Title:  Process for preparing of aqueous formulation for ophthalmic use

United States Patent:  6,277,829

Assignee:  S.I.F.I. Societa Industria Farmaceutica Italiana S.p.A. (Lavinaio, IT)

Filed:  December 27, 1999

Foreign Application Priority Data:  Aug 09, 1999[IT] (MI99A1803)

The present invention describes a process for the preparation of aqueous formulations containing azithromycin for ophthalmic use, as well any formulations obtained by this process and their topical use in the ocular bacterial infections, more preferably in the treatment of conjunctivitis, keratitis and blepharitis.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The objects described above and other of the present invention, which will become better understood from the following description, have been surprisingly achieved through a process for the preparation of an aqueous ophthalmic formulation containing azithromycin which comprises the solubilization of ophthalmically acceptable polybasic phosphate in a concentration range from 7.8 to 68.6 g/l, citric acid monohydrate in an amount ranging from 0.9 to 35.94 g/l, and the subsequent addition of azithromycin in an amount ranging from 0.1 to 100 g/l, within a temperature range from 15 to 25^oC., wherein the molar ratio of azithromycin to citric acid is about 1:0.67 to 1:1.5; wherein pH is adjusted to a value of 5.5-7.6, and up to a final osmolality between about 130 to about 300 mOsm/Kg.

In one preferred embodiment of the present invention an ophthalmically acceptable polybasic phosphate is sodium phosphate, more preferably disodium phosphate dodecahydrate. The solution, under the process of the present invention, has preferably a pH ranging from about 6.4 to about 7.6, wherein the most preferred molar ratio of azithromycin to citric acid is equal to 1.5:1.

The process of the present invention allows to obtain an extremely high solubility of azithromycin in aqueous solution, also superior than 10% w/v. Formulations containing azithromycin at concentration ranging from 0.01 to 10% w/v, more particularly between 0.3 and 5% w/v, are the most preferred.

According to another preferred aspect, the process of the present invention, comprises, subsequently to the azithromycin dissolution, the addition of at least a tonicity agent and/or a viscosity-increasing agent and/or a gelling agent and/or a stabilizing agent and a preservative agent, in amounts ophthalmically acceptable.

Aqueous ophthalmic formulations obtained as defined in the process of the present invention are novel and, according to another preferred aspect, comprise, in combination with azithromycin, at least another therapeutic agent having antibacterial activity and/or a therapeutic steroidal or nonsteroidal agent having antiinflammatory activity in amounts ophthalmically acceptable to the eye.

In particular, the therapeutic agent having antibacterial activity is selected from the group consisting of aminoglycosides (e.g. netilmicin), fluoroquinolones, tetracyclines, polymyxin, glycopeptides, glycoproteins (e.g. lactoferrin), natural and/or synthetic peptides, .beta.-lactam antibiotics, as well as other antibacterial agents, whereas the therapeutic steroidal agent having antiinflammatory activity is selected from the group made up of desonide 21-phosphate, dexamethasone, clobetasone, mometasone, betamethasone, fluticasone and other similar steroidal antiinflammatory agents. Non-steroidal agent having antiinflammatory activity is selected from the group made up of naproxen, diclofenac, nimesulide, flurbiprofen and other similar non-steroidal antiinflammatory agents.

It is a preferred object to realize the formulations of the present invention as aqueous solutions, ointment or gel forms as well as other systems of release ophthalmically compatible to the ocular structures.

Formulations of the present invention can be advantageously utilized for the preparation of a medicine in the treatment of ocular pathologies requiring antibacterial therapy, more preferably in the treatment of conjunctivitis, keratitis and blepharitis.

Based on the lower mean observed for the reduction of the bacterial burden into the corneas treated with azithromycin (2%), with respect to the vehicle, it is possible to sustain that higher concentrations of azithromycin (>2%), administered as ointment or gel pharmaceutical forms and other ocular release systems as well, are effective in the ocular therapy of bacterial keratitis.

The process of the present invention is able to overcome any difficulties in preparing aqueous compositions containing azithromycin. In fact, it has been discovered a process in which, without being necessary to synthesize azithromycin salts in presence of organic solvents, it is possible, by adding appropriate amounts of citric acid/phosphate buffer ratio to the azithromycin suspension, to obtain a stable aqueous pharmaceutical form which is compatible to the ocular structures. Aqueous solutions of azithromycin prepared as defined in the process of the present patent, wherein pH ranges from 5.5 to 7.6 and osmolality ranges from 130 to 300 mOsm/Kg, are able to achieve tissue concentrations above the MIC values of the most common ocular pathogens (e.g. Staphylococcus aureus, Staphylococcus epidermidlis, Streptococcus pneumoniae Streptococcus viridans, Streptococcus pyogenes, Pseudomonas aeruginosa, Serratia marcescens, Klebsiella pneumoniae, Enterobacter, Citrobacter, Haemophilus influenzae, Chlamydia spp.) making them effective in the treatment of the major ocular bacterial infections.

Ophthalmic formulations prepared as defined in the process of the present invention can comprise, in an amount ophthalmically acceptable, a polybasic phosphate buffer; viscosity-increasing agents and gelling agents (e.g. salts of hyaluronic acid, ophthalmically acceptable, with a molecular weight range of from about 200.000 to about 5.000.000 Dalton, Lutrol.RTM. F127 (BASF), Kollidon.RTM. (BASF), hydroxypropyl metilcellulose, Carbopol.RTM. (Goodrich), stabilizing agents (e.g., polyethylene glycol, propylene glycol, Cremophor.RTM. (BASF), polysorbate, ascorbate, ionic surfactants) preservatives (e.g. benzalkonium chloride, cetrimide, thimerosal, chlorobutanol, p-hydroxybenzoate, polyhexamethylen biguanide, clorexidine, sorbates), tonicity agents (sodium chloride and/or potassium chloride, glycerol, mannitol) and/or other excipients (e.g., vaseline, paraffin oil, lanolin, etc.) commonly utilized in ophthalmic formulations for human and veterinary use.

The surprising effect of the citric acid in solubilizing azithromycin, together with the unexpected opportunity to obtain elevated concentration of azalide in physiological pH range, have been exploited for preparing various azithromycin eye drops at different concentrations and pH range, in order to evaluate their stability, pharmacokinetics, safety and efficacy.

Claim 1 of 14 Claims

What is claimed is:

1. A process for the preparation of an aqueous azithromycin containing ophthalmic formulation, comprising:

dissolving, in an aqueous medium, ophthalmically acceptable polybasic phosphate in an amount ranging from 7.8 to 68.6 g/l and citric acid monohydrate in an amount ranging from 0.9 to 35.94 g/l; and

solubilizing azithromycin in the aqueous medium in an amount ranging from 0.1 to 100 g/l at a temperature of 15 to 25^oC. wherein the molar ratio of azithromycin to citric acid ranges from 1:0.67 to 1:1.5, the pH is adjusted to range from 5.5 to 7.6 and the final osmolality ranges from 130 to 300 mOsm/kg.

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