OA17084A - Taste masked dispersible tablets. - Google Patents

Abstract

The present invention relates to a tastemasked dispersible tablet comprising a drug, a cation exchange resin, and other pharmaceutically acceptable excipients, such that the said drug and the said cation exchange resin are present in an un-complexed form in the tablet. It further relates to a process for the preparation of the same.

Description

TASTE MASKED DISPERSIBLE TABLETS

- Field ofthe Invention

The présent invention relates to a taste-masked dispersible tablet comprising a drug, a cation exchange resin, and other pharmaceutically acceptable excipients, such that the said drug and the said cation exchange resin are présent in an un-complexed form ln the tablet. It further reiates to a process for the préparation of the same.

Background of the Invention

It Is weli known that oral administration constitutes a preferred route of administration for a majority of drugs. However, a drug having an Inherentiy bitter taste constitutes a disadvantage with certain types of oral préparations, particularly when intended for use in the pédiatrie population. Unpleasant taste leads to poor adhérence in children which in tum causes treatment failure. Therefore, taste-masking can prove to be an essential tool to improve patient compliance, especially of pédiatrie patients, by increasing the palatabliity of such bitter-tasting drugs. This assumes more Importance for drugs that are used for a long-term cure and where treatment adhérence is an important requlsite.

Several methods are known in the prior art for taste-masking. To some extent, the bitter taste may be masked by the use of sweetening and/or flavoring agents. However, this method is not always satisfactory and an unpleasant taste may remain In the mouth. Additionally, there may be circumstances ln which It Is undesirable to use a sweetening agent and/or flavoring agent. Use of lon-exchange resins Is an altematïvely known method to mask the bitter taste ln such cases.

U.S. Publication No. 2004/0067216 relates to a complex comprising a cation exchange resin and an HIV protease inhibitor and formulation of this drug-resin complex into a capsule dosage form.

U.S. Publication No. 2002/0032245 relates to a rapid-release reslnate composition comprising an ion exchange resin loaded with an active substance, wherein the said active substance is anisotropically distributed throughout said ion exchange resin partide.

ln the prior art, the drug-resin complexes are generally formed by mixing a drug with an aqueous suspension of a resin, after which the complex is filtered, washed, and dried. Ail these usual complexation steps are time-consumlng and increase the cost of manufacturlng. Further, this method is not suitable for drugs which are prône to hydrolysis and show poor stability in a solution form. The Inventors hâve now developed a taste-masked dispersible tablet comprising a drug and a cation exchange resin which can be prepared by a simple procedure, does not involve the usual time consumlng and costly steps of filtering, washing, drying, etc., and is suitable for drugs which are prone to hydrolysis. The inventors hâve also surprisîngly found that /

i the dispersible tablets wherein the drug-resin complex is formed In situ exhibit better stability than the dispersible tablets comprising the drug-resin complexes prepared by the usual complexation methods.

Summary of the Invention

In one general aspect, the présent invention relates to a taste-masked dispersible tablet comprising a drug, a cation exchange resin, and other pharmaceutically acceptable excipients, such that the said drug and the said cation exchange resin are présent in an un-complexed form In the tablet.

In one embodiment of the above aspect, the said drug and the said cation exchange resin form a complex within 30 seconds to 15 minutes of dispersing the taste-masked dispersible tablet in water.

In another embodiment of the above aspect, the cation exchange resin may be Amberiite® IRP64.

In the above aspect and embodiments, the other pharmaceutically acceptable excipients may be selected from diluents, blnders, lubricants/glidants, disintegrants, flavoring agents, sweetenlng agents, coloring agents, or combinations thereof.

In another general aspect, the invention relates to a process for the préparation of a taste-masked dispersible tablet comprising a drug, a cation exchange resin, and other pharmaceutically acceptable excipients, such that the said drug and the said cation exchange resin are présent In an un-complexed form In the tablet, wherein the process comprises the steps of direct compression, dry granulation, or wet granulation.

In an embodiment of the above aspect, the process comprises the steps of:

a) sifting ail the Ingrédients, i.e., the drug, the cation exchange resin, and other pharmaceutically acceptable excipients separateiy through suitable sleves;

b) blending the sifted Ingrédients in a blender for a suitable time;

c) compressing the résultant blend Into a dispersible tablet using appropriate tooling.

In another embodiment of the above aspect, the process comprises the steps of:

a) sifting the ingrédients, i.e., the drug, the cation exchange resin, and other pharmaceutically acceptable excipients through suitable sieves;

b) blending the sifted ingrédients in a blender for a suitable time;

c) granulating the résultant blend with a binder solution;

d) drying the granules;

e) mlxing the granules with the extragranular excipient(s); and

f) compressing the résultant blend Into a dispersible tablet using appropriate tooling.

ln another general aspect, the présent Invention relates to a method of orally administering to a human a taste-masked dispersible tablet comprising a drug, a cation exchange resin, and other pharmaceutically acceptable excipients ln water, such that the said drug and the said cation exchange resin are présent ln an un-complexed form in the tablet, wherein the method comprises dispersing said tablet in a sufficlent quantity of water prior to administration.

ln one embodiment of the above aspects, the said drug Is tenofovir disoproxil fumarate.

Detailed Description of the Invention

The cation exchange resin, as recited herein, can be, for example, a copolymer of styrene or acrylic or methacrylic acid with a vinyl aromatic compound such as divinylbenzene, and the resin may dérivé its exchange activity from either weakly or strongly acidic groups such as carboxytic acid or sulphonic acid groups. Examples of suitable resins are those that are copolymers of styrene and divinylbenzene which are suiphonated, or copolymers of methacrylic acid and divinylbenzene, Including those available commercialiy as Dowex* resins or Amberiite* resins. The resin may be ln acid form or in the form of a sait with an alkali métal, (e.g., sodium or potassium). Particulariy prefened is Amberiite® which is an insoluble, weakly acidic, hydrogen form, cation exchange resin supplied as dry, fine powder. It is derived from a porous copolymer of methacrylic acid and divinylbenzene.

The taste-masked dispersible tablet, as recited herein, means that the tablet is to be dispersed ln a sufficlent quantity of water to form a taste-masked dispersion, prior to administration. The underiying principle of this particular tablet Is that the said drug and the said cation exchange resin are présent in an un-complexed form in the tablet. Upon dispersing the tablet in water prior to administration, the said drug and the said cation exchange resin form a complex within 30 seconds to 15 minutes of dispersing the said tablet ln water. This resuits In the desired taste-masking of the drug.

The taste-masked dispersible tablets may further comprise one or more of other pharmaceutically acceptable excipients that are routinely used and may be selected from diluents, blnders, lubricants/glidants, désintégrants, flavoring agents, sweetening agents, coloring agents, or combinations thereof.

Suitable diluents that may be used include, but are not limited to, microcrystalline cellulose, silicified mlcrocrystailine cellulose, microfine cellulose, lactose, starch, pregeiatinized starch, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnésium carbonate, magnésium oxide, or combinations thereof.

Suitable binders that may be used inciude, but are not limited to, acacia, guar gum, alginic acid, carbomer, dextrin, maltodextrin, methylceilulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium, magnésium alumlnum silicate, polymethacrylates, crospovidones, povidones, copovidones, gelatin, starch, or combinations thereof. When a wet granulation process Is followed for the préparation of the tablets, the granulating fluid can be either a solvent or a binder dissolved in a solvent. The solvents that may be used inciude, but are not limited to, dichloromethane, ethyl alcohol, or Isopropyl alcohol.

Suitable lubricants/glldants that that may be used inciude, but are not limited to, magnésium stéarate, zinc stéarate, calcium stéarate, stearic acid, colloïdal silicon dioxlde, glyceryi palmitostearate, vegetable oils, polyethylene glycols, polyvinyl alcohols, talc, sodium benzoate, sodium stearyl fumarate, magnésium oxide, poloxamer, sodium lauryl sulphate, polyoxyethylene monostearate, cocoa butter, hydrogenated vegetable oils, minerai oil, polysaccharides, or combinations thereof.

Suitable dislntegrants that may be used Inciude, but are not limited to, cross linked calcium or sodium carboxy methyl cellulose, starch, sodium starch glycolate, pregelatinlzed starch, crosslinked polyvinyl pyrrolidone, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, ion exchange resin, cross-linked polyacrylic acid, alglnates, colloïdal magnesium-aluminum silicate, calcium silicate, or combinations thereof.

Additional taste-masking agents that may be used inciude flavoring agents and sweetening agents. Flavoring agents may be chosen from naturel and synthetic flavor liqulds and inciude, but are not limited to, volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems, or combinations thereof. The sweetening agents may be chosen from the following non-limiting list: sucrose, dextrose, invert sugar, fructose, and mixtures thereof; saccharin, aspartame, acesulfame, sucralose; or sugar alcohols such as sorbitol, mannitol and xytitol.

Suitable coloring agents that may be used inciude, but are not limited to, titanium dioxide pigments, lake colors, and iron oxide pigments.

The taste-masked dispersible tablets, as defined herein, may be manufactured using conventional tabletting techniques like direct compression, dry granulation, or wet granulation,

Preferred taste-masked dispersible tablets of the présent invention may take the form of several different embodiments.

In one embodiment, the présent Invention relates to a taste-masked dispersible tablet comprising a drug, the cation exchange resin Amberiite® IRP64, and other pharmaceutically acceptable excipients.

ln another embodiment, the drug is tenofovir disoproxil fumarate, the cation exchange resin Is Amberlite® IRP64, and the other pharmaceutically acceptable excipients are sucralose, flavor, croscarmellose sodium, mannitol, magnésium stéarate, and colloïdal sllicon dioxide.

ln another embodiment, the drug is tenofovir disoproxil fumarate, the cation exchange resin is Amberlite* IRP64, and the other pharmaceutically acceptable excipients are microcrystalline cellulose, sucralose, flavor, corscarmellose sodium, ethylcellulose, mannitol, xylitol, and magnésium stéarate.

ln another embodiment, the drug is tenofovir disoproxil fumarate, the cation exchange resin Is Amberlite* IRP64, and the other pharmaceutically acceptable excipients are microcrystalline cellulose, sucralose, flavor, croscarmellose sodium, ethylcellulose, crospovidone, mannitol, xylitol, and magnésium stéarate.

In another embodiment, the présent Invention relates to a process for the préparation of a taste-masked dispersible tablet comprising tenofovir disoproxil fumarate, Amberlite® IRP64, and other pharmaceutically acceptable excipients, wherein the process comprises the steps of:

a) sifting the Ingrédients, I.e., tenofovir disoproxil fumarate, Amberlite® IRP64, and other pharmaceutically acceptable excipients separately through suitable sieves;

b) blending the sifted ingrédients in a blender for a suitable time;

c) compressing the résultant blend Into a dispersible tablet using appropriate tooling.

In another embodiment, the présent Invention relates to a process for the préparation of a taste-masked dispersible tablet comprising tenofovir disoproxil fumarate, Amberlite* IRP64, and other pharmaceutically acceptable excipients, wherein the process comprises the steps of:

a) sifting the ingrédients, I.e., tenofovir disoproxil fumarate, Amberlite® IRP64, and other pharmaceutically acceptable excipients through suitable sieves;

b) blending the sifted ingrédients ln a blender for a suitable time;

c) granulating the résultant blend with a binder solution;

d) drying the granules;

e) mixing the granules with the extragranular excipient(s); and

f) compressing the résultant blend Into a dispersible tablet using appropriate tooling.

ln another embodiment, the présent invention relates to a method of orally administering to a human, a taste-masked dispersible tablet as described in the above embodiments, wherein the method comprises dispersing the tablet in a sufficient quantity of water prior to administration so that tenofovir disoproxil fumarate and Amberlite* IRP64 form a complex within 30 seconds to 15 minutes of dispersing the said taste-masked dispersible tablet in water. The sufficient quantity of water may be from 1 mL to 200 mL or a quantity of water comfortably consumed by the human, such as a glass of water routinely consumed.

From the above, it is apparent that various modifications and combinations of the dispersible tablets detailed in the text may be made without departing from the spirit and scope 5 of the Invention. The Invention, as described herein, may be iilustrated by the following examples but is not to be construed to be limited by them.

EXAMPLES

Examples 1-4:

S. No.	Ingrédients	Quantity (mg/tablet)
Example 1	Example 2	Example 3	Example 4
1.	Tenofovir disoproxil fumarate	70.0	150.0	100.0	100.0
2.	Amberlite®IRP64	210.0	450.0	45.0	45.0
3.	Povidone	-	-	3.0	10.0
4.	Microcrystalline cellulose	-	-	100.0	205.0
5.	Ethyicellulose	-	-	7.0	14.0
6.	Hydroxypropyî cellulose	-	-	50.0
7.	Sucralose	70.0	150.0	75.0	75.0
8.	Fiavor	15.0	15.0	20.0	15.0
9..	Croscarmellose sodium	20.0	20.0	60.0	60.0
10.	Crospovidone	-	-	-	25.0
11.	Mannitol	109.0	110.0	305.0	266.0
12.	Xylitol	-	-	125.0	125.0
13.	Magnésium stéarate	2.0	2.5	10.0	10.0
14.	Colloïdal silicon dioxide	4.0	4.5	-	-
15.	Dichloromethane	-	-	q.s.*	q.s.‘
	Total Weight	500.0	902.0	900.0	950.0

Procedures:

Examples 1-2:

a) Ail the above ingrédients were slfted separately through suitable sieves;

b) The sifted ingrédients were blended in a blender for a suitable time; and

c) The résultant blend was compressed into dispersible tablet using appropriate tooltng.

Examples 3-4:

a) Tenofovir disoproxil fumarate, microcrystaliine cellulose (first portion; Example 4), and Amber1ite®IRP64 were sifted through a suitable mesh;

b) The sifted Ingrédients of step a) were transferred into a rapid mixer granulator and dry mixed for a suitable time;

c) Ethylcellulose and povidone were dissolved In dichloromethane, and the solution thus formed was used to granulate the mixture of step b) in the rapid mixer granulator;

d) The résultant granules were dried in a fluid bed dryer and sifted through a suitable mesh to get uniform size granules;

e) Mannitol, sucralose, xylitol, croscarmellose sodium, microcrystalline cellulose (second portion; Example 4), and crospovidone (Example 4) were sifted through a suitable mesh;

f) The sifted extragranular ingrédients of step e) were mixed with the dried granules of step

d) in a suitable blender;

g) Flavor and magnésium stéarate were sifted through a suitable mesh and mixed with the blend of step f); and

h) The résultant blend was compressed Into dispersible tablets using appropriate tooling.

A taste-masked dispersible tablet comprising a drug-resin complex was prepared as per the usual complexation method for comparison and Is described In Table 1 below:

Table 1 : Comparative Example of a taste-masked dispersible tablet comprising the drug resln-complex prepared as per the usual complexation method

Ingrédients	Quantlty In mg/tabiet
Tenofovir + Amberiite® IRP64 resin complex	280.00
Polyplasdone® XL	20.00
Aspartame	15.00
Acesulfame Potassium	7.00
Lactose	22.00
Magnésium stéarate	3.00
Mint flavor	3.00
Total weight	350.00

Procedure for the Comparative Example:

(I) Drug-Resln Complex Préparation Process

a) A required quantity of Amberlite® IRP64 was added to dîstil led water to make about 10% w/w slurry;

b) The slurry was stirred for a sufficient time to get a uniform/lump free dispersion;

c) A specified quantity of tenofovir disoproxil fumarate was added slowly under stlrring to the above dispersion to make a drugiresln ratio of 1:3;

d) The entire mixture was stirred for about 4 hours and the dispersion was kept aslde for setting;

e) The solid resin was separated by filtration and subsequently dried to get the desired tenofovir disoproxil fumarate-Amberlite® IRP64 complex.

(Il) Tablet Préparation Process

a) The drug-resln complex prepared as per the above process, magnésium stéarate, and all other excipients were separately sifted through suitable sleves;

b) The above sifted Ingrédients were mixed for a sufficient time to get a unlform blend;

c) The résultant blend was compressed Into a dispersible tablet using approprlate tooling.

A comparative stability analysis was performed by subjecting the tablets prepared as per the above Example 1 and tablets prepared as per the Comparative Example to an accelerated stability testlng at 40*0/75% relative humldity. The assay values are summarlzed In Table 2 below.

Table 2: Assay results of tenofovir disoproxil fumarate in taste-masked dispersible tablets prepared as per the above Exampie 1 and the Comparative Exemple when stored at 40°C/75% relative humldity

S. No.	Stability Condition	Assay Results
Example 1	Comparative Example
1.	Initial	94.0%	89.3%
2.	1 month 40°C/75% RH	94.0%	78.6%
3.	2 month 40°C/75% RH	95.4%	Not performed
4.	3 month 40°C/75% RH	94.5%	Not performed

The assay results cleariy indicate that the tablets In which the drug*resîn complex Is formed In situ exhlbit better stability than the tablets comprising the drug-resln complex prepared by the usual complexation method.

Claims (7)

1. We claim:

   1. A taste-masked dispersible tabiet comprising a drug, a cation exchange resin, and other pharmaceutically acceptable excipients, such that the said drug and the said cation exchange resin are présent in an un-complexed form in the tabiet.
2. 2. The taste-masked dispersible tabiet according to claim 1, wherein the said drug and the said cation exchange resin form a complex within 30 seconds to 15 minutes of disperslng the taste-masked dispersible tabiet in water.
3. 3. The taste-masked dispersible tabiet according to claim 1, wherein the cation exchange resin is Amberlite® IRP64.
4. 4. The taste-masked dispersible tabiet according to claim 1, wherein the other pharmaceutically acceptable excipients are selected from diluents, binders, lubricants/glidants, disintegrants, flavoring agents, sweetening agents, coloring agents, and combinations thereof.
5. 5. A process for the préparation of a taste-masked dispersible tabiet according to claim 1, wherein the process comprises the steps of direct compression, dry granulation, or wet granulation.
6. 6. A taste-masked dispersible tabiet comprising tenofovir disoproxll fumarate, a cation exchange resin, and other pharmaceutically acceptable excipients, such that tenofovir disoproxil fumarate and the cation exchange resin are présent in an un-complexed form in the tabiet.
7. 7. The taste-masked dispersible tabiet according to claim 6, wherein the cation exchange resin Is Amberlite® IRP64.