Technical Field of the Invention
The present invention relates to pharmaceutical formulations of valaciclovir, particularly those formulations that can be conveniently administered to pediatric and geriatric patients, who otherwise face problems swallowing solid unit dosage forms, for example conventional tablets, capsules. The present invention also relates to process of preparation of such dosage forms, e.g. suspensions, solutions and dry powder for reconstitution.
Background of the Invention
Valaciclovir is the L- valyl ester of the antiviral drug aciclovir. Chemically valaciclovir is known as L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester. It is commercialized as the monohydrochloride salt and is structurally designated as:
(Formula Removed)
In the United States of America, valaciclovir is available as VALTREX™ caplets for oral administration from GlaxoSmithKline. Each caplet contains valaciclovir hydrochloride equivalent to 500 mg or 1 gram valaciclovir. Valaciclovir is indicated in adult patients for the treatment and/or prophylaxis of herpes labialis, genital herpes and herpes zoster. The US Patent Number 4,957,924 discloses valaciclovir and process of preparation thereof. It also discusses pharmaceutical compositions containing valaciclovir.
Valaciclovir is also indicated for the treatment of cold sores in paediatric patient ≥ 12 years of age, wherein the recommended dosage is 2gm twice daily for one day taken 12 hours apart. It is also indicated for the treatment of chicken pox in immunocompetent paediatric patients 2 to < 18 years of age. The recommended dosage is 20mg/kg administered three times daily for 5 days. The total dosage should not exceed 1gm three times daily.
Valaciclovir is however very difficult to formulate into a suitable dosage form, owing to several factors. One of the most significant formulation problems encountered related to valaciclovir is that it has an extremely bitter taste. This undesirable taste factor is influences patient compliance negatively, especially for the paediatrics and geriatrics.
US Patent Number 5,879,706 discloses tablet compositions of valaciclovir and colloidal silicon dioxide, along with other excipients and the process of preparation thereof.
VALTREX™ package insert in the USA, describes an oral suspension (25mg/ml_ or 50mg/mL) formulation that may be prepared extemporaneously from the 500mg VALTREX™ (valaciclovir) caplets by crushing the said tablets and processing with other excipients.
The PCT Publication WO/2001/82905 discloses pharmaceutical composition comprising carrier beads coated with one or more layers of pharmaceutically acceptable substances, wherein at least one of the said layers comprises valaciclovir, or a pharmaceutically acceptable derivative thereof, as the active ingredient.
The PCT Publication WO/2009/049648 teaches solid dosage forms comprising valaciclovir in combination with dibasic calcium phosphate.
The most successful methods for masking taste have typically involved coating valaciclovir particles with a barrier or coating that will not dissolve in the mouth but will readily dissolve in gastric fluids. However, such coatings may adversely impact bioavailability and/or retard release of the drug. Moreover, such processes are cumbersome and involve high costs.
The most frequently adopted techniques available in the pharmaceutical industry for masking bitter taste of drugs include taste masking with ingredients such as flavours, several types of sweeteners. The use of flavouring agents and sweeteners have been proposed for use with and as well used extensively with bitter tasting drugs. Likewise, the prior art has shown extensive use of one or a combination of different flavouring and sweetening methodologies to mask the bitter taste of drugs. For example, a flavour/sweetener can be selected that complements the taste of the preparation, or a flavour with a longer intensity and stronger taste than the drug can be used. High levels of sweetening agents are often used to overwhelm bitterness with sweetness. The taste buds may also be anesthetized by menthol or mint flavors. These approaches are though, not very reliable in masking the taste of strongly bitter tasting drugs, for example valaciclovir. The problem associated with these sweetening and flavouring agents is that usually a bitter, prominent and prolonged after-taste. Also, it is noted that flavouring/sweetening system that works with one drug often does not apply to another drug.
Therefore, in the present invention, the problem associated with bitter tasting formulations of valaciclovir is addressed convincingly. It relates to a patient-compliant, convenient, industrially applicable, and cost-efficient method of preparation of valaciclovir formulations, wherein the use of a specific combination of natural sugars or sugar alcohols with artificial sweeteners has provided efficient long-lasting taste-masking effects.
Summary of the Invention
In one general aspect, it relates to a taste-masked pharmaceutical formulation which comprises of valaciclovir and sweetening agents comprising of a) at least one sugar or sugar alcohol; and b) at least one artificial sweetener.
In another general aspect, it relates to a taste-masked pharmaceutical formulation which comprises of valaciclovir and sweetening agents comprising of a) at least one sugar or
sugar alcohol; and b) at least one artificial sweetener, wherein the said artificial sweetener is sucralose.
In another general aspect, it relates to a taste-masked pharmaceutical formulation which comprises of valaciclovir and sweetening agents comprising of a) at least one sugar or sugar alcohol; and b) at least one artificial sweetener, wherein the said amount of sugar or a sugar alcohol is present in a concentration of about 200 to about 800mg/ml.
In another general aspect, it relates to a taste-masked pharmaceutical formulation which comprises of valaciclovir and sweetening agents comprising of a) at least one sugar or sugar alcohol; and b) at least one artificial sweetener, wherein the said artificial sweetener is present in a concentration of about 0.1 to about 4.0 mg/ml.
In another general aspect, it relates to a taste-masked pharmaceutical formulation which comprises of valaciclovir and sweetening agents comprising of a) at least one sugar or sugar alcohol; and b) at least one artificial sweetener, wherein the said formulation further comprises a moisture adsorbing agent.
In another general aspect, it relates to a taste-masked pharmaceutical formulation which comprises of valaciclovir and sweetening agents comprising of a) at least one sugar or sugar alcohol; and b) at least one artificial sweetener, wherein the said formulation is a solid dosage form or a liquid dosage form.
In another general aspect, it relates to a process for the preparation of a taste-masked pharmaceutical formulation which comprises of valaciclovir and sweetening agents comprising of a) at least one sugar or sugar alcohol; and b) at least one artificial sweetener,
wherein the process comprises of blending the said valaciclovir with the said sweetening agents, and processing the blend so obtained as a powder for reconstitution.
In another general aspect, it relates to a process for the preparation of a taste-masked pharmaceutical formulation which comprises of valaciclovir and sweetening agents comprising of a) at least one sugar or sugar alcohol; and b) at least one artificial sweetener, wherein the process comprises of blending the said valaciclovir with the said sweetening agents, and processing the blend so obtained as a suspension dosage form.
In another general aspect, it relates to a process for the preparation of a taste-masked pharmaceutical formulation which comprises of valaciclovir and sweetening agents comprising of a) at least one sugar or sugar alcohol; and b) at least one artificial sweetener, wherein the process comprises of blending the said valaciclovir with the said sweetening agents, and processing the blend so obtained as a solution dosage form.
Detailed Description of the Invention
The term 'taste-masked pharmaceutical formulation' as used herein includes without limitation, solid and liquid dosage forms, and includes syrup, a ready-to-use suspension, or extemporaneously prepared liquid syrup or suspension such as, for example, dry powder for reconstitution with water, liquid concentrate for dilution, dispersible tablet or capsule. It also encompasses granules, dispersions, sublingual tablets, buccal tablets, mouth-dissolving tablets, rapidly disintegrating tablets, chewable tablets, lozenges, gums, pellets, sachets, pills, sprinkles, troches, triturates, and the like.
Valaciclovir present in the said pharmaceutical formulation is in "therapeutically effective amount" i.e., in an amount that result in the alleviation and/or prophylaxis of the symptoms of the disease or condition being treated by the drug in adult, paediatric or geriatric patient population. The recommended dose of VALTREX™ caplets or extemporaneously prepared
suspension may be considered as standard dose. Suitably, the said formulations contain valaciclovir in an amount of about 1% to about 99%, particularly about 5% to about 25% by weight of the said formulation.
The term 'valaciclovir' include without limitation, free drug and the pharmaceutically acceptable salts, esters, solvates, enantiomers, diastereomers, and polymorphs thereof, which upon administration is capable of providing valaciclovir or an physiologically and pharmaceutically active metabolite or residue thereof. In one embodiment, valaciclovir is in the form of its hydrochloride salt.
Sweetening agents in the taste masked pharmaceutical formulation as recited herein comprises of a combination of (a) at least one sugar or a sugar alcohol; and (b) at least an artificial sweetener.
Representative examples of sugars include glucose, fructose, invert sugar, sucrose, maltose, xylose, ribose, mannose, corn syrup solids, and mixtures thereof. The sugar alcohol includes without limitation, xylitol, mannitol, sorbitol, and combinations thereof. The sugar and/or sugar alcohol may be present in amounts of about 10% to about 99%, particularly about 20% to about 80%, by weight of the formulation. The concentration of the sugar and/or sugar alcohol present in the formulation may be about 200 to about 800mg per ml_, particularly about 350 to about 550 mg per mL of the liquid dosage form, or when the solid dosage form is reconstituted to form a liquid dosage form.
The artificial sweeteners that may be used in the present invention include, and are not limited to aspartame, cyclamates, saccharin, saccharin sodium, acesulfame-K, sucralose or combinations thereof. The concentration of the artificial sweetener present in the formulation may be about 0.1 to about 4.0 mg per mL, particularly 1.5 to about 3.0 mg per mL of the liquid dosage form, or when the solid dosage form is reconstituted to form a liquid
dosage form. In one embodiment, the artificial sweetener used is sucralose. Sucralose is a highly potent artificial sweetener chemically known as 1,6-Dichloro-1,6-dideoxy-b-D-fructofuranosyl-4-chloro-4- deoxy-a-D-galactopyranoside, also known as 1',4',6'-trichlorogalactosucrose; and 4,1',6'-trichloro-4,1',6'-trideoxy-galacto-sucrose. It has a sweetening power approximately 300-1000 times that of sucrose and has no aftertaste. It was originally disclosed in GB 1543167. In one embodiment, sucralose when used in combination with sugar/sugar alcohol results in a formulation of valaciclovir which have strong and prolonged taste-masking effects.
The taste-masked pharmaceutical formulation may further comprise one or more of other pharmaceutically acceptable excipient(s).
The term "pharmaceutically acceptable excipients" as recited herein includes pharmaceutical additives conventionally used in the preparation of solid and liquid dosage forms known in the art, such as diluent(s), binder(s), disintegrant(s), superdisintegrant(s), flavouring agent(s), preservative(s), thickening agent(s), pH-stabilizing agent(s), lubricants(s), solvent(s), glidants(s), moisture adsorbing agent(s) or combinations thereof.
Diluents may be selected from saccharides like lactose, dextrose, sucrose, fructose, maltose; sugars like mannitol, erythritol, sorbitol, xylitol and lactitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose; starch and pregelatinized starch; dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate, kaolin and the like.
Binders that may be used include, but are not limited to, starch derivatives like com starch and pregelatinized starch; cellulose ethers such as carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose; carboxy vinyl polymers like carbomers; acrylates such as Eudragits; polyvinylpyrrolidone,
polyvinylpyrrolidone/vinyl acetate copolymer; xanthan gum, guar gum and other such materials routinely used in the art of pharmaceutical manufacturing.
Disintegrants and superdisintegrants may be selected from the group consisting of alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, guar gum, magnesium aluminium silicate, sodium starch glycolate, corn starch, potato starch, pregelatinized starch, low-substituted hydroxypropylcellulose, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, and methacrylic acid divinylbenzene copolymer salts.
The flavouring agent(s) includes without limitation, natural flavours, natural fruit flavours, artificial flavours; and artificial fruit flavours. Examples of the same include banana, spearmint, strawberry flavours, and the like.
The pharmaceutical formulation may also contain a 'pH-stabilizing agent', to maintain a desired pH, for e.g. during the process of manufacturing the said formulation, and/or upon reconstitution into solution or suspension. The desired pH may range from about 4 to about 10. The term 'pH-stabilizing agent' encompasses buffers and pH-altering agents. Suitable pH-altering agents include without limitation tribasic sodium phosphate, anhydrous sodium carbonate, potassium bicarbonate, glycine, citric acid, tartaric acid and the like or mixtures thereof. The buffer system comprising of an aqueous mixture of an acid such as phosphoric, succinic, tartaric, lactic, or citric acid, and a base, in particular sodium hydroxide, potassium hydroxide, disodium hydrogen phosphate or sodium hydrogen carbonate may be used.
The preservative(s) includes without limitation, one or more of benzoic acid and the sodium or potassium salts thereof, sorbic acid and the sodium or potassium salts thereof, benzyl alcohol, or other preservatives well known in the art of pharmaceutical manufacturing.
Suitable thickening agents are used to increase the viscosity of the pharmaceutical liquid dosage forms. Essentially any suitable thickening agent may be used. In practice the thickening agent is selected from the group consisting of methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxy ethyl propyl cellulose, starches (such as maize or corn starch, potato starch, rice starch, tapioca starch, and wheat starch), carboxyvinyl polymers (carbomers such as Carbopol™), carboxymethyl cellulose and salts thereof, microcrystalline cellulose and arabic gum, guar gum, and xanthan gum, and mixtures thereof.
Lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, powdered stearic acid, magnesium oleate, calcium palmitate, potassium laureate, sodium suberate, vegetable oil, mineral oil, and the like. Glidants may be selected from talc, colloidal silicon dioxide, corn starch and the like.
Suitable solvents may be used include without limitation, water, ethanol, methanol, isopropyl alcohol, methylene chloride, acetone and the like.
The moisture adsorbing agent includes without limitation, colloidal silicon dioxide, anhydrous calcium phosphate, starch, magnesium carbonate, bentonite, kaolin, magnesium silicate, magnesium oxide and silicon dioxide and the like.
The taste-masked pharmaceutical formulation may be prepared using conventional methods known in the art, namely blending, mixing, granulation techniques. The formulation
so formed may be administered directly or incorporated into/processed to pharmaceutical compositions for oral administration. The said formulation may be introduced into a single dose or multi dose container, as a dry powder for constitution with an ingestible liquid such as water before use for administration as a suspension/solution. Typically, the dry powder after constitution with an ingestible liquid is set to provide a liquid suspension/solution containing about 10mg to about 250mg valaciclovir per mL of liquid suspension/solution.
In one embodiment, a taste-masked pharmaceutical formulation comprises of valaciclovir and sweetening agents comprising of a) a sugar and b) an artificial sweetener.
In one embodiment, a taste-masked pharmaceutical formulation comprises of valaciclovir and sweetening agents comprising of a) a sugar alcohol and b) an artificial sweetener.
In one embodiment, a taste-masked pharmaceutical formulation comprises of valaciclovir and sweetening agents comprising of a) sucrose and b) an artificial sweetener.
In one embodiment, a taste-masked pharmaceutical formulation comprises of valaciclovir and sweetening agents comprising of a) xylitol and b) an artificial sweetener.
In one embodiment, a taste-masked pharmaceutical formulation comprises of valaciclovir and sweetening agents comprising of a) a sugar and b) sucralose.
In one embodiment, a taste-masked pharmaceutical formulation comprises of valaciclovir and sweetening agents comprising of a) a sugar alcohol and b) sucralose.
In one aspect of the above embodiments, a taste masked pharmaceutical composition further comprises of a moisture adsorbing agent.
In one aspect of the above embodiments, a moisture adsorbing agent is colloidal silicon dioxide.
From the above it is apparent that various modifications and combinations of the formulations detailed in the text may be made without departing from the spirit and scope of the invention. The invention as described herein may be illustrated by the following examples but is not to be construed to be limiting by them.
Examples 1-5: (Table Removed)
Procedure:
Example 1
All ingredients were weighed. Xylitol, Valaciclovir hydrochloride, Strawberry TSL flavour and sucralose were passed through a 30 mesh sieve and charged to a double cone blender and blended for at least 30 minutes. The requisite quantity of powder was filled in HDPE bottles to be reconstituted with water on administration.
Example 2
All ingredients were weighed. Xylitol was added and dissolved in a stainless steel container containing purified water equivalent to 90% v/v of batch size, followed by stirring at high speed using a mechanical stirrer for a period of at least 1 hour to get a clear solution at a temperature NMT 40° C. Valaciclovir hydrochloride, Strawberry TSL flavour and sucralose were added and dissolved in the xylitol solution so obtained. The solution so formed was continuously stirred for at least 1 hour to get a clear solution. The batch volume was made up using purified water. The resulting solution was filled in HDPE bottles, and sealed with child resistant caps.
Example 3
All ingredients were weighed. Sucrose was added and dissolved in a stainless steel container containing purified water equivalent to 90% v/v of batch size, followed by stirring at high speed using a mechanical stirrer for a period of at least 1 hour to get a clear solution at a temperature NMT 40° C. Valaciclovir hydrochloride, Strawberry TSL flavour and sucralose was added and dissolved in the solution of sucrose so obtained, with continuous stirring for at least 1 hour to get a clear solution. The batch volume was made up with purified water. The resulting solution was filled in HDPE bottles, and sealed with child resistant caps.
Example 4
All ingredients were weighed. Mannitol was added and dissolved in a stainless steel container containing purified water equivalent to 90% v/v of batch size, followed by stirring at high speed using a mechanical stirrer for a period of at least 1 hour to get a clear solution at a temperature NMT 40° C. Valaciclovir hydrochloride, Strawberry TSL flavour and sucralose were added and dissolved in the solution of sucrose so obtained, with continuous stirring for at least 1 hour to get a clear solution. The batch volume was made up with purified water. The resulting solution was filled in HDPE bottles, and sealed with child resistant caps.
Example 5
All ingredients were weighed. Colloidal silicon dioxide and sodium benzoate were passed through a 44 mesh sieve and mixed with Valaciclovir hydrochloride, xylitol, strawberry TSL flavor and sucralose. The material so obtained was passed through a 30 mesh sieve, and blended for at least 30 minutes in a double cone blender. The requisite quantity of powder was filled in HDPE bottles to be reconstituted with water on administration.

WE CLAIM:
1) A taste-masked pharmaceutical formulation which comprises of: valaciclovir and sweetening agents comprising of a) at least one sugar or sugar alcohol; and b) at least one artificial sweetener.
2) The taste-masked pharmaceutical formulation according to claim 1, wherein the said artificial sweetener is sucralose.
3) The taste-masked pharmaceutical formulation according to claim 1, wherein the said sugar is selected from glucose, fructose, invert sugar, sucrose, maltose, xylose, ribose, mannose, corn syrup solids, and mixtures thereof.
4) The taste-masked pharmaceutical formulation according to claim 1, wherein the said sugar alcohol is selected from sorbitol, mannitol, xylitol and mixtures thereof.
5) The taste-masked pharmaceutical formulation according to claim 1, wherein the said formulation further comprises diluent(s), binder(s), disintegrant(s), superdisintegrant(s), flavouring agent(s), preservative(s), thickening agent(s), pH-stabilizing agent(s), lubricants(s), solvent(s), glidants(s), moisture adsorbing agent(s) or combinations thereof.
6) The taste-masked pharmaceutical formulation according to claim 5, wherein the at least one moisture adsorbing agent is colloidal silicon dioxide.
7) The taste-masked pharmaceutical formulation according to claim 1, wherein the said
formulation is a solution.
8) The taste-masked pharmaceutical formulation according to claim 1, wherein the said
formulation is a suspension.
9) The taste-masked pharmaceutical formulation according to claim 1, wherein the said
formulation is a dry powder.
10) The taste-masked pharmaceutical formulation which comprises of: valaciclovir and
sweetening agents comprising of a) at least one sugar or sugar alcohol; and b) at least one
artificial sweetener, and process for the preparation thereof substantially as described and
illustrated by examples herein.