Field of the Invention

The present invention relates to a dual -chamber pack for a multi-dose oral liquid pharmaceutical composition wherein the compositions of the first and second chambers are mixed at the time of first administration.

Background of the Invention

Liquid pharmaceutical compositions are generally used in patients having difficulty in swallowing solid dosage forms, 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.

U.S. Patent No. 8,002,734 discloses a dual-chamber container for an injectable composition comprising a solid lyophilizate and a liquid reconstituting medium thereof, wherein the cylindrical body has a closure at each of two ends. One of the ends allows for reconstitution and the other end allows for administration by injection.

U.S. Patent No. 4,982,875 discloses a cap, a reservoir, and a dispensing dropper assembly package wherein a reservoir having reduced thickness at the bottom is inserted internally on the upper mouth of the container for an ophthalmic composition. The cap helps to push the delivery piston downwards by a screw-based mechanism, which in turn cuts the bottom of the reservoir at all points except one, where the bottom remains attached to the reservoir. Summary of the Invention

The present invention provides an alternative pack for a multi-dose oral liquid pharmaceutical composition comprising of two chambers, wherein the pack is adaptable for low to high dose drugs. The pack allows the patient ease of dispensing with only a few simple steps required for reconstitution.

The present invention provides a dual -chamber pack for a multi-dose oral liquid pharmaceutical composition comprising of:

(a) a first chamber in the form of a container (8) provided with an opening (7) at an upper end, comprising a liquid vehicle containing one or more

pharmaceutically acceptable inert excipients;

(b) a second chamber comprising:

(i) a plunger (3) adapted to fit into a plug (4) having a top flat surface, containing a solid composition comprising a drug in an amount of from about 50 mg to about 130 g and optionally one or more pharmaceutically acceptable inert excipients; and

(ii) the plug (4), with a breakable polymeric membrane (5), adapted to fit into the opening (7) from a lower end and into a cap (1) from the upper end; and

(c) the cap (1) over the second chamber comprising a means to exert pressure onto the plunger (3) so as to partially rupture the breakable polymeric membrane (5) of the plug (4) and deliver the solid composition into the container (8) wherein the compositions of both chambers are mixed at the time of first administration by applying pressure on the cap (1).

Brief Description of the Drawings

Figure 1 : Schematic diagram of the components of a dual -chamber pack wherein a dome-shaped plunger (3) ruptures the polymeric membrane (5) by a screw-based mechanism.

Figure 2: Schematic diagram of the components of a dual -chamber pack wherein a flute-shaped plunger (3) fitted in a snuggly fitted plug (4) ruptures the polymeric membrane (5) by a screw-based mechanism. Figure 3: Schematic diagram of the components of the dual-chamber pack wherein a flute -shaped plunger (3) fitted in a screw fitted plug (4) ruptures the polymeric membrane (5) by a screw-based mechanism.

Detailed Description of the Invention

A first aspect of the present invention relates to dual-chamber pack for a multi- dose oral liquid pharmaceutical composition comprising of:

(a) a first chamber in the form of a container (8) provided with an opening (7) at an upper end comprising a liquid vehicle containing one or more

pharmaceutically acceptable inert excipients;

(b) a second chamber comprising:

(i) a plunger (3) adapted to fit into a plug (4) having a top flat surface, containing a solid composition comprising a drug in an amount of from about 50 mg to about 130 g and optionally one or more pharmaceutically acceptable inert excipients; and

(ii) the plug (4), with a breakable polymeric membrane (5), adapted to fit into an opening (7) from a lower end and into a cap (1) from the upper end; and

(c) the cap (1) over the second chamber comprising a means to exert pressure onto the plunger (3) so as to partially rupture the breakable polymeric membrane (5) of the plug (4) and deliver the solid composition into the container (8) wherein the compositions of both chambers are mixed at the time of first administration by applying pressure on the cap (1).

The term "multi-dose" as used herein, refers to a drug product which is to be administered in multiple doses after reconstitution, over a period of time varying from 1 day to 1 month, in particular from 1 week to 1 month.

The reconstituted composition is stable for a period of 1 month whereby the multiple doses are administered as per the dosing schedule of the drug. In particular, stability studies were carried out for metformin powder for oral suspension and cefprozil powder for oral suspension. Both of the liquid compositions, after being reconstituted, were found to be stable for at least one month. The term "stable" as used herein, refers to no significant changes in the drug product with respect to assay, viscosity, and total related substances, including highest unknown impurity, when subjected to stability conditions of 40°C and 75% RH for 1 month before and after reconstitution.

According to another embodiment of this aspect, the reconstituted liquid pharmaceutical composition is stable when exposed to stability conditions of 40°C and 75% RH for a period of 1 month.

According to one embodiment of this aspect, the container (8) is in the form of a glass or a plastic or a metallic bottle. The first chamber may be sealed at the opening (7) of the container (8) using a heat seal or a pressure seal or an induction seal using a bottle liner (6). This liner provides protection against any spill from the first chamber during manufacturing as well as storage. Also, it acts as an enhanced barrier for ingression of moisture from the first chamber to the second chamber.

According to another embodiment of this aspect, the multi-dose oral liquid composition is in the form of a suspension or a solution dosage form. In case of a suspension, the solid composition of the second chamber is dispersed into the liquid vehicle of the first chamber at the time of first administration. In case of a solution, the solid composition of the second chamber is dissolved in the liquid vehicle of the first chamber at the time of first administration.

According to another embodiment of this aspect, the liquid vehicle of the first chamber may comprise purified water or a mixture of purified water and one or more suitable organic solvents. The organic solvents may be selected from the group consisting of ethanol, glycerin, propylene glycol, polyethylene glycol, and mixtures thereof. The amount of the liquid composition may vary from about 5 mL to about 350 mL.

The liquid composition of the first chamber may further comprise

pharmaceutically acceptable inert 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 another embodiment of this aspect, the solid composition of the second chamber 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.

According to another embodiment of this aspect, the drug in the second chamber is a soluble, a water-insoluble, or a poorly-soluble drug. The drug may have a stability problem due to which the drug is reconstituted using a liquid composition at the time of administration. This dual-chamber pack can be used for drugs 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, propanolol

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, isotretinoin, oseltamivir, cholestyramine, nystatin, and a combination of artemether and lumefantrine. This dual -chamber pack is suitable for both low dose and high dose drugs. The dose of the drug may vary between about 50 mg and about 130 g.

According to another embodiment of this aspect, the plunger (3) is inversely fitted into the plug (4) which is subsequently screwed or snuggly fitted on the opening (7) of the container (8). The plunger (3) may be screwed or snuggly fitted into the plug (4). The plunger (3) may be flute shaped (as in Figure 2 and 3) or may exhibit two or more projections (as in Figure 1) to rupture the polymeric membrane (5). The plug (4) and the plunger (3) may be made up of a plastic or a metallic material.

According to another embodiment of this aspect, the compositions of the first and second chambers of the container are separated by a polymeric membrane (5) of the plug (4) which is easily breakable. The plunger (3) helps to rupture the polymeric membrane (5) upon the application of pressure by a screw-based mechanism. When pressure is applied on the cap (1), not more than three-fourths of the circumference of the polymeric membrane (5) is ruptured by the plunger (3). The intact polymeric membrane remains attached to the circumference of the plug. In cases where a bottle liner (6) exists between the first and the second chambers, the plunger (3) would break the bottle liner (6) in the same manner as it ruptures the polymeric membrane (5). The unabridged part of the bottle liner (6) remains attached to the opening (7) of the container (8).

According to another embodiment of this aspect, the dual -chamber pack further comprises a cap (1) with a tamper-evident tear band (2). The cap (1), upon application of pressure by a screw-based mechanism, pushes the plunger (3) downwards, which in turn ruptures the polymeric membrane (5) allowing the contents of two chambers to be mixed. The cap (1) may be designed to have child-resistant properties.

The term "tamper-evident tear band" as used herein, refers to a band attached co- axially to the cap (1) from above. The band breaks easily on pulling apart. The tamper- evident tear band (2) ensures the overall integrity of the product until the time of first administration. A second aspect of the present invention provides a method of providing a multi- dose oral liquid pharmaceutical composition in a dual-chamber pack, comprising the steps of:

a) providing a container (8) comprising a first chamber, a second chamber, and a cap (1);

b) filling the first chamber partially with a liquid vehicle;

c) filling a plunger (3) of the second chamber at least partially with a solid composition comprising the drug;

d) fixing the plunger (3) into a plug (4) of the second composition and mounting the plug (4) on an opening (7) of the first chamber;

e) activating the dual-chamber pack at the time of first administration by screwing the cap (1) so that the plunger (3) ruptures three-fourths of the circumference of a polymeric membrane (5) (as given in Figure 1); and f) shaking the container to allow the mixing of the two compositions to obtain the liquid pharmaceutical composition.

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.