DUAL-CHAMBER PACK
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 t e 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 t e 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 t e 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) t e 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 t e 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 t e present invention relates to dual-chamber pack for a multidose
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 1month, in particular from 1 week to 1month.
The reconstituted composition is stable for a period of 1month 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 t e 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 t e group consisting of surfactants, wetting agents, ant i
oxidants, 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 coaxially
to the cap (1) from above. The band breaks easily on pulling apart. The tamperevident
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 multidose
oral liquid pharmaceutical composition in a dual-chamber pack, comprising t e 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.

We claim:
1. 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; and
(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) a 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) t e cap (1) over t e 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).
2 . The dual-chamber pack according to claim 1, wherein the liquid vehicle is present
in an amount of from about 5 mL to about 350 mL.
3 . The dual-chamber pack according to claim 1, wherein the solid composition of the
second chamber is in the form of a powder, a paste, beads, granules, gel, or a
compressed tablet.
4 . The dual-chamber pack according to claim 1, wherein the multi-dose oral liquid
pharmaceutical composition is in the form of a suspension or a syrup dosage form.
5 . The dual-chamber pack according to claim 1, wherein the plunger (3) is activated
by pressure or a screw-based mechanism.
6 . The dual-chamber pack according to claim 1, wherein the plug (3) may be screwed
or snuggly fitted onto the opening (7) of the container (8).
7 . The dual-chamber pack according to claim 1, wherein the plunger (3) may be flute
shaped or may exhibit two or more sharp projections.
8. The dual-chamber pack according to claim 1, wherein the plunger (3) is inversely
fitted into t e plug (4) and the plug (4) is then mounted on the opening (7) of the
container (8).
9 . The dual-chamber pack according to claim 1, wherein not more than three-fourths
of the circumference of the polymeric membrane (5) is ruptured by the plunger (3)
when pressure is applied on the cap (1).
10. The dual-chamber pack according to claim 1, wherein the cap (1) further comprises
a tamper-evident tear band (2) .
11. The dual-chamber pack according to claim 1, wherein the reconstituted oral liquid
pharmaceutical composition formed after mixing for first administration is stable at
40°C and 75% RH for a period of 1month.