FIELD OF INVENTION

The invention in general relates to pharmaceutical formulations. In particular this invention relates to ready-to-dilute azithromycin liquid pharmaceutical composition for intravenous administration.

BACKGROUND OF INVENTION

Azithromycin is the U.S.A.N. (generic name) for 9a~aza-9a-methyl-9-deoxo-9ahomoerythromycin A, a broad spectrum antimicrobial derived from erythromycin A. Azithromycin was independently discovered by Bright, (see U.S. Patent No. 4,474,768 and Kobrehel et al., U.S. Patent No. 4,517,359). These patents disclose that azithromycin and certain derivatives thereof possess antibacterial properties and are accordingly useful as antibiotics. Azithromycin is a macrolide antibiotic used for treating infections Azithromycin is currently sold in tablet form, powder for oral suspension form and in an injectable intravenous form. The tablet form is marketed as Zithromax® tablet and is available as film coated tablets, whereas the powder for oral suspension is marketed as Zithromax® for oral suspension in the single dose packet; the entire contents of the packet should be mixed thoroughly with two ounces (approximately 60 mL) of water & must be consumed immediately. The injectable intravenous form of Zithromax® is supplied in lyophilized form in a 10-mL glass vial equivalent to 500 mg of azithromycin for intravenous administration. This lyophilized product has to be first reconstituted with 4.8 mL of water for Injection to obtain 100 mg/mL azithromycin solution; which needs to be further diluted with compatible intravenous fluid, such as dextrose or sodium chloride to obtain a final infusion solution with azithromycin in the concentration range of 1.0-2.0 mg/mL. The reconstituted solution & the diluted solution obtained thereof are only stable for 24 hours at room temperature.

Hence, Zithromax® for injection currently available in the market requires a first step of reconstitution with water for injection followed by a second step of dilution with diluents or compatible intravenous fluid prior to the administration of the patient. Other disadvantages associated with this product include the potential for contamination, dosage errors, during the reconstitution & dilution steps. The reconstitution of the azithromycin lyophilized powder is time consuming and cumbersome. Moreover, lyophilization of solids on a commercial scale requires specialized equipment and incurs significant expense. As such, formulations of azithromycin that do not require lyophilization and/or reconstitution are needed and which could be administered directly to the patient with a simple step of dilution with intravenous fluids are needed. The pharmaceutical compositions and methods described herein overcome these disadvantages. In particular, ready-to-dilute injectable formulations described herein are stable in liquid state; allow medical personal to easily administer injectable formulation with just a single step of mixing the azithromycin injectable concentrate with intravenous fluid; avoid potential contamination problems, and eliminate dosage errors. Also the manufacturing process adopted for the present invention does not involve the use lyophilization process & is more economical.

SUMMARY OF INVENTION

In one aspect, the invention provides ready-to-dilute azithromycin liquid pharmaceutical composition for intravenous administration wherein the said composition is packed in a dual chamber container. In another aspect it discloses a process for preparing ready-to-dilute azithromycin liquid pharmaceutical composition for intravenous administration.

DESCRIPTION OF INVENTION

The invention provides ready-to-dilute azithromycin liquid pharmaceutical composition for intravenous administration where in the said composition is packed in a dual chamber container. In one embodiment the invention provides ready-to-dilute azithromycin liquid pharmaceutical composition for intravenous administration packed in a dual chamber container. The dual chamber container is a glass vial or an infusion bag. One chamber of the container houses azithromycin injection liquid concentrate whereas the other chamber of the infusion bag houses a diluent or compatible intravenous fluid. In case of a dual chamber infusion bag, the two chambers of the bag are separated by the frangible seal which can be opened by a pressure applied from outside to cause the chambers to communicate with each other. Azithromycin concentrate solution can therefore be mixed with the diluent aseptically while being held out of contact with outside air. The dual chamber infusion bags are made up plastics and are flexible and readily deformable, so that the bag and the cover constituting the bag can be disposed of without the necessity of separation, more easily than containers wherein glass or metal is used.

A ready-to-dilute azithromycin injection liquid concentrate of the present invention comprises of azithromycin, citric acid and ethanol and optionally stabilizers. The stabilizers used in the present invention comprises Polyvinylpyrrolidone (Povidone), hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, polysaccharides, polyvinyl alcohol, dextran, guar gum, hyaluronates, starch derivatives, PEG-derivatized lipid, a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate and copolymers of vinyl acetate, vinyl alcohol. The azithromycin concentrate was found to be stable at room temperature in a liquid state. The diluent or compatible intravenous fluid used in the present invention comprises:

— Normal Saline (0.9% sodium chloride)

— 1/2 Normal Saline (0.45% sodium chloride)

— 5% Dextrose in Water

— Lactated Ringer's Solution

— 5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride) with 20 mEq KC1

— 5% Dextrose in Lactated Ringer's Solution

— 5% Dextrose in 1/3 Normal Saline (0.3% sodium chloride)

— 5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride)

— Normosol®-M in 5% Dextrose

— Normosol®-R in 5% Dextrose

In another embodiment the invention provides a process for preparing ready-to-dilute azithromycin liquid pharmaceutical composition for intravenous administration. The said process comprises involves preparation of azithromycin injection liquid concentrate and filling of this concentrate solution in one of the chambers of the container followed by filling of a compatible diluent in the other chamber of the container. Azithromycin injection liquid concentrate was prepared by dissolving azithromycin in a solution of citric acid & ethanol; followed by making up the volume with ethanol to obtain a clear solution. The clear solution was filtered through 0.2|x PVDF filter to obtain azithromycin injection liquid concentrate. The following non-limiting examples illustrate certain aspects of the invention. It should be understood, however, that the spirit and scope of the invention is not to be limited to the specific conditions or details described in the examples.

- Azithromycin injection liquid concentrate was prepared by dissolving azithromycin in a solution of citric acid & ethanol; followed by making up the volume with ethanol to obtain a clear solution. The clear solution was filtered through 0.2 (j, PVDF filter to obtain azithromycin injection liquid concentrate. Azithromycin injection liquid concentrate was prepared by dissolving the polymer, Povidone K-12 in a solution of citric acid & ethanol to obtain a polymeric solution. Azithromycin was then dissolved in the polymeric solution; followed by making up the volume with ethanol to obtain a clear solution. The clear solution was filtered through 0.2)4, PVDF filter to obtain azithromycin injection liquid concentrate.

We Claim,

1. A ready-to-dilute azithromycin liquid pharmaceutical composition for intravenous administration where in the said composition is packed in a dual chamber container.

2. A ready-to-dilute azithromycin liquid pharmaceutical composition according to claim 1, where dual chamber container is an infusion bag or a glass vial.

3. A ready-to-dilute azithromycin liquid pharmaceutical composition according to claim 2, where in one chamber of the container houses azithromycin injection liquid concentrate whereas the other chamber of the container houses a diluent or compatible intravenous fluid.

4. A ready-to-dilute azithromycin liquid pharmaceutical composition according to claim 3, where in azithromycin injection liquid concentrate comprises of azithromycin, citric acid, ethanol and optionally stabilizers.

5. A ready-to-dilute azithromycin liquid pharmaceutical composition according to claim 4, where in stabilizers comprises polyvinylpyrrolidone (povidone), hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, polysaccharides, polyvinyl alcohol, dextran, guar gum, hyaluronates, starch derivatives, PEG-derivatized lipid, a copolymer of l-vinyl-2-pyrrolidone and vinyl acetate and copolymers of vinyl acetate and vinyl alcohol.

6. A ready-to-dilute azithromycin liquid pharmaceutical composition according to claim 3, where in the diluent or compatible intravenous fluid comprises normal saline (0.9% sodium chloride), 1/2 normal saline (0.45% sodium chloride), 5% dextrose in water, lactated ringer's solution, 5% dextrose in 1/2 normal Saline (0.45% sodium chloride) with 20 mEq KCl, 5% Dextrose in lactated ringer's solution, 5% dextrose in 1/3 normal saline (0.3% sodium chloride), 5% dextrose in 1/2 Normal saline (0.45% sodium chloride), Normosol®-M in 5% Dextrose, Normosol®-R in 5% Dextrose.