WO2021144625A1

WO2021144625A1 - The oral synergistic composition and its process for the preparation

Info

Publication number: WO2021144625A1
Application number: PCT/IB2020/057280
Authority: WO
Inventors: Vinay Sapte; Ganesh Giram
Original assignee: Maneesh Pharmaceuticals Ltd
Priority date: 2020-01-18
Filing date: 2020-07-31
Publication date: 2021-07-22

Abstract

The present invention relates to solid oral composition of doxylamine, pyridoxine in combination with natural extract as synergistic additive and pharmaceutically acceptable excipients. The present invention also relates to solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients, wherein the solid oral composition in the form of granules/ powder is filled into sachets or compressed into tablets, especially chewable tablets. The present invention also relates to solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients for the treatment of nausea and vomiting. The present invention more specifically to method for the preparation of oral solid composition comprising steps of sifting, mixing, granulating, dry mixing, wet milling, rasping, lubricating and sachet filling or compressing into tablets.

Description

THE ORAL SYNERGISTIC COMPOSITION AND ITS PROCESS FOR THE PREPARATION

FIELD OF THE INVENTION The present invention relates to solid oral composition of doxylamine, pyridoxine in combination with natural extract as synergistic additive and pharmaceutically acceptable excipients.

The present invention also relates to solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients.

The present invention also relates to solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients, wherein the solid oral composition in the form of granules/ powder is filled into sachets or compressed into tablets, especially chew able tablets.

The present invention specifically relates to solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients for the treatment of nausea and vomiting.

The present invention specifically relates to solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive, wherein the composition comprising granulating agent, stabilizing agent, taste masking agent, bulking agents, solubilizer, viscosity increasing agent, disintegrants, glidants or lubricants, sweetening agents, preservatives, buffering agent, diluents and other pharmaceutically acceptable excipients. The present invention more specifically relates to method for the preparation of oral solid composition comprising steps of sifting, mixing, granulating, dry mixing, wet milling, rasping, lubricating and sachet filling or compressing into tablets.

BACKGROUND OF THE INVENTION

Oral powders, granules and liquids normally provide greater dosing flexibility than oral solid single-unit dosage forms. Oral powders and granules are having more surface area which exhibits quick release thereby more bioavailability of active ingredient in systemic circulation and showed more therapeutic efficacy than oral solid single-unit dosage forms. The advantage with oral powders or granules is those having more physical and chemical stability when compare to liquid formulations which means less prone to microbial growth and these formulations having the greater dosing flexibility with reconstitution water or any another acceptable liquid. Some oral solid single-unit dosage forms such as dispersible or effervescent preparations are intended to be dispersed, suspended or dissolved prior to administration.

Oral powders are the preparations consisting of solid, loose, dry particles of varying degrees of fineness. They contain one or more active ingredients, with or without excipients and, an authorized colouring matter and flavouring substances should be added if preferable. Oral powders are generally administered in or with water or another suitable liquid. They may also be swallowed directly and which are presented as single-dose or multi-dose preparations. Granules are preparations containing solid, dry aggregated groups of smaller powder particles, or individual larger particles that may have overall dimensions greater than lOOOpm.

Therefore, the powder formulations have good chemical and physical stability, good application properties, user friendliness or good doing compliance, having good biological activity and enhanced efficacy combined with high selectivity.

Oral powders preparations can be supplied as oral powder sachets or tablets such as chewable tablets, wherein the granular powder composition can be filled into sachets or compressed into chewable tablets.

Doxylamine Succinate:

Doxylamine is a first- generation antihistamine and is a potent anticholinergic agent first reported in 1949 as sleep aid with weak hypnotic and calming effects. Doxylamine acts primarily as an antagonist or inverse agonist of the histamine HI receptor. This action is responsible for its antihistamine and sedative properties. To a lesser extent, doxylamine acts as an antagonist of the muscarinic acetylcholine receptors, an action responsible for its minor hypnotic, anticholinergic, and (at high doses) deliriant effects. Doxylamine in its succinic acid salt form in combination with vitamin B6 (pyridoxine) used to prevent morning sickness in pregnant women.

Doxylamine succinate is chemically, ethanamine, N, N-dimethyl-2-[l-phenyl- l-(2-pyridinyl)ethoxy]-, butanedioate (1:1). The empirical formula is C₁₇H₂₂N₂O C H₆0 and the molecular mass is 388.46 g/mol, the structural formula is:

Doxylamine succinate is a white to creamy white powder, is an antihistamine with sedative and hypnotic properties. It is very soluble in water and alcohol, freely soluble in chloroform and very slightly soluble in ether and benzene.

Pyridoxine Hydrochloride:

Pyridoxine (also called pyridoxol) is one form of vitamin B6. Its hydrochloride salt, pyridoxine hydrochloride, is used as a vitamin B6 dietary supplement. Pyridoxine hydrochloride is a vitamin B6 analog. The chemical name for pyridoxine hydrochloride is 3,4-pyridinedimethanol,5-hydroxy-6-methyl-, hydrochloride. The empirical formula is C_XH iN(¾·HO and the molecular mass is 205.64 g/mol and the structural formula is:

Pyridoxine HC1 is a white or practically white crystalline powder or crystals. Pyridoxine HC1 is freely soluble in water, slightly soluble in alcohol and insoluble in ether. Pyridoxine is one of the compounds analog with pyridoxal and pyridoxamine that are referred to as vitamin B6. Pyridoxine HC1 is used in oral vitamin supplements and injectable vitamin formulation products.

Ginger powder Ginger is the root or underground stem (rhizome) of the ginger plant Zingiber officinale belongs to Zingiberaceae family. Ginger plant is a flowering plant whose rhizome, ginger root or ginger, is widely used as a spice and a folk medicine. It is an herbaceous perennial grows annual pseudostems about one meter tall bearing narrow leaf blades. Ginger powder is used in food preparations intended primarily for pregnant or nursing women.

The present invention is an improvement over the prior art in that it delivers doxylamine succinate and pyridoxine hydrochloride in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients for the treatment of nausea and vomiting.

US Pat No. 6,340,695 B1 discloses the formulation comprising combination of doxylamine succinate and pyridoxine HC1, preferably in form of an enterically coated tablet, a medicament comprising synergistic duo of active ingredients is useful in the treatment of nausea and vomiting, during pregnancy “NVP”, wherein the “rapid onset” formulation comprising the following non- active excipients: a filler or binder, a disintegrating agent, a lubricant, a silica flow conditioner and a stabilizing agent, wherein the formulation exhibiting a dissolution profile indicative of a rapid onset.

US Pat No. 9,089,489 B2 discloses the dual release oral dosage system comprising doxylamine or analog, derivative, prodrug, metabolite and salt thereof and pyridoxine or analog, derivative, prodrug, metabolite and salt thereof, wherein said dual release oral dosage system comprising an immediate release component and delayed release component.

US Pub. No. 2007/0048367 A1 discloses herbal composition for treating morning sickness includes a mixture of vitamin B6, folic acid, ginger root extract, and red raspberry leaf.

US Pub. No. 2014/0335176 A1 discloses the disintegrant-free delayed release doxylamine succinate and pyridoxine HC1 formulation and a manufacturing process by using direct compression or dry granulation.

Porndee Chittumma et al., in Journal of the Medical Association of Thailand, year 2007, volume 90, No. 1, pages 15-19 disclose the effectiveness of 2 gm of ginger and the daily recommended dose (25 mg three times a day) of vitamin B6 were compared for treatment of nausea and vomiting in early pregnancy. Moreover, this article discloses that ginger was more effective than vitamin B6 based on the results obtained form the randomized double-blind controlled trial in pregnant womens.

Doxylamine preparations are available typically in combination with Pyridoxine that may also contain folic acid. Different combinations of Ginger and vitamin B6 (Pyridoxine) or combination of vitamin B6, vitamin B12 and folic acid are available in market. None of the prior-art reported the combination formulation comprising doxylamine or its salt, pyridoxine or its salt and in combination with natural extract such as ginger powder as synergistic additive, in the form of oral solid composition.

There is a need in the art to provide solid oral compositions having two active ingredients in combination with natural extract such as ginger powder as synergistic additive (1) providing better treatment for nausea and vomiting by administering combination formulation of two active ingredients with the natural extract such as ginger powder to provide synergistic effect and enhanced efficacy and less toxicity (2) maintaining the stability of the product during storage.

There are several combinations available in the market like diclegis enteric coated delayed release tablets which contains 10 mg of doxylamine succinate and 10 mg of pyridoxine hydrochloride; Bonjesta extended release tablets which contains 20 mg of doxylamine succinate and 20 mg of pyridoxine hydrochloride. The solid oral composition comprising doxylamine succinate and pyridoxine hydrochloride in combination with ginger powder or in the form of chewable tablet is not available in the market.

All the prior art references related to the mono products as well as combination of doxylamine succinate and pyridoxine hydrochloride in preparing different modified release compositions like extended release and delayed release tablets. However, the inventors of present invention provide solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients for the treatment of nausea and vomiting. The inventors of present invention also provide an efficient process for the preparation of oral solid composition comprising steps of sifting, mixing, granulating, dry mixing, wet milling, rasping, lubricating and sachet filling or compressing into tablets. It was surprisingly and unexpectedly found by the present inventors that a fixed combination of two active ingredients comprising doxylamine succinate, pyridoxine hydrochloride and ginger powder as synergistic additive in the ratio of 1:1:10 to 1:1:15 which was formulated in powder/granular or chewable tablet formulation possesses enhanced efficacy, in nausea and vomiting treatment as compared with commercial modified release such as delayed release, extended release formulations of mono products as well as combination products.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide solid oral composition of doxylamine, pyridoxine in combination with natural extract as synergistic additive and pharmaceutically acceptable excipients.

Another objective of the present invention is to provide solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients.

Another objective of the present invention is to provide solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients for the treatment of nausea and vomiting.

Another objective of the present invention is to provide solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients, wherein the solid oral composition in the form of granules/ powder is filled into sachets or compressed into tablets, especially chewable tablets.

Another objective of the present invention is to provide solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive, wherein the composition comprising granulating agent, stabilizing agent, taste masking agent, bulking agents, solubilizer, viscosity increasing agent, disintegrants, glidant or lubricants, sweetening agents, preservatives, buffering agent, diluents and other pharmaceutically acceptable excipients.

Still another objective of the present invention is to provide method for the preparation of oral solid composition comprising steps of sifting, mixing, granulating, dry mixing, wet milling, rasping, lubricating and sachet filling or compressing into tablets.

SUMMARY OF INVENTION

Accordingly, the present invention provides solid oral composition of doxylamine, pyridoxine in combination with natural extract as synergistic additive and pharmaceutically acceptable excipients.

In one embodiment, the present invention provides solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients.

In one embodiment, the present invention provides solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients for the treatment of nausea and vomiting.

In one embodiment, the present invention provides solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients, wherein the solid oral composition in the form of granules/ powder is filled into sachets or compressed into tablets, especially chew able tablets.

In another embodiment, the present invention provides solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive, wherein the composition comprising granulating agent, stabilizing agent, taste masking agent, bulking agents, solubilizer, viscosity increasing agent, disintegrants, glidants or lubricants, sweetening agents, preservatives, buffering agent, diluents and other pharmaceutically acceptable excipients.

In yet another embodiment, the present invention provides solid oral composition comprising of:

0.1% to 5% (w/w) of first active ingredient,

0.1% to 5% (w/w) of second active ingredient,

30% to 56.5% (w/w) of natural extract as synergistic additive,

10% to 18.5% (w/w) of bulking agent or taste masking agent,

0.5% to 3.0% (w/w) of solubilizer or solubility enhancer,

0.5% to 1.75 % (w/w) of viscosity increasing agent,

0.1% to 1.5% (w/w) of granulating agent,

0.05% to 1.75 % (w/w) of stabilizing agent,

1% to 5% (w/w) of one or more disintegrants,

0.5% to 2.5% (w/w) of glidant or lubricant,

0.01% to 0.65% (w/w) of sweetening agents,

0.01% to 0.65% (w/w) of buffering agent,

5% to 35.5% (w/w) of diluent or filler,

0.01% to 0.15% (w/w) of preservative, and

0.01% to 5% other pharmaceutically acceptable excipients.

0.1% to 5% (w/w) of doxylamine or its salt,

0.1% to 5% (w/w) of pyridoxine or its salt,

30% to 56.5% (w/w) of ginger powder as synergistic additive,

10% to 18.5% (w/w) of mannitol,

0.5% to 3.0% (w/w) of beta cyclodextrin, 0.5% to 1.75 % (w/w) of polyvinyl pyrrolidone,

0.1% to 1.5% (w/w) of maize starch,

0.05% to 1.75 % (w/w) of colloidal silicon dioxide,

1% to 5% (w/w) of croscarmellose sodium and sodium starch glycolate,

0.5% to 2.5% (w/w) of magnesium stearate,

0.01% to 0.65% (w/w) of neotame,

0.01% to 0.65% (w/w) of citric acid anhydrous,

5% to 35.5% (w/w) of lactose,

0.01% to 0.15% (w/w) of methyl paraben, and

0.01% to 5% other pharmaceutically acceptable excipients.

In yet another embodiment, the present invention provides method for the preparation of oral solid composition comprising steps of sifting, mixing, granulating, dry mixing, wet milling, rasping, lubricating and sachet filling or compressing into tablets.

In yet another embodiment, the present invention provides a process for preparing solid oral composition, the process comprising steps of:

(a) sifting of first active ingredient, second active ingredient, natural extract powder, stabilizing agent, diluent, bulking agent or taste masking agent, solubilizer or solubility enhancer, granulating agent through the sieve,

(b) warming purified water in SS Vessel,

(c) adding and dissolving preservative to the warm purified water obtained from the step (b) with stirring,

(d) adding and mixing viscosity increasing agent to the mixture obtained from the step (c) with stirring until to obtain clear mixture,

(e) adding purified water to granulating agent for preparing slurry, then adding this slurry to mixture obtained form step (d),

(f) filter the obtained mixture or paste through the # 100 mesh nylon filter cloth and cooled to room temperature, (g) unloading Step (a) materials into Rapid mixer granulator and mixing upto 30 minutes at slow speed,

(h) granulating the above mixture obtained from step (g) by adding paste obtained from step (f),

(i) passing through multimill fitted with 8 mm screen & collecting wet mass into fluidized bed dryer,

(j) drying the wet granules in fluidized bed dryer at 60°C of inlet temperature and 35-45°C of outlet temperature, till to obtain the desired Loss on drying (LOD) of 1-2%.

(k) sifting of dried granules obtained from step (j) through #20 mesh, separating the passed and retained granules separately,

(l) passing retained granules through multimill using 1.5 mm screen at fast speed with knife forward method and passing gain through #20 mesh,

(m) sifting the disinterants, stabilizing agent, sweetening agent, glidant, and buffering agent through sieve,

(n) loading sifted granules in blender and mixing for 3 minutes,

(o) adding all sifted ingredients except glidant and/or lubricant to the above obtained granules and mixing for 7 minutes,

(p) adding final lubricant to the above step (o) in blender and lubricate for 3 minutes, and

(q) filling the required quantity of lubricated blend into sachet by automatic sachet filling machine in 4 ply aluminum laminates or foil or compressing the lubricated blend using 12.4 mm round punches into tablets, specifically chew able tablets.

(a) sifting of doxylamine or its salt, pyridoxine or its salt, ginger powder, colloidal silicon dioxide, lactose, mannitol, beta cyclodextrin, maize starch through the sieve, (b) warming purified water in SS Vessel,

(c) adding and dissolving methyl paraben to the warm purified water obtained from the step (b) with stirring,

(d) adding and mixing polyvinyl pyrrolidone to the mixture obtained from the step (c) with stirring until to obtain clear mixture,

(e) adding purified water to maize starch for preparing slurry, then adding this slurry to mixture obtained form step (d),

(f) filter the obtained mixture or paste through the # 100 mesh nylon filter cloth and cooled to room temperature,

(g) unloading Step (a) materials into Rapid mixer granulator and mixing upto 30 minutes at slow speed,

(m) sifting the croscarmellose sodium and sodium starch glycolate, colloidal silicon dioxide, neotame, magnesium stearate, and citric acid anhydrous through sieve,

(n) loading sifted granules in blender and mixing for 3 minutes,

(o) adding all sifted ingredients except magnesium stearate to the above obtained granules and mixing for 7 minutes,

(p) adding final magnesium stearate to the above step (o) in blender and lubricate for 3 minutes, and (r) filling the required quantity of lubricated blend into sachet by automatic sachet filling machine in 4 ply aluminum laminates or foil or compressing the lubricated blend using 12.4 mm round punches into tablets, specifically chew able tablets.

DETAILED DESCRIPTION OF THE INVENTION

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

The present invention provides solid oral composition of doxylamine, pyridoxine in combination with natural extract as synergistic additive and pharmaceutically acceptable excipients.

The present invention provides solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients.

The present invention provides solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients for the treatment of nausea and vomiting.

The present invention provides solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients, wherein the solid oral composition in the form of granules/ powder is filled into sachets or compressed into tablets, especially chew able tablets.

The present invention provides solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive, wherein the composition comprising granulating agent, stabilizing agent, taste masking agent, bulking agents, solubilizer, viscosity increasing agent, disintegrants, glidants or lubricants, sweetening agents, preservatives, buffering agent, diluents and other pharmaceutically acceptable excipients.

The term “active ingredients” of the present invention are doxylamine, pyridoxine, ginger powder combination is effective in treatment of nausea and vomiting.

The “active ingredients” used in the present invention can be used as pharmaceutically acceptable salts.

The pharmaceutically acceptable salts used in the present invention are doxylamine in its succinate salt form as first active ingredient and pyridoxine in its hydrochloride salt form as second active ingredient.

The synergistic additive ginger powder is used in the present invention is obtained from market which is freely available.

In a preferred embodiment, the solid oral composition of the invention comprises first active ingredient is doxylamine succinate. The concentration of doxylamine succinate used in the solid oral composition of the invention is from 0.1% to 5%, preferably 3.6% (w/w).

In a preferred embodiment, the solid oral composition of the invention comprises second active ingredient is pyridoxine hydrochloride. The concentration of pyridoxine hydrochloride used in the solid oral composition of the invention is from 0.1% to 5%, preferably 3.6% (w/w). In a preferred embodiment, the solid oral composition of the invention comprises natural extract as synergistic additive is ginger powder. The concentration of ginger powder used in the solid oral composition of the invention is from 30% to 56.5%, preferably 36.0% to 54% (w/w). The fixed combination of two active ingredients comprising doxylamine succinate, pyridoxine hydrochloride and ginger powder as synergistic additive in the weight ratio of 1:1:10 to 1:1:15.

The solid oral composition according to the present invention comprise bulking agent or taste masking agent which includes mannitol, calcium carbonate, glycine, polydextrose, raffinose, sucralose, attapulgite, bentonite, carrageenan, Erythritol, glyceryl palmitostearate, neohesperidin dihydrochalcone, tributyl citrate. Preferably, the bulking agent or taste masking agent used in the solid oral composition is mannitol. The concentration of bulking agent or taste masking agent used in the solid oral composition of present invention is from 10% to 18.5% (w/w). Most preferably used concentration of bulking agent or taste masking agent is from 13.5% to 18.5% (w/w).

The solid oral composition according to the present invention comprise solubilizer or solubility enhancer which includes cyclodextrin in its beta form, Hydroxypropyl Betadex, Sulfobutylether b-Cyclodextrin, Meglumine. Preferably, the solubilizer or solubility enhancer used in the solid oral composition is beta cyclodextrin. The concentration of solubilizer or solubility enhancer used in the solid oral composition of present invention is from 0.5% to 3.0% (w/w). Most preferably used concentration of solubili er or solubility enhancer is from 0.9% to 2.7% (w/w).

The solid oral composition according to the present invention comprise viscosity increasing agent which includes but not limited to sodium carboxy methyl cellulose, polyvinyl pyrrolidone, carbomer, crosslinked polyacrylic acid polymers, gellan gum, xanthan gum and carrageenan. Preferably, the viscosity increasing agent used in the solid oral composition is polyvinyl pyrrolidone. The concentration of viscosity increasing agent used in the solid oral composition of present invention is from 0.5% to 1.75% (w/w). Most preferably used concentration of viscosity increasing agent is from 0.9% to 1.62% (w/w).

The solid oral composition according to the present invention comprise granulating agent which includes acacia, alginic acid, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, ethylcellulose, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar gum, magnesium aluminum silicate, maltodextrin, polyethylene oxide, polymethacrylates, povidone, sodium alginate, tragacanth, microcrystalline cellulose, maize starch and zein. Preferably, the granulating agent used in the solid oral composition is maize starch.

The concentration of granulating agent used in the solid oral composition of present invention is from 0.1% to 1.5% (w/w). Most preferably used concentration of granulating agent is from 0.9% to 1.35% (w/w).

The solid oral composition according to the present invention comprise stabilizing agent which includes but not limited to calcium carbonate, colloidal silicone dioxide, microcrystalline cellulose, kaolin, activated charcoal, dibasic calcium phosphate, Bentonite, natural clay, activated alumina, zeolites and the like. Preferably, the stabilizing agent used in the solid oral composition is colloidal silicone dioxide.

The concentration of stabilizing agent used in the solid oral composition of present invention is from 0.05% to 1.75% (w/w). Most preferably used concentration of stabilizing agent is from 0.9% to 1.62% (w/w).

The solid oral composition according to the present invention comprise disintegrants which includes croscarmellose sodium, alginic acid, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose (low substituted), microcrystalline cellulose, powdered cellulose, crospovidone, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, starch, disodium disulfite, disodium edathamil, disodium edetate, disodiumethylenediaminetetraacetate (EDTA) crosslinked polyvinylpyrollidines, pregelatinized starch, carboxymethyl starch, sodium carboxymethyl starch, microcrystalline cellulose. Preferably, the disintegrants used in the solid oral composition is of one or more disintegrants includes crosscarmelose sodium and sodium starch glycolate.

The concentration of disintegrants used in the solid oral composition of present invention is from 1% to 5% (w/w). Most preferably used concentration of disintegrants is from 2.7% to 4.45% (w/w).

The solid oral composition according to the present invention comprise glidant or lubricant which includes include calcium stearate, magnesium oxide, magnesium stearate, mineral oil, poloxamer, polyethylene glycol, sodium lauryl sulfate, sodium stearate fumarate, stearic acid, talc and, zinc stearate, glyceryl behanate, magnesium lauryl sulfate, boric acid, sodium benzoate, sodium acetate, combination of sodium benzoate and sodium acetate. Preferably, the glidant or lubricant used in the solid oral composition is magnesium stearate.

The concentration of glidant or lubricant used in the solid oral composition of present invention is from 0.5% to 2.5% (w/w). Most preferably used concentration of glidant or lubricant is from 1.35% to 2.25% (w/w). The solid oral composition according to the present invention comprise sweetening agents which includes neotame, saccharin, aspartame, sucralose, thaumatin, acesulfame potassium, stevioside, stevia extract, paramethoxy cinnamic aldehyde, neohesperidyl dihydrochalcone and perillartine. Preferably, the sweetener used in the solid oral composition is neotame.

The concentration of sweetening agents used in the solid oral composition of present invention is from 0.01% to 0.65% (w/w). Most preferably used concentration of sweetening agents is from 0.18% to 0.54% (w/w).

The solid oral composition according to the present invention comprise buffering agent which includes, citric acid, lactic acid, tartaric acid, sodium hydroxide, sodium dihydrogen phosphate and its hydrates, sodium phosphate and its hydrates, disodium hydrogen phosphate and its hydrates, disodium sulfate, sodium hydrogen sulfate, sodium carbonate, sodium hydrogen carbonate, calcium hydrogen carbonate. Preferably, the buffering agent used in the solid oral composition is citric acid.

The concentration of buffering agent used in the solid oral composition of present invention is from 0.01% to 0.65% (w/w). Most preferably used concentration of buffering agent is from 0.3% to 0.54% (w/w).

The solid oral composition according to the present invention comprise diluent or filler which includes cellulose or derivatives, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, cellulose acetate, hydroxypropylcellulose, microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, potato starch and combinations thereof. Preferably, the diluent diluent used in the solid oral composition is lactose.

The concentration of diluent or filler used in the solid oral composition of present invention is from 5% to 35.5% (w/w). Most preferably used concentration of diluent or filler is from 5.54% to 34.45% (w/w).

The solid oral composition according to the present invention comprise preservative which include, parabens such as methyl paraben, propyl paraben, benzyl alcohol, sodium benzoate, phenol, benzalkonium chloride, thimerosal, chlorobutanol, benzoic acid, sodium bisulfite, and sodium proprionate. Preferably, the preservative used in the solid oral composition is methyl paraben.

The concentration of preservative used in the solid oral composition of present invention is from 0.01% to 0.15% (w/w). Most preferably used concentration of preservative is from 0.045% to 0.135% (w/w).

According to the present invention solid oral composition comprising doxylamine succinate, pyridoxine hydrochloride and ginger powder can be filled in suitable volume container or sachet. Suitable volume container includes 4 ply aluminum foil sachet with different sizes ranges and the solid oral composition comprising doxylamine succinate, pyridoxine hydrochloride and ginger powder can be compressed into tablets, specifically chewable tablets. The following examples describes the nature of the invention which are given only for the purpose of illustrating the present invention in more detail and are not limitative and relate to solutions, which have been particularly effective on bench scale.

EXAMPLES Solid oral powder sachet composition

EXAMPLE 1

EXAMPLE 2

EXAMPLE 3

Solid oral chewable tablet composition

EXAMPLE 4

EXAMPLE 5

EXAMPLE 6

Manufacturing procedure: The present invention provides a process for preparing solid oral powder composition or solid oral chewable tablet composition, the process comprising steps includes first active ingredient, second active ingredient, natural extract powder, stabilizing agent, diluent, bulking agent or taste masking agent, solubilizer or solubility enhancer, granulating agent were sifted through the sieve, purified water was added in SS Vessel and warmed and preservative is added and dissolved in the warm purified water with stirring, viscosity increasing agent is added and mixed with stirring until clear mixture obtained, purified water added to granulating agent for preparing slurry, then this slurry is added to previously obtained clear mixture, the obtained mixture or paste was filtered through the # 100 mesh nylon filter cloth and cooled to room temperature, unloaded sifted materials into Rapid mixer granulator and mixing upto 30 minutes at slow speed, granulated the obtained mixture by adding paste, obtained mixture passed through multimill fitted with 8 mm screen and wet mass is collected into fluidized bed dryer, wet granules were dried in fluidized bed dryer at 60°C of inlet temperature and 35-45°C of outlet temperature, till to obtain the desired Loss on drying (LOD) of 1-2%, dried granules were sifted through #20 mesh, separating the passed and retained granules separately, retained granules were passed through multimill using 1.5 mm screen at fast speed with knife forward method and passing gain through #20 mesh, disinterants, stabilizing agent, sweetening agent, glidant, and buffering agent were sifted through appropriate sieve, sifted granules were loaded in blender and mixing for 3 minutes, all sifted ingredients except glidant and/or lubricant were added to obtained granules and mixed for 7 minutes, then finally, lubricant was added in blender and lubricated for 3 minutes, filling the required quantity of lubricated blend into sachet by automatic sachet filling machine in 4 ply aluminum laminates or foil or compressing the lubricated blend using 12.4 mm round punches into tablets, specifically chewable tablets.

Claims

We Claim:

1. The solid oral composition of doxylamine, pyridoxine in combination with natural extract as synergistic additive and pharmaceutically acceptable excipients.

2. The solid oral composition as claimed in claim 1, wherein the natural extract as synergistic additive is ginger powder.

3. The solid oral composition as claimed in claim 1, wherein the solid oral composition of doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients, wherein the solid oral composition in the form of granules/ powder is filled into sachets or compressed into tablets, especially chewable tablets.

4. The solid oral composition as claimed in claim 3, wherein the composition further comprise pharmaceutically acceptable excipients selected from granulating agent, stabilizing agent, taste masking agent, bulking agents, solubilizer, viscosity increasing agent, disintegrants, glidants or lubricants, sweetening agents, preservatives, buffering agent, diluents and other pharmaceutically acceptable excipients.

5. The solid oral composition as claimed in claim 4, wherein the bulking agent or taste masking agent is selected from mannitol, calcium carbonate, glycine, polydextrose, raffinose, sucralose, attapulgite, bentonite, carrageenan, Erythritol, glyceryl palmitostearate, neohesperidin dihydrochalcone, tributyl citrate, wherein the bulking agent is in the concentration ranges from 10% to 18.5% (w/w).

6. The solid oral composition as claimed in claim 4, wherein the solubilizer or solubility enhancer is selected from cyclodextrin in its beta form, Hydroxypropyl betadex, Sulfobutylether b-Cyclodextrin, Meglumine, wherein the solubilizer or solubility enhancer is in the concentration ranges from 0.5% to 3.0% (w/w).

7. The solid oral composition as claimed in claim 4, wherein the viscosity increasing agent is selected from sodium carboxy methyl cellulose, polyvinyl pyrrolidone, carbomer, crosslinked polyacrylic acid polymers, gellan gum, xanthan gum and carrageenan, wherein the viscosity increasing agent is in the concentration ranges from 0.5% to 1.75% (w/w).

8. The solid oral composition as claimed in claim 4, wherein the granulating agent is selected from acacia, alginic acid, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, ethylcellulose, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar gum, magnesium aluminum silicate, maltodextrin, polyethylene oxide, polymethacrylates, povidone, sodium alginate, tragacanth, microcrystalline cellulose, maize starch and zein, wherein the granulating agent is in the concentration ranges from 0.1% to 1.5% (w/w).

9. The solid oral composition as claimed in claim 4, wherein the stabilizing agent is selected from calcium carbonate, colloidal silicone dioxide, microcrystalline cellulose, kaolin, activated charcoal, dibasic calcium phosphate, Bentonite, natural clay, activated alumina, zeolites and the like, wherein the stabilizing agent is in the concentration ranges from 0.05% to 1.75% (w/w).

10. The solid oral composition as claimed in claim 4, wherein the disintegrants used alone or in combination are selected from croscarmellose sodium, alginic acid, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose (low substituted), microcrystalline cellulose, powdered cellulose, crospovidone, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, starch, disodium disulfite, disodium edathamil, disodium edetate, disodiumethylenediaminetetraacetate (EDTA) crosslinked polyvinylpyrollidines, pregelatinized starch, carboxymethyl starch, sodium carboxymethyl starch, microcrystalline cellulose, wherein the disintegrants is in the concentration ranges from 1% to 5% (w/w).

11. The solid oral composition as claimed in claim 4, wherein the glidant or lubricant is selected from calcium stearate, magnesium oxide, magnesium stearate, mineral oil, poloxamer, polyethylene glycol, sodium lauryl sulfate, sodium stearate fumarate, stearic acid, talc and, zinc stearate, glyceryl behanate, magnesium lauryl sulfate, boric acid, sodium benzoate, sodium acetate, combination of sodium benzoate and sodium acetate, wherein the glidant or lubricant is in the concentration ranges from 0.5% to 2.5% (w/w).

12. The solid oral composition as claimed in claim 4, wherein the sweetening agent is selected from the neotame, saccharin, aspartame, sucralose, thaumatin, acesulfame potassium, stevioside, stevia extract, paramethoxy cinnamic aldehyde, neohesperidyl dihydrochalcone and perillartine, wherein the sweetening agent is in the concentration ranges from 0.01% to 0.65% (w/w).

13. The solid oral composition as claimed in claim 4, buffering agent is selected from the citric acid, lactic acid, tartaric acid, sodium hydroxide, sodium dihydrogen phosphate and its hydrates, sodium phosphate and its hydrates, disodium hydrogen phosphate and its hydrates, disodium sulfate, sodium hydrogen sulfate, sodium carbonate, sodium hydrogen carbonate, calcium hydrogen carbonate, wherein the buffering agent is in the concentration ranges from 0.01% to 0.65% (w/w).

14. The solid oral composition as claimed in claim 4, wherein the diluent or filler is selected from the cellulose or derivatives, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, cellulose acetate, hydroxypropylcellulose, microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, potato starch and combinations thereof, wherein the diluent or filler is in the concentration ranges from 5% to 35.5% (w/w).

15. The solid oral composition as claimed in claim 4, wherein the preservative is selected from parabens such as methyl paraben, propyl paraben, benzyl alcohol, sodium benzoate, phenol, benzalkonium chloride, thimerosal, chlorobutanol, benzoic acid, sodium bisulfite, and sodium proprionate, wherein the preservative is in the concentration ranges from 0.01% to 0.15% (w/w).

16. The solid oral composition as claimed in claim 1, composition of solid oral powder or chewable tablet composition comprising:

(a) 0.1% to 5% (w/w) of first active ingredient,

(b) 0.1% to 5% (w/w) of second active ingredient,

(c) 30% to 56.5% (w/w) of natural extract as synergistic additive,

(d) 10% to 18.5% (w/w) of bulking agent or taste masking agent,

(e) 0.5% to 3.0% (w/w) of solubilizer or solubility enhancer,

(f) 0.5% to 1.75 % (w/w) of viscosity increasing agent,

(g) 0.1% to 1.5% (w/w) of granulating agent,

(h) 0.05% to 1.75 % (w/w) of stabilizing agent,

(i) 1% to 5% (w/w) of one or more disinte grants,

(j) 0.5% to 2.5% (w/w) of glidant or lubricant,

(k) 0.01% to 0.65% (w/w) of sweetening agents,

(l) 0.01% to 0.65% (w/w) of buffering agent,

(m) 5% to 35.5% (w/w) of diluent or filler,

(n) 0.01% to 0.15% (w/w) of preservative, and (o) 0.01% to 5% other pharmaceutically acceptable excipients.

17. The solid oral composition as claimed in claim 16, wherein the active ingredients and synergistic additive in the weight ratio of 1:1:10 to 1:1:15.

18. A process for preparing solid oral composition, the process comprising steps of:

(b) warming purified water in SS Vessel,

(k) sifting of dried granules obtained from step (j) through #20 mesh, separating the passed and retained granules separately, (l) passing retained granules through multimill using 1.5 mm screen at fast speed with knife forward method and passing gain through #20 mesh,

(m) sifting the disinterants, stabilizing agent, sweetening agent, glidant, and buffering agent through sieve, (n) loading sifted granules in blender and mixing for 3 minutes,

(p) adding final lubricant to the above step (o) in blender and lubricate for 3 minutes, and (q) filling the required quantity of lubricated blend into sachet by automatic sachet filling machine in 4 ply aluminum laminates or foil or compressing the lubricated blend using 12.4 mm round punches into tablets, specifically chew able tablets.

19. The solid oral composition as claimed in claim 1, wherein the solid oral composition comprising doxylamine, pyridoxine in combination with ginger powder as synergistic additive and pharmaceutically acceptable excipients for the treatment of nausea and vomiting.