Indian Patents. 272075:TASTE MASKING OF DRUGS USING ION EXCHANGE RESINS

Title of Invention	TASTE MASKING OF DRUGS USING ION EXCHANGE RESINS
Abstract	The invention relates to bitter drugs cation exchange resins of various grades which are complexed in various ratios to mask the bitter taste of drugs. Such resin complexes or resonates can be used to formulate various oral dosage forms acceptable to various profiles of the populations.

Full Text	FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "TASTE MASKING OF DRUGS USING ION EXCHANGE RESINS 2. APPLICANT (S) (a) NAME: Chaudhari, Pravin Digambar (b)NATIONALITY: Indian (c) ADDRESS: A-1,303, Tushar Residency, Rahatani-Jagtap Dairy Road, Pimple Saudagar, Pune-411027, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention. Technical field of the invention: The invention relates to the taste masking of drugs to reduce its bitterness, increase its palatability and thus to improve patient compliance. Particularly the invention relates to the use of ion exchange resins to mask the bitterness of drugs by preparing drug-resin complexes. Such complexes can be used to formulate various palatable oral drug dosage forms of the bitter drugs. Background and prior art: Most drugs have slightly to extremely bitter taste. This bitter taste leads to unpleasantness and poor mouth feel leading to cases of extremely compromised patient compliance and ineffective therapies in many therapeutic conditions. It is usually a challenge to the person skilled in the art of formulation development to mask the taste of the drug. Such masking techniques should not only effectively and totally mask the bitter taste but should also be simple, not affect drug efficacy, not involve too many additional excipients and processing steps and be acceptable to the general target subject group. Some commonly used techniques for taste masking include using polymeric coatings, complexation with cyclodextrins, salt formation, use of flavours, use of flavour enhancers, use of natural and synthetic sweeteners and such like. The most common ingredient used for masking bitter taste is sugar. But sugar is not acceptable to a large part of the population in the proportions used to mask the taste and thus affects patient compliance. Ion exchange resins of various types with a variety of polymers are available and can be employed for taste masking. US 6514492 relates to the formulation of oral liquid products of quinolones or derivatives thereof using ion exchange resins, such as methacrylic acid polymer 2 crosslinked with divinylbenzene, as the carrier, thereby eliminating the extreme bitterness of the quinolones oral liquid formulation. EP 1674078 claims an orally consumable solid film that dissolves in a mouth of a consumer, comprising: at least one water soluble polymer, and at least one pharmaceutical agent and at least one taste masking agent; wherein said at least one taste masking agent is selected from the group consisting of ion exchange resin, magnesium trisilicate, cellulose, ethyl cellulose and combinations thereof. But there exists a need to evolve a simple technique for masking bitter taste of drugs resulting in the further formulation of such drugs into any palatable oral dosage form. There also exists a need to develop techniques that can be employed with minimal amount of agents used to mask the taste with minimal processing, and yet effectively mask the bitter taste. Objectives of the invention: The objective of the invention is to prepare drug-resin complexes to mask the bitter taste of drugs. Another objective of the invention is to improve patient compliance affected due to bitter taste of drugs. A further objective of the invention is to mask the bitter taste using resins, which are acceptable across all population profiles. Yet another objective is to mask the bitter taste drugs using a simple technique involving minimal use of excipients, processing steps and parameters to be controlled. Another objective is to formulate the drug-resin complexes as palatable oral dosage forms of bitter drugs. 3 Summary of the inevntion: In the instant invention bitter drugs and cation exchange resins of various grades are complexed in the ratios ranging from 1:0.5 to 1:5 (drug:resin) to mask the bitter taste of drugs. Such resin complexes or resinates can be used to formulate various oral dosage forms acceptable to various profiles of the populations. Such complexes do not break down at pH 6-7 of saliva, but exhibit solubility at gastric pH of 1 -3. Detailed description of the invention: Ion exchange resins are used in pharmaceutical formulation for a variety of purposes. They aid in disintegration and dissolution of drugs and also in taste masking. Ion exchange resins are solid, insolubilised high molecular weight polyelectrolytes that can exchange their mobile ions of equal charge with the surrounding medium reversibly and are available in desired size ranges. Bitter cationic drugs can get adsorbed onto the weak cation exchange resins of carboxylic acid functionality to form the complex, which is non-bitter. The complex of cationic drugs and weak cation exchange resin does not break at pH 6-7, of saliva with cation concentration of 40meq/lt. But at high cation concentration of stomach and pH of 1-3, free drug is immediately released and is available to exert its therapeutic effect. In the instant invention the drug is complexed with the resin in the ratios ranging from 1:0.5 to 1:5 to form resinates that possess no bitter taste. Such resinates can be used to formulate various palatable oral dosage forms. Ion exchange resins were selected from the group comprising cross-linked polyacrylic matrix type pharmaceutical grade ion exchange resins with -coo functional group and particle size equal or lesser than 0.15 mm, and methacrylic acid polymer crosslinked with divinylbenzene. The preferred resin to mask the taste was polyacrylic matrix type pharmaceutical grade ion exchange resins with -coo functional group and particle size 4 equal or lesser than 0.15 mm. This was due to the fact that the taste masking was occurring to the desired extent with the various resins, but the % of drug bound to resin was highest with cross linked polyacrylic resins, overcoming the poor binding of resins of methacrylic acid polymer crosslinked with divinylbenzene with the drug. The process of preparing the resinate was as follows: 1. Preparing a slurry of resin in deionised water and allowed to swell for 30 minutes; 2. Adding the drug to the slurry of step 1; 3. Stirring the slurry of step 2 for 6-7 hours, allowing to sediment and filtering; 4. Washing the residue with deionised water. The effect of acid and alkali activation, optimum time required for drug loading and the optimum pH conducive for drug loading was determined and the release of the drug from the resinate was studied. Such resinates formed can be formulated as tablets, granules, capsules, granules filled in capsules or sachets, mouth melting tablets, fast dissolving dosage forms, controlled release dosage forms, oral liquids such as syrups, suspensions, emulsions, dry syrups for unstable drugs and such like. Example 1 Rizatriptan benzoate, a bitter drug used to treat migraine was formulated after masking its taste with cross linked polyacrylic matrix type pharmaceutical grade ion exchange resin. Optimum results were obtained for drug loading and taste masking parameters at the drug :resin ratio of 1:2, with the drug loaded at pH 7. Example 2 Taste masking trials of Rizatriptan benzoate The following table is the results of the volunteers' opinion test of rizatriptan benzoate before and after taste masking using ion exchange resins of the instant invention. A 5 panel of 10 members using time intesnsity method did taste evaluation. Sample equivalent to usual dose was held in the mouth for 10 seconds and bitterness levels were recorded instantly and after 10 seconds, 1, 2, 5, 10 and 15 minutes. The opinion was rated on a scale wherein 0 is no bitterness, 1 is acceptable bitterness, 2 is slightly bitter, 3 is moderately bitter and 4 is strongly bitter. SrNo Tine in seconds Before taste masking (Mean) After taste masking (Mean) 1 10 2.3 0.2 2 60 3.3 0.5 3 120 3.4 0.4 4 300 3.8 0.1 5 600 3.8 0 6 900 4.0 0 Many changes, modifications, variations and applications of the subject invention will become apparent to those skilled in the art after consideration of the specification. All such changes, modifications, alterations and other uses and applications that do not depict from the spirit and scope of the invention are deemed to be covered by the invention. Dated this 15th day of November 2006 Dr. Gopakumar G. Nair Agent for the Applicant 6

Full Text

FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"TASTE MASKING OF DRUGS USING ION EXCHANGE RESINS
2. APPLICANT (S)
(a) NAME: Chaudhari, Pravin Digambar (b)NATIONALITY: Indian
(c) ADDRESS: A-1,303, Tushar Residency, Rahatani-Jagtap Dairy Road, Pimple Saudagar, Pune-411027, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention.

Technical field of the invention:
The invention relates to the taste masking of drugs to reduce its bitterness, increase its palatability and thus to improve patient compliance. Particularly the invention relates to the use of ion exchange resins to mask the bitterness of drugs by preparing drug-resin complexes. Such complexes can be used to formulate various palatable oral drug dosage forms of the bitter drugs.
Background and prior art:
Most drugs have slightly to extremely bitter taste. This bitter taste leads to unpleasantness and poor mouth feel leading to cases of extremely compromised patient compliance and ineffective therapies in many therapeutic conditions. It is usually a challenge to the person skilled in the art of formulation development to mask the taste of the drug. Such masking techniques should not only effectively and totally mask the bitter taste but should also be simple, not affect drug efficacy, not involve too many additional excipients and processing steps and be acceptable to the general target subject group.
Some commonly used techniques for taste masking include using polymeric coatings, complexation with cyclodextrins, salt formation, use of flavours, use of flavour enhancers, use of natural and synthetic sweeteners and such like. The most common ingredient used for masking bitter taste is sugar. But sugar is not acceptable to a large part of the population in the proportions used to mask the taste and thus affects patient compliance.
Ion exchange resins of various types with a variety of polymers are available and can be employed for taste masking.
US 6514492 relates to the formulation of oral liquid products of quinolones or derivatives thereof using ion exchange resins, such as methacrylic acid polymer
2

crosslinked with divinylbenzene, as the carrier, thereby eliminating the extreme bitterness of the quinolones oral liquid formulation.
EP 1674078 claims an orally consumable solid film that dissolves in a mouth of a consumer, comprising: at least one water soluble polymer, and at least one pharmaceutical agent and at least one taste masking agent; wherein said at least one taste masking agent is selected from the group consisting of ion exchange resin, magnesium trisilicate, cellulose, ethyl cellulose and combinations thereof.
But there exists a need to evolve a simple technique for masking bitter taste of drugs resulting in the further formulation of such drugs into any palatable oral dosage form. There also exists a need to develop techniques that can be employed with minimal amount of agents used to mask the taste with minimal processing, and yet effectively mask the bitter taste.
Objectives of the invention:
The objective of the invention is to prepare drug-resin complexes to mask the bitter taste of drugs.
Another objective of the invention is to improve patient compliance affected due to bitter taste of drugs.
A further objective of the invention is to mask the bitter taste using resins, which are acceptable across all population profiles.
Yet another objective is to mask the bitter taste drugs using a simple technique involving minimal use of excipients, processing steps and parameters to be controlled.
Another objective is to formulate the drug-resin complexes as palatable oral dosage forms of bitter drugs.
3

Summary of the inevntion:
In the instant invention bitter drugs and cation exchange resins of various grades are complexed in the ratios ranging from 1:0.5 to 1:5 (drug:resin) to mask the bitter taste of drugs. Such resin complexes or resinates can be used to formulate various oral dosage forms acceptable to various profiles of the populations. Such complexes do not break down at pH 6-7 of saliva, but exhibit solubility at gastric pH of 1 -3.
Detailed description of the invention:
Ion exchange resins are used in pharmaceutical formulation for a variety of purposes. They aid in disintegration and dissolution of drugs and also in taste masking. Ion exchange resins are solid, insolubilised high molecular weight polyelectrolytes that can exchange their mobile ions of equal charge with the surrounding medium reversibly and are available in desired size ranges. Bitter cationic drugs can get adsorbed onto the weak cation exchange resins of carboxylic acid functionality to form the complex, which is non-bitter.
The complex of cationic drugs and weak cation exchange resin does not break at pH 6-7, of saliva with cation concentration of 40meq/lt. But at high cation concentration of stomach and pH of 1-3, free drug is immediately released and is available to exert its therapeutic effect.
In the instant invention the drug is complexed with the resin in the ratios ranging from 1:0.5 to 1:5 to form resinates that possess no bitter taste. Such resinates can be used to formulate various palatable oral dosage forms.
Ion exchange resins were selected from the group comprising cross-linked polyacrylic matrix type pharmaceutical grade ion exchange resins with -coo functional group and particle size equal or lesser than 0.15 mm, and methacrylic acid polymer crosslinked with divinylbenzene. The preferred resin to mask the taste was polyacrylic matrix type pharmaceutical grade ion exchange resins with -coo functional group and particle size
4

equal or lesser than 0.15 mm. This was due to the fact that the taste masking was occurring to the desired extent with the various resins, but the % of drug bound to resin was highest with cross linked polyacrylic resins, overcoming the poor binding of resins of methacrylic acid polymer crosslinked with divinylbenzene with the drug.
The process of preparing the resinate was as follows:
1. Preparing a slurry of resin in deionised water and allowed to swell for 30 minutes;
2. Adding the drug to the slurry of step 1;
3. Stirring the slurry of step 2 for 6-7 hours, allowing to sediment and filtering;
4. Washing the residue with deionised water.
The effect of acid and alkali activation, optimum time required for drug loading and the optimum pH conducive for drug loading was determined and the release of the drug from the resinate was studied.
Such resinates formed can be formulated as tablets, granules, capsules, granules filled in capsules or sachets, mouth melting tablets, fast dissolving dosage forms, controlled release dosage forms, oral liquids such as syrups, suspensions, emulsions, dry syrups for unstable drugs and such like.
Example 1
Rizatriptan benzoate, a bitter drug used to treat migraine was formulated after masking its taste with cross linked polyacrylic matrix type pharmaceutical grade ion exchange resin. Optimum results were obtained for drug loading and taste masking parameters at the drug :resin ratio of 1:2, with the drug loaded at pH 7.
Example 2
Taste masking trials of Rizatriptan benzoate
The following table is the results of the volunteers' opinion test of rizatriptan benzoate
before and after taste masking using ion exchange resins of the instant invention. A
5

panel of 10 members using time intesnsity method did taste evaluation. Sample equivalent to usual dose was held in the mouth for 10 seconds and bitterness levels were recorded instantly and after 10 seconds, 1, 2, 5, 10 and 15 minutes. The opinion was rated on a scale wherein 0 is no bitterness, 1 is acceptable bitterness, 2 is slightly bitter, 3 is moderately bitter and 4 is strongly bitter.

SrNo Tine in seconds Before taste masking (Mean) After taste masking (Mean)
1 10 2.3 0.2
2 60 3.3 0.5
3 120 3.4 0.4
4 300 3.8 0.1
5 600 3.8 0
6 900 4.0 0
Many changes, modifications, variations and applications of the subject invention will become apparent to those skilled in the art after consideration of the specification. All such changes, modifications, alterations and other uses and applications that do not depict from the spirit and scope of the invention are deemed to be covered by the invention.
Dated this 15th day of November 2006

Dr. Gopakumar G. Nair Agent for the Applicant
6

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Patent Number

272075

Indian Patent Application Number

1894/MUM/2006

PG Journal Number

12/2016

Publication Date

18-Mar-2016

Grant Date

16-Mar-2016

Date of Filing

15-Nov-2006

Name of Patentee

CHAUDHARI, PRAVIN DIGAMBAR

Applicant Address

A-1, 303, TUSHAR RESIDENCY, RAHATANI-JAGTAP DAIRY ROAD, PIMPLE SAUDAGAR, PUNE,

Inventors:

#	Inventor's Name	Inventor's Address
1	CHAUDHARI, PRAVIN DIGAMBAR	A-1, 303, TUSHAR RESIDENCY, RAHATANI-JAGTAP DAIRY RAOD, PIMPLE SAUDAGAR, PUNE 411027,
2	KOLHE SMITA RAMDAS	A-1, 303, TUSHAR RESIDENCY, RAHATANI-JAGTAP DAIRY RAOD, PIMPLE SAUDAGAR, PUNE 411027

PCT International Classification Number

A61K9/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA