DESC:The following specification particularly describes the invention and the manner in which it is to be performed.
TASTE MASKED COMPOSITION OF ZINC SALT
TECHNICAL FIELD OF THE INVENTION
The present invention relates to oral pharmaceutical composition containing therapeutically efficacious amount of zinc salt. The invention further relates to taste masked liquid composition of zinc salt for the treatment of diarrhea in children and process of preparing the same.
BACKGROUND OF THE INVENTION
Diarrhea is a leading cause of deaths among infant and young children causing death of around 2195 children every day globally. There are nearly 1.7 billion cases of childhood diarrheal disease every year. Diarrhoea accounts for 20% of all paediatric deaths in India.
Diarrhea has increased prevalence in low and middle income countries due to lack of safe water and adequate sanitation. Worldwide, 780 million individuals lack access to improved drinking water and 2.5 billion lack improved sanitation. Safe-drinking water is critical in preventing diarrhea.
Diarrhea can be treated using oral rehydration solution and zinc supplementation. Routine use of zinc supplementation, at a dosage of 20 mg per day for children older than six months or 10 mg per day in those younger than six months, for 10–14 days is recommended in addition to oral rehydration solution for management of diarrhea. A 10-14 day supplemental treatment course of 20 mg zinc salt shortens diarrhea duration and improves outcome. Zinc salts are commercially available in the form of tablets, capsules, powder/granules for reconstitution, and suspension. Tablets contain either 10 or 20 mg of elemental zinc and the concentration of elemental zinc in liquid solutions may be 2.5mg/5ml, 10mg/5ml, 15mg/5ml, 20mg/5ml, 55mg/5ml etc. Decisions about the strength to be used should depend on compliance and adherence to treatment by patient.
Solid oral dosage forms like tablets and capsules are the most preferred dosage form among adults. But these are not preferable for pediatric patients as they are difficult to swallow. Dosage form such as syrup, suspension, powder/granules for reconstitution are considered better for pediatric patients. Powder/granules for reconstitution require dilution with water before administration and there is a possibility of adding contaminated water during reconstitution. Contaminated water may result in further episodes of diarrhoea and will increase the time taken for recovery. Liquid compositions like oral solutions are most preferable and avoid need of reconstitution by caretaker. Due to very high water solubility of zinc salts, commercially available oral solutions are not suitable particularly when a high concentration of zinc salt is to be used in composition.
Water-soluble zinc salts have a strong bitter metallic after-taste. The characteristic bitterness of zinc is experienced as soon as the zinc compound is released and proceeds to break down in the mouth. It is very necessary to completely mask metallic after-taste to ensure compliance and adherence to therapy. Adherence to the treatment regimen for 10 to 14 days is essential to ensure the full effect of zinc for the prevention and treatment of diarrhea. However, adherence to treatment can be obtained only if the composition is acceptable to infants and young children.
A variety of compositions and methods have been prepared and attempted to lessen or mask entirely the bitter taste and aftertaste of zinc compounds.
JP5162812 discloses an oral liquid preparation of Zinc compound with collagen peptide and cone peptide having about 1mg/ml zinc compound.
CN102716150 discloses oral liquid composition of zinc sulphate, sucrose as sweetener, phenylethyl ester as preservative, citric acid, sodium citrate as pH stabilizer.
US5002970 discloses that the taste of ionizable zinc compounds can be masked with anethole.
US4292324 discloses palatable aqueous zinc solutions containing a complex forming carboxylic acid selected from the group consisting of citric acid, tartaric acid, malic acid etc. and maleic anhydrides.
CN105077280 discloses liquid composition of zinc having erythritol, polydextrose, Aspartame, potassium sorbate, citric acid and sodium carboxymethylcellulose.
WO2002041920 discloses a preparation of blend of active ingredient and cyclodextrin and wherein preparation is in the form of aqueous dispersion and wherein said blend is not a complex.
WO2005117911 discloses a liquid composition of sulfo-alkyl ether- cyclodextrin and Sertaline in specific molar ratio.
US5024997 covers palatable aqueous base ibuprofen solution suitable for oral administration having hydroxypropyl beta cyclodextrin and a sweetening agent which can be formulated into clear solutions for oral administration.
Addition of taste masking and flavoring agent is not sufficient to mask the bitter and metallic taste of zinc sulphate or any other pharmaceutically acceptable salt of zinc when in solution, more particularly when it is to be used in concentration to be equivalent of 20mg/mL of elemental zinc. Techniques like coating zinc salt with polymeric material are also not suitable for liquid dosage form. Moreover such coating affects solubility and bioavailability of zinc salt in water. Chemical or solubility modification of drug product by taste masking agents (using Acrysol K150 & Cremophore RH40) alters solubility and pose processing challenges. It is desirable to have monophasic dosage form for acceptable organoleptic properties. So, composition of liquid dosage form having a concentrated zinc salt that is easily released without affecting solubility and bioavailability is challenging.
Cyclodextrins are known to mask taste of few drugs but taste masking of highly bitter salts like zinc having high water solubility and bitter metallic taste and after-taste by cyclodextrin is not known.
There is thus an unmet need to formulate a liquid composition having high concentration of zinc salt which is easier to administer to infants and children and also having an acceptable taste, with no need of reconstitution to avoid contamination.
It has been surprisingly found that cyclodextrins can completely mask the bitter taste of zinc salt when administered in liquid composition. Accordingly, the invention provides a palatable concentrated, liquid oral composition of zinc salt.
OBJECT OF THE INVENTION
It is an object of the invention to provide a taste masked liquid composition of zinc salt.
It is another object of the invention to provide a taste masked liquid composition of zinc sulphate.
It is another object of the invention to provide a taste masked liquid composition of zinc salt having higher concentration of elemental zinc.
It is another object of the invention to provide a taste masked liquid composition of zinc salt having atleast 10mg/ml concentration of elemental zinc.
It is another object of the invention to provide a taste masked liquid composition of zinc salt having 15 mg/ml concentration of elemental zinc.
It is another object of the invention to provide a taste masked liquid composition of zinc salt having 20 mg/ml concentration of elemental zinc.
It is another object of the invention to provide a taste masked liquid composition of zinc salt having 25 mg/ml concentration of elemental zinc.
It is another object of the invention to provide a taste masked liquid composition comprising zinc salt and cyclodextrin.
It is another object of the invention to provide a taste masked liquid composition of zinc salt wherein taste masking agent is ß cyclodextrin.
It is another object of the invention to provide a taste masked liquid composition of zinc salt wherein weight ratio of elemental zinc to ß cyclodextrin ranges from 1:0.1 to 1:20.
It is another object of the invention to provide a taste masked liquid composition of zinc salt wherein taste masking agent is hydroxypropyl ß cyclodextrin.
It is another object of the invention to provide a taste masked liquid composition of zinc salt wherein weight ratio of elemental zinc to hydroxypropyl ß cyclodextrin ranges from 1:0.1 to 1:20.
It is another object of the invention to provide process of preparation of taste masked liquid composition of zinc salt.
It is another object of the invention to provide a taste masked liquid composition comprising zinc salt, cyclodextrin and pharmaceutically acceptable excipients.

DESCRIPTION OF INVENTION
The terms “zinc salt” or “pharmaceutically acceptable zinc salt” are similar and these terms can be used interchangeably.
The term “cyclodextrin” as used in specification refers to any pharmaceutically acceptable cyclodextrin.
A taste masked liquid composition of zinc salt having higher concentration of zinc salt would be a significant improvement to the state of art. Advantages of such composition include increased compliance among pediatric patients, decreased risk of adding contaminated water during reconstitution and thus decrease in possibility of diarrheal episodes.
Accordingly, the present invention relates to taste masked liquid composition comprising higher concentration of zinc salt which is characterized in that taste masking agent is cyclodextrin.
In one embodiment of the present invention, taste masked liquid composition comprising zinc salt and cyclodextrin is provided.
In one embodiment of present invention taste masked liquid composition comprising zinc salt and cyclodextrin is provided wherein cyclodextrin can be selected from alpha cyclodextrin, beta cyclodextrin, hydroxypropyl ß cyclodextrin, gamma cyclodextrin or any other pharmaceutically acceptable cyclodextrin.
In one embodiment of present invention a taste masked liquid composition of zinc salt, cyclodextrin and pharmaceutically acceptable excipients is provided.
In one embodiment of present invention taste masked liquid composition of zinc salt is prepared by process comprising the steps of dissolving cyclodextrin in water, adding zinc salt, optionally adding other pharmaceutical excipients.
As used herein zinc salt can be any water soluble zinc salt which is pharmaceutically acceptable for ex. zinc acetate, zinc gluconate, zinc sulphate. These salts are equally efficacious for management of diarrhea.
Zinc sulphate monohydrate is the most widely used zinc salt. A person skilled in art will be able to calculate amount of zinc sulphate monohydrate equivalent to 10 or 20 mg of elemental zinc. For example, 54.9 mg of zinc sulphate monohydrate is equivalent to 20 mg of elemental zinc.
As used herein cyclodextrin refers to cyclic oligosaccharides. Cyclodextrin have a toroidal shape, with a lipophilic central cavity and a relatively hydrophilic outer surface. This structure enables cyclodextrins to bind appropriately sized non-polar guest molecules, or moieties of guest molecules, within the lipophilic central cavity, to form clathrate complexes.
Cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring.
a (alpha)-cyclodextrin: 6-membered sugar ring molecule
ß (beta)-cyclodextrin: 7-membered sugar ring molecule
? (gamma)-cyclodextrin: 8-membered sugar ring molecule
Hydroxpropyl ß cyclodextrin is partially substituted ether of ß cyclodextrin.
Taste masked liquid composition of zinc salt can be prepared using ß cyclodextrin and other pharmaceutically acceptable excipients.
Taste masked liquid composition of zinc salt can be prepared using ß cyclodextrin wherein weight ratio of elemental zinc to ß cyclodextrin can range from 1:0.1 to 1:20. Taste masked liquid composition of zinc salt can be prepared using ß cyclodextrin wherein weight ratio of elemental zinc to ß cyclodextrin can range from 1:0.3 to 1:1.5. Taste masked liquid composition of zinc salt can be prepared using ß cyclodextrin wherein weight ratio of elemental zinc to ß cyclodextrin is 1:0.36.
Taste masked liquid composition of zinc salt can be prepared using hydroxypropyl ß cyclodextrin and other pharmaceutically acceptable excipients.
Hydroxpropyl ß cyclodextrin have improved water solubility and safety as compared to other cyclodextrins.
Taste masked liquid composition of zinc salt can be prepared using hydroxypropyl ß cyclodextrin wherein weight ratio of elemental zinc to hydroxypropyl ß cyclodextrin can range from 1:0.1 to 1:20. Taste masked liquid composition of zinc salt can be prepared using hydroxypropyl ß cyclodextrin wherein weight ratio of elemental zinc to hydroxypropyl ß cyclodextrin can be 1:1.25, 1:1.5, 1:2, 1:2.25, 1:2.5, 1:3.75, 1:5, 1:7.5, 1:12.5. Taste masked liquid composition of zinc salt can be prepared using hydroxypropyl ß cyclodextrin wherein weight ratio of elemental zinc to hydroxypropyl ß cyclodextrin is 1:2.5.
As used herein taste masked liquid composition encompasses composition in solution form containing zinc salt, cyclodextrin and other pharmaceutically acceptable excipients like preservatives, sweetener, acidifying agent, alkalinizing agent, flavors, bitter suppressants etc.
The suitable sweeteners of present invention can be selected from the group of one or more of sucrose, glucose, glycerol, sorbitol, saccharin sodium, aspartame, xylitol, mannitol, maltitol, sucralose, cyclamate. Preferably sweetener is combination of maltitol and sucralose.
Preservative of present invention can be selected from sodium methyl paraben, sodium propyl paraben, sodium benzoate, benzoic acid, sodium propionate, potassium sorbate, benzalkonium chloride, cetyl pyridinium chloride, thiomersal, nitromersol, phenylmercuric nitrate, phenylmercuric acetate etc. Preferably preservative is combination of sodium methyl paraben and sodium propyl paraben.
Flavors of present invention can be common to areas where the composition is to be used and selected any fruity flavors acceptable to the pediatric patients like orange, strawberry, banana and the like may be used, but it is not limited thereto.
Composition may contain acidifying and alkalinizing agent to maintain pH. Acidifying agent may be citric acid, lactic acid, phosphoric acid etc. The pH adjuster may be an alkalizing agent can be selected from group of sodium hydroxide, potassium hydroxide, sodium bicarbonate, ammonia solution, potassium citrate, triethanolamine, sodium acetate and sodium citrate.
Bitter suppressants like NaCl, LiCl, KCl, L-arginine, L-aspartic acid, Na-acetate and Na-gluconate can also be added in the composition. Preferably bitter suppressant is NaCl.
Taste masked liquid composition of zinc can be prepared by adding zinc salt slowly to aqueous solution of hydroxypropyl ß cyclodextrin with continuous stirring and optionally adding other pharmaceutical ingredients.
The following examples will further describe certain specific aspects and embodiments of the invention in greater details and are not intended to limit the scope of invention.
Example 1
S. No. Ingredients Amount in mg/mL
1. Zinc sulphate monohydrate 54.90 54.90 54.90
2. Beta cyclodextrin (Kleptose STD) 30.00 10.98 7.14
3. Sodium Methyl Paraben 1.00 1.00 1.00
4. Sodium Propyl Paraben 0.10 0.10 0.10
5. Maltitol solution 600.00 600.00 600.00
6. Citric acid anhydrous 2.50 2.50 2.50
7. Sucralose 40.00 40.00 40.00
8. Sodium acetate trihydrate 4.00 4.00 4.00
9. Sodium saccharin 3.00 3.00 3.00
10. Orange Juicy L-1507 0.06 0.06 0.06

Beta Cyclodextrin was added to purified water and dissolved with continuous stirring. Zinc sulphate monohydrate is added slowly to above step, stirred to form complexation. Sodium methyl paraben and Sodium propyl paraben added to the solution and dissolved with continuous stirring. Maltitol solution, Citric acid anhydrous and sodium acetate trihydrate, Sucralose is added and dissolved with continuous stirring. Flavor is added to the above solution with continuous stirring. Finally the volume made up with purified water and stirred for 10 minutes.
Example 2
S. No. Ingredients mg/mL
1. Zinc sulphate monohydrate 54.90
2. Hydroxy Propyl Beta cyclodextrin 400.00
3. Sodium Methyl Paraben 1.00
4. Sodium Propyl Paraben 0.10
5. Maltitol solution 500.00
6. Citric acid anhydrous 2.50
7. Sucralose 40.00
8. Sodium acetate trihydrate 4.00
9. Orange Juicy L-1507 0.04

Hydroxypropyl ß cyclodextrin was dissolved in purified water with continuous stirring. Zinc sulphate monohydrate was added to above step and dissolved with continuous stirring, for 30 minutes. Maltitol solution, Sodium methyl paraben and Sodium propyl paraben, Citric acid anhydrous were sequentially sadded and dissolved with continuous stirring. Sodium acetate trihydrate, Sucralose, Flavor was added to the above solution with continuous stirring. Finally the volume made up with purified water and stirred for 10 minutes. 400 mg of hydroxypropyl ß cyclodextrin as complexing agent was able to mask the bitter taste. A clear and colorless solution is obtained having a pH of 3.54.
Example 3
S. No. Ingredients mg/mL
1. Zinc sulphate monohydrate 54.9
2. Hydroxypropyl ß – cyclodextrin 25.0
3. Sodium chloride 5.49
4. Sodium Methyl Paraben 1.0
5. Sodium Propyl Paraben 0.1
6. Maltitol solution 450.0
7. Citric acid anhydrous 2.5
8. Sucralose 40.0
9. Sodium acetate, trihydrate 4.0
10. Orange Juicy L-1507 0.04
11. Purified water q.s

Composition can be prepared in a similar manner as above. Assay values of the composition were found to be satisfactory.
Example 4
S. No. Ingredients mg/mL
1. Zinc sulphate monohydrate 54.9
2. Hydroxypropyl ß – cyclodextrin 50.0
3. Sodium chloride 5.49
4. Sodium Methyl Paraben 1.0
5. Sodium Propyl Paraben 0.1
6. Maltitol solution 450.0
7. Citric acid anhydrous 2.5
8. Sucralose 40.0
9. Sodium acetate, trihydrate 4.0
10. Orange Juicy L-1507 0.04
11. Purified water q.s

Composition can be prepared in a similar manner as above. Assay values of the composition were found to be satisfactory
,CLAIMS:WE CLAIM:
1) A taste masked liquid composition of zinc salt comprising zinc salt, cyclodextrin and optionally one or more pharmaceutically acceptable excipients selected from preservatives, sweetener, acidifying agent, alkalinizing agent, flavors and bitter suppressants.
2) A taste masked liquid composition of zinc salt as claimed in claim 1 wherein zinc salt is selected from the group consisting of zinc acetate, zinc gluconate and zinc sulphate.
3) A taste masked liquid composition of zinc salt as claimed in any of the preceding claims, wherein composition contains at least 10mg/ml of elemental zinc.
4) A taste masked liquid composition of zinc salt as claimed in claim 1, wherein cyclodextrin is selected from the group consisting of alpha cyclodextrin, beta cyclodextrin, hydroxypropyl ß cyclodextrin, and gamma cyclodextrin.
5) A taste masked liquid composition of zinc salt as claimed in claim 4, wherein weight ratio of elemental zinc to ß cyclodextrin range from 1:0.1 to 1:20.
6) A taste masked liquid composition of zinc salt as claimed in claim 5, wherein weight ratio of elemental zinc to ß cyclodextrin is 1:0.36.
7) A taste masked liquid composition of zinc salt as claimed in claim 4, wherein weight ratio of elemental zinc to hydroxypropyl ß cyclodextrin range from 1:0.1 to 1:20.
8) A taste masked liquid composition of zinc salt as claimed in claim 7, wherein weight ratio of elemental zinc to hydroxypropyl ß cyclodextrin is 1:2.5.
9) A process of preparing taste masked liquid composition of zinc salt comprising the steps of dissolving cyclodextrin in water, adding zinc salt and optionally adding other pharmaceutical excipients.
10) A taste masked liquid composition of zinc salt and process of preparation thereof as substantially described herein with specification and examples.