 g skim milk powder 135.55 g sorbitol 108.70 g honey flavor 0.76 g banana flavor 1.09 g magnesium stearate 0.76 g The tablets produced in this example had a thickness of approximately 7.7 mm and a hardness of 23 Kp as measured by a Schleuniger tablet hardness tester, weighed 2.3 g WO 03/053415 PCT/GB02/05825 each, contained 10.6 mg of calcium and 8.1 mg of phosphorous per tablet, and had a pleasant and sweet taste when dissolved in the oral cavity.

Sm f e SStanardization B tter Sweet SaltINa Buing 1hrithiinesthitc- asiaMs it;- As M 7 24 20 20 28 20 20 20 20 60 28 1.2 1 1 1.4 I I I I 3 1.4 3 56 20 52 20 20 20 20 20 80 1 2.8 1 2.6 1 1 1 1 I 4 1 The therapeutic agent has an unpleasant taste and an aftertaste due to a heartily chalky heetagilone sensation.

A sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

Example No. 2 In this example, the taste-masking effect is demonstrated in a tablet that includes two therapeutic agents, namely, calcium phosphate dibasic and vitamin D 3 which is known to have a strong and unpleasant vitamin taste.

calcium phosphate dibasic 3.12 g vitamin D 3 0.17 g skim milk powder 109.14 g dextrose 86.96 g magnesium stearate 0.61 g The tablets produced in this example had a thickness of approximately 7.8 mm and a hardness of 11 Kp as measured by a Schleuniger tablet hardness tester, weighed 2.3 g each, contained 10.6 mg of calcium, 8.1 mg of phosphorus, and 5pg of vitamin D 3 per tablet, and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GB02/05825 Example No. 3 In this example, the taste-masking effect is demonstrated by a tablet that includes calcium phosphate dibasic and acerola which is an excellent source of vitamin C and is recognized as having an unpleasant acidic taste.

calcium phosphate dibasic 3.90 g.

acerola 38.37 g skim milk powder 97.18 g fructose 108.70 g wild berry flavor 1.09 g magnesium stearate 0.76 g The tablets produced in this example had a thickness of approximately 7.5 mm and a hardness of 27 Kp as measured by a Schleuniger tablet hardness tester, weighed 2.3 g each, contained 10.6 mg of calcium, 8.1 mg of phosphorus, and 60 mg of vitamin C per tablet, and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GBO2/05825 MO g tinfZM' 2040 2 20 20 20 20 20 20 52 20 52 2 1 1 1 1 1 2.6 1 2.6 60 20 24 24 20 20 20 20 64 1 3 1 1 1 1 3.2 The therapeutic agents have an unpleasant bitter and acid persistent taste.

A sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

Example No. 4 This example demonstrates the taste-masking effect in a tablet that includes a combination of vitamins each of which is known to have a strong and unpleasant vitamin taste.

vitamin B 1 mononitrate 0.07 g vitamin B 6 0.09 g vitamin PP 0.82 g skim milk powder 57.80 g fructose 40.90 g magnesium stearate 0.32 g The tablets produced in this example had a thickness of approximately 7.7 mm and a hardness of 20 Kp as measured by a Schleuniger tablet hardness tester, weighed 2.3 g each, contained 1.50 mg of vitamin B, 2.00 mg of vitamin B 6 and 18.00 mg of vitamin PP per tablet, and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GB02/05825 3.2 1 1.4 1 1 1.8 1 1 3.2 1.2 3.4 64 20 40 20 20 20 20 20 68 28 72 3.2 1 2 1 1 I I 1 3.4 1.4 3.6 72 20 40 20 20 24 20 20 72 24 72 3.8 1 2 1 1 1.2 1 1 3.6 1.2 3.6 44 24 40 20 20 20 20 20 56 1 2.2 1.2 2 I I I 1 1 2.8 I Example No. This example demonstrates the taste-masking effect in a tablet that includes ginseng extract which is known to have an unpleasant bitter taste.

ginseng extract 4.55 g skim milk powder 54.00 g sorbitol 40.90 g glycirriza flavor 0.23 g magnesium stearate 0.32 g The tablets produced in this example had a thickness of approximately 7.4 mm and a hardness of 22 Kp as measured by a Schleuniger tablet hardness tester, weighed 2.2 g each, contained 100.00 mg of ginseng extract per tablet, and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GB02/05825 at s pIC un psau n 20 20 24 20 20 20 20 64 28 3 I 1 1.2 1 I i I I 3.2 1.4 3 a 20 44 20 32 44 20 20 20 48 68 1 2.2 I 1.6 2.2 1 1 1 I 2.4 3.4 1 Example No. 6 This example demonstrates the taste-masking effect in a tablet that includes guarana extract, another therapeutic agent which is known to have an unpleasant bitter taste.

guarana extract 2.27 g skim milk powder 56.05 g dextrose 40.90 g white chocolate flavor 0.46 g magnesium stearate 0.32 g The tablets produced in this example had a thickness of approximately 7.4 mm and a hardness of 23 Kp as measured by a Schleuniger tablet hardness tester, weighed 2.2 g each, contained 50.00 mg of guarana extract per tablet, and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GB02/05825 I The therapeutic agent has an unpleasant bitter taste and aftertaste.

A sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

Example No. 7 This example demonstrates the taste-masking effect in a tablet that includes clemastine fumarate, a pharmaceutical agent which is known to have an unpleasant bitter taste.

clemastine fumarate 0.09 g skim milk powder 58.23 g sorbitol 40.90 g white chocolate flavor 0.46 g magnesium stearate 0.32 g The tablets produced in this example had a thickness of approximately 7.4 mm and a hardness of 25 Kp as measured by a Schleuniger tablet hardness tester, weighed 2.2 g each, contained 2.00 mg of clemastine fumarate per tablet, and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GB02/05825 4.2 1 1 1.2 1 1.2 1.2 1.8 3.6 1.2 3.6 40 20 40 24 20 20 20 20 52 24 40 20 40 24 20 20 20 20 52 4 The therapeutic agent has an unpleasant bitter taste and aftertaste.

A sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

Example No. 8 This example demonstrates the taste-masking effect in.a tablet that includes cetirizine di-HCl, a pharmaceutical agent which is known to have an unpleasant bitter taste.

cetirizine di-HCI 0.45 g skim milk powder 57.87 g dextrose 40.90 g white chocolate flavor 0.46 g magnesium stearate 0.32 g The tablets produced in this example had a thickness of approximately 7.4 mm and a hardness of 18 Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 2.2 g. each, contained 10.00 mg. of cetirizine di-HCI per tablet, and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GB02/05825 Ann umber, of a ioEift; EliTh ngi nethiAfe nr~ ~~I Weell7 testers:~l 5 _tseplasan u We~Ant 20 24 28 36 32 20 28 52 24 3 1 1.2 1.4 1.8 1.6 1 1.4 2.6 1.2 3 24 40 20 40 20 20 20 20 24 60 24 1.2 2 1 2 1 1 1 1 1.2 3 1.2 Therapeutic agent shows a bitter taste and aftertaste, accompanied by a light burning and anesthetic sensations.

A sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

Example No. 9 This example demonstrates the taste-masking effect in a tablet that includes famotidine, a pharmaceutical agent which is known to have an unpleasant bitter taste.

famotidine 0.91 g skim milk powder 57.41 g saccharose 40.90g white chocolate flavor 0.46 g magnesium stearate 0.32 g The tablets produced in this example had a thickness of approximately 7.4 mm and a hardness of 18 Kp as measured by a Schleuniger tablet hardness tester, weighed 2.2 g each, contained 20.00 mg of famotidine, and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GB02/05825 Example No. This example demonstrates the taste-masking effect in a tablet that includes prednisolone sodium phosphate, a pharmaceutical agent which is known to have an unpleasant bitter taste.

prednisolone sodium phosphate 2.73 g skim milk powder 55.82 g fructose 40.90 g glycyrrhiza flavor 0.23 g magnesium stearate 0.32 g The tablets produced in this example had a thickness of approximately 7.4 mm and a hardness of 20 Kp as measured by a Schleuniger tablet hardness tester, weighed 2.2 g each, contained 60.00 mg of prednisolone sodium phosphate, and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GB02/05825 The therapeutic agent has a bitter and light salty taste.

A sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

Example No. 11 This example demonstrates the taste-masking effect in a tablet that includes imipramine HCI, a pharmaceutical agent which is known to have an unpleasant bitter taste.

imipramine HCI 1.14 g skim milk powder 57.41 g fructose 40.90 g glycyrrhiza flavor 0.23 g magnesium stearate 0.32 g The tablets produced in this example had a thickness of approximately 7.4 mm and a hardness of 23 Kp as measured by a Schleuniger tablet hardness tester, weighed 2.2 g each, contained 25.00 mg of imipramine HCI, and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GB02/05825 -i The therapeutic agent has an unpleasant bitter taste and aftertaste. Burning and anesthetic S sensation is very evident.

SA sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

Example No. 12 This example demonstrates the taste-masking effect in a tablet that includes vitamin PP, a therapeutic agent which is known to have an unpleasant taste.

vitamin PP 15.00 g skim milk powder 213.33 g aspartame 6.67 g vanilla flavor 8.34 g magnesium stearate 6.67 g The above ingredients were blended mechanically for 15 minutes at room temperature in a cube mixer. The resulting mixture was tableted by a single punch tableting machine using a plane punch of 12 mm in diameter to yield tablets with a thickness of approximately 3 mm and a hardness of 7.5 Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 300 mg each, contained 18.00 mg of vitamin PP, and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GB02/05825 72 20 .40 20 20 24 20 20 72 ':24 72 3.8 2 I I 1.2 I I 3.6 1.2 3.6 24 44 20 40 24 20 20 20 24 60 24 1.2 2.2 1 2 1.2 1 1 1 1.2 3 1.2 SThe therapeutic agent has an unpleasant bitter taste and aftertaste.

S A sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

Example No. 13 This example demonstrates the taste-masking effect in a tablet that includes Nacetylcysteine, a pharmaceutical agent which is known to have an unpleasant taste.

N-acetylcysteine 1 g skim milk powder 98.70 g honey flavor 0.1 g polyvinylpyrrolidone 0.2 g The N-acetylcysteine and skim milk powder were placed in an Aeromatic Strea 1 fluidized bed coating apparatus and granulated with an aqueous solution of the polyvinylpyrrolidone in 30 ml water. The mixture was dried for about 30 minutes at and then cooled. The honey flavor was added to the granules and the resulting mixture was blended for 15 minutes to reach homogeneity. The mixture was packaged in sachets of 20 g each to obtain a single dosage form of 200 mg of Nacetylcysteine for use in a 2 deciliter aqueous solution. The resulting solution had a pleasant taste in the oral cavity.

WO 03/053415 PCT/GB02/05825 48 2 1 2.4 I I 1 2 I 2.6 1.6 3 60 20 40 20 20 20 20 20 72 1 3 1 2 1 1 I I 1 3.8 I IN-accylysCInC 51snws a su rio typical tasic anu :r tasic.

A sweet sensation is obtained in the oral cavity, when the milk is added. Tablets have a pleasant taste.

Example No. 14 This example demonstrates the taste-masking effect in a chewable tablet that includes prednisolone sodium phosphate, a pharmaceutical agent which is known to have an unpleasant bitter taste.

prednisolone sodium phosphate 13.44 g skim milk powder 370.56 g chocolate flavor 14.0 g polyethylene glycol 20.0 g sorbitol 80.0 g xylitol 40.0 g mannitol 130.0 g citric acid 6.0 g aspartame 16.0 g magnesium stearate 10.0 g The skim milk powder, sorbitol, xylitol, mannitol, citric acid and aspartame were placed in an Aeromatic Strea 1 fluidized bed coating apparatus and granulated with an aqueous solution containing polyethylene glycol in 50 ml of demineralized water.

The granules were dried for about 40 minutes at about 55C and then cooled. The WO 03/053415 PCT/GB02/05825 remaining materials were added to the granules and the mixture was blended for minutes to reach homogeneity. The mixture was tableted by a single punch tableting machine using a toroidal punch of 12 mm in diameter to yield tablets with a thickness of approximately 4 mm and a hardness of about 1 Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 350 mg each, contained 6.72 mg ofprednisolone sodium phosphate, and had a pleasant taste when dissolved in the oral cavity.

mer Stanidardization Bitter Sweet aBi tatg 20 40 20 24 20 20 20 36 28 S. 3 1 2 1 1.2 1 I 1 1.8 1.4 T"l.e" 20 56 20 36 20 20 20 20 20 48 x mple-t- 1 2.8 1.8 I I I I I1 2.4 T i yg-i The therapeutic agent has a bitter and light salty taste.

,V l fE A sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

Example No. This example demonstrates the taste-masking effect in a chewable tablet that includes guaifenesin, a pharmaceutical agent which is known to have an unpleasant bitter taste.

guaifenesin 10.0 g skim milk powder 59.3 g chocolate flavor 2.25 g polyethylene glycol 3.2 g sorbitol 12.88 g xylitol 6.41 g WO 03/053415 PCT/GB02/05825 mannitol 20.83 g citric acid 0.96 g aspartame 2.57 g magnesium stearate 1.6 g The skim milk powder, sorbitol, xylitol, mannitol, citric acid and aspartame were granulated and dried in the manner described in Example 14. The remaining materials were added to the granules and the mixture was blended for 15 minutes to reach homogeneity. The mixture was tableted by a single punch tableting machine using a toroidal punch of 16 mm in diameter to yield tablets with a thickness of approximately 7 mm and a hardness of about 1.5 Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 1.2 g each, contained 100 mg of guaifenesin, and had a pleasant taste when dissolved in the oral cavity.

irofSanidation Bit Sweet Sa arm Cool Bning Irritating Anstheti Genera enerally tsters: 5 ste pleasant unipleasant TerapeutMic 72 20 40 20 20 36 20 20 80 20 agentalone 5" 3.6 1 2 I 1 1.8 1 I 4 I 4 T !of 28 48 20 40 20 20 20 20 36 48 28 E p'Ie 1.4 2.4 I 2 I 1 1.8 2.4 1.4 No ^1-S l 1.4 2.4 1 2 1 1 1 1 1.8 2.4 1.4 Example No. 16 This example demonstrates the taste-masking effect in a chewable tablet that includes guaifenesin and phenylephrine HCI, pharmaceutical agents which are known to have an unpleasant bitter taste.

guaifenesin 10.0 g WO 03/053415 PCT/GB02/05825 phenylephrine HC1 0.25 g skim milk powder 59.05 g chocolate flavor 2.25 g polyethylene glycol 3.2 g sorbitol 12.88 g xylitol 6.41 g mannitol 20.83 g citric acid 0.96 g aspartame 2.57 g magnesium stearate 1.6 g The skim milk powder, sorbitol, xylitol, mannitol, citric acid and aspartame were granulated and dried in the manner described in Example 14. The remaining materials were added to the granules and the mixture was blended for 15 minutes to reach homogeneity. The mixture was tableted by a single punch tableting machine using a toroidal punch of 16 mm in diameter to yield tablets with a thickness of approximately 7 mm and a hardness of about 1.5 Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 1.2 g each, contained 100 mg of guaifenesin and 2.5 mg of phenylephrine HCI and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GB02/05825 40 28 2.6 1 2 1 I I 1 1 2.2 1.4 3.2 44 28 24 28 20 20 20 20 44 44 44.

i2.2 .4 "1.2 1.4 I 1 I I 2.2 2.2 .2.2 hea eu i a en Therapeutic agents show a unpleasant bitter taste.

SA sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

Example No. 17 This example demonstrates the taste-masking effect in a fast melt tablet that includes guaifenesin and dextromethorphan HBr pharmaceutical agents which are known to have an unpleasant bitter taste.

guaifenesin 10.0 g dextromethorphan HBr 0.5 g skim milk powder 37.25 g chocolate flavor 2.25 g polyethylene glycol 4.62 g sorbitol 18.61 g xylitol 9.26 g mannitol 30.10 g citric acid 1.39 g aspartame 3.71g magnesium stearate 2.31 g The skim milk powder, sorbitol, xylitol, mannitol, citric acid and aspartame were granulated and dried in the manner described in Example 14. The remaining WO 03/053415 PCT/GB02/05825 materials were added to the granules and the mixture was blended for 15 minutes to reach homogeneity. The mixture was tableted by a single punch tableting machine using a toroidal punch of 16 mm in diameter to yield tablets with a thickness of approximately 7 mm and a hardness of about 2 Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 1.2 g each, contained 100 mg of guaifenesin and 5 mg of dextromethorphan HBr, and had a pleasant taste when dissolved in the oral cavity.

G72 24 76 84 20 20 20 20 40 36 20 72 24 76 i 4.2 1 1 1 I 2 1.8 1 3.6 1.2 3.8 Tlef4 36 36 20 24 20 20 20 20 32 56 32 1 1.1. 8 8 I 1.2 I I I 1 1.6 2.8 1.6 STherapeutic agents show a very bitter taste and aftertaste and results burning and irritating.

It is very unpleasant.

lt o .xampe A sweet sensation is obtained in the oral cavity, when the milk is added. Tablets have a Spleasant taste.

Example No. 18 This example demonstrates the taste-masking effect in a fast melt tablet that includes prednisolone sodium phosphate, a pharmaceutical agent which is known to have an unpleasant bitter taste.

prednisolone sodium phosphate 1.0 g skim milk powder 45.76 g chocolate flavor 2.64 g polyethylene glycol 3.0 g sorbitol 20.3 g xylitol 10.1 g WO 03/053415 WO 03/53415PCT/GB02/05825 mannitol 32.8 g citric acid 1.4 g aspartame 1.8 g magnesium stearate 1.2 g The skim milk powder, sorbitol, xylitol, mannitol, citric acid and aspartame were granulated and dried in the manner described in Example 14 except that 10 ml of demineralized water was used instead of 20 ml. The remaining materials were added to the granules and the mixture was blended for 15 minutes to reach homogeneity.

The mixture was tableted by a single punch tableting machine using a toroidal punch of 13 mm in diameter to yield tablets with a thickness of approximately 6 mm. and a hardness of about, 1 Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 600 mg each, contained 5 mg of prednisolone sodium.

phosphate, and had a pleasant taste when dissolved in the oral cavity.

N~imer, f Ater eneallyCZn...l *tAdardi:zatid61 Batter. SiVt gait7 W.'Aii coot B'irnn irrfti After~ .ti~~teis:taste; l .r ~fl uplesant /C 60 20 40 20 24 20 20 20 36 28 52 :agent alon 3 1 2 1 1.2 1 1 2.6 0altf 20 56 20 40 20 20 20 20 20 68 S 1 2.8 1 2 1 1 1. 1 1 3.4. 1 The therapeutic agent has a bitter and light salty taste.

4 i~b~t *E 'anipe., sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

WO 03/053415 PCT/GB02/05825 Example No. 19 This example demonstrates the taste-masking effect in a chewable tablet that includes acetaminophen, a pharmaceutical agent which is known to have an unpleasant bitter taste.

acetaminophen 22 g skim milk powder 53.02 g white chocolate flavor 2 g polyethylene glycol 2.86 g sorbitol 11.45 g xylitol 5.72 g mannitol 18.6 g citric acid 0.86 g aspartame 2.29 g magnesium stearate 1.2 g The skim milk powder, sorbitol, xylitol, mannitol, citric acid and aspartame were granulated and dried in the manner described in Example 19. The remaining materials were added to the granules and the mixture was blended for 15 minutes to reach homogeneity. The mixture was tableted by a single punch tableting machine using a toroidal punch of 13 mm in diameter to yield tablets with a thickness of approximately 5 mm and a hardness of about 5.5 Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 600 mg each, contained 110 mg of acetaminophen, and had a pleasant taste when dissolved in the oral cavity.

WO 03/053415 PCT/GB02/05825 20 28 36 20 20 20 20 52 24 48 2 I 1.4 1.8 1 I 1 I 2.6 1.2 24 56 20 32 28 20 20 20 28 60 i 1 2.8 I 1.6 1.4 I I I 1.4 3 1 e ec i t shows a slight bitter taste and aftertaste, similar to vanilla flavor.

abI o E-xamniple A sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste..

Example No. This example demonstrates the taste-masking effect of the present invention in a fast melt tablet that includes cetirizine di-HCI, a pharmaceutical agent which is known to have an unpleasant bitter taste.

cetirizine di-HCl 5.0 g skim milk powder 75.0 g caramel flavor 5.0 g polyethylene glycol 5.0 g sorbitol 30.0 g xylitol 20.0 g mannitol 51.5 g citric acid 2.0 g aspartame 4.0 g magnesium stearate 2.5 g The skim milk powder, sorbitol, xylitol, mannitol, citric acid and aspartame were granulated and dried in the manner described in Example 14. The remaining materials were added to the granules and the mixture was blended for 15 minutes to WO 03/053415 WO 03/53415PCT/GB02/05825 reach homogeneity. The mixture was tableted by a single punch tableting machine using a toroidal punch of 12 mun in diameter to yield tablets with a thickness of approximately 4.5 mmn and a hardness of about I Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 400 mg each, contained 10 mg of cetirizine di-HCl, and had a pleasant taste when dissolved in the oral cavity.

iner ofi Sti-dardizain Baii Sw~ 5atEM fi! C6o ~~Irr litating W ieic taste S e- 60 20 24 28 36 32 20 28 52 24 3 1 1.2 1.4 1.8 1.6 1 1.4 2.6 1.2 /Cbet~ Vra :3 0 20 26 26 20 20 20 40 7 19 2.5 1 1.3 1.3 1 1 1 2 3.6 STherapeutic agent shows a bitter taste and aftertaste, accompanied by a light bur Therpeui~ gentaloe ~anesthetic sensations.

~bi~h~f 1 l~J sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

Example No. 21 This example demonstrates the taste-masking effect in a fast melt tablet that includes fexofenadine, a pharmaceutical agent which is known to have an unpleasant bitter taste.

fexofenadine 20.0 g skim milk powder 100.0 g caramel flavor polyethylene glycol 8.33 g sorbitol 129.67 g Xylitol 50.0 g WO 03/053415 PCT/GB02/05825 mannitol 75.67 g citric acid 4.0 g aspartame 4.0 g magnesium stearate 3.33 g The skim milk powder, sorbitol, xylitol, mannitol, citric acid and aspartame were granulated and dried in the manner described in Example 14, except that 40 ml of demineralized water was used instead of 20 ml. The remaining materials were added to the granules and the mixture was blended for 15 minutes to reach homogeneity.

The mixture was tableted by a single punch tableting machine using a toroidal punch of 16 mm in diameter to yield tablets with a thickness of approximately 7.5 mm and a hardness of about 1 Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 1.2 g each, contained 60 mg of fexofenadine, and had a pleasant taste when dissolved in the oral cavity.

.of' Afl Generally Geherill Standardiatin Bitter Sweet Salty Warm Cool Burning I fing Anesthietic aters: 5 pleasantr unpleasant Therapeutic 60 20 20 20 20 52 40 20 48 20 56 agent alone- 3 I I I I 2.6 2 1 2.4 I 2.8 a 60 44 20 20 20 20 20 20 40 44 48 Eapile am I 5 3 2.2 1 I I I I 1 2 2.2 2.4 6 Fii-p F nt-, Fexofenadine shows a bitter taste and aftertaste, accompanied by a burning and irritating hInerap eut cr,.agen' lo sensation.

6Eanl A sweet sensation is obtained in the oral cavity. Tablets have a pleasant taste.

For Example Nos. 22 through 25, the ingredients were blended mechanically for 20 minutes at room temperature in a cube mixer. The resulting mixtures were tableted by a single punch tableting machine using a plane punch of 12 mm in diameter to yield tablets with a thickness of approximately 3 mm and a hardness of WO 03/053415 PCT/GB02/05825 about 6 Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 300 mg each, contained 18.00 mg of vitamin PP, and had a pleasant taste when dissolved in the oral cavity.

Example No. 22 This example demonstrates the taste-masking effect in a chewable tablet that includes vitamin PP, a therapeutic agent which is known to have an unpleasant taste, and pregelatinized starch.

vitamin PP 7.50 g skim milk powder 100.42 g aspartame 3.34 g vanilla flavor 4.17 g pregelatinized starch 6.25 g magnesium stearate 3.34 g Example No. 23 This example also demonstrates the taste-masking effect in a chewable tablet that includes vitamin PP, and a polyethylene oxide resin.

vitamin PP 7.50 g skim milk powder 104.17 g aspartame 3.34 g vanilla flavor 4.17 g polyethylene oxide resin 2.50 g magnesium stearate 3.34 g WO 03/053415 PCT/GB02/05825 Example No. 24 This example also demonstrates the taste-masking effect in a chewable tablet that includes vitamin PP and hydroxypropyl methylcellulose.

vitamin PP 15.00 g skim milk powder 171.67 g aspartame 6.67 g vanilla flavor 8.34 g hydroxypropyl methylcellulose 41.67 g magnesium stearate 6.67 g Example No. This example also demonstrates the taste-masking effect in a chewable tablet that includes vitamin PP and gum arabic.

vitamin PP 0.18 g skim milk powder 1.71 g gum arabic 1.41 g Example No. 26 This example also demonstrates the taste-masking effect in a chewable tablet that includes calcium carbonate.

Cal-carb 4450PG 2729.26 g skim milk powder 1000 g aspartame 20 g magnesium stearate 28 g vanilla flavor 22.74 g WO 03/053415 PCT/GB02/05825 Cal-carb 4450PG is a calcium carbonate supplied by CHR Hansen, Inc. of Vineland, NJ, that contains 91.6 in calcium carbonate with the balance comprising maltodextrin and pregelatinized starch. The above ingredients were blended mechanically for 5 minutes at room temperature in a cube mixer to homogeneous granules. The resulting mixture was tableted by a single punch tableting machine to yield tablets with a thickness of approximately 9 mm and a hardness of about 9 Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 3.8 g each, contained 1000 mg of calcium carbonate, and had a pleasant taste when chewed.

of StI: tartliti Biweet f .m Co1 BuFrnl g lVtitinh 1 tras slUC *i '-,sleasant 20 40 60 20 20 20 20 100 20 92 1 I I 2 3 1 I 1 I 5 I 4.6 Tb1 f O20 80 20 20 20 20 20 20 20 100 N a4 1 1 4 1'1 I 1 I I Galcfti;' oat Calcium carbonate shows an unpleasant taste and aftertaste.

Tablet-i i e A sweet sensation is obtained in the oral cavity when the tablets are chewed.

Example No. C-1 This comparative example demonstrates the unacceptable properties of a vitamin PP-containing tablet that includes albumin, a protein found in skim milk powder.

albumin 71.11 g vitamin PP 5 g aspartame 2.22 g vanilla flavor 2.78 g 4 WO 03/053415 PCT/GB02/05825 magnesium stearate 2.22 g The above ingredients were blended mechanically to homogeneity for about minutes at about room temperature in a cube mixer. The resulting mixture was tableted by a single punch tableting machine using a plane punch of 12 mm in diameter to yield tablets with a thickness of approximately 12mm and a hardness of about 0.1 Kp as measured by a Schleuniger tablet hardness tester. The resulting tablets weighed 300 mg each and contained 18 mg of vitamin PP. It was noted that the tablets were unacceptably friable due to the poor binding properties of albumin.

Claims (9)

1. A pharmaceuticalcomposition comprising a therapeutically effective amount of a therapeutic agent having an unpleasant taste and skim milk powder in an amount sufficient to mask the unpleasant taste of the therapeutic agent.

2. A composition of claim 1 wherein the ratio of skim milk powder to therapeutic agent is from about 1:1 to about 1,000,000:1.

3. A composition of claim 1 or 2 further comprising a pharmaceutical excipient,

4. An oral dosage formulation comprising a composition of claim 1, 2 or 3. A formulation of claim 4 in the form of a tablet.

6. A tablet of claim 5 in the form of a chewable tablet, swallowable tablet, effervescent tablet, or fast melt tablet.

7. The formulation of claim 4 in the form of a multiparticulate capsule, dry syrup, powder, sprinkle or sachet.

8. A method of producing a pharmaceutical composition comprising the step of dry blending a therapeutic agent having an unpleasant taste and skim milk powder in an amount sufficient to mask the unpleasant taste of the therapeutic agent.

9. The method of claim 8 wherein the ratio of skim milk powder to therapeutic agent is from about 1:1 to about 1,000,000: 1. di. WO 03/053415 PCT/GB02/05825 A method of treating a person with a pharmaceutical composition comprising the step of administering to the person an oral dosage form comprising a composition of claim 1, 2 or 3.

11. Use of skim milk powder as a taste-masking agent in the manufacture of a pharmaceutical composition e.g. as an oral dosage form. DATED: 25 JUNE 2004 PHILLIPS ORMONDE FITZPATRICK ATTORNEYS FOR: ALPEX PHARMA SA Qera^'^ldh