DESC:TECHNICAL FIELD OF THE INVENTION

The present invention relates to a stable powder composition of pilocarpine for oral administration. In particular, the invention relates to a pilocarpine reconstitutable powder compositions for oral liquid formulation. It further describes the process of preparation of said compositions and their use in the treatment of xerostomia, symptoms of dry mouth and dry eyes in Sjogren’s syndrome patients and other diseases or disorders responsive to pilocarpine therapy.

BACKGROUND OF THE INVENTION

Pilocarpine is a muscarinic cholinergic agonist, chemically known as (3S-cis)-2(3H)-Furanone, 3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl) methyl] monohydrochloride. It has the following structure:

Pilocarpine is commercially available as film coated tablets (SALAGEN®) indicated for the treatment of radiation-induced xerostomia in head and neck cancer patients and treatment of symptoms of dry mouth and dry eyes in Sjogren’s syndrome patients. Pilocarpine is also available in various ophthalmic formulations which is meant for the reduction of elevated intra-ocular pressure in patients with open angle glaucoma or ocular hypertension, management of acute glaucoma or other eye diseases.
However, in its currently available tablet form, pilocarpine can be difficult or impossible to administer in patients who are unable (critically ill patients, children, elderly, patients suffering from dysphagia) or patients who are either unwilling or unable to swallow tablets or capsules. For these patients, suitable dosage forms for drugs may be e.g. liquid forms, e.g. solutions, suspensions, syrups or emulsions. Therefore, it is desirable to formulate liquid formulation of pilocarpine which would provide improved patient compliance. Liquid dosage forms may also have the advantage of more reproducible bioavailability over solid dosage forms.
In few countries, pilocarpine is extemporaneously compounded in hospitals and in community pharmacies as oral solution or suspensions. Eye-drops provide a convenient source of pilocarpine for the preparation of an oral solution by the community pharmacist. However, no liquid oral formulation of pilocarpine is commercially available till date.
United States Patent. No. 4,209,505 discloses Pilocarpine mouthwash for dry mouth relief comprising from about 0.025% to about 1.0% by weight pilocarpine, pilocarpine nitrate or pilocarpine hydrochloride, in a sweetened mouthwash carrier.
Fawcett J.P., et al. (International Journal of Pharmacy Practice 3.1 (1994): 14-18) discloses pilocarpine oral solution containing glycerol, hydroxybenzoate preservatives and lemon spirit. It discloses stability study of a pilocarpine formulation buffered to pH 5.5 and pH 7.5 as well as unbuffered formulations. In a formulation having pH 7.5, pilocarpine decomposed to isopilocarpine, pilocarpic acid and isopilocarpic acid. Pilocarpine oral solution prepared from powder or eye-drops in pH 5.5 buffer were stable for 60 or 90 days when stored at 25°C or 4°C, respectively.
Watanabe, Machiko et al. (Journal of pharmaceutical health care and sciences vol. 4 4. 1 Mar. 2018) discloses a new low-dose liquid formulation of pilocarpine comprising sodium alginate, sodium bicarbonate, paraben, citric acid monohydrate and trisodium citrate to form a solution having pH 6.2 for treating dry mouth in Sjögren's syndrome which is stable for 28 days when stored at 4°C in Hybripack tube.
There exists a need in the art to develop a stable reconstitutable oral powder composition of pilocarpine to overcome the issues (like stability, requirement of special storage conditions like refrigerated temperature) associated with oral liquid preparation of pilocarpine. The inventors of the present invention have developed a pilocarpine drug delivery system comprising a reconstitutable powder composition for an oral liquid formulation which is easy to administer, more patient compliant, offers immediate effects, has high physical stability and longer shelf life.

SUMMARY OF THE INVENTION

The invention relates to a stable reconstitutable oral powder composition of pilocarpine for oral administration.
In one aspect of the present invention, there is provided a stable reconstitutable powder composition for an oral liquid formulation, comprising a therapeutically effective amount of pilocarpine or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
In one embodiment, the powder is reconstituted in an oily vehicle for the oral liquid.
In another embodiment of the above aspect, the powder is reconstituted in purified water for the oral liquid.
In another embodiment, the pharmaceutically acceptable excipients are selected from one or more of a sweetener, flavoring agent, buffering agent, stabilizing agent, complexing agent, diluent, viscosity modifying agent or a preservative.
In another embodiment, oral liquids include, but are not limited to, solutions, suspensions, emulsions, syrups, slurries, juices, elixirs, dispersions, and the like.
In another embodiment, pilocarpine or its pharmaceutically acceptable salt is present in a concentration of about 0.1mg/ml to about 20mg/ml, preferably in a concentration of about 0.5mg/ml to about 10mg/ml, more preferably in a concentration of about 1mg/ml to about 5mg/ml in the reconstituted liquid formulation. In another embodiment, pilocarpine or its pharmaceutically acceptable salt is present in a concentration of about 1mg/ml in the reconstituted liquid formulation.
In a preferred embodiment, the reconstituted liquid formulation is solution for oral administration.
In another embodiment, the pilocarpine powder composition is packaged into aluminium pouches or sachets.
In another embodiment, the pilocarpine powder composition is packaged into bottles.
In another embodiment, the pilocarpine powder composition is further compounded into tablets, which can be reconstituted into liquid formulation.
In another embodiment, the pilocarpine tablets are reconstituted with purified water to form an oral solution.
In another embodiment, the pilocarpine tablets are reconstituted with an oily vehicle to form an oral suspension.
In another embodiment, the pilocarpine powder composition is further compounded into granules, which can be reconstituted into liquid formulation.
In another embodiment, when the powder is reconstituted into an oral liquid, the liquid is homogenous and stable for at least three days at ambient or refrigerated conditions.
In another embodiment, when the powder is reconstituted into an oral liquid, the liquid is homogenous and stable for at least seven days at ambient or refrigerated conditions.
In another embodiment, the powder is stable for at least three months or at least six months or at least twelve months or at least twenty four months at ambient, accelerated or refrigerated conditions having total impurities of not more than 10% w/w or not more than 5% w/w or not more than 3% w/w upon storage.
In another aspect of the present invention, there is provided a stable reconstitutable oral powder composition for an oral liquid formulation preferably oral solution, comprising a therapeutically effective amount of pilocarpine or its pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient selected from sweeteners, preservative, flavoring agent, buffering agent, diluent, viscosity modifying agent or mixture thereof.
In another embodiment of the above aspects, the powder when reconstituted into an oral liquid preferably oral solution, the liquid contains not more than 10% w/w or about not more than 5% w/w or not more than 3% w/w of total impurities, when stored for at least three days at refrigerated conditions.
In another embodiment of the above aspects, the powder when reconstituted into an oral liquid preferably oral solution, the liquid is characterized by having no substantial change in the in vitro dissolution release profile upon storage for at least three days.
In another aspect of the present invention, there is provided an oral liquid pharmaceutical composition comprising a therapeutically effective amount of pilocarpine or its pharmaceutically acceptable salt thereof, pharmaceutically acceptable excipients and a pharmaceutically acceptable liquid carrier.
In another embodiment, the powder when reconstituted into an oral liquid preferably oral solution, the pH of the oral liquid composition is less than about 7.0 or less than 6.0 or less than 5.0.
In another embodiment, the powder when reconstituted into an oral liquid preferably oral solution, the pH of the oral liquid composition is in the range of about 3.5 to about 6.0.
In another embodiment, the liquid composition is present in the form of solutions, suspensions, emulsions, syrups, slurries, juices, elixirs, dispersions. Preferably in solution form.
In another embodiment, the liquid composition is substantially free of alcohol.
In another aspect of the present invention, there is provided an oral liquid pharmaceutical composition which comprises a therapeutically effective amount of pilocarpine or its pharmaceutically acceptable salt thereof, pharmaceutically acceptable excipients selected from group of sweetener, preservative, flavoring agent, diluent or mixture thereof and a pharmaceutically acceptable liquid carrier.
In an embodiment of the above aspects, pilocarpine or its pharmaceutically acceptable salt thereof, is present in an amount of about 0.1% w/w to about 20% w/w or about 0.1% w/w to about 10% w/w or about 1% w/w to about 5% w/w of the total composition.
In an embodiment of the above aspects, the oral liquid preferably oral solution composition of the present invention is administered at least once a day, twice a day, thrice a day or four times in a day.
In another embodiment of the above aspects, the composition of the present invention is a immediate release composition or controlled release composition.
In another embodiment of the above aspects, the composition of the present invention is administered with or without food.
In another embodiment of the above aspects, the oral powder composition of the present invention is sprinkled on food for oral administration.
In one of the embodiments, a pharmaceutical kit is provided, comprising a first container and a second container, wherein the first container comprises stable reconstitutable oral powder composition of pilocarpine, and the second container comprises pharmaceutically acceptable liquid carrier.
In a preferred embodiment, a pharmaceutical kit is provided, comprising a reconstitutable oral powder composition of pilocarpine in sachet or pouch and a glass bottle comprising a pharmaceutically acceptable liquid carrier.
In another preferred embodiment, a pharmaceutical kit may also comprises of measuring cup or spoon for proper administration of oral liquid formulation.
In another aspect, there is provided a process of preparation of stable reconstitutable oral powder composition of pilocarpine comprising the step of direct blending pilocarpine and one or more pharmaceutically acceptable excipients.
In an embodiment of the above aspect, powders are passed through a mesh screen prior to and/or after mixing.
In an embodiment, there is provided a process for preparation of a stable reconstitutable powder for oral liquid formulation comprising of following steps:
(a) Sifting, blending and mixing of pilocarpine hydrochloride and all excipients.
(b) Compacting the blend obtained in step (a) using a roller compaction followed by milling, sifting or/and blending of compacts.
(c) Filling the powder obtained in step (b) into an aluminium sachets/pouches.
In another aspect of the present invention, there is provided a method of treating xerostomia or symptoms of dry mouth and dry eyes in Sjogren’s syndrome patients or associated conditions and other conditions responsive to pilocarpine therapy comprising administering to a patient in need thereof an oral liquid formulation of pilocarpine as described herein.
In an embodiment of the above aspect, the maximum daily dose of pilocarpine hydrochloride administered to patient is 30 mg / day.
The aforementioned aspects and embodiments, and other aspects, objects, features advantages of the present invention will be apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

There is provided a pharmaceutical composition in the form of a reconstitutable oral powder for an oral liquid formulation preferably oral solution, which comprises a therapeutically effective amount of pilocarpine or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The powder is reconstituted in purified water or an oily vehicle for the liquid formulation. Preferably, the powder is reconstituted in purified water.
The present invention also relates to a stable oral liquid pharmaceutical composition which comprises a therapeutically effective amount of pilocarpine or its pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable liquid carrier.
The term "pharmaceutically acceptable", as used herein, refers to a compound that is not biologically or otherwise undesirable, i.e., the compound may be incorporated into a pharmaceutical formulation of the invention and administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained.
As used herein, a “therapeutically effective amount” is a sufficient amount to provide a therapeutic benefit for the treatment or management of the disease or to delay or minimize symptoms associated with the disease.
As used herein, the term “about”, as used herein, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The term “stable” as used herein means that in the pharmaceutical composition pilocarpine does not degrade much and complies with pharmacopeia limits of impurities. The pilocarpine may decompose into isopilocarpine, pilocarpic acid and isopilocarpic acid. Also, the formulation should be physically stable without any visible phase separation of contents when stored at ambient or refrigerated conditions for a period of at least 3 months, or at least 2 months, or at least 1 month or at least 3 weeks, or at least 2 weeks, or at least 1 week, or at least 5 days, or at least 4 days, or at least 3 days, or at least 2 days, or at least 1 day. The powder composition of the present invention is stable for at least one month, at least two months, at least three months, at least four months, at least six months, at least twelve months, at least eighteen months, at least twenty-four months at ambient, accelerated or refrigerated conditions. The powder when reconstituted into an oral liquid, the liquid is homogenous and contains not more than 15% , not more than 13%, not more than 12%, not more than 11%, not more than 10% , not more than 9%, not more than 8%, not more than 7%, not more than 6%, not more than 5%, not more than 4%, not more than 3%, not more than 2%, not more than 1% of the total impurities when stored for at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least seven days, for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 12 weeks at ambient or refrigerated conditions. Further, the powder when reconstituted into an oral liquid, the liquid is characterized by having no substantial change in the in vitro dissolution release profile upon storage.
The term “pilocarpine”, as used herein, refers to pilocarpine and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline or amorphous forms thereof. Preferably pilocarpine is present as pilocarpine hydrochloride. In some embodiments, pilocarpine is present in an amount of about 0.1% w/w to about 60% w/w, about 0.1% w/w to about 40% w/w, about 0.5% w/w to about 30% w/w, about 1% w/w to about 20% w/w, about 1% w/w to about 15% w/w, or about 1% w/w to about 10% w/w of the powder composition. In a preferred embodiment, pilocarpine is present in an amount 1% w/w to 5% w/w of the powder composition. In some embodiments, the pilocarpine or its salt is present in a concentration of about 0.1mg/ml to about 20mg/ml, about 0.5mg/ml to about 10mg/ml, about 1mg/ml to about 5mg/ml in the liquid formulation. In some embodiments, the pilocarpine or its salt is present in a concentration of about 0.1mg/ml , about 0.2mg/ml, about 0.5mg/ml, about 1mg/ml, about 1.5mg/ml, about 2.0mg/ml, about 3.0mg/ml, about 4.0mg/ml, about 5.0mg/ml, about 10mg/ml, about 15mg/ml, or about 20mg/ml in the liquid formulation or in the reconstituted liquid formulation. In a preferred embodiment, the pilocarpine or its salt is present in a concentration of 1 mg/ml in the liquid formulation.
The term “salts”, as used herein, refers to acidic and/or basic salts, formed with inorganic and/or organic acids and bases. Suitable pharmaceutically acceptable salts of pilocarpine include, without limitation, pilocarpine hydrochloride, pilocarpine nitrate, pilocarpine sulfate, pilocarpine acetate, pilocarpine citrate, pilocarpine tartrate, pilocarpine zinc chloride monohydrate, pilocarpine salicylate, and combinations thereof. Preferably, the pharmaceutically acceptable salt of pilocarpine used in the present invention is pilocarpine hydrochloride.
The term “pharmaceutically acceptable excipients”, as used herein, includes excipients that may be added to the pilocarpine powder composition or to pilocarpine liquid composition. Examples of suitable pharmaceutically acceptable excipients include, but are not limited to sweeteners, preservative, buffering agent, flavoring agent, complexing agent, viscosity enhancer, diluent, and mixtures thereof. Additional excipients such as glidants, bulking agents, tonicity agents and coloring agents are within the scope of the invention.
Examples of sweeteners include, but are not limited to, glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomaltulose, Isomalt™ (hydrogenated isomaltulose), lactitol, sorbitol, mannitol, erythritol, trehalose, maltodextrin, polydextrose, and the like. Other sweeteners illustratively include glycerin, inulin, erythritol, maltol, acesulfame and salts thereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodium cyclamate, saccharin and salts thereof, e.g., saccharin sodium or saccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin, and the like. In an embodiment the liquid formulation preferably contains a sweetener that imparts a sweet taste but does not increase the blood glucose levels of the patient. Examples include a sugar alcohol and non-nutritive sugars. Examples of sugar alcohols include erythritol, theritol, ribitol, arabinitol, xylitol, mallitol, dulcitol, glucitol, sorbitol, mannitol, altritol, iditol, maltitol, lactitol, isomalt, hydrogenated starch hydrolysate and the like. Examples of non-nutritive include L-sugars, aspartame, alitame, acesulfame-K, cyclamate, stevioside, glycyrrhizin, sucralose, neohesperidin, dihydrochalcone, thaumatin saccharin and its pharmaceutically acceptable salts (e.g., calcium), and the like. In a preferred embodiment, the sweeteners may be selected from glucose, fructose, sucrose, xylitol, sucralose, trehalose, maltodextrin and sugar alcohols, present in an amount of about 0.1% w/w to about 10% w/w or about 0.1% w/w to about 5% w/w or about 0.5% w/w to about 3% w/w of the total composition.
Examples of preservatives include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, paraben salts, benzoic acid, sodium benzoate, potassium sorbate, vanillin, and mixtures thereof. In a preferred embodiment, the preservative is selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), methyl paraben, ethyl paraben, propyl paraben, butyl paraben, paraben salts, benzoic acid, sodium benzoate, potassium sorbate and mixtures thereof, present in an amount of about 0.01% w/w to about 2% w/w or about 0.1% w/w to about 1% w/w of the total composition.Buffering agents or pH adjusting agents maintain the pH when pilocarpine powder compositions are reconstituted into a liquid form. Examples of buffering agents include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate co precipitate, a mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents/pH adjusting agents include sodium citrate, citric acid monohydrate, sodium tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. Some buffering agents also impart effervescent qualities when a powder is reconstituted in a solution. In an embodiment, buffering agent is present in the range of about 0.1% w/w to about 10% w/w or about 0.1% w/w to about 5% w/w or about 0.1% w/w to about 2.5% w/w of the total composition.
Examples of flavoring agents include, but are not limited to, tutti-frutti flavor, peppermint flavor, strawberry and orange flavors and the like or others known in the art. In a preferred embodiment, the flavoring agent is present in an amount of about 0.1% w/w to about 5% w/w or about 0.5% w/w to about 3% w/w of the total composition.
Examples of viscosity enhancers (thickeners) include, but are not limited to, dextrin, cellulose derivatives (ethylcellulose, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, microcrystalline cellulose, hypromellose, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose and the like) , starches, pectin, polyethylene glycol, polyethylene oxide, trehalose and certain gums (xanthan gum, locust bean gum, etc.). In some embodiments, thickeners may at as stabilizing agent.
Examples of diluent, include, but are not limited to, lactose, dibasic calcium phosphate, saccharide, microcrystalline cellulose, sucrose, dextrose, starch, mannitol, xylitol, and sorbitol, or a mixture thereof. In a preferred embodiment, the diluent is present in an amount of about 60% w/w to about 99% w/w or about 70% w/w to about 99% w/w or 80% w/w to about 99% w/w or 85% w/w to about 99% w/w.
In some embodiments, some of the diluents may act as stabilizing agent.
The stabilizing agents are used to help the active pharmaceutical ingredient (API) maintain the desirable properties of the product until it is consumed by the patient. In the present invention, the diluents may act as stabilizing agents. In some embodiments, the thickeners may act as stabilizing agents.
Examples of complexing agent, include, but are not limited to, ethylene diamine tetraacetate (EDTA) or cyclodextrin or derivative thereof, such as 2-hydroxypropyl-ß-cyclodextrin, methyl-ß-cyclodextrin, randomly methylated-ß-cyclodextrin, ethylated-ß-cyclodextrin, triacetyl-ß-cyclodextrin, peracetylated-ß-cyclodextrin, carboxymethyl-ß-cyclodextrin, hydroxyethyl-ß-cyclodextrin, hydroxypropyl- ß -cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-ß-cyclodextrin, glucosyl-ß-cyclodextrin, maltosyl-ß-cyclodextrin, sulfobutyl ether-ß-cyclodextrin, branched-ß-cyclodextrin, hydroxypropyl-?-cyclodextrin, randomly methylated-?-cyclodextrin, trimethyl-?-cyclodextrin, and any combination(s) thereof. Further, examples of complexing agents include ion exchange resins. An ion-exchange resin having the polymeric matrix with an anionic functional group is a cation exchange resin and that having a cationic functional group is an anionic exchange resin. Examples of ion-exchange resins include, but are not limited to, Amberlite® IRP64, Amberlite® IRP69, Amberlite® IRP88, DOWEX® RTM. resins, Tulsion®335, Tulsion® 339, Tulsion® 344, Indion® 204, Indion® 214, Indion® 234, Indion® 234S, Indion® 294, Purolite® C115 HMR, Purolite® C115 E, Purolite® C100 HMR, Purolite® 100 MR and the like. In an embodiment, the complexing agent is present in an amount not more than 25% w/w or not more than 20% w/w of the total composition.
The invention relates to a stable reconstitutable powder composition for an oral liquid formulation preferably oral solution, comprising a therapeutically effective amount of pilocarpine or its pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
The reconstitutable oral powder composition of the present invention may be packaged in a sachet, pouch or bottle. Alternatively, the powder composition of pilocarpine hydrochloride is compounded into granules, tablets, mini-tablets or capsules, which may then be reconstituted into liquid formulation for oral administration. The pilocarpine powder composition, granules, tablets, mini-tablets or capsules may be reconstituted with purified water or an oily vehicle to form a liquid formulation. The liquid formulation can be a solution, suspension, emulsion, syrup, slurry, juice, elixir, or a dispersion.
In a preferred embodiment, the reconstituted liquid formulation is solution for oral administration.
In another embodiment of the above aspects, the oral powder composition of the present invention is sprinkled on food for oral administration.
The reconstitutable oral powder of the present invention is stable for at least three months or at least six months or at least twelve months at ambient, accelerated or refrigerated conditions having total impurities of not more than 10% w/w or not more than 5% w/w or not more than 3% w/w upon storage.
In another aspect of the present invention, there is provided a stable reconstitutable oral powder composition for an oral liquid formulation preferably oral solution, comprising a therapeutically effective amount of pilocarpine or its pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipient selected from sweeteners, preservative, flavoring agent, buffering agent, diluent, viscosity modifying agent or mixture thereof.
In a preferred embodiment, the recontituable powder for oral liquid formulation preferably oral solution comprises of:
(a) Pilocarpine hydrochloride in an amount of about 1% w/w to 5% w/w;
(b) Sucralose in an amount of about 0.5% w/w to about 3% w/w;
(c) Sodium benzoate in an amount of about 0.1% w/w to about 1% w/w;
(d) Tutti-frutti flavor in an amount of about 0.5% w/w to about 3% w/w;
(e) Mannitol in an amount of about 85% w/w to about 99% w/w;
The reconstituted oral liquid preferably oral solution is homogenous and stable for at least 3 days or 5 days or 7 days or 10 days or 14 days or 21 days or 30 days at ambient or refrigerated conditions. The liquid contains not more than 10% or about not more than 5% or not more than 3% w/w of total impurities, when stored for at least three days at refrigerated conditions.
In another embodiment of the above aspects, the powder when reconstituted into an oral liquid preferably oral solution, the liquid is characterized by having no substantial change in the in vitro dissolution release profile upon storage for at least three days.
The powder when reconstituted into an oral liquid preferably oral solution, the pH of the oral liquid composition is less than about 7.0 or less than 6.0 or less than 5.0.
In another embodiment, the powder when reconstituted into an oral liquid, the pH of the oral liquid composition is in the range of about 3.5 to about 6.0.
In another embodiment of the present invention, there is provided an oral liquid pharmaceutical composition comprising a therapeutically effective amount of pilocarpine or its pharmaceutically acceptable salt thereof, pharmaceutically acceptable excipients and a pharmaceutically acceptable liquid carrier.
In another aspect of the present invention, there is provided an oral liquid pharmaceutical composition which comprises a therapeutically effective amount of pilocarpine or its pharmaceutically acceptable salt thereof, pharmaceutically acceptable excipients selected from group of sweetener, preservative, flavoring agent, buffering agent, diluent or mixture thereof and a pharmaceutically acceptable liquid carrier.
The composition of the present invention may be substantially free of alcohol. The term “substantially free" of alcohol means that the composition contains less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1% by weight or by volume of alcohol.
The pH of oral solution of pilocarpine is less than about 7.0 or less than 6.0 or less than 5.0. Preferably, in the range of about 3.5 to about 6.0.
In another embodiment, pilocarpine or its pharmaceutically acceptable salt is present in a concentration of about 0.1mg/ml to about 20mg/ml, preferably in a concentration of about 0.5mg/ml to about 10mg/ml, more preferable in a concentration of about 1mg/ml to about 5mg/ml in the reconstituted liquid formulation. In another embodiment, pilocarpine or its pharmaceutically acceptable salt is present in a concentration of about 1mg/ml in the reconstituted liquid formulation.
In a preferred embodiment, pilocarpine as described hereinbefore is pilocarpine hydrochloride.
The composition of the present invention may be a immediate release composition or controlled release composition.
In another embodiment of the above aspects, the composition of the present invention is administered with or without food.
The composition of the present invention is suitable for administration once a day, twice a day, three times a day or four times over a 24 hour period. The composition may be administered with food, before food or after food. Alternatively, the composition may be mixed with the food for administration. The powder composition or the liquid composition of the invention may be sprinkled on food for administration. The maximum daily dose of pilocarpine hydrochloride that can be administered to patient is 10mg/day, 20mg/day, 30 mg/day, 40mg/day or 50mg/day. Preferably, the maximum daily dose is 30mg/day.
In a preferred embodiment, the present oral powder composition when reconstituted with purified water delivers about 1 mg of pilocarpine hydrochloride upon each ml of solution.
The present invention also discloses a pharmaceutical kit, comprising a first container and a second container, wherein the first container comprises powder composition of pilocarpine, and the second container comprises a pharmaceutically acceptable carrier. The kit may further comprise a dosing syringe, adapter or both or a measuring cup or spoon. The liquid composition can be prepared by dispersing pilocarpine powder into a predefined volume of reconstitution media (carrier) for single use or in a bottle for multi-use. Alternatively, all the content of the first container may be added to the second container to make a liquid composition for single use or multiple use. In an embodiment, the dosing syringe or measuring cup or spoon is used to transfer a predetermined amount of the pilocarpine from liquid composition. Preferably, measuring cup is used to administered pre-determined amount of pilocarpine oral solution.
In a preferred embodiment, a pharmaceutical kit is provided, comprising a reconstitutable oral powder composition of pilocarpine in sachet or pouch and a glass bottle comprising a pharmaceutically acceptable liquid carrier.
Pilocarpine powder compositions described herein are prepared by the known pharmaceutical method such as granulation or direct blending. The present invention discloses a process of preparation of stable reconstitutable oral powder composition of pilocarpine comprising the step of direct blending pilocarpine and one or more pharmaceutically acceptable excipients. In direct blending process, pilocarpine and all the pharmaceutically acceptable excipients are blended. The powder may be passed through a mesh screen prior to and/or after blending/mixing.
In an embodiment, there is provided a process for preparation of a stable powder for oral liquid formulation comprising of following steps:
(a) Sifting, blending and mixing of pilocarpine hydrochloride and all excipients.
(b) Compacting the blend obtained in step (a) using a roller compaction followed by milling, sifting or/and blending of compacts.
(c) Filling the powder obtained in step (b) into an aluminium sachets/pouches.
The present invention also provides a method of treating xerostomia, symptoms of dry mouth and dry eyes in Sjögren’s syndrome patients or associated conditions and other conditions responsive to pilocarpine therapy comprising administering to a patient in need thereof an oral liquid formulation of pilocarpine as described herein.
In an embodiment, the reconstitutable powder composition of the present invention as described hereinbefore, when administered after reconstituation with purified water is found to be bioequivalent to the commercially available SALAGEN® (5mg film coated tablet).
The pharmaceutical composition of the present invention may further comprise an additional active agent or may be administered in combination with an additional active agent.
The present invention is illustrated below by reference to the following examples.

EXAMPLES
Example 1-7: PILOCARPINE HYDROCHLORIDE ORAL POWDER COMPOSITION
S.NO. Ingredients Quantity (w/w %)
1 2 3 4 5 6 7
1. Pilocarpine HCl 3.000 3.000 3.00 1.579 1.530 1.530 1.530
2. Citric acid monohydrate 0.600 0.600 - 2.621 2.540 2.540 2.540
3. Sodium benzoate 0.750 0.750 0.750 0.395 0.383 0.383 0.383
4. Sucralose 1.500 1.500 1.500 0.789 0.765 0.765 0.765
5. Tutti-frutti Flavour 1.500 1.500 1.500 0.789 0.765 0.765 0.765
6. Hydroxypropyl betadex - 18.00 - - - - -
7. Mannitol 92.65 74.65 93.25 - - - -
8. Microcrystalline Cellulose & CMC Sodium - - - 93.83 90.95 90.95 90.95
9. Avicel PH 101 - - - - - - -
10. Stearic acid - - - - - - -
11. Xanthan gum - - - - 3.061 - -
12. Hydroxyethyl cellulose - - - - - 3.061 -
13. Sodium CMC - - - - - - 3.061
Fill weight per sachet 5 g 5 g 5 g 9.5 g 9.8 g 9.8 g 9.8 g

Manufacturing Process:

(a) Sifting, blending and mixing of pilocarpine hydrochloride and all excipients.
(b) Compacting the blend obtained in step (a) using a roller compaction followed by milling, sifting or/and blending of compacts.
(c) Filling the powder obtained in step (b) into an aluminium sachets or pouch.

The prepared oral powder composition was evaluated at initial and on stability under room temperature (25°C/60% RH), ambient temperature (30°C/65% RH) and accelerated temperature (40°C/75% RH) conditions for following parameters such as pH, impurities and assay as represented in Table 1.

Table 1: Stability Studies of prepared Oral powder composition
Time Points Room temperature (25°C/60% RH) Ambient temperature (30°C/65% RH) Room temperature (40°C/75% RH)
pH Total impurities (%) Assay (%) pH Total impurities (%) Assay (%) pH Total impurities (%) Assay (%)
Initial 5.29 0.42 98.9 5.29 0.42 98.9 5.29 0.42 98.9
3 M 5.29 0.66 98.2 5.50 0.59 100.2 5.35 1.49 98.2
6 M 5.58 0.90 98.9 5.59 1.03 99.4 5.61 2.29 98.2
9 M 5.35 1.17 98.3 5.3 1.28 97.5 NA NA NA
11 M 5.52 1.12 97.2 5.31 1.26 97.0 NA NA NA

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

,CLAIMS:We claim:
1. A reconstitutable powder composition for oral solution comprising a therapeutically effective amount of pilocarpine or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipients.
2. The powder composition for oral solution as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipients are selected from sweeteners, preservative, flavoring agent, diluent and mixtures thereof.
3. The powder composition for oral solution as claimed in claim 2, wherein preservative is selected from butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), methyl paraben, ethyl paraben, propyl paraben, butyl paraben, paraben salts, benzoic acid, sodium benzoate, potassium sorbate and mixtures thereof.
4. The powder composition for oral solution as claimed in claim 2, wherein diluent is selected from lactose, dibasic calcium phosphate, saccharide, microcrystalline cellulose, sucrose, dextrose, starch, mannitol, xylitol, and sorbitol and mixture thereof.
5. A reconstitutable powder composition for oral solution comprises:
(a) Pilocarpine hydrochloride in an amount of about 1% w/w to 5% w/w;
(b) Sucralose in an amount of about 0.5% w/w to about 3% w/w;
(c) Sodium benzoate in an amount of about 0.1% w/w to about 1% w/w;
(d) Tutti-frutti flavor in an amount of about 0.5% w/w to about 3% w/w;
(e) Mannitol in an amount of about 85% w/w to about 99% w/w;
wherein the powder is to be reconstituted with purified water before administration to form a homogenous solution having pH about 3.5 to about 6.0.
6. The powder composition for oral solution as claimed in claim 5, wherein the pilocarpine hydrochloride is present in a concentration of about 0.1 mg/ml to about 10 mg/ml or preferably about 0.5 mg/ml to about 10 mg/ml or more preferably about 1 mg/ml to about 5 mg/ml in the reconstituted oral solution.
7. The powder composition for oral solution as claimed in claim 5, is to be administered at least once in a day.
8. The process of preparing powder composition for oral solution as claimed in any of the preceding claims comprises of following steps:
(a) Sifting, blending and mixing of pilocarpine hydrochloride and all excipients.
(b) Compacting the blend obtained in step (a) using a roller compaction followed by milling, sifting or/and blending of compacts.
(c) Filling the powder obtained in step (b) into an aluminium sachets/pouches.
9. The powder composition for oral solution as claimed in any of the preceding claims is used for the treatment of xerostomia and symptoms of dry mouth and dry eyes in Sjogren’s syndrome patients.

Dated this 30th day of October 2020.

Signature…(Digitally signed)
Dr. Pramod Sagar
Deputy General Manager