The human body is susceptible to bacterial and parasitic infections arising from both traumatic and non-traumatic related events. Infections are a concern after surgery, and precautions are correspondingly taken to prevent the onset of infection. However, even without the invasive trauma of a surgical procedure, infections in the eye, ears, mouth, skin and other superficial tissues can occur.
Treating infections in superficial tissues can be challenging and/or problematic because of the difficulty in delivering an antibiotic to the affected tissue. The simple and direct approach of topically applying the antibiotic has several benefits, including the avoidance of side effects, bypassing the hepatic first pass, and the reduced chance of developing resistant strains of bacteria as compared to systemic administration. However, for a variety of reasons, many antibiotics are not amenable or suitable for topical application.
For example, in order for a topical application to be effective, the antibiotic must be able to penetrate the desired tissue. Also, the permeability must be sufficient to impart an effective dose. Many drugs do not possess a requisite solubility or permeability with regard to superficial tissues. It should be noted that the permeability of the superficial tissues are quite different from that of the tissues encountered in the stomach and intestinal tract. Thus, while a certain drug may be readily absorbed in the intestines and introduced into the blood supply for systemic administration, the same drug may be incapable of being absorbed by or passing through the substantially avascular outer layers of superficial tissues at a minimally acceptable therapeutic concentration. Moreover, the mechanism of transport or uptake of the drug is entirely different for topical administration than for oral administration.
Azithromycin (U.S. Pat. No. 4,517,359) is a well-known antibiotic belonging to the macrolide class (of which erythromycin is the precursor). Notwithstanding the structural similarity, azithromycin can be considered as unique within the macrolides class, such as to be included in a new class of antibiotics known as azalides. In particular, the specific characteristics of azithromycin make this molecule more stable, tolerated and effective than its precursor erythromycin (S. Alvarez-Elcoro, M. J. Enzler, “The macrolides: Erythromycin, clarithromycin, and azithromycin”, Mayo. Clinic Proceeding, 1999, 74: 613-634).
Azithromycin, even in comparison to other recent macrolides, shows a superior antibacterial activity against some gram-negative organisms, while retaining the same efficacy against gram-positive organisms. Moreover azithromycin has an extensive intracellular distribution into specific tissues after oral administration [R. P. Glaude et al., Antimicrob. Agents and Chemother., 1989, 33(3): 277-82]. The extended half-life of azithromycin makes it potentially suitable for once-daily administration against infections of the respiratory tract, skin and soft tissues [A. P. Ball et al., J. Int. Med. Res., 1991, 19(6): 446-50; A. E. Girard et al., Antimicrob. Agents and Chemother., 1987, 31(12): 1948-1954].
Efficient methods for preparing high concentration and well tolerated aqueous azalide formulations have been elusive. Generally, azalide antibiotics are poorly soluble in water. The aqueous solubility at pH 7.4 at 37° C. is 39 mg/ml. Aqueous solubility can be improved when the antibiotic is converted to a salt form. For example, azithromycin dihydrochloride has good water solubility. However, there are potential safety problems associate with the topical use of its salts.
U.S. Pat. No. 6,277,829 discloses a process for the preparation of an aqueous ophthalmic formulation containing azithromycin which comprises the 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 azithromycin in an amount ranging from 0.1 to 100 g/l, within a temperature range from 15 to 25° C., 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. However, these solutions utilize phosphate buffer system comprising of phosphoric acid in combination with a polymeric suspending agent with increased residence time can be irritating to the eye. Additionally, phosphate buffered system can promote fungus growth in the formulation.
As such there remains a need for concentrated yet well tolerated aqueous formulations of azalide antibiotics for topical application.
All documents scientific and patent, cited herein are incorporated by reference in their entirety.