DESC:FIELD OF THE INVENTION
The present invention is in the technical field of drug delivery system for delivering drugs which are unstable or less stable in the liquid form for longer period of time. More particularly, the present invention is in the technical field of designing of bottle, optional additional container inside the bottle and its closure system for dispensing liquid dosage form.

The present invention relates to a drug delivery system or device for delivery of final liquid dosage form. In this system there are two different compositions which are placed separately in single unit and mixed at the time of dispensing a first dose.

The system is useful for all types of dosage forms and are very much useful for the drugs or pharmaceutical actives which are unstable or not stable in the liquid form i.e. either aqueous or non-aqueous.

The present invention relates to a drug delivery system or device in the form of single or multiple dosages for delivery of final liquid dosage form comprising, (a) a container/bottle filled with liquid base/pharmaceutically acceptable composition of drug (preferably in a liquid dosage form); (b) a cap of the container/bottle mechanised with one or more preformed holes and one or more pins, filled with a pharmaceutically acceptable composition comprising a drug; and (c) optionally an additional container inside the bottle filled with pharmaceutically acceptable composition optionally with one or more preformed holes and one or more pins in the cap of the bottle.

The system can be used for delivering immediate release as well as modified release of drug in the liquid form to mammals. Further, the system of the present invention can also be used for any type of liquid dosage form including oral, injectable or spray.

BACKGROUND OF THE INVENTION
Liquid pharmaceutical compositions are generally used in patients having difficulty in swallowing solid dosage forms such as tablets and capsules, in particular pediatric or geriatric patients. These compositions are further advantageous because the dose of the drug may be adjusted easily to meet the patient's requirement. Further, such compositions are a viable option for formulating water-insoluble or poorly-soluble drugs. In addition, the bitter taste of drugs can be reduced by formulating them in the form of a suspension.

Liquid pharmaceutical compositions commonly have the drug dissolved or suspended in water or another liquid diluent. However, certain drugs are susceptible to degradation in the presence of water or other aqueous mediums. In conventional packs, to minimize the degradation in the presence of water, the drug is placed inside the bottle and is formulated by the addition of a liquid diluent or water at the time of administration by the patient, which makes it susceptible to administration errors and contamination.

Further, modified release (e.g. extended release) solid compositions are preferred dosage forms over immediate release solid compositions, especially for active ingredients showing fluctuations in the plasma concentration and for active ingredients having short half-lives. Extended release solid compositions can be in the form of tablets or capsules, wherein the release of the active ingredient is controlled by using a reservoir or a matrix system. However, extended release solid compositions suffer from certain drawbacks such as difficulty in swallowing, particularly for certain groups of patients, e.g., pediatrics and geriatrics, resulting in poor patient compliance. Further, high doses of active ingredients lead to large-sized compositions which aggravates this problem. Also, there remains a tendency to divide extended release solid compositions such as tablets into small pieces in order to facilitate administration, which may ultimately lead to inaccurate dosing and/or dose dumping. In view of all this, extended release liquid compositions provide the best alternative over extended release solid compositions. Extended release liquid compositions are easy to administer, thereby leading to enhanced patient compliance. Additionally, extended release liquid compositions provide a unique advantage of having a flexible dosing regimen.

Extended release liquid compositions are conventionally administered as powder for suspensions which are to be reconstituted by the end users at the time of administration using household pre-boiled and cooled water. Alternatively, the diluent or purified water is supplied separately along with the bottle having the extended release powder for suspension. These conventional packs lack patient compliance and may lead to contamination due to improper quality of water. Further, there remains a possibility of dosing errors if the diluent or water is not added to the marked level.

US 3156369, US 3603469, US 3840136, US 4982875, US 20070193894, WO 2016016845, WO 2016178132 and WO 2017191485 disclose the use of dual-chamber packs for separately storing two compositions in two compartments which can be admixed at the time of use. The two compartments are separated by a breakable membrane which is ruptured by the depression of a plunger so that the one composition gets released into another and is mixed. However, there remains a possibility that the membrane fragments may get detached and fall into the final product. This may lead to undesirable contamination and can pose serious health hazards. Furthermore, the dual-chamber packs disclosed in the prior art have a limited capacity for the compartments which may not be suitable for high-dose drugs or for drugs which require chronic administration. Also, the liquid composition may get permeated into the solid composition across the membrane during storage which can lead to the agglomeration of the solid composition. This may result in poor flow of the solid composition, thus affecting the content uniformity of the final product. Also, the liquid composition on permeation can affect the stability of moisture-sensitive drugs.

The present invention provides a patient compliant drug delivery system or device for delivery of final liquid dosage form with a significant improvement over the prior art and which fulfills the unmet need of incorporating variety of active ingredients. The present drug delivery system can be suitable for any class of active ingredients including the high-dose active ingredients, active ingredients requiring chronic administration, and/or moisture-sensitive active ingredients. Further, the preformed hole and pin mechanism used in the drug delivery system of the instant invention is designed in a way such that the breakable preformed holes remain adhered to the pins at the time of the activation and membrane fragments do not fall into the final product. During activation, the drug delivery system ensures that the final product remains safe for the use of patients. The drug delivery system also ensures that the solid composition is completely released into the liquid composition thereby maintaining the content uniformity of the final product. Further, the drug delivery system also ensures that there is no permeation of moisture into the cap having solid composition comprising the active ingredient, and the stability of the active ingredient remains unaffected during storage.

OBJECTS OF THE INVENTION
It is therefore one of the principal object of the present invention to provide a drug delivery system or device for delivery of final liquid dosage form. In this system there are two different compositions which are placed separately in single unit and mixed at the time of dispensing a first dose.

It is one of the further object of the present invention to provide a drug delivery system or device in the form of single or multiple dosages for delivery of final liquid dosage form comprising, (a) a container/bottle filled with liquid base/pharmaceutically acceptable composition of drug (preferably in a liquid dosage form); (b) a cap of the container/bottle mechanised with one or more preformed holes and one or more pins, filled with a pharmaceutically acceptable composition comprising a drug; and (c) optionally an additional container inside the bottle filled with pharmaceutically acceptable composition optionally with one or more preformed holes and one or more pins in the cap of the bottle.

It is one of the further object of the present invention to provide a drug delivery system useful for delivering immediate release as well as modified release of drug in the liquid form to mammals.

It is one of the further object of the present invention to provide a drug delivery system useful for any type of liquid dosage form including oral, injectable or spray.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 shows the bottle with a cap.
Figure 2 shows a top of the bottle fitted with a separate container inside the bottle which is filled with one composition of the dosage with which the bottle is closed.
Figure 3 shows a cap of the bottle with few preformed holes.
Figure 4 shows a cap of the bottle with a single hole.

DETAILED DESCRIPTION OF THE INVENTION
Many pharmaceutically active ingredients are unstable in the liquid dosage form and therefore formulating such active ingredients into solid dosage forms e.g. tablets and capsules is must. But such solid dosage forms of the active ingredients (e.g. tablets and capsules) sometimes become difficult for a patient to swallow (e.g. paediatric and geriatric patients). Therefore preparation of drugs into liquid dosage forms is advantageous but at the same time it is also a fact that all drugs are not stable in the liquid dosage forms and it is therefore difficult to prepare liquid dosage forms for such drugs.

In order to overcome above said limitations, the present invention provides a drug delivery system or device using which pharmaceutical active drug can be administered in a liquid dosage form by separating solid dosage form comprising drug from its vehicle/suspension base in a single unit which provides stability during its shelf life as well as allow patient to dispense uniform finished dosage form in a liquid state by shaking just before dispensing first dose.

Therefore according to the first embodiment of the present invention, the drug delivery system of the present invention is in the form of single unit wherein there are two or more than two compartments viz. (a) a bottle or a container comprising liquid vehicle or a liquid pharmaceutical composition comprising an active ingredient and one or more pharmaceutically acceptable excipients; (b) a cap fitted above the bottle/container mechanized with one or more preformed holes and one or more pins comprising solid pharmaceutical composition comprising an active ingredient and one or more pharmaceutically acceptable excipients; and (c) optionally comprising an additional container fitted above the bottle mechanized with at least one preformed hole and one pin comprising solid or liquid pharmaceutical composition comprising an active ingredient and one or more pharmaceutically acceptable excipients, wherein the liquid vehicle or liquid pharmaceutical composition comprising an active ingredient contained in the bottle is mixed with the solid pharmaceutical composition contained in the cap and solid or liquid pharmaceutical composition contained in the additional container to form a final liquid dosage form upon activation of the drug delivery system of the present invention. The final liquid dosage form according to the present invention can be used as mono drug therapy or fixed dose drug-combination therapy.

According to one of the further embodiments of the present invention, there are two pharmaceutically acceptable compositions together in the drug delivery system of the present invention wherein the first pharmaceutical composition is in the solid dosage form (e.g. powder for oral solution/suspension or reconstitution) placed in the cap or additional container of the delivery system and the second pharmaceutical composition is the liquid dosage form placed in the container/bottle which upon activation of the drug delivery system forms the finished dosage form which is useful as fixed dose combination of two or more than two drugs.

According to one of the further embodiments of the present invention, a unit or drug delivery system delivering single or multiple doses is useful for all types of liquid dosage forms including spray, oral, injection etc.

According to one of the further embodiments of the present invention, a drug delivery system is in the form of single unit comprising single or multiple doses for delivery of final liquid dosage form which comprises (a) a container/bottle filled with a liquid/suspension base or a pharmaceutically acceptable composition comprising drug; (b) a cap of the container/bottle mechanised with one or more preformed holes and one or more pins filled with a solid pharmaceutically acceptable composition; and (c) optionally additional container with at least one preformed hole and pin placed inside the container/bottle comprising solid or liquid pharmaceutically acceptable composition.

In a detailed embodiment, Figure 1 of the present invention, represents a container/bottle with a cap comprising one or more preformed holes and one or more preformed pins as shown in Figure 3 wherein the container/bottle is filled with a liquid base (e.g. vehicle/suspension) or a liquid pharmaceutical composition comprising drug and the cap comprises solid pharmaceutical composition comprising drug. The container/bottle can optionally be fitted with an additional container as shown in Figure 2, optionally comprising at least one preformed hole and at least one pin as shown in Figure 4, which can be filled with a second solid or liquid composition of the dosage. At the time of administration the bottle is opened and the content in the additional container is released inside the bottle and by shaking it well the final liquid dosage form/finished dosage form will be ready for use.

At the time of the final use of the drug delivery system according to the present invention, the cap fitted with the container/bottle is turned anti-clockwise to open and the upper part of the cap is pressed so that pins of the cap get pressed on the preformed holes which pierces the bottom of the cap through which the solid composition comprised in the cap drops in the container/bottle which already comprises liquid base (e.g. vehicle or suspension) or liquid pharmaceutical composition comprising second drug. The container/bottle is shaken well before use resulting in the final formula/liquid dosage form/finished dosage form ready for use. The thus formed final formula/liquid dosage form/finished dosage form can be in the form of a solution or a suspension or a syrup.

The drug delivery system of the present invention is useful for multiple doses and therefore the cap as shown in Figure 3 will be removed after preparation of the formula. The first dose can be dispensed from the container/bottle and after dispensing the first dose the cap shown in Figure 3 can be replaced with any conventional cap suitable for protecting the liquid dosage form contained in the container/bottle or with child-resistant cap.
In a further embodiment of the present invention, when the additional container as shown in Figure 2 is used then the cap of the container is as shown in Figure 4 where there will be single preformed hole and single pin only. Such a delivery system can be used for administering fixed dose combinations of two or more than two drugs. The pharmaceutical composition comprising first drug either as solid or liquid composition can be placed in the container with the cap as shown in Figure 4 and the pharmaceutical composition comprising second drug in the liquid form can be placed in the bottle. At the time of the final use of the drug delivery system according to the present invention, the cap as shown in Figure 4 fitted with the container as shown in Figure 2 is turned anti-clockwise to open and the upper part of the cap is pressed so that pin of the cap gets pressed on the preformed hole which pierces the bottom of the cap through which the solid or liquid composition comprised in the cap drops in the bottle which already comprises liquid pharmaceutical composition comprising second drug. The bottle is shaken well before use resulting in the final formula ready for use. The thus formed final formula can be in the form of a solution or a suspension used for oral, injection or spray deliveries. The cap as shown in Figure 3 can also be used if more than two drugs are intended to be administered in a combination therapy.

According to one of the further embodiments of the present invention, the container/bottle is prefilled with a pharmaceutically acceptable vehicle and the cap is prefilled with a solid composition of an active ingredient. Alternatively, the cap is prefilled with a liquid concentrate composition of an active ingredient.

According to one of the further embodiments of the present invention, the solid composition is mixed with the pharmaceutically acceptable vehicle to form a final liquid dosage form/finished dosage form upon activation of the drug delivery system of the invention.

According to one of the further embodiments of the present invention, the final liquid dosage form/finished dosage form is a solution or a suspension or syrup.

According to one of the further embodiments of the present invention, the drug delivery system is used for multi-dose administration of the final liquid dosage form/finished dosage form.

According to one of the further embodiments of the present invention, the cap is made up of polymeric materials selected from the group comprising polyolefin, polyethylene, polypropylene, polyvinyl chloride, cyclic olefin polymer, cyclic olefin co-polymer, polyethylene terephthalate, polyethylene terephthalate-G, polypropylene, and polycarbonate.

According to one of the further embodiments of the present invention, the cap additionally includes one or more moisture barrier additives.

According to one of the further embodiments of the present invention, the moisture barrier additives are selected from the plastic additive group comprising of monomers and copolymers that get activated through polymerization process to form an effective organic chemical.

According to one of the further embodiments of the present invention, the moisture barrier additives improve the moisture barrier properties by up to 50%. In particular, the moisture barrier additives improve the moisture barrier properties by up to 30%.

According to one of the further embodiments of the present invention, the cap having pierce able bottom prevents moisture permeation from the container/bottle into the cap.

According to one of the further embodiments of the present invention, the cap is a conventional cap or a child-resistant cap.

According to one of the further embodiments of the present invention, the cap as shown in Figure 1 and Figure 3 is opened at both the ends.

According to one of the further embodiments of the present invention, the final liquid dosage form/finished dosage form is a taste-masked composition.

The active ingredient used to form a solid composition of the present invention may be present in a form to provide an immediate release or an extended release. The solid composition may comprise of an active ingredient directly mixed with one or more pharmaceutically acceptable excipients. Alternatively, the solid composition may comprise of cores of an active ingredient, optionally admixed with one or more pharmaceutically acceptable excipients. The cores may be coated with an immediate release or an extended release coating. The immediate release coating may comprise a film-forming agent to mask the taste of bitter active ingredients or to improve the stability. Said coating remains insoluble in the reconstituted liquid pharmaceutical composition during storage and releases the active ingredient only once ingested. The film-forming agent can be a water-soluble polymer in which the release of active ingredient is prevented by using a high molar concentration of the solutes in the reconstituted composition, wherein the solutes have a higher affinity towards water. The high molar concentration of the solutes generates hypertonic conditions leading to high osmolality and thus prevents the leaching of the active ingredient from the coated cores. This would help to mask the taste of the bitter active ingredients or to improve the stability of active ingredients.

Further, the film-forming agent can be having a pH-dependent solubility in which the release of active ingredient is prevented by using a pre-adjusted pH of the reconstituted composition such that the film-forming agent does not get dissolved in the reconstituted composition but get dissolved when exposed to the physiological conditions.

Alternatively, the solid composition comprises of active ingredient in a complex form such as ion-exchange resin complex or a cyclodextrin complex, optionally admixed with one or more pharmaceutically acceptable excipients. In this case, the active ingredient is released when exposed to the physiological conditions upon ingestion. The extended release coating may comprise of a pH-dependent release-controlling agent, a pH-independent release-controlling agent, or mixtures thereof.
Non-limiting examples of pH-dependent release-controlling agents are selected from the group comprising acrylic copolymers such as methacrylic acid and methyl methacrylate copolymers, e.g., Eudragit® L 100 and Eudragit® S 100, methacrylic acid and ethyl acrylate copolymers, e.g., Eudragit® L 100-55 and Eudragit® L 30 D-55, dimethylaminoethyl methacrylate and butyl methacrylate and methyl methacrylate copolymers e.g., Eudragit® E 100, Eudragit® EPO, methyl acrylate and methacrylic acid and octyl acrylate copolymers, styrene and acrylic acid copolymers, butyl acrylate and styrene and acrylic acid copolymers, and ethylacrylate-methacrylic acid copolymer; cellulose acetate phthalate; cellulose acetate succinates; hydroxyalkyl cellulose phthalates such as hydroxypropylmethyl cellulose phthalate; hydroxyalkyl cellulose acetate succinates such as hydroxypropylmethyl cellulose acetate succinate; vinyl acetate phthalates; vinyl acetate succinate; cellulose acetate trimelliate; polyvinyl derivatives such as polyvinyl acetate phthalate, polyvinyl alcohol phthalate, polyvinyl butylate phthalate, and polyvinyl acetoacetal phthalate; zein; shellac; and mixtures thereof.

Non-limiting examples of pH-independent release-controlling agents are selected from the group comprising cellulosic polymers such as ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, and carboxy methylcellulose; acrylic copolymers such as methacrylic acid copolymers, e.g., Eudragit® RS, Eudragit® RL, Eudragit® NE 30 D; cellulose acetate; polyethylene derivatives e.g., polyethylene glycol and polyethylene oxide; polyvinyl alcohol; polyvinyl acetate; gums e.g., guar gum, locust bean gum, tragacanth, carrageenan, alginic acid, gum acacia, gum arabic, gellan gum, and xanthan gum; triglycerides; waxes, e.g., Compritol®, Lubritab®, and Gelucires®; lipids; fatty acids or their salts/derivatives; a mixture of polyvinyl acetate and polyvinyl pyrrolidone, e.g., Kollidon® SR; and mixtures thereof.

The term "liquid concentrate composition" as used herein refers to a concentrated liquid composition comprising an active ingredient which upon reconstitution gives the desired strength.

According to one of the further embodiments of the present invention, the core is in the form of a bead, a pellet, a granule, a spheroid, or the like. According to another embodiment of the above aspects, the active ingredient is layered onto an inert particle to form the core.

According to one of the further embodiments of the present invention, the solid pharmaceutical composition comprising an active ingredient prefilled in the cap is present in an amount from 0.5 CC to about 30 CC. According to one of the further embodiments of the present invention, the liquid vehicle or liquid pharmaceutical composition comprising an active ingredient in the container or bottle is present in an amount from 1 ml to 350 ml.

The pharmaceutically acceptable vehicle of the instant invention without limitation may comprise of purified water, one or more suitable organic solvents, and mixtures thereof. The organic solvents without limitation may be selected from the group consisting of ethanol, glycerin, propylene glycol, polyethylene glycol, and mixtures thereof. The pharmaceutically acceptable vehicle may optionally have one or more pharmaceutically acceptable excipients.

The term "activation" as used herein means a process which reconstitutes the solid composition with the pharmaceutically acceptable vehicle to form a liquid pharmaceutical composition. The activation can be done by the end-users such as patients or pharmacists or caregiver. The activation process starts by screwing the cap.
The term "multi-dose" as used herein, means the liquid pharmaceutical composition is to be administered in multiple doses after reconstitution, over a period of time e.g., for more than seven days, or more than a month, or more than three months.

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 "pharmaceutically acceptable excipients" as used herein, refers to excipients that are routinely used in pharmaceutical compositions. The pharmaceutically acceptable excipients may comprise lubricants, diluents, surfactants, disintegrants, osmotic agents, colouring agents, glidants, sweeteners, suspending agents, anti-caking agents, wetting agents, preservatives, buffering agents, flavoring agents, anti-oxidants, chelating agents, solutes, and combinations thereof.

The average diameter of the coated cores ranges from about 10 µm to about 2000 µm, particularly from about 50 µm to about 1000 µm, and more particularly from about 150 µm to about 500 µm. The finer sizes of the cores help in avoiding grittiness in the mouth and are therefore more acceptable.

According to the one of the further embodiments of the present invention, the liquid composition prefilled in the container/bottle as shown in Figure 1 or Figure 2 may further comprise pharmaceutically acceptable excipients selected from the group consisting of surfactants, wetting agents, thickening agents, anti-oxidants, sweeteners, buffering agents, osmotic agents, preservatives, coloring agents, and mixtures thereof.

According to one of the further embodiment of the present invention, the solid composition prefilled in the cap of the bottle as shown in Figure 3 or an additional container as shown in Figure 2 comprising a drug is in the form of powder, paste, beads, granules, gel, or a compressed tablet. The compressed tablet may be a tablet for oral suspension. The solid composition may be formulated into a suitable form using pharmaceutically acceptable inert excipients selected from the group consisting of surfactants, wetting agents, antioxidants, buffering agents, preservatives, coloring agents, lubricants, diluents, disintegrants, and mixtures thereof.

This drug delivery system can be used for a soluble, a water-insoluble, or a poorly- soluble active ingredient. The active ingredient may have a stability problem due to which the active ingredient is reconstituted using a pharmaceutically acceptable vehicle at the time of administration. This drug delivery system can be used without limitation for active ingredients such as valacyclovir, metformin, azithromycin, cloxacillin, clarithromycin, erythromycin, amoxicillin alone or in combination with clavulanic acid, cefdinir, cefuroxime axetil, cefixime, cefadroxil, cefpodoxime, cefaclor, cefprozil, fluconazole, voriconazole, acarbose, miglitol, voglibose, repaglinide, nateglinide, glibenclamide, glimepride, glipizide, gliclazide, chloropropamide, tolbutamide, phenformin, alogliptin, sitagliptin, linagliptin, saxagliptin, rosiglitazone, pioglitazone, troglitazone, faraglitazar, englitazone, darglitazone, isaglitazone, zorglitazone, liraglutide, muraglitazar, peliglitazar, tesaglitazar, canagliflozin, dapagliflozin, remogliflozin, sergliflozin, verapamil, albuterol, salmeterol, acebutolol, sotalol, penicillamine, norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, trovafloxacin, gatifloxacin, tetracycline, demeclocycline hydrochloride, losartan, irbesartan, eprosartan, valsartan, diltiazem, isosorbide mononitrate, ranolazine, propafenone, hydroxyurea, hydrocodone, delavirdine, pentosan polysulfate, abacavir, amantadine, acyclovir, ganciclovir, valganciclovir, saquinavir, indinavir, nelfinavir, lamivudine, didanosine, zidovudine, nabumetone, celecoxib, mefenamic acid, naproxen, propoxyphene, cimetidine, ranitidine, albendazole, mebendazole, thiobendazole, pyrazinamide, praziquantel, chlorpromazine, sumatriptan, bupropion, aminobenzoate, pyridostigmine bromide, potassium chloride, niacin, tocainide, quetiapine, fexofenadine, sertraline, chlorpheniramine, rifampin, methenamine, nefazodone, modafinil, metaxalone, morphine, sevelamer, lithium carbonate, flecainide acetate, simethicone, methyldopa, chlorthiazide, metyrosine, procainamide, entacapone, metoprolol, propranolol hydrochloride, chlorzoxazone, tolmetin, tramadol, bepridil, phenytoin, gabapentin, terbinafine, atorvastatin, doxepine, rifabutin, mesalamine, etidronate, nitrofurantoin, choline magnesium trisalicylate, theophylline, nizatidine, methocarbamol, mycophenolate mofetil, tolcapone, ticlopidine, capecitabine, orlistat, colsevelam, meperidine, hydroxychloroquine, guaifenesin, guanfacine, amiodarone, quinidine, atomoxetine, felbamate, pseudoephedrine, carisoprodol, venlafaxine, etodolac, chondroitin, lansoprazole, pantoprazole, esomeprazole, dexlansoprazole, dexmethylphenidate, methylphenidate, sodium oxybate, valproic acid or its salts, divalproex, topiramate, carbamazepine, oxcarbazepine, isotretinoin, oseltamivir, cholestyramine, nystatin, artemether, lumefantrine, melatonin, imatinib mesylate, zonisamide, capacitabine, clopidogrel, temozolomide, rosuvastatin, lenalidomide, sildenafil, methotrexate, sirolimus, everolimus, tacrolimus, irinotecan, aprepitant or combination thereof.

The liquid pharmaceutical composition of the present invention may comprise of two or more different active ingredients or incompatible active ingredients.

Non-limiting examples of film-forming agents include cellulosic polymers e.g., hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl acetate, polyvinyl pyrrolidone, acrylic polymers such as these commercially available under the trade mark Eudragr® E and Eudragii® EPiX lipid coating substances such as stearic acid, palmitic acid, and glycerol monostearate; hydrophilic colloids such as alginate, chitosan, carboxymethylcellulose, xanthan gum, carboxy vinyl polymers e.g., Carbomer® 94, polylysine, gelatin; and mixtures thereof.

The ion-exchange resins such as cation-arid anion-exchange matrices are well- known in the art. Few exemplary resin particles that can be used according to the invention include, but are not limited to, Dowex®resins and others made by Dow Chemical; Amberlite®, Amberlyst® and other resins made by Rohm and Haas; Indion® resins made by Ion Exchange, Ltd. (India), Diaion® resins by Mitsubishi; Type AGW and other resins by BioRad; Sephadex®and Sepharose® made by Amersham; resins by Lewatii sold by Fluka; Toyopearl® resins by Toyo Soda; IONAC® 1 and Whatman® resins sold by VWR; and BakerBond® resins sold by J T Baker; resins having polymer backbones comprising styrene-divinyl benzene copolymers and having pendant ammonium or tetraalkyf ammonium functional groups, available from Rohm and Haas, Philadelphia, and sold under the tradename DUOL1TE™ API 43.

Non-limiting suspending agents are selected from the group comprising cellulose derivatives such as co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its salts/derivatives, and microcrystalline cellulose; carbomers; gums such as locust bean gum, xanthan gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such as xylitol and mannitol; colloidal silica; and mixtures thereof. Co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium have been marketed under the trade names Avicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel® CL-611.

Non-limiting glidants are selected from the group comprising silica, calcium silicate, magnesium silicate, colloidal silicon dioxide, cornstarch, talc, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, and mixtures thereof.

Non-limiting sweeteners are selected from the group comprising saccharine or its salts such as sodium, potassium, or calcium, cyclamate or its salt, aspartame, alitame, acesulfame or its salt, stevioside, glycyrrhizin or its derivatives, sucralose, and mixtures thereof.

Non-limiting anti-caking agents are selected from the group comprising colloidal silicon dioxide, tribasic calcium phosphate, powdered cellulose, magnesium trisilicate, starch, and mixtures thereof.

Non-limiting wetting agents are selected from the group comprising anionic, cationic, nonionic, or zwitterionic surfactants, or combinations thereof. Suitable examples of wetting agents are sodium lauryl sulphate; cetrimide; polyethylene glycols; polyoxyethylene-polyoxypropylene block copolymers such as poloxamers; polyglycerin fatty acid esters such as decaglyceryl monolaurate and decaglyceryl monomyristate; sorbitan fatty acid esters such as sorbitan monostearate; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene sorbitan monooleate; polyethylene glycol fatty acid esters such as polyoxyethylene monostearate; polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether; polyoxyethylene castor oil; and mixtures thereof.

Non-limiting preservatives are selected from the group comprising parabens such as methyl paraben and propyl paraben; sodium benzoate; and mixtures thereof.
Non-limiting buffering agents are selected from the group comprising citric acid, sodium citrate, sodium phosphate, potassium citrate, acetate buffer, and mixtures thereof.

Non-limiting flavoring agents are selected from the group consisting of peppermint, grapefruit, orange, lime, lemon, mandarin, pineapple, strawberry, raspberry, mango, passion fruit, kiwi, apple, pear, peach, apricot, cherry, grape, banana, cranberry, blueberry, black currant, red currant, gooseberry, lingon berries, cumin, thyme, basil, camille, valerian, fennel, parsley, chamomile, tarragon, lavender, dill, bargamot, salvia, aloe vera balsam, spearmint, eucalyptus, and combinations thereof.

Non-limiting anti-oxidants are selected from the group comprising butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium metabisulfite, ascorbic acid, propyl gallate, thiourea, tocopherols, beta-carotene, and mixtures thereof.
Suitable chelating agents are selected from the group comprising ethylenediamine tetraacetic acid or derivatives/salts thereof, e.g., disodium edetate; dihydroxyethyl glycine; glucamine; acids, e.g., citric acid, tartaric acid, gluconic acid, and phosphoric acid; and mixtures thereof.

The term "solute" as used herein, refers to pharmaceutically acceptable inert agents that have high affinity for the pharmaceutically acceptable vehicle. The solutes generates hypertonic conditions leading to high osmolality and thus prevents the leaching of the active ingredient from the coated cores. The solutes can be present in the pharmaceutically acceptable vehicle or in the solid composition or both. Non-limiting solutes are selected from the group comprising carbohydrates such as xylitol, mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, dextrose and raffinose; water-soluble salts of inorganic acids such as magnesium chloride, magnesium sulfate, potassium sulfate, lithium chloride, sodium chloride, potassium chloride, lithium hydrogen phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium dihydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, and sodium phosphate tribasic; water-soluble salts of organic acids such as sodium acetate, potassium acetate, magnesium succinate, sodium benzoate, sodium citrate, and sodium ascorbate; water-soluble amino acids such as glycine, leucine, alanine, methionine; urea or its derivatives; propylene glycol; glycerin; polyethylene oxide; xanthan gum; hydroxypropylmethyl cellulose; and mixtures thereof. Particularly, the solutes used are xylitol, mannitol, glucose, lactose, sucrose, and sodium chloride.

The cores of the present invention comprising the active ingredient can be prepared by any method known in the art, e.g., extrusion-spheronoization, wet granulation, dry granulation, hot-melt extrusion granulation, spray drying, and spray congealing.

Alternatively, the active ingredient can be layered onto an inert particle to form the core. Further, the active ingredient particles can be directly coated with a film forming layer to form the microparticles or microcapsules. The microparticles or microcapsules can be prepared by a process of homogenization, solvent evaporation, coacervation phase separation, spray drying, spray congealing, polymer precipitation, or supercritical fluid extraction. The ion-exchange resins comprise loading a plurality of the resin particles with the active ingredient to form drug-resin cores. Methods of loading active ingredients onto the resin particles are generally known in the art.

In a further embodiment of the present invention, the container/bottle (Figure 1) is in the form of a glass or a plastic or a metallic bottle. The additional container (Figure 2) is in the form of a plastic or a metallic. The cap (Figure 3 or Figure 4) is in the form of a plastic or made up of any other suitable material which can easily pierced before use and is non-corrosive and resistant to heat and moisture upon storage.

BEST MODE OF CARRYING OUT THE INVENTION
EXAMPLES
The present invention may be further illustrated with reference to the following examples. These examples are provided by way of illustration of the present invention only and should not be construed as to limit the scope of the invention in any manner.
Example-1: A liquid oral pharmaceutical composition comprising Melatonin
Ingredient Quantity (mg/mL)
Melatonin 1.0
Sodium benzoate 0.625
Citric acid monohydrate Q.S. to pH 3-7
Sucralose 0.1-100
Strawberry flavour 0.001-10
Purified water Q.S.
Q.S. = Quantity Sufficient

Method of preparation for liquid base: A liquid base for the pharmaceutical composition comprising Melatonin as active ingredient was prepared using Sodium benzoate, Citric acid monohydrate, Sucralose, Strawberry flavour and Purified water following below mentioned process comprising steps of:
(a) Required quantity of purified water was added and desirable pH was adjusted using required quantity of citric acid monohydrate;
(b) Required quantities of sucralose and strawberry flavor were added into the mixture obtained in Step (a); and
(c) The final volume was adjusted with purified water.
(d) Thus prepared liquid base was filled in the container/bottle as shown in Figure 1.

Example-2: Stability studies of the pharmaceutical composition prepared in Example-1
The oral liquid pharmaceutical composition prepared according to Example-1 exhibits unexpected stability profile when tested after three (3) months under the conditions 40±2°C/25±5% RH and 25±2°C/60±5% RH. The liquid composition according to the present invention possess very less amount of impurities and highest degree of purity. The results of the stability tests conducted are summarized in the table below.
TESTS RESULTS
INITIAL 40±2°C/25±5% RH 25±2°C/60±5% RH
3 months ? 3 months ?
Description Clear Colorless Solution Clear Colorless Solution Clear Colorless Solution
pH 4.32 4.31 4.29
Assay of Melatonin (%) 99.6 97.8 98.3
Any Individual Impurity (%) BQL 0.06 BQL
Total Impurities (%) 0.06 0.13 BQL
BQL = Below Quantitation Limit

Example-3: A liquid oral pharmaceutical composition comprising Imatinib mesylate
Ingredients Quantity (mg /ml)
Imatinib Mesylate (Active ingredient) 80.0
Liquid maltitol (Sweetening agent) 100.0
Glycerine (Solvent) 300.0
Sodium benzoate (Preservative) 0.2
Acesulfame potassium (Sweetening agent) 1.0
Citric acid monohydrate (Buffering agent) Q.S. to pH 4.0-5.0
Strawberry flavour (Flavouring agent) 0.1
Purified Water (Vehicle) Q.S.

Method of preparation for liquid base: A liquid base for the pharmaceutical composition comprising Imatinib mesylate as active ingredient was prepared using liquid maltitol, glycerine, sodium benzoate, acesulfame potassium, citric acid monohydrate, strawberry flavour and purified water following below mentioned process comprising steps of:
(a) Take required quantity of purified water.
(b) Add required quantity of glycerin and mix till get homogenously mixed.
(c) Add required quantity of liquid maltitol and mix till get homogenously mixed.
(d) Add required quantity of sodium benzoate and mix till completely dissolved.
(e) Add citric acid monohydrate till desired pH is attained.
(f) Add required quantity of strawberry flavour and mix till completely dissolved.
(g) Make up the final desired volume with purified water.
(h) Thus prepared liquid base was filled in the container/bottle as shown in Figure 1.

Example-4: Stability studies of the pharmaceutical composition prepared in Example-3
The oral liquid pharmaceutical composition prepared according to Example-3 exhibits unexpected stability profile when tested after three (3) and six (6) months under the conditions 40±2°C/25±5% RH and 25±2°C/40±5% RH. The liquid composition according to the present invention possess very less amount of impurities and highest degree of purity. The results of the stability tests conducted are summarized in the table below.
Stability conditions pH Single maximum unknown impurity
NMT 0.2% Total impurities
NMT 1.0%
Initial 4.44 ND ND
40°C±2°C/
25±5% RH 1M 4.4 ND ND
2M 4.42 0.08 0.37
3M 4.64 0.06 (RRT 0.68) 0.63
6M 4.6 0.07 (RRT 0.68) 0.69
25°C±2°C/
40±5% RH 3M 4.55 0.06 (RRT 0.68) 0.55
6M 4.55 0.06 (RRT 0.68) 0.57
ND = Not detected

Example-5: A liquid oral pharmaceutical composition comprising Zonisamide
Ingredients mg/ml
Zonisamide 20.00
Avicel RC591 (Microcrystalline Cellulose & Carboxymethylcellulose Sodium Dispersion) 20.00
Sodium benzoate 2.00
Xanthan gum 3.50
Citric acid monohydrate pH 4-5
Tri-sodium citrate dihydrate pH 4-5
Sucralose 2.00
Strawberry flavour 0.10
Purified water Q.S to

Method of preparation for liquid base: A liquid base for the pharmaceutical composition comprising Imatinib mesylate as active ingredient was prepared using sodium benzoate, citric acid monohydrate, tri-sodium citrate and sucralose in purified water, followed by dispersing required quantities of Avicel® RC 591 (Microcrystalline cellulose & carboxymethylcellulose Sodium Dispersion), xanthan gum and strawberry flavour separately in purified water, mixing both the mixtures, homogenizing it and making up the final volume to the required quantity of batch size with purified water. Thus prepared liquid base was filled in the container/bottle as shown in Figure 1.

Example-6: Stability studies of the pharmaceutical composition prepared in Example-5
The oral liquid pharmaceutical composition prepared according to Example-5 exhibits unexpected stability profile when tested after three (3) and six (6) months under the conditions 40±2°C/25±5% RH and 25±2°C/40±5% RH. The liquid composition according to the present invention possess very less amount of impurities and highest degree of purity. The results of the stability tests conducted are summarized in the table below.
Parameters Results
Initial 40±2°C/25±5% RH 25±2°C/40±5% RH
1 month 3 months 6 months 3 months 6 months
Description White to Off white suspension Complies Complies Complies Complies Complies
pH 4.32 4.18 4.30 4.27 4.30 4.26
Assay of Zonisamide (%) 97.2 102.3 101.3 102.7 101.2 103.0
Impurity A ND ND ND ND ND ND
Unknown Impurities (%) 0.06 0.06 0.06 0.05 0.06 0.06
Total Impurities (%) 0.07 0.08 0.09 0.05 0.10 0.06
ND = Not detected

It should be understood that various changes and modifications to the presently preferred embodiments, examples and processes described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present subject matter and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims. ,CLAIMS:WE CLAIM,
1. A drug delivery system in the form of single unit for delivery of liquid dosage form comprising,
(a) A container or a bottle prefilled with a liquid vehicle or a liquid pharmaceutical composition comprising an active ingredient; and
(b) A cap above the bottle mechanised with one or more preformed holes and one or more pins, wherein said cap is prefilled with a solid pharmaceutical composition comprising an active ingredient;
wherein the liquid vehicle or a liquid pharmaceutical composition contained in the container/bottle is mixed with the solid pharmaceutical composition contained in the cap to form a final liquid dosage form upon activation of the drug delivery system.
2. A drug delivery system according to claim 1 wherein the system optionally further comprises an additional container with at least one pin and one preformed hole fitted inside the bottle and prefilled with a solid or a liquid pharmaceutical composition comprising an active ingredient;
wherein the liquid vehicle or a liquid pharmaceutical composition contained in the bottle is mixed with the solid or liquid pharmaceutical composition contained in the container to form a final liquid dosage form upon activation of the drug delivery system.
3. A drug delivery system according to any one of claim 1 or claim 2 wherein the solid pharmaceutical composition is in the form of a powder, a paste, beads, granules, gel, or a compressed tablet.
4. A drug delivery system according to any one of claim 1 or claim 2 wherein the liquid composition further comprises pharmaceutically acceptable excipients selected from the group consisting of surfactants, wetting agents, thickening agents, anti-oxidants, sweeteners, buffering agents, osmotic agents, preservatives, coloring agents, and mixtures thereof.
5. A drug delivery system according to any one of claims 1 to 3 wherein the solid pharmaceutical composition further comprises pharmaceutically acceptable excipients selected from the group consisting of surfactants, wetting agents, antioxidants, buffering agents, preservatives, coloring agents, lubricants, diluents, disintegrants, and mixtures thereof.
6. A drug delivery system according to claim 1 wherein the liquid vehicle is selected from the group comprising of aqueous or non-aqueous vehicles or combinations thereof.
7. A drug delivery system according to any one of claim 1 or claim 2 wherein the active ingredient is selected from the group comprising valacyclovir, metformin, azithromycin, cloxacillin, clarithromycin, erythromycin, amoxicillin alone or in combination with clavulanic acid, cefdinir, cefuroxime axetil, cefixime, cefadroxil, cefpodoxime, cefaclor, cefprozil, fluconazole, voriconazole, acarbose, miglitol, voglibose, repaglinide, nateglinide, glibenclamide, glimepride, glipizide, gliclazide, chloropropamide, tolbutamide, phenformin, alogliptin, sitagliptin, linagliptin, saxagliptin, rosiglitazone, pioglitazone, troglitazone, faraglitazar, englitazone, darglitazone, isaglitazone, zorglitazone, liraglutide, muraglitazar, peliglitazar, tesaglitazar, canagliflozin, dapagliflozin, remogliflozin, sergliflozin, verapamil, albuterol, salmeterol, acebutolol, sotalol, penicillamine, norfloxacin, ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, trovafloxacin, gatifloxacin, tetracycline, demeclocycline hydrochloride, losartan, irbesartan, eprosartan, valsartan, diltiazem, isosorbide mononitrate, ranolazine, propafenone, hydroxyurea, hydrocodone, delavirdine, pentosan polysulfate, abacavir, amantadine, acyclovir, ganciclovir, valganciclovir, saquinavir, indinavir, nelfinavir, lamivudine, didanosine, zidovudine, nabumetone, celecoxib, mefenamic acid, naproxen, propoxyphene, cimetidine, ranitidine, albendazole, mebendazole, thiobendazole, pyrazinamide, praziquantel, chlorpromazine, sumatriptan, bupropion, aminobenzoate, pyridostigmine bromide, potassium chloride, niacin, tocainide, quetiapine, fexofenadine, sertraline, chlorpheniramine, rifampin, methenamine, nefazodone, modafinil, metaxalone, morphine, sevelamer, lithium carbonate, flecainide acetate, simethicone, methyldopa, chlorthiazide, metyrosine, procainamide, entacapone, metoprolol, propranolol hydrochloride, chlorzoxazone, tolmetin, tramadol, bepridil, phenytoin, gabapentin, terbinafine, atorvastatin, doxepine, rifabutin, mesalamine, etidronate, nitrofurantoin, choline magnesium trisalicylate, theophylline, nizatidine, methocarbamol, mycophenolate mofetil, tolcapone, ticlopidine, capecitabine, orlistat, colsevelam, meperidine, hydroxychloroquine, guaifenesin, guanfacine, amiodarone, quinidine, atomoxetine, felbamate, pseudoephedrine, carisoprodol, venlafaxine, etodolac, chondroitin, lansoprazole, pantoprazole, esomeprazole, dexlansoprazole, dexmethylphenidate, methylphenidate, sodium oxybate, valproic acid or its salts, divalproex, topiramate, carbamazepine, oxcarbazepine, isotretinoin, oseltamivir, cholestyramine, nystatin, artemether, lumefantrine, melatonin, imatinib mesylate, zonisamide, capacitabine, clopidogrel, temozolomide, rosuvastatin, lenalidomide, sildenafil, methotrexate, sirolimus, everolimus, tacrolimus, irinotecan, aprepitant or combination thereof.
8. A drug delivery system according to any one of claim 1 or claim 2, wherein the final liquid dosage form comprises one or more than one active ingredients.
9. A drug delivery system according to any one of claim 1, claim 2 or claim 8, wherein the final liquid dosage form is in the form of a solution, a suspension, or a syrup dosage form.
10. A drug delivery system according to any one of claim 1, claim 2, claim 8 or claim 9 wherein the final liquid dosage form is suitable for oral, injectable or spray administration.