FIELD OF THE INVENTION
The present invention relates to a taste masked pharmaceutical composition comprising hydroxychloroquine or its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipient(s). More particularly, the pharmaceutical composition is a powder for oral suspension or ready to use oral suspension dosage form. The invention also provides a process for manufacturing such compositions and use of said compositions in the treatment of various diseases like uncomplicated malaria, rheumatoid arthritis and various other therapeutic indications under investigation.
BACKGROUND OF THE INVENTION
Hydroxychloroquine is an aminoquinoline like chloroquine, approved for the treatment of uncomplicated malaria and was developed by Concordia Pharmaceuticals. It is also a prescribed medication in the treatment of other disease like rheumatoid arthritis, chronic discoid lupus erythematosus, and systemic lupus erythematosus. Hydroxychloroquine sulfate is chemically described as 2-[[4-[(7-Chloro-4-quinolyl) amino]pentyl] ethylamino]ethanol sulfate (1:1). The structural formula of Hydroxychloroquine sulfate is as follows:

In the United States, hydroxychloroquine is available as Plaquenil® tablets for oral administration in 200mg strength. Each tablet contains 200mg hydroxychloroquine sulfate, equivalent to 155mg base. Hydroxychloroquine is indicated in adult patients for the treatment of uncomplicated malaria due to P. falciparum, P.malariae, P. ovale, and P. vivax, for the treatment of chronic discoid lupus erythematosus, systemiclupus erythematosus and rheumatoid arthritis.
Plaquenil® tablet, for oral administration contains inactive ingredients like dibasic calcium phosphate, hypromellose, magnesium stearate, polyethylene glycol, polysorbate, corn starch, titanium dioxide, carnauba wax, shellac and black iron oxide.
At present, in United States hydroxychloroquine is available in tablet dosage form. However, many patients, particularly the elderly, pediatric and other patients experience difficulty in swallowing or chewing of a tablet dosage forms. This has resulted in a widespread practice of crushing tablets to form powder and powder being combined with Ora-sweet and/or Ora-Plus to produce suspension prior to administration. In Hospitals for pediatric dosing extemporaneous suspensions are prepared, there is a practice that pharmacists strip the outer film-coating, crush the tablets and then suspend the powder in water with a flavoring and sweetening agent like ORA-PLUS. This stripping and crushing process is cumbersome and the process results in a loss of active pharmaceutical ingredient. Such extemporaneous preparations have raised concerns over this practice, as they are prone to inaccurate dosing and contamination. Also, hydroxycloroquine is a very bitter drug and extemporaneous suspensions do not mask the bitter taste leading to non-compliance.
There is a long-felt need for medicines to be available in taste masked liquid dosage form or powder for suspension composition which are suitable for oral administration while maintaining a suitable bioavailability of the drug and/or its active metabolite(s) after oral administration. As such, the present invention aims to address the above mentioned problems by providing a pharmaceutical composition comprising hydroxychloroquine or pharmaceutically acceptable salts thereof, which is suitable for oral administration in liquid or powder for oral suspension form. The developed dosage form is stable, palatable and exhibit desired pharmaceutical technical attributes.
SUMMARY OF THE INVENTION
It is an object of the present invention to develop a pharmaceutical composition comprising hydroxychloroquine or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof with one or more pharmaceutically acceptable excipient and/or carrier and process for its preparation.
Another object of the present invention is to develop a taste masked pharmaceutical composition in the form of a powder for suspension comprising hydroxychloroquine or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof with one or more pharmaceutically acceptable excipient and/or carrier and process for their preparation.
Another object of the present invention is to develop a taste masked pharmaceutical composition of hydroxychloroquine in the form of a dry powder for suspension which can be sprinkled on applesauce, chocolate syrup, jelly or soft foods or can be suspended in water or pharmaceutically acceptable carrier and is suitable for administration to children or elderly patients.
It is another object of the present invention, to provide an oral pharmaceutical composition in the form of a powder for suspension comprising hydroxychloroquine or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof with one or more pharmaceutically acceptable excipient and/or carrier including a thickening agent/viscosity agent, taste masking agents, disintegrants, antioxidants, anticaking agent, antifoaming agent, pH adjusting agent, coloring agent, sweetening agent, flavoring agent, solubilizer/wetting agent, buffer, diluent, preservative and stabilizer.
Yet another object of the present invention is to develop a suspension comprising hydroxychloroquine or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof by a manufacturing process which is consistent and therefore feasible for industrial production, while maintaining stability, palatability and pharmaceutical equivalence to the reference formulation(s). The following embodiments further describe the objects of the present invention in accordance with the best mode of practice, however, disclosed invention is not restricted to the particular embodiments hereinafter described.

DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples.
As used herein, the term “composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising an active or its pharmaceutically acceptable salts or derivatives thereof, and the other inert ingredient(s) (i.e., pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with “formulations” and “dosage forms”. Pharmaceutical compositions of the invention include, but are not limited to, powder for oral suspension, multiparticulates, pellets, beads, spherules, beadlets, microcapsules, millispheres, microspheres, powder, granules, spheroids and the like, filled in a capsule or sachet, or compressed into tablets. Preferably, the pharmaceutical composition refers to powder, granules, pellets, multiparticulates the like, filled into capsules or sachets and ready to use suspension.
The “dry powder composition” or “unit dosage form” or “powder for oral suspension” can be in the form of a powder, granules, pellets, bead, cores, spheroids or multiparticulates (MUPs) and/or combinations thereof, irrespective of their size, shape or morphology.
The term “core” as used herein refers to pellets, spheres, granules, beads, microspheres, spherules, beadlets, microcapsules, multiparticulates, millispheres, powder and the like comprising at least one or more excipients selected from diluent, binder, disintegrant, lubricant, glidant, surfactant, wetting agent, solubilizer, stabilizer, sweetener, flavoring agent, coloring agent, carrier and taste masking agents, etc. and one or more active pharmaceutical ingredients (API).
The phrase “inert core,” as used herein, includes a core that may be microcrystalline cellulose spheres, sugar spheres, non-pariel seeds, and water insoluble and non-swellable beads.
The term "excipient" means a pharmacologically inactive component such as a diluent, binder, disintegrant, control release polymer, antioxidant, lubricant, glidant, surfactant, wetting agent, solubilizer, stabilizer, anticaking agent, sweetener, flavoring agent, coloring agent, carrier and one or more taste masking agent, etc., or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of the present invention. Further, the excipient may be in the form of powders or in the form of a dispersion. Combinations of excipients performing the same function may be used to achieve desired formulation characteristics.
As used herein, the term "about" means ± approximately 20% of the indicated value, such that "about 10 percent" indicates approximately 8 to 12 percent. The term “w/w” as used herein refers the total weight of the composition.
The term “sachet” as used herein refers to any suitable container, foil, package or bag to contain the composition. The sachet may be formed of any suitable material, including plastic, metal foil, paper or a combination thereof. Sachet can be three layered with sandwiched polyethylene terephthalate (PET) /aluminum/polyethylene layers or four layered or more with addition of more layers of PET/aluminum/polyethylene to provide robust protection to moisture sensitive drugs or a stick pack. The sachet may be provided with any suitable means for opening thereof, including a perforated region or a nick in the edge of the sachet for ease of tearing. The sachet may be of any suitable size. The sachet can be sealed using any appropriate method. Particularly, the sachet is disposable. The sachet can be a child resistant container.
The term “stable” refers to the compositions of the present invention, wherein substantially no analogues or degradation product of any API is generated during storage of the dosage form for at least 3 months, preferably for at least 6 months. The stability of the solid oral composition may be evaluated at “long term” conditions 25°C/60% RH, at intermediate conditions 30°C/65% RH, at “accelerated conditions” 40°C/75% RH, in the final container or pack either measured as the assay or drop in dissolution. Stability testing may be conducted according to the current ICH and FDA guidelines.
Unless otherwise stated the weight percentages expressed herein are based on the final weight of the composition, the core or granules or pellets, the coated core or coated granules or coated pellets.
As used herein, the term “immediate release” refers to pharmaceutical compositions that release at least 75% of the active ingredient within a small period of time, typically less than 30 minutes.
“Cushioning agent” as used herein refers to excipients that help in reducing drug-drug interactions, or reduce the drug degradation by stabilizing the drugs. Suitable cushioning agents include, but are not limited to glyceryl monostearate, microcrystalline cellulose, silicon dioxide, silicified microcrystalline cellulose, stearates like calcium stearate and magnesium stearate, lactose, polyethylene glycols, polypropylene glycols and mixtures thereof.
The term “taste masked pharmaceutical composition” as used herein refers to coated drug particles, inclusion complexes of drug using cyclodextrins, drug resin complexes and other processes known in the art.
It is a challenge to mask the bitter taste of drugs in the development of most oral formulations. It is also necessary to choose the masking process which involves the minimum number of excipients, minimum processing steps, is rapid and easy to prepare, can be carried out at room temperature, is of low cost, and is environmental friendly. Various methods have been reported to achieve taste masking of bitter drugs, i.e., polymer coating, ion-exchange resins, spray-or freeze-drying, complexation, congealing with lipids, making multiple emulsions, liposomes, microcapsules, or polymeric membranes. Inventors of the present invention proposed taste masking with polymer coating technique using various grades of Eudragit®, complexation technique using ion exchange resins, solid dispersion using various carriers and cyclodextrin derivatives.
Ion-exchange resins (IERs) are cross-linked, water-insoluble, high molecular-weight polyelectrolytes that can reversibly exchange their mobile ions of equal charge with the surrounding medium stoichiometrically. Since most drugs have ionic sites in their molecule, the resin’s charge provides a means to loosely bind such drugs. This complex prevents the drug release in the saliva, thus resulting in taste masking; however, it is weak enough to be broken down by hydrochloric acid present in the stomach. Thus, the drug resin complex is absolutely tasteless, and its bioavailability remains unaffected.
A critical factor to prepare a Drug-Resin complex (DRC) is the choice of the right IER. Hydroxychloroquine sulfate contains an exchangeable secondary amine moiety i.e. cationic center. Therefore, cation exchange resins were selected for the complex formation. Weak cation acid ion exchange resins such as Indion 204, Indion 214 as well as a strong cation acid resin such as PuroliteC100CaMR, Amberlite IRP-69 and Dowex-50 were tested in order to form the DRC.
Polymer coating of drug is another approach used for taste masking, polymers like, methyl methacrylates copolymers are used. The inventors of the present invention have found that these polymers are more effective in preventing the perception of taste of hydroxychloroquine (as it is very bitter) as compared to other taste masking techniques. Unlike conventional polymer coatings such as ethyl cellulose known for their properties of providing a dissolution barrier, the methyl methacrylates copolymers have proven to be superior for their taste masking properties when used in a specific ratio.
The present invention is a stable pharmaceutical composition directed to dry powder for suspension compositions suitable for use as a liquid suspension or sprinkled on to the food or beverages for administration to a subject in need thereof which comprises hydroxychloroquine or its pharmaceutically acceptable salts. The suspension dosage form is capable of masking the taste of the drug and also provides the drug in a suitable dosage form, thereby providing patient compliance, especially for children and the elderly.
A first aspect of the present invention provides a taste masked pharmaceutical composition comprising hydrochloroquine or its pharmaceutically acceptable salts thereof, a taste masking agent and one or more pharmaceutically acceptable excipients.
A second aspect of the present invention provides a taste masked pharmaceutical composition comprising:
a) about 0.5 to 70% by weight of hydrochloroquine or a pharmaceutically acceptable salt thereof,
b) about 1 to 50% by weight of taste masking agent,
c) about 1 to 30% by weight suspending agent,
d) about 5 to 50% by weight of diluent,
e) optionally about 1 to 15% by weight of cushioning agent and
f) one or more pharmaceutically acceptable excipient
wherein the composition is in the form of a free-flowing powder for oral suspension suitable for reconstitution with a pharmaceutically acceptable carrier.
A third aspect of the present invention provides a taste masked pharmaceutical composition, wherein the one or more pharmaceutical excipients are selected from the group consisting of binders, diluents, suspending agents, taste masking agents, lubricants, surfactants, sweeteners, glidants, disintegrants, preservatives, pH modifying agents and flavoring agents.
A fifth aspect of the present invention provides a taste masked pharmaceutical composition, wherein the powder for oral suspension is in the form of pellets, granules, multiparticulates, powder, beads, spheroids, spheres, microspheres, spherules, beadlets, microcapsules and millispheres.
A sixth aspect of the present invention provides a taste masked pharmaceutical composition, wherein no granules have a particle size greater than 850µm and wherein the composition after reconstitution has a pH range from 4.0 -6.5.
A seventh aspect of the present invention provides a taste masked pharmaceutical composition, wherein the taste masking agent is selected from the group comprising sulfobutyl Ether7 ß-Cyclodextrin (SBE7-ß-CD), ß-cyclodextrin, ?-cyclodextrin or hydroxypropyl ß-cyclodextrin (HP-ß-CD) or mixtures thereof; cation exchange resins such as Indion 204, Indion 214 as well as a strong cation acid resin such as PuroliteC100CaMR, Amberlite IRP-69, Amberlite IRP-88 and Dowex-50; methyl methacrylates copolymers such as Eudragit RS, Eudragit RL, Eudragit RS100, Eudragit RL100, EPO or the same polymers in aqueous solution like “Eudragit RS30D” or “Eudragit RL30D”, Eudragit RSPO and RLPO, cellulose esters such as cellulose acetate and cellulose propionate, polymers that dissolve at acidic or alkaline pH such as Eudragit E, cellulose acetate phthalate, and hydroxypropylmethyl cellulose phthalate or combinations thereof.
An eighth aspect of the present invention provides a taste masked pharmaceutical composition, wherein the hydroxychloroquine or its pharmaceutically acceptable salts thereof and taste masking agent have a ratio ranging from about 0.1:10 to about 10:0.1 by weight.
A ninth aspect of the present invention provides a process of preparing a taste masked pharmaceutical composition, wherein process comprises of
i. dispersing the drug and taste masking agent in a solvent and evaporating the solvent to get taste masked drug
ii. mixing taste masked drug with one or more pharmaceutically acceptable excipients;
iii. granulating the mixture of step (ii) using a solvent;
iv. drying the granulated mixture of step (iii);
v. milling the mixture of step (iv) to form granules; and
vi. mixing the granules of step (v) optionally with one or pharmaceutically acceptable excipients to form the suspension powder for reconstitution.
A tenth aspect of the present invention provides a taste masked pharmaceutical composition comprising:
a) about 0.5 to 70% by weight of hydroxychloroquine or a pharmaceutically acceptable salt thereof,
b) about 1 to 50% by weight of taste masking agent,
c) about 1 to 30% by weight suspending agent,
d) about 5 to 50% by weight of diluent,
e) optionally about1 to 15% by weight of cushioning agent and
f) one or more pharmaceutically acceptable excipient
wherein the composition is in the form of a free-flowing powder for oral suspension suitable for reconstitution with a pharmaceutically acceptable carrier and no granules have a particle size greater than 850µm and wherein the composition when reconstituted has a pH range from 4.0 -6.5.
An eleventh aspect of the present invention provides a taste masked pharmaceutical composition, wherein the composition is packed in a packaging material selected from the group consisting of a sachet, foil, pouch, capsule, bottle, container.
Another aspect of the present invention relates to process for preparing the powder for suspension comprising hydroxychloroquine or their pharmaceutically acceptable salts, wherein the process is selected from blending, direct compression, dry granulation, wet granulation, extrusion-spheronization, drug layering, coating, spray drying and hot melt extrusion.
Another aspect of the present invention relates to a stable pharmaceutical composition comprising hydroxychloroquine or their pharmaceutically acceptable salts, wherein the dose of hydroxychloroquine is about 10 mg to about 400 mg. Preferably, the dose of hydroxychloroquine is about 25 mg to about 300 mg, more preferably, the dose of hydroxychloroquine is about 25 mg to about 200 mg. Preferably, the salt of hydroxychloroquine is hydroxychloroquine sulphate.
Another aspect of the present invention provides a taste masked pharmaceutical composition comprising hydroxychloroquine or their pharmaceutically acceptable salts, having a desired bulk density and tapped density.
Yet another aspect of the present invention relates to a taste masked pharmaceutical composition comprising hydroxychloroquine or their pharmaceutically acceptable salts, wherein the formulation exhibits a desired release profile.
Yet another aspect of the present invention relates to a taste masked pharmaceutical composition comprising hydroxychloroquine or their pharmaceutically acceptable salts, which is stable at 40°C and 75% ± 5% relative humidity at least for a period of about 3 months.
In yet another aspect the present invention relates to a taste masked pharmaceutical composition comprising hydroxychloroquine or their pharmaceutically acceptable salts, used in the treatment of for the treatment of uncomplicated malaria due to P. falciparum, P.malariae, P. ovale, and P. vivax, for the treatment of chronic discoid lupus erythematosus , systemiclupus erythematosus, rheumatoid arthritis and various other indications under investigation.
In another aspect of the present invention, there is provided a process for the preparation of granules of drugs or pharmaceutically acceptable salts thereof, by using conventional methods known in the art including, but not limited to blending, mixing, dry granulation, wet granulation, direct compression, drug layering, coating, hot-melt extrusion, extrusion spheronization, spray drying, and spray coating techniques. Suitable solvents include aqueous or organic solvents. Preferable solvents include, but are not limited to, water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol; dichloromethane, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether and combinations thereof. Preferably, the solvent used during wet mass preparation is water or a hydro alcoholic solvent.
In another aspect of the invention, wet granulation can be performed using a rapid mixer granulator, a fluid bed granulator, a planetary mixer and the like; dry blending can be performed in a V-blender or a key blender; spheronization can be performed using a Fuji Paudal spheronizer or by any other appropriate method known in the art.
The pharmaceutical composition of this invention comprises one or more pharmaceutically acceptable excipients selected from the group comprising binders, diluents, lubricants, glidants, taste masking agents, suspending agents, disintegrants, surfactants, cushioning agents, basic stabilizers, pH controlling agents, coloring agents and flavoring agents.
Diluents or fillers or carriers are substances which usually provide bulk to the composition. Various useful fillers or diluents include, but are not limited to, microcrystalline cellulose, calcium carbonate, calcium phosphate, dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, starch, pregelatinized starch, sucrose and mixtures thereof. The diluents may be present in an amount of about 2% w/w to about 70% w/w, preferably from about 5% w/w to about 40% w/w and more preferably from about 5% w/w to about 30% w/w.
Binders impart cohesiveness to formulation, various useful binders include, but are not limited to hypromellose, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropylcellulose, maltose, methylcellulose, povidone, copovidone, starch, polyvinyl alcohol or polyethylene oxide, or mixtures thereof. The binder may be present in an amount of about 2% w/w to about 40% w/w, preferably from about 5% w/w to about 30% w/w and more preferably from about 5% w/w to about 20% w/w.
Disintegrants according to the present invention are selected from the group comprising crospovidone, modified starches, croscarmellose sodium, sodium starch glycolate, low substituted hydroxypropyl cellulose, microcrystalline cellulose, and carboxymethylcellulose calcium. These disintegrants are also known as super-disintegrants. The disintegrant may be present in an amount of about 1% w/w to about 40% w/w, preferably from about 1% w/w to about 20% w/w and more preferably from about 1% w/w to about 10% w/w.
Glidants improve flowability and accuracy of dosing. Glidants used in the composition include, but are not limited to, tribasic calcium phosphate, calcium silicate, cellulose powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch and talc or mixtures thereof. The amount of glidant ranges from about 0.1% w/w to about 5% w/w of the total composition.
Surfactants contemplated in the present invention include but are not limited to anionic surfactants, amphoteric surfactants, non-ionic surfactants and macromolecular surfactants. Suitable examples of surfactants include but are not limited to sodium lauryl sulphate, lecithin, stearyl alcohol, cetyl stearyl alcohol, , polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 20, polyoxyethylene fatty acid glycerides such as macrogol 1000 glycerol monostearate, polyoxyethylene fatty acid esters such as polyoxyl 40 stearate, polyoxyethylene fatty alcohol ethers such as polyoxyl 10 oleyl ether, and glycerol fatty acid esters such as glycerol monostearate. The surfactant may be present in an amount of about 0.5% w/w to about 10% w/w, preferably from about 1% w/w to about 5% w/w and more preferably from about 0.5 % w/w to about 2% w/w.
Disintegrants according to the present invention are selected from the group comprising crospovidone, modified starches, croscarmellose sodium, sodium starch glycolate, low substituted hydroxypropyl cellulose, microcrystalline cellulose, and carboxymethylcellulose calcium. These disintegrants are also known as super-disintegrants. The disintegrant may be present in an amount of about 1% w/w to about 40% w/w, preferably from about 1% w/w to about 20% w/w and more preferably from about 1% w/w to about 10% w/w.
Various useful preservatives according to the present invention include, but are not limited to, parabens such as methylparaben, propylparaben, butyl paraben or their salts, benzoic acid or its salts, sodium benzoate, potassium benzoate, calcium benzoate, methyl hydroxybenzoate, ethyl para-hydroxybenzoate, sodium ethyl para-hydroxybenzoate, sodium metabisulphite, chlorhexidine, diazolidinyl urea, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, and the like. In particular, the preservative is selected from benzoic acid or its salts, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA) and parabens. The preservative may be present in an amount of about 0.5% w/w to about 10% w/w, preferably from about 0.5% w/w to about 2% w/w.
Cushioning agents according to the present invention include, but are not limited to, glyceryl monostearate, microcrystalline cellulose, silicon dioxide, silicified microcrystalline cellulose (silicified MCC), stearates like calcium stearate and magnesium stearate, lactose, polyethylene glycols, polypropylene glycols, polytetramethylene glycols, polybutylene glycols, polybutadiene diols and triols, low molecular weight hydroxy-containing polyesters, hydroxy-containing polyester amides, polyalkylene ether glycol compounds, hydroxy-containing oils and mixtures thereof. The cushioning agents may be present in an amount of about 0.5% w/w to about 10% w/w, preferably from about 1% w/w to about 5% w/w.
Various useful sweetening agents according to the present invention include, but are not limited to, sugar or a sugar alcohol such as sucrose, dextrose, sucralose, sorbitol, neotame, aspartame, Acesulfame K, fructose, mannitol and invert sugar and sugar substitutes such as saccharin sodium. Preferably, the sweetening agent used is sodium saccharin, sucralose, or neotame. The sweetening agent may be present in an amount of about 1% w/w to about 40% w/w, preferably from about 1% w/w to about 20% w/w and more preferably from about 1% w/w to about 10% w/w.
Various useful flavoring agents according to the present invention include, but are not limited to, flavors such as banana, lemon, orange, grape, lime and grapefruit, vanilla, apple, banana, pear, peach, strawberry, raspberry, cherry, plum, wild cherry, walnut, pineapple, apricot; and combinations thereof. Preferably, wild cherry, walnut, chocolate, pineapple, apricot, anise, banana and orange. The flavoring agent may be present in an amount of about 5% w/w or less, 2% w/w or less, 1% w/w or less, 0.5% w/w or less, 0.2% w/w or less. The concentration of flavoring agent is flavor specific and may be modulated depending upon the flavor(s) used.
Suitable coloring agents according to the present invention are selected from the group comprising FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents, natural coloring agents, natural juice concentrates, pigments such as iron oxide, titanium dioxide, and zinc oxide, and combinations thereof. The coloring agent may be present in an amount of about 0.1% w/w to about 2% w/w, preferably from about 0.1% w/w to about 1.0% w/w.
Suitable suspending agents according to the present invention are selected from the group comprising gums such as xanthan gum, carrageenan gum, acacia, guar gum, locust bean gum, gum tragacanth, celluloses such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, mixture of microcrystalline cellulose and carboxymethylcellulose (Avicel® RC), polyvinylpyrrolidone, alginic acid, alginate, sodium alginate, bentonite, carbomers (carboxyvinyl polymers) such as those available under the trade name Carbopol®, cetostearyl alcohol, maltodextrin, polyvinyl alcohol, colloidal silicon dioxide, propylene carbonate, propylene glycol, sodium starch glycolate, starch, and acrylic polymers, etc. The suspending agents may be present in an amount of about 0.1% w/w to about 20% w/w, preferably from about 0.5% w/w to about 10.0% w/w.
Various useful taste masking agents according to the present invention include, but are not limited to, water soluble and/or insoluble polymeric excipients, water insoluble non-polymeric excipients, adsorbent, carbomer, alkali metal chlorides or an alkaline earth metal chlorides or a derivative, Cyclodectrin derivatives such as SBE7-ß-CD, ß-cyclodextrin, ?-cyclodextrin or hydroxypropyl ß-cyclodextrin or mixtures thereof; ion exchange resins such as Indion 204, Indion 214 as well as a strong cation acid resin such as PuroliteC100CaMR, Amberlite IRP-69, Amberlite IRP-88 and Dowex-50, methyl methacrylates copolymers such as Eudragit RS, Eudragit RL, Eudragit RS100, Eudragit RL100, EPO or the same polymers in aqueous solution like “Eudragit RS30D” or “Eudragit RL30D”, Eudragit RSPO and RLPO, cellulose esters such as cellulose acetate and cellulose propionate, polymers that dissolve at acidic or alkaline pH such as Eudragit E, cellulose acetate phthalate, and hydroxypropylmethyl cellulose phthalate or combinations thereof. The taste masking agents may be present in an amount of about amount of about 0.1% w/w to about 60%w/w, preferably from about 5.0% w/w to about 50% w/w.
Taste masking of the pharmaceutically active ingredient may be performed by the processes selected from suspending, dissolving, or dispersing the pharmaceutically active ingredient in a solution or dispersion of polymer coating material and spray drying, fluid-bed coating, simple or complex coacervation, coevaporation, co-grinding, melt dispersion and emulsion-solvent evaporation techniques and so on.
The polymer coated drug powder or the drug resin complex can be applied for the preparation of reconstitutable powders, i.e., dry powder drug products that are reconstituted as suspensions in a liquid vehicle such as water before usage or sprinkled on food beverages before administration. The reconstitutable powders have a long shelf life and the suspensions, once reconstituted, have adequate taste masking.
The final formulations or drug according to the present invention may be coated or uncoated. For coating, additional excipients such as film-forming polymers, plasticizers, anti-adherents and opacifiers are used.
Various water-soluble polymers used to form a barrier/seal or film over the core. Examples include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkylcellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose, vinylpyrrolidone vinyl acetate copolymer (PVP/VA) polymers, sodium carboxymethyl cellulose, etc., polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances. The water-soluble polymers may be present in an amount of about 1% w/w to about 80% w/w, preferably from about 5% w/w to about 70% w/w and more preferably from about 10% w/w to about 60% w/w.
If desired, the films may contain additional adjuvants for coating such as plasticizers, polishing agents, colorants, pigments, antifoaming agents, opacifiers, anti-sticking agents, and the like.
In another embodiment of the present invention, suitable acrylate and water insoluble polymers suitable for use in the present invention include, but are not limited to, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), ethylcellulose (EC), polyvinyl acetate phthalate methylcellulose acetate phthalate (MCAP) and methacrylic acid copolymers or its derivatives. Acrylate polymers or Methacrylic acid copolymers or its derivatives are selected from the group comprising different grades of Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2:1, Poly(methacrylic acid, methyl methacrylate) 1:2, Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2, Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, Poly(methacrylic acid, ethyl acrylate) 1:1.
Examples of the membrane forming agents as used herein include, for example, one or more water-insoluble polymers or one or more water-soluble polymers. The membrane forming agent is not particularly limited, so long as it is pharmaceutically acceptable and biocompatible. These membrane forming agents may be added alone or as a combination thereof, in an appropriate amount(s).
Another aspect of the present invention includes particle size of free drug particulate form of hydroxychloroquine or their pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein the particle diameter at 90% cumulative volume (d90) is less than about 200 µm, preferably less than 100 µm. Particle diameter at X% cumulative particle size reduction can be performed by techniques including but not limited to fluid energy milling, ball milling, colloid milling, roller milling, hammer milling and the like. Particle size and particle size distribution can be measured by techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy and the like.
In yet another aspect of the invention, the taste masked pharmaceutical composition of hydroxychloroquine or its pharmaceutically acceptable salts, is packed in a packaging material selected from the group comprising a foil, a pouch, a blister, a sachet, stick pack, capsule, bottle, container or other suitable package.
In yet another aspect of the invention, the taste masked pharmaceutical composition of hydroxychloroquine or its pharmaceutically acceptable salts, In-Vitro taste-masking efficiency study will be done using electronic tongue system (E-tongue), optimization of drug: resin ratio and drug: cyclodextrin ratio will be done based on various parameters.
The pharmaceutical oral dosage form prepared according to the present invention can be subjected to in vitro dissolution evaluation according to Test 711 "Dissolution" in the United States Pharmacopoeia 37, United States Pharmacopoeial Convention, Inc., Rockville, Md., 2014 ("USP") to determine the rate at which the active substance is released from the dosage form, and the content of the active substance can be determined in solution by high performance liquid chromatography. When comparing the test and reference products, dissolution profiles should be compared using a similarity factor (f2). The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves.
f2 = 50 • log {[1 + (1/n)St=1n (Rt - Tt)2]-0.5 • 100}
Two dissolution profiles are considered similar when the f2 value is equal to or greater than 50.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the methods for the preparation and testing of the pharmaceutical compositions. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. The following examples are set out to illustrate the invention and do not limit the scope of the present invention.
EXAMPLES
The following non-limiting examples are intended to further illustrate certain preferred embodiments of the invention. They are, however not intended to be limiting to the scope of the present invention.
Pharmaceutical composition of hydroxychloroquine powder for oral suspension may be prepared by using quantitative formula as given in Table 1 and 2:
TABLE 1: Taste masked drug particles/complexes
Components Example 1 Example 2 Example 3 Example 4 Example 5
Quantity % w/w
Hydroxychloroquine sulphate 0.1-30 0.1-50 0.1-30 0.1-40 0.1-10
ß-CD 1.0-50 -- -- -- --
SBE7-ß-CD -- 1.0-40 -- -- --
Eudragit L100 -- -- 1.0-30
Indion 204 -- -- -- 1.0-50 --
Amberlite IRP-69 -- -- -- -- 1.0-40
Purified water/Hydro alcoholic solvent q.s q.s q.s q.s q.s

TABLE 2: Powder for oral suspension
Powder for oral suspension
Components Example 6 Example 7 Example 8
Quantity % w/w
Taste masked drug particles/complex 0.1-70 0.1-60 0.1-50
Microcrystalline cellulose 1.0-50 1.0-60 1.0-30
Hypromellose 1.0-20 -- 1.0-20
Hydroxypropylcellulose 1.0-20 1.0-20 --
Povidone -- 1.0-20 --
Crospovidone 0.1-10 0.1-5.0 0.1-3.0
Citric acid 0.1-5.0 0.1-3.0 0.1-2.0
Sucralose 0.1-5.0 -- 0.1-10
Aspartame -- 0.1-10 --
Colloidal silicon dioxide 0-20 0-20 0-20
Flavoring agents 0.1-2 0.1-2 0.1-2
Purified water q.s. q.s. q.s.

Process for preparing drug resin complexes: Hydroxychloroquine with cation exchange resins are complexed in various stoichiometric ratios i.e., 0.5:1, 1:1 and 1:2 of drug: resin
a) Drug and resin were weighed accurately.
b) The resin was added into distilled water and the suspension was stirred on a magnetic stirrer or overhead stirrer for 30-60 minutes followed by the addition of the drug.
c) The contents of step c) were stirred for another 2-4 hours at 37 ºC
d) The drug resin complex was separated by filtration
e) The drug resin complex of step d) was washed with distilled water to remove the free drug and other ions
f) The drug resin complex of step e) dried at 40 ºC till the required moisture content.
Process for preparing drug coated with polymer:
a) Methylmethacrylate polymers and drug were dissolved in a solvent,
b) Cushioning agent was added to the suspension of step a),
c) The suspension of step b) was spray died at an inlet air temperature of less than 55° C, and
d) The spray dried particles were dried.
Preparation of Powder for oral suspension using taste masked drug:
Preferred method of manufacture of powder for suspension: extrusion-spheronization, wet granulation, dry granulation and direct compression.
The wet granulation process includes the following steps:
Step 1: All the excipients (excluding the lubricant) were weighed and mixed
Step 2: Binder solution was added to step 1 mixture for preparing a damp mass
Step 3: Dampened powder was screened into pellets or granules.
Step 4: Pellets or granules of step 3 were dried at a suitable temperature.
Step 5: The dried granule were sized using a dry screen of appropriate mesh size and
Step 6: dried granules were lubricated.
The direct compression process includes pre-milling of formulation ingredients (active drug substance and excipients), mixing of active drug substance with the powdered excipients (including the lubricant).
The dry granulation process includes weighing formulation ingredients, mixing of formulation ingredients, compression of mixed powders into slugs, milling and sieving of slugs, mixing with disintegrant and lubricant.
A uniformly blended mixture of taste masked hydroxychloroquine, diluent or pharmaceutically acceptable excipient was granulated into an over wetted dough using binder solution. The plastic mass was extruded, spheronized and dried to prepare uncoated spheroids.
Pellets or granules prepared using above mentioned processes are either encapsulated into capsules or filled into a sachet or a stick pack.

CLAIMS:We claim:
1. A taste masked pharmaceutical composition comprising:
a) from 0.5 to 70% by weight of hydroxychloroquine or a pharmaceutically acceptable salt thereof,
b) 1 to 50% by weight of taste masking agent,
c) 1 to 30% by weight suspending agent,
d) 5 to 50% by weight of diluent,
e) about 1 to 15% by weight of cushioning agent and
f) one or more pharmaceutically acceptable excipient
wherein the composition is in the form of a powder for oral suspension suitable for reconstitution with a pharmaceutically acceptable carrier and no granules have a particle size greater than 850µm and wherein the composition when reconstituted has a pH range from 4.0 -7.0.
2. The taste masked pharmaceutical composition as claimed in claim 1, wherein the powder for oral suspension is in the form of pellets, granules, multiparticulates, powder, beads, spheroids, spheres, microspheres, spherules, beadlets, microcapsules and millispheres.

3. The taste masked pharmaceutical composition as claimed in claim 1, wherein the one or more pharmaceutical excipients are selected from the group consisting of binders, lubricants, surfactants, sweeteners, glidants, disintegrants, preservatives, pH modifying agents and flavoring agents.

4. The taste masked pharmaceutical composition as claimed in claim 1, wherein the process of preparing powder for oral suspension is selected from dry granulation, wet granulation, direct compression, drug layering, coating, hot melt extrusion, extrusion spheronization or spray drying.

5. The taste masked pharmaceutical composition as claimed in claim 1, wherein the taste masking agent is selected from the group comprising SBE7-ß-CD, ß-cyclodextrin, ?-cyclodextrin or hydroxypropyl ß-cyclodextrin or mixtures thereof; ion exchange resins such as Indion 204, Indion 214 as well as a strong cation acid resin such as Purolite, Amberlite IRP-69, Amberlite IRP-88 and Dowex-50, methyl methacrylates copolymers such as Eudragit RS, Eudragit RL, EPO, Eudragit RS100, Eudragit RL100, cellulose esters such as cellulose acetate and cellulose propionate, cellulose acetate phthalate, and hydroxypropylmethyl cellulose phthalate or combinations thereof.

6. The taste masked pharmaceutical composition as claimed in claim 1, wherein the hydroxychloroquine or its pharmaceutically acceptable salts thereof and taste masking agent have a ratio ranging from 0.1:10 to about 10:0.1 by weight.

7. The taste masked pharmaceutical composition as claimed in claim 1, wherein the diluent is selected from the group comprising microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic anhydrous, calcium phosphate dibasic dihydrate, calcium phosphate tribasic, calcium sulphate, cellulose powdered, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, trehalose and xylitol, or mixtures thereof.

8. The taste masked pharmaceutical composition as claimed in claim 1, wherein the suspending agent is selected from the group comprising xanthan gum, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), ethyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium alginate and carbomers.

9. A taste masked pharmaceutical composition of hydroxychloroquine or its pharmaceutically acceptable salts thereof with one or more pharmaceutically acceptable excipients prepared by a process comprising following steps:
a) dispersing the drug and taste masking agent in a solvent and evaporating the solvent to get taste masked drug
b) mixing taste masked drug with one or more pharmaceutically acceptable excipients;
c) granulating the mixture of step (b) using a solvent;
d) drying the granulated mixture of step (c);
e) milling the mixture of step (d) to form granules; and
f) mixing the granules of step (e) with one or pharmaceutically acceptable excipients to form the suspension powder for reconstitution.

10. The taste masked pharmaceutical composition as claimed in claim 1 and 9, wherein the said composition is packed in a packaging material selected from the group consisting of a sachet, foil, pouch, capsule, bottle, container.