DESC:FIELD OF THE INVENTION

The invention disclosed herein relates to the stable pharmaceutical composition for acid labile drug(s), comprising multitude of units, wherein each unit comprises acid labile drug(s) loaded core surrounded by polymeric barrier coating(s); enteric coating(s) and functional coating(s). The composition is suitable for reconstitution in to suspension by admixing with suitable carrier. The composition developed herein retains physical and/or chemical stability. The invention further provides method for production and use of said stable pharmaceutical composition.

BACKGROUND OF THE INVENTION

Several therapeutic active substances are fairly stable at neutral to alkaline pH values in-vitro and in-vivo, however may demonstrate instability at low pH values as found in stomach on account of acid sensitive chemical nature. The stability of such active substances is also affected by moisture, heat, organic solvent and in some instances by light. Prominent examples of acid labile substances include but not limited to erythromycins, penicillin’s, nucleosides, proton pump inhibitors, etc.

Various proton pump inhibitors (PPI), most commonly the benzimidazole derivatives are useful in the treatment of disorders originating from increased gastric acid secretion. These represent first choice of medicine in prevention and treatment of esophagitis, peptic ulcer diseases, nonerosive reflux diseases, functional dyspepsia, Zollinger-Ellison syndrome, etc. Few examples of such PPIs include omeprazole, esomeprazole, pantoprazole, lansoprazole, rabeprazole, leminoprazole and the like. On account of their tendency to decompose in acidic and neutral environment, it is of prime importance to protect such active drugs from the effect of acids. Most of the PPIs exhibit low solubility along with rapid degradation in acidic medium thereby forming colored degradation products. Therefore fabrication of suitable dosage form for such acid labile drugs needs consideration of several factors. In view of stability short comings of active substances like PPI, oral solid dosage form must be protected from contact with the acidic gastric juice and the active substances must be transferred in intact form to that part of the gastrointestinal tract where pH is near neutral and where rapid absorption can occur.

Formulating oral dosage forms like granules, pellets, tablets, capsules, etc, for acid labile drugs such as PPIs, involve use of enteric coating which offers protection from acidic environment of stomach along with rapid dissolution in alkaline medium of the intestine. Also due to acid labile nature of such PPIs, these may need to be incorporated in dosage form in the form of their alkaline salts such as sodium or together with alkaline substances. Occasionally enteric coating materials used in the dosage form may induce decomposition of acid labile PPI, therefore application of seal coat or barrier coat may prevent the degradation of these active drugs in dosage form. Several researchers have reported different approaches to develop dosage forms for acid sensitive drugs.

US 5,026,560, US 5,045,321, 5,093,132, US 5,879,708, US 5,433,959, US 6,017,560 US 6,123,962, US 6,296,875, 6,379,705, US 4,689,333, US 4,853,230 disclose stabilized pharmaceutical compositions such as granules, tablets, etc, for substituted benzimidazoles using inorganic alkaline salts.

US Publication No. 2005003005 discloses enteric coated granules comprising high content of an acid-unstable medicament like PPI (about 12% by weight or more based on the total granule weight) and basic inorganic salt along with intermediate coating layer.

US Publication No. 20050214371 discloses a stable pharmaceutical composition for acid labile drug comprising inner core coated with drug; first intermediate coating devoid of alkaline stabilizing agent and second intermediate coating comprising an alkaline stabilizing agent and outer enteric layer.

US 5,626,875 discloses stable oral preparation containing acid labile benzimidazole compound comprising inert core, non-alkaline inert water soluble polymer, non-alkaline reacting excipients and inert non-alkaline coating disposed along with outer enteric coating.

US 20120321702 discloses oral solid dosage form for lansoprazole comprising mixture of pellets comprising drug, being free of alkaline-reacting compounds and pellets comprising drug with at least one alkaline-reacting compound.

US 20130216617 discloses stable pharmaceutical composition comprising a core comprising (R)-lansoprazole or salt thereof and at least two functional coating layers over the core, wherein the first functional coating layer comprises polymeric substance soluble in pH range of 6.0 to7.5 and second functional coating layer comprises a polymeric substance soluble in the pH range of 5.0 to 6.0.

US 6,346,269 discloses oral formulation containing acid-sensitive drugs comprising a core, active drug containing layer and sub-coating layer followed by enteric coating layer. US 5,753,265 discloses multiple unit tablet comprising enteric coated core of PPI, wherein the enteric coating layer provides mechanical strength to withstand compression during tableting.

US 20070231388 discloses pellet comprising a starter pellet layered with an active ingredient such as PPI and a disintegrant wherein the layer is formed by spraying a suspension of the disintegrant onto the starter pellet.

WO 2004004690 discloses liquid suspension comprising enteric coated micro-granules of acid-labile drug.

WO 2006068596 discloses solid oral preparation for PPI in the form of rapidly-gelling granulate mixture comprising multitude of enteric coated pellets and a suspension modifying granulate free from bicarbonate and carbonate salts.

DiGiacinto, J.L. et al 2000; Ensom, M.H.H. et al 2007; Morrison, J.T., et al 2013 disclose preparation and stability of oral extemporaneous suspension of lansoprazole in 8.4% sodium bicarbonate vehicle. These studies indicated limited stability of lansoprazole ranging from 8 hours to 48 hours when stored in amber colored plastic oral syringes at room temperature and from 7 days to 14 days when refrigerated.
Ensom, M.H.H. et al 2007 discloses stability up to 91 days; however the preparation needs storage in amber glass bottles. Moreover such suspensions in 8.4% sodium bicarbonate vehicle are unpalatable for oral administration.

WO2017145146 discloses PPI composition suitable for forming viscous suspension comprising plurality units, each comprising a drug core and outer coating comprising gel forming agent.

Despite of known & available formulation approaches, there is continuing need of pharmaceutical composition for acid-labile drugs which would demonstrate physical and/or chemical stability, especially upon reconstitution into suspension during storage as well as during its use in acidic medium.

Further there is unmet need of a stable and palatable pharmaceutical dosage form for acid labile drugs which can attract better patient compliance, particularly in patients such as pediatrics or geriatrics who experience difficulties in swallowing conventional dosage forms. Accordingly inventors have provided herein a stable and palatable pharmaceutical composition suitable for reconstitution in to suspension which retains physical and/or chemical stability. The invention further provides method for production and use of said stable pharmaceutical composition.

OBJECTIVES OF THE INVENTION

The main object of the invention is to provide a stable pharmaceutical composition for acid labile drug(s), comprising multitude of units, wherein each unit comprises a) acid labile drug(s) loaded core surrounded by polymeric barrier coating(s) and an enteric coating layer(s); and b) functional coating layer(s) surrounding said coated drug(s) loaded core; wherein the composition is suitable for reconstitution into a suspension by admixing with suitable carrier.

Another object of the invention is a stable pharmaceutical composition for acid labile drug(s), comprising multitude of units, wherein each unit comprises
a) acid labile drug(s) loaded core surrounded by polymeric barrier coating(s) and an enteric coating layer(s); and
b) functional coating layer(s) surrounding said coated drug(s) loaded core;
wherein the composition is suitable for reconstitution into a suspension by admixing with suitable carrier and wherein the composition is stable for at least three months when stored at 40°C and 75% relative humidity

Another object of the invention is a stable pharmaceutical composition for acid labile drug(s), comprising multitude of units, wherein each unit comprises
a) acid labile drug(s) loaded core surrounded by polymeric barrier coating(s) and an enteric coating layer(s); and
b) functional coating layer(s) surrounding said coated drug(s) loaded core;
wherein the composition is suspension produced upon reconstitution with suitable carrier.

Another object of the invention is a stable pharmaceutical composition for acid labile drug(s), comprising multitude of units, wherein each unit comprises
a) acid labile drug(s) loaded core surrounded by polymeric barrier coating(s) and an enteric coating layer(s); and
b) functional coating layer(s) surrounding said coated drug(s) loaded core;
wherein the composition is suspension produced upon reconstitution with suitable carrier and wherein the suspension is stable for one month when stored at 25°C and 60% relative humidity.

Another object of the invention is a stable pharmaceutical composition for acid labile drug(s), comprising multitude of units, wherein each unit comprises
a) acid labile drug(s) loaded core surrounded by polymeric barrier coating(s) and an enteric coating layer(s); and
b) functional coating layer(s) surrounding said coated drug(s) loaded core;
wherein the composition is suspension produced upon reconstitution with suitable carrier and wherein the suspension is stable for at least one week when stored at 25°C and 60% relative humidity.

Another object of the invention is a process of preparing a stable pharmaceutical composition for acid labile drug(s).

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made to the exemplary embodiments and specific language will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein, and additional applications of the principles of the inventions as illustrated herein, which would occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in the specification and appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly directs otherwise.

The invention provides herein a stable pharmaceutical composition for one or more of acid labile drug(s), comprising multitude of units, wherein each unit comprises a) one or more of acid labile drug(s) loaded core surrounded by polymeric barrier coating(s) and an enteric coating layer; and b) a functional coating layer surrounding said coated drug(s) loaded core; wherein the composition is suitable for reconstitution into a suspension by admixing with suitable carrier.

Surprisingly it was found that application of functional coating to the enteric coated acid labile drug(s) loaded core improves physical and/or chemical stability, especially upon reconstitution into suspension during storage as well as during its use in acidic medium. Pharmaceutical composition thus produced is suitable for reconstitution into a stable suspension by admixing with suitable carrier.

The invention is suitable for acid labile drugs in general. The term "acid labile drug" refers to any drug, medicament or active pharmaceutical ingredient (API) that will degrade at a pH of about 3.5 or less. Non limiting examples of "acid labile drug" include one or more of pharmaceutically active agents such as substituted benzimidazole compounds (proton pump inhibitors (PPI) and the like), statins (pravastatin, fluvastatin atorvastatin and the like), antiobiotics (penicillin G, ampicillin, streptomycin, clarithromycin, azithromycin and the like), peptides, proteins, nucleosides, nucleotides, DNA, RNA, glycosaminoglyacan, dideoxyinosine (ddI or didanosine), dideoxyadenosine (ddA), dideoxycytosine (ddC), digoxin, pancreatin and the like. The foregoing list of acid-labile drugs is not meant to be exhaustive, but merely illustrative as a person of ordinary skill in the art would understand that many other acid-labile drugs or combination of acid-labile drugs could also be used.

In embodiments, the acid labile drug is a proton pump inhibitor, salt, prodrug, enantiomer, derivatives and/or combinations thereof. Non limiting examples of proton pump inhibitors (PPI) include lansoprazole, omeprazole, pantoprazole, rabeprazole, tenaprazole and the like. The compounds may be used in neutral form or in the form of an alkaline salt such as magnesium, calcium, sodium, potassium and the like.

The stable pharmaceutical composition according to the invention comprise but are not limited to solid, semisolid, liquid dosage forms. Non limiting examples of the composition of the invention include powder, granules, pellets, beads, tablet, orally disintegrating tablet, mini tablets, caplet, capsule, pellets in capsules, tablets in capsules, microcapsule, solution, suspension, emulsion, gel, film dosage form, matrix formulations, microencapsulated dosage forms and the like. In one of the embodiment composition of the invention is semisolid or liquid suspension produced upon reconstitution by admixing with suitable carrier.

Preferably, composition of the invention comprise particles, powder, granules, pellets, beads, tablet, orally disintegrating tablet, caplet, capsule, microcapsule suitable for reconstitution into suspension. More preferably, the composition of the invention comprise pellets for reconstitution into suspension.
Core
Acid labile drug(s) loaded core of the present invention may be prepared by said drug(s) layering on the inert cores. In one of the embodiment acid labile drug(s) loaded core of the invention may be prepared by coating with aqueous or non-aqueous solution/ dispersion/ suspension essentially comprising said acid labile drug(s) and optionally pharmaceutically acceptable excipients such as binder, stabilizers surfactant, filler, anti-tacking agent and the like. In another embodiment of the invention, the acid labile drug(s) loaded core can also be prepared by extrusion / spheronization. Alternatively the core material can be prepared by using spray drying or spray congealing technique. The inert core may be in the form of pellets, granules, beads or spheroids. The inert core may be acidic, alkaline or neutral depending on the type of the composition. The inert core of present invention may comprise water-soluble, water-swellable or water-insoluble excipients. Non limiting examples of inert core includes non-pareil seeds (NPS) or sugar spheres, microcrystalline cellulose spheres such as CELPHERE® , starches, and the like. The inert core may also include coarse grade silicon beads. The size of inert core may comprise in the range of 50 µ to 1400 µ. Preferably the size of inert core is selected in the range of 50 µ to 500 µ. More preferably the size of inert core is selected in the range 50 µ to 250 µ. The acid labile drug(s) loaded core of the invention may also comprise one or more pharmaceutically acceptable excipients such as binders, diluents, disintegrants, lubricants/glidants, solubilizers/wetting agents and the like.

In another embodiment of the invention, the acid labile drug(s) loaded core may be prepared by mixing of the said active drug(s) with one or more of pharmaceutically acceptable excipients thereby forming a matrix type core. In one of the embodiment of the invention, the acid labile drug(s) loaded core may be prepared by mixing of the said active drug(s) with one or more of alkaline substances and optionally further mixed with suitable additives thereby forming core material.

Polymeric barrier coating(s)
The acid labile drug(s) loaded core may be further coated with one or more of polymeric barrier coating(s) prior to the enteric coating layer. The barrier coat may be located between the acid labile drug(s) loaded core and the enteric coating layer. The barrier coating provides physical separation between the active part of the core which comprises acid labile drug(s) and the outer enteric coating. The barrier coating(s) layer may comprise one or more of water-soluble polymers, water-insoluble polymers. The polymeric barrier coating(s) may comprise one or more of cellulose derivatives (Non limiting examples include hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl cellulose, sodium carboxymethyl cellulose and the like), methacrylic acid polymers, (Non limiting examples include Eudragit EPO, and the like), polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol and the like.

The polymeric barrier coating may also comprise additives such as but not limited to plasticizers, colorants, pigments, fillers, taste masking agents, anti-tacking, antistatic agents and the like. Non limiting examples of additives include such as sucrose, mannitol, magnesium stearate, titanium dioxide, talc, triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates and the like.

The polymeric barrier coating in the composition may comprise in the range of about 5% to about 15% (w/w) of total weight of the acid labile drug(s) loaded core. Preferably, the amount of the polymeric barrier coating is in the range of about 5% to about 10% (w/w) of the total weight of the acid labile drug(s) loaded core.

Enteric Coating(s)
The composition of the invention may comprise one or more of enteric coating(s) layer applied onto the acid labile drug(s) loaded core coated with the polymeric barrier coating(s). The enteric coating layer may comprise one or more polymer such as but not limited to cellulose acetate phthalate, cellulose acetate trimeliitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethylcellulose, shellac, methacrylic acid derivatives, polymethacrylic acid, polymethyl methacrylate, polyethyl methacrylate, polyethyl acrylate and the like. Non limiting examples of the enteric coating polymer include Eudragit NE30D, Eudragit L, Eudragit S, Eudragit L30D55, Eudragit L 100 55 or any combinations and mixtures thereof.

The enteric coating layer may also comprise additives such as but not limited to plasticizers, colorants, pigments, fillers, taste masking agents, anti-tacking, antistatic agents such as magnesium stearate, titanium dioxide, talc and the like. Non limiting examples of additives may include triacetin, citric acid esters, phthalic acid esters, Plasacryl HTP20, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates and the like.

The enteric coating layer in the composition may comprise in the range of about 10% to about 35% (w/w) of total weight of the barrier coated acid labile drug(s) loaded core. Preferably, the amount of the enteric coating is in the range of about 20% to about 30% (w/w) of total weight of the barrier coated acid labile drug(s) loaded core.

Functional Coating(s)

The composition of the invention may further comprise one or more of functional coating layer over the enteric coat applied on the acid labile drug(s) loaded core. Said functional coating layer may prevent potential agglomeration of enteric coating layered core and protects the enteric coating layer from cracking. Further it also prevents penetration of carrier media such as water with neutral to alkaline pH into the drug(s) loaded core which reduces decomposition of the drug(s) in reconstituted suspension. All these factors contribute to impart physical and / or chemical stability to the composition during storage as well as in reconstituted form.

The functional coating layer of the composition may comprise one or more of water soluble, water swellable, water insoluble polymers. The functional coating layer may comprise one or more of methacrylic acid copolymer (such as Eudragit EPO, Eudragit E 100 and the like), polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium and the like used alone or in mixtures thereof.

Preferably the functional coating layer comprise one or more polymers with pH dependent solubility. In one of the embodiments methacrylic acid copolymers which are soluble in aqueous solution up to pH 5.0 are preferred. Particularly preferred pH-dependent water-soluble polymethacrylates are methacrylate copolymers having tertiary amino groups, such as dimethyl aminoethyl methacrylate copolymer, e.g. Eudragit EPO or Eudragit E 100.

The functional coating layer may also comprise additives such as but not limited to plasticizers, gel-forming agents, viscosity imparting agents, binders, thickeners, and/or emulsifiers colorants, pigments, fillers, taste masking agents, anti-tacking, antistatic agents and the like. Non limiting examples of additives may include magnesium stearate, titanium dioxide, talc triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates and the like.

The functional coating layer in the composition may comprise in the range of about 10% to about 50% (w/w) of total weight of the enteric coated core. Preferably, the amount of the polymeric barrier coating is in the range of about 30% to about 40% (w/w) of the total weight of the enteric coated core.

Different coatings as described above may be applied to the core material by using coating or layering techniques known in the art using suitable equipments such as but not limited to coating pan, coating granulator or in a fluidized bed apparatus using suitable solvents for the coating process. Alternatively other coating techniques such as powder coating, spray coating, spray congealing technique can also be used.

In one of the embodiment of the invention, the stable pharmaceutical composition comprises acid labile drug(s) loaded core prepared by mixing of the said active drug(s) with one or more of alkaline substances and optionally further mixed with suitable additives wherein the composition is free of enteric coating layer. Non limiting examples of suitable alkaline substances include sodium, potassium, calcium, magnesium and aluminum salts of phosphoric acid, citric acid or other suitable weak inorganic or organic acids; aluminum hydroxide/sodium bicarbonate coprecipitate; substances normally used in antacid preparations such as aluminum, calcium and magnesium hydroxides; magnesium oxide or composite substances; organic pH-buffering substances such as trihydroxymethylaminomethane, basic amino acids and their salts or other similar, pharmaceutically acceptable pH-buffering substances.

In another embodiment of the invention, the stable pharmaceutical composition for acid labile drug(s), comprises multitude of units, wherein each unit comprises a) acid labile drug(s) loaded core surrounded by polymeric barrier coating(s) and an enteric coating layer(s); and b) functional coating layer(s) surrounding said coated drug(s) loaded core; wherein the composition is suitable for reconstitution into a suspension by admixing with suitable carrier and wherein the composition is free of alkaline substances. In one of the preferred embodiment of the invention, the stable pharmaceutical composition is free of sodium bicarbonate.

The stable pharmaceutical composition of the invention means the composition which is stable under specified storage conditions. The stability of the composition is monitored according to the pharmaceutical industry standard, under accelerated conditions of 40 °C and 75% relative humidity for at least three months. The term "stable" herein means that at least 90%, preferably at least 95%, more preferably at least 98% and most preferably at least 99%, by weight of the acid labile drug in the pharmaceutical composition remains unaffected when stored at accelerated conditions of 40 °C and 75% relative humidity for at least three months. In one of the embodiment the stability of the pharmaceutical composition may be expressed in terms of amount of related substance (total impurities content) found in the composition upon storage at specified storage conditions wherein the stable composition contains not more than 3 %, preferably not more than 2.5 %, most preferably not more than 1 % by weight of total impurity.

According to one of the principle disclosed herein the stable pharmaceutical composition comprises multitude of pellets wherein the individual pellets can be prepared by using one or more techniques such as wet granulation, dry granulation, direct compression, fluidized bed processor or any other techniques known in the art. In another embodiment granules can be prepared by wet granulation, dry granulation, direct compression, fluidized bed processor or any other techniques known in the art. In another embodiment wherein pellets or granules are produced by wet granulation, wherein granulation liquid can be aqueous, non-aqueous or hydroalcoholic.

In another embodiment, stable pharmaceutical composition of the invention is in the form of suspension produced upon reconstitution with suitable carrier. The carrier for reconstitution according to the invention may comprise hydrophilic and / or lipophilic (lipid) system, either as solution or dispersion. The carrier may comprise single carrier excipient or mixture of several components.
In one of the embodiment of the present invention, the carrier for reconstitution is aqueous or hydrophilic system. Non limiting examples of aqueous or hydrophilic carrier system include water, orange or lime juices, hydroalcoholic liquids, or mixtures thereof.
In another embodiment of the present invention, the carrier is lipophilic (lipid) system. Non limiting examples of lipophilic (lipid) carrier system include acetylated monoglycerides, corn oil glycerides, medium chain partial glycerides, medium chain triglycerides, caprylic-capric triglycerides, caprylic/capric/linoleic triglycerides, caprylic/capric/succinic triglycerides, propylene glycol dicaprylate/dicaprate, ethyl oleate, glycerol mono/dioleate, glycerol monolinolate, macrogolglycerol caprylocaprate, macrogolglycerol linoleate, oleic acid, polyoxyl castor oil, polyoxyl hydrogenated castor oil, propylene glycol monocaprylate, propylene glycol monolaurate, refined animal derived oil, refined soybean oil, refined vegetable oil, sorbitan monostearate, triacetin, triethyl citrate or mixtures thereof.
The carrier may further include additives such as but not limited to suspending agents, pH stabilizing agents, surfactants, thickeners, glidants, flavouring agents, sweetening agents, buffers, coloring agents or preservatives and the like. Lecithin may be used as common excipient of the carrier. It may be used as a glidant of the highly concentrated suspension, prevents blocking of ducts and pumps and ensures high mass uniformity of the formulation. Furthermore Lecithin acts as a surfactant, which may improve distribution of the formulation droplets during in-vitro dissolution testing as well as in-vivo for drug resorption. Furthermore it may also improve wetting of the active substance crystals.
Preferably, the carrier for reconstitution comprise aqueous or hydrophilic system. More preferably the carrier comprise mixture of sodium benzoate, xanthan gum, sucrose in purified water.

According to one of the principles disclosed herein, the stable pharmaceutical composition is a suspension produced upon reconstitution with suitable carrier. The stability of the suspension is monitored according to the pharmaceutical industry standard, at 25 °C and 60% relative humidity. In one of the embodiment of the invention, the suspension produced upon reconstitution is stable for one month when stored at 25 °C and 60% relative humidity. In one of the preferred embodiment of the invention, the suspension produced upon reconstitution is stable for at least one week when stored at 25 °C and 60% relative humidity. In another preferred embodiment of the invention, the suspension produced upon reconstitution is stable for at least 6 days when stored at 25 °C and 60% relative humidity. Suspension produced upon reconstitution with suitable carrier according to the invention, is stable when at least 90%, preferably at least 95%, more preferably at least 98% and most preferably at least 99%, by weight of acid labile drug remains unaffected when stored at 25°C and 60% relative humidity. In one of the embodiment the stability of the suspension produced upon reconstitution may be expressed in terms of amount of related substance (total impurities content) found in the suspension upon storage at specified storage conditions wherein the stable suspension contains not more than 3 %, preferably not more than 2.5 %, most preferably not more than 1 % by weight of total impurity.

The stable pharmaceutical composition of the invention may be stored in suitable container. The term container used herein refers to a receptacle for holding and/or storing the pharmaceutical composition. The container can be single-dose or multidose, and/or disposable or refillable. The container may be refillable or a single use disposable container. Non limiting examples of container suitable for storing the pharmaceutical composition according to the invention may include sachets, stick packs, vials, ampoules, bottles (glass bottles, plastic bottles and the like), foils, strips, boxes, syringes, injectors and the like. In one of the embodiment of the invention the container comprises plastic bottle. Preferably, the container comprises polyethylene terephthalate (PET) bottle.

The term "pharmaceutically acceptable" as used herein refers to a compound or combination of compounds that will not impair the physiology of the recipient human or animal to the extent that the viability of the recipient is compromised. Preferably, the administered compound or combination of compounds will elicit, at most, a temporary detrimental effect on the health of the recipient human or animal.

The terms 'pharmaceutically acceptable excipient(s)' or “additives” used in the stable pharmaceutical composition of the invention comprise but not limited to diluents, binders, pH stabilizing agents, disintegrants, surfactants, glidants, lubricants, suspending agents, flavouring agents, sweetening agents, buffers, coloring agents or preservatives and the like.

The amount of excipient(s) employed will depend upon how much active agent is to be used.

Binders as used in the present invention comprises but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, sodium carboxy methyl cellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, poly- N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations thereof and other materials known to one of ordinary skill in the art and mixtures thereof.

Fillers or diluents as used in the present invention comprises but not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.

Lubricants as used in the present invention comprises but not limited to magnesium stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, talc and the like.

Glidants as used in the present invention comprises but not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art.

Disintegrants as used in the present invention comprises but not limited to starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked polyvinyl pyrrolidone or crospovidone, e.g., POLYPLASDONE XL, cross-linked sodium carboxymethylcellulose or croscarmellose sodium, e.g., AC-DI-SOL from FMC; and cross-linked calcium carboxymethylcellulose; soy polysaccharides; and guar gum.

Suspending agents as used in the present invention comprises but not limited to gums like xanthan gum, guar gum; sorbitol; glycerol; polyvinyl alcohol; polyvinyl pyrrolidone; polyethylene oxide; cellulose derivatives, such as hydroxypropylmethylcellulose or a salt thereof, alkyl ether of cellulose, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellose and mixtures thereof.
Examples of gums that may be used in the present invention comprise but not limited to xanthan gum, acacia, tragacanth and the like.

Thickeners may adjust the viscosity of composition like suspension. Non limiting examples of thickeners may be used in the present invention comprise oleogel forming excipients, such as colloidal silica or bentonit, or lipophilic or amphiphilic excipients of high viscosity, such as bees wax, glycerol monostearate, hydrogenated vegetable oil, partially hydrogenated vegetable oil or hard fats.

Buffering agent as used in the present invention comprises but not limited to monosodium citrate, sodium phopsphate, disodium phosphate, sodium acetate and the like.

Coloring agents as used in the present invention comprises but not limited to titanium dioxide, amaranth, tartarazine, wherein the most prefereble coloring agent is titanium dioxide.

Examples of sweetening agents and flavouring agents comprises but not limited to sugar alcohols, sugars, liquid glucose, sucrose, sachharine sodium, banana flavouring, vanilla flavouring, tutti frutty flavor, xylitol, sorbitol, mannitol, erythritol and the like.

Examples of sugar alcohols that may be used in the present invention include but not limited to sorbitol, erythritol, mannitol, sucrose and the like.

Examples of preservatives used in the invention comprises but are not limited to, sodium benzoate, chlorhexidine; methyl paraben; propyl paraben; butyl paraben and their salts; diazolidinyl urea; quaternary compounds like benzalkonium chloride and cetylpyridinium chloride, phenyl ethyl alcohol and the like. More preferably, compositions of the invention comprises sodium benzoate as preservative.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example, those skilled in the art will recognize that the invention may be practiced using a variety of different compounds within the described generic descriptions.

Examples:
Table 1. depicts the exemplary examples illustrating qualitative and quantitative composition of Lansoprazole according to the invention. The examples should not be considered as limiting the scope of this invention in any way, as these examples and other equivalents thereof will become apparent to those versed in the art, in the light of the present disclosure, and the claims.
Example
I Example
II Example III Example IV Example V Example VI Example VII Example VIII Example IX Example X
Inert core Qty (mg) Qty (mg) Qty (mg) Qty (mg) Qty (mg) Qty (mg) Qty (mg) Qty (mg) Qty (mg) Qty (mg)
Microcrystalline cellulose spheres 50 50 50 50 50 50 50 50 50 50
Drug loading
Lansoprazole USP 15 15 15 15 15 15 15 15 15 15
Light magnesium carbonate 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5 5.5
Low substituted Hydoxypropyl cellulose 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5
HPC SL 6 6 6 6 6 6 6 6 6 6
Purified Water qs qs qs qs qs qs qs qs qs qs
Barrier coat
HPMC E5 USP 6 -- 6 -- 6 -- 6 -- 6 --
Mannitol 1 1 1 1 1 1 1 1 1 1
PVPK 30 -- 6 -- 6 -- 6 -- 6 -- 6
Purified water qs qs qs qs qs qs qs qs qs
Enteric coat
Eudragit L30 D55 18.375 7.35 7.35 11.02 11.02 22.05 22.05 25.72 25.72
Plasacryl HTP20 3.125 1.25 1.25 1.88 1.88 3.75 3.75 4.38 4.38
HPMC Phthalate HP55 -- 18.375 -- -- -- -- -- -- -- --
Triethyl citrate -- 3.125 -- -- -- -- -- -- -- --
Isopropyl alcohol -- qs -- -- -- -- -- -- -- --
Dichloromethane -- qs -- -- -- -- -- -- -- --
Purified water qs -- qs qs qs qs qs qs qs qs
Functional coat
Eudragit EPO 32.25 32.25 47.3 47.3 39.56 39.56 27.95 27.95 29.03 29.03
Talc 8.07 8.07 11.83 11.83 9.89 9.89 6.988 6.988 7.25 7.25
Isopropyl alcohol qs qs qs qs qs qs qs qs qs qs
Purified water qs qs qs qs qs qs qs qs qs qs
qs: quantity sufficient
Following is the exemplary process illustrating embodiments of the invention in reference to the examples in Table 1.
Procedure:
A. For Drug Loading Stage:
1. Lansoprazole and Light Magnesium carbonate were sifted together through suitable mesh and added to portion of purified water under stirring
2. Low substituted Hydoxypropyl cellulose and HPC SL were sifted through suitable sieve and added to remaining portion of purified water separately taken under stirring.
3. Step 1 and step 2 dispersions were mixed, stirred and filtered.
4. Microcrystalline Cellulose spheres were loaded in the Fluidized Bed Processer (FBP) and Wurster coating process was followed using step 3 dispersion under stirring at temperature about 36 ± 4 °C.
5. The pellets were dried in FBP at temperature of about 40 ± 5 °C till the Loss on Drying at 105 °C of NMT 3.5 % is achieved.
6. The drug loaded core thus obtained in the form of pellets were sifted through suitable sieve.

B. For Barrier Coating Stage:
1. Mannitol and polymeric barrier coating material were sifted and added to purified water under stirring.
2. The drug loaded pellets were loaded to the FBP at temperature of about 39 ± 4 °C and Wurster coating process was followed using step 1 solution.
3. The barrier coated pellets were dried at same temperature till LOD at 105 °C of NMT 3.5 % was achieved.
4. The dried barrier coated drug loaded core in the form of the pellets were sifted through suitable sieve.

C. For Enteric Coating Stage:
1. The enteric polymer was added to purified water under stirring.
2. Plasacryl HTP 20 was added to the purified water separately under stirring.
3. Step 1 and strep 2 dispersion were mixed together and diluted with remaining water.
4. The barrier coated drug loaded pellets were loaded to the FBP and Wurster coating process was carried out using step 3 dispersion under stirring at a temperature of about 35 ± 4°C.
5. Coated pellets were dried at same temperature till LOD at 105 °C of NMT 4.0 % was achieved.
5. The enteric coated pellets thus obtained were sifted through suitable sieve.

D. For Functional Coating Stage:
1. Talc was added to water isopropyl alcohol mixture (16 % of total solution quantity of Isopropyl Alcohol-water mixture) under stirring and homogenized.
2. The homogenized Talc dispersion was added to Isopropyl Alcohol (84 % of total quantity of Isopropyl Alcohol-Water mixture) under stirring.
3. Eudragit EPO was added to the step 2 dispersion and stirred.
4. The enteric coated drug loaded pellets were loaded to FBP and Wurster coating process was carried out using step 3 dispersion under stirring at temperature of about 30 ± 3 °C.
5. At the end of coating drying was continued in FBP at same parameters till LOD at 105 °C NMT 5.0 % is achieved.
6. The Eudragit EPO coated dry pellets thus obtained were sifted through suitable sieve.

Stability Tests
The composition produced is reconstituted up to 80 ml with aqueous carrier comprising sodium benzoate, xanthan gum and sucrose in purified water. For analysis dose equivalent to 30 mg (20 ml) is mixed with diluent [methanol: 0.1N sodium hydroxide (15:85 %)] and homogenized for about 10 min. Drug content & related substance determination was carried out by liquid chromatography using HPLC. Provided herein the stability study of Examples I & II carried out under specified conditions. Table 2. Depicts the results of assay in terms of drug content.

Table 2. Assay Determination
Period (Months) Example I Example II
Initial 98.4 % 93.9%
At 3 Months 95.1% 90.1%
(*Upon storage at 40 °C and 75% relative humidity for a period of three months)

Table 3 displays results of related substances determination for Examples I & II in terms impurities observed.
Table 3. Related Substances Determination
Period (Months) Impurity D
(%) Impurity E
(%) Impurity A
(%) Impurity B
(%) Impurity C
(%) Thioketone
(%) HU
(%) Total Impurity (%)
Example I
Initial 0.141 0.068 BQL 0.042 0.066 0.083 0.049 0.449
At 3 Months 0.240 0.176 BQL BQL 0.136 0.107 0.103 0.762
Example II
Initial 0.142 BQL ND 0.032 0.134 0.126 0.117 0.727
At 3 Months 0.371 0.472 ND 0.041 0.466 0.232 0.375 2.445
(*Storage at 40 °C and 75% relative humidity; ND: Not detected; BQL: Below quantification limit; HU: Highest unknown impurity)

Table 4 displays results of related substances determination for Examples I & II reconstituted suspension in terms impurities observed.

Table 4. Related substances determination for reconstituted suspension
Period (Months) Impurity D
(%) Impurity E
(%) Impurity A
(%) Impurity B
(%) Impurity C
(%) Thioketone
(%) HU
(%) Total Impurity (%)
Example I
At Day 6 of reconstitution 0.226 0.098 BQL 0.05 0.043 0.096 0.478 0.903
Example II
At Day 7 of reconstitution 0.204 0.119 ND BQL 0.105 0.115 0.262 0.893
(*Storage at 25 °C and 60 % relative humidity; ND: Not detected; BQL: Below quantification limit HU: Highest unknown impurity)

Stability was also ascertained in acid environment (0.1N Hydrochloric acid). Dose equivalent to 15 mg (10 ml) was added in 500 ml of 0.1N Hydrochloric acid and subjected to dissolution studies using USP II (Paddle) at 75 rpm. Table 5 depicts results for dissolution test Example I & II.

Table 5. Dissolution in acidic medium
Period (Months) Example I Example II
Initial 10 % 20 %
At 3 Months 32 % 29 %

Table 6 denotes results of viscosity determination for Examples I & II reconstituted suspension (analyzed at about 25°C). The suspension was found to exhibit acceptable consistency.
Table 6. Viscosity determination for Examples I & II reconstituted suspension
Conditions
Speed (rpm) Torque
(%) Viscosity
(Cp)
Example I 50 37.4 897.4
75 45.7 731.0
100 52.6 631.1
150 63.6 508.7
200 75.5 452.9
Example II 50 39.6 950.2
75 49.0 783.8
100 57.0 683.9
150 69.6 556.7
200 80.1 480.5
,CLAIMS:Claim 1. A stable pharmaceutical composition for acid labile drug(s), comprising multitude of units, wherein each unit comprises
a) acid labile drug(s) loaded core surrounded by polymeric barrier coating(s) and an enteric coating layer(s); and
b) functional coating layer(s) surrounding said coated drug(s) loaded core;
wherein the composition is suitable for reconstitution into a suspension by admixing with suitable carrier.
Claim 2. The pharmaceutical composition according to claim 1, wherein one or more of acid labile drug(s) is/are proton pump inhibitor agent(s).
Claim 3. The composition of claim 2, wherein the proton pump inhibitor comprises one or more of lansoprazole, omeprazole, pantoprazole, rabeprazole, tenaprazole and pharmaceutically acceptable salts thereof.
Claim 4. The pharmaceutical formulation according to claim 1 is a dosage form selected from particles, powder, granules, pellets, beads, tablet, caplet, capsule, microcapsule suitable for reconstitution into suspension.
Claim 5. The pharmaceutical formulation according to claim 1, wherein the polymeric barrier coating comprises at least one or more of water soluble polymer or water insoluble polymers and combinations thereof.
Claim 6. The pharmaceutical formulation according to claim 1, wherein the enteric coating layer comprises one or more of polymer(s) selected from cellulose acetate phthalate, cellulose acetate trimeliitate, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethylcellulose, shellac, methacrylic acid derivatives, polymethacrylic acid, polymethyl methacrylate, polyethyl methacrylate, polyethyl acrylate & combinations thereof.
Claim 7. The pharmaceutical composition according to claim 1, wherein the functional coating comprises one or more of polymer(s) selected from methacrylic acid copolymer, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose sodium & combinations thereof.
Claim 8. The pharmaceutical composition according to claim 7, wherein the functional coating comprises methacrylic acid copolymer Eudragit EPO.
Claim 9. A stable pharmaceutical composition for acid labile drug(s), comprising multitude of units, wherein each unit comprises
a) acid labile drug(s) loaded core surrounded by polymeric barrier coating(s) and an enteric coating layer(s); and
b) functional coating layer(s) surrounding said coated drug(s) loaded core;
wherein the composition is suitable for reconstitution into a suspension by admixing with suitable carrier and wherein the composition is stable for at least three months when stored at 40°C and 75% relative humidity.
Claim 10. A stable pharmaceutical composition for acid labile drug(s), comprising multitude of units, wherein each unit comprises
a) acid labile drug(s) loaded core surrounded by polymeric barrier coating(s) and an enteric coating layer(s); and
b) functional coating layer(s) surrounding said coated drug(s) loaded core; wherein the composition is suspension produced upon reconstitution with suitable carrier.