Herpes simplex virus (HSV) infections are ubiquitous, with approximately 80% of the adult population infected with HSV type 1 and approximately 20% of the adult population also infected with HSV type 2. HSV type 1 is the cause of herpes labialis, also called orofacial herpes, or cold sores, and HSV encephalitis. HSV type 2 is the primary cause of initial and recurrent genital herpes, and neonatal HSV. The typical manifestation of a primary HSV-1 or HSV-2 genital infection is clusters of inflamed papules and vesicles on the outer surface of the genitals resembling cold sores. (Gupta et al., 2007, Lancet 370(9605): 2127-37). Varicella zoster virus, also known as chickenpox, varicella virus, zoster virus, and human herpes virus type 3 (HHV-3), results in chickenpox which generally occurs in children and young people. Even when clinical symptoms of chickenpox have resolved, varicella zoster virus remains dormant in the nervous system of the infected person (virus latency), in the trigeminal and dorsal root ganglia. In about 10-20% of cases, varicella zoster virus reactivates later in life causing herpes zoster or shingles, an illness with very different symptoms.
Herpes viruses cycle between periods of active disease, presenting as blisters containing infectious virus particles that typically persists for a period between 2-21 days, followed by a remission period, during which the sores disappear. Many HSV infected people experience recurrence within the first year of infection. During recurrence, fewer lesions are likely to develop, lesions are less painful, and lesions heal faster than those occurring during the primary infection. Subsequent outbreaks tend to be periodic or episodic, occurring on average four to five times a year when the patient is not using antiviral therapy.
Treatment of initial HSV infection and reactivated latent HSV infection typically includes the topical application of an antiviral nucleoside compositions to lesions at the first sign of outbreak, and at recurring intervals until remission of the lesions. Current prescription topical treatments for herpes labialis include Zovirax™ cream (5% acyclovir, GlaxoSmithKline/Biovail Pharmaceuticals) which is FDA approved for the treatment of recurrent herpes labialis (cold sores) in adults and adolescents over 12 years of age. Another topical treatment is Denavir™ (1% penciclovir, Novartis), which is FDA approved for the treatment of recurrent cold sores in adults. These treatments inhibit viral replication, shortening healing time and duration of symptoms. Zovirax™ ointment (5% acyclovir, GlaxoSmithKline/Biovail Pharmaceuticals) is approved for topical administration and is indicated in the management of initial genital herpes and in limited non-life-threatening mucocutaneous Herpes simplex virus infections in immunocompromised patients. Side effects include mild pain upon application, pruritis, and rash.
Patient satisfaction with current remedies, particularly for HSV-1, herpes labialis, has been poor, as topical acyclovir therapy lacks efficacy in comparison with oral or parenteral administrations. This may be due to poor absorption, because acyclovir concentrations in the skin following topical application is about 2-3 times lower than concentrations following oral administration. Thus, this lack of efficacy of acyclovir following topical treatment may be related to the poor water-solubility and lipophilicity of the drug, resulting in its inadequate skin or mucous membrane penetration. Despite this limited solubility and efficacy, local administration of acyclovir is still considered safer than systemic administration. Viral resistance to acyclovir is common and may result from qualitative and quantitative changes in the viral TK and/or DNA polymerase; particularly in immunocompromised patients. Clearly, there is room for improvement in topical antiviral compositions for the rapid, efficacious treatment of HSV infections.
In view of the foregoing, there is a need for topical formulations that comprise a less toxic and more generally effective topical drug product that can be used daily for preventing reactivation of latent HSV infection and recurrence of herpes skin and mucus membrane lesions.
USPTO Backgrounds
USPTO Backgrounds