(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 26 April 2012 (26.04.2012) WO 2012/054334 Al (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, A01N 43/16 (2006.01) A61K 31/35 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, PCT/US201 1/05635 1 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 14 October 201 1 (14.10.201 1) NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (25) Filing Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (26) Publication Language: English ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/394,931 20 October 2010 (20.10.2010) US kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant (for all designated States except US): GAL- UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, DERMA S.A. [CH/CH]; Zugerstrasse 8, CH-6330 RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, CHAM (CH). DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, (72) Inventors; and SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, (75) Inventors/ Applicants (for US only): PARKS, Dean, L . GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). [—/US]; 4185 SE 20th Street, Ocala, FL 34471 (US). PARKS, Jeffrey, D . [—/US]; Parks Dermatology Center Published: P.A., 400 Lakebridge Plaza Drive, Ormond Beach, FL — with international search report (Art. 21(3)) 32174 (US). — before the expiration of the time limit for amending the (74) Agent: LI, Yi; MEL VEST K. SILVERMAN & ASSOCS., claims and to be republished in the event of receipt of P.C., 500 West Cypress Creek Road, Suite 350, Fort amendments (Rule 48.2(h)) Lauderdale, FL 33309 (US). (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, © o- (54) Title: METHOD OF TREATING HERPES VIRUS INFECTION USING MACROCYCLIC LACTONE COMPOUND (57) Abstract: A method of treating herpes simplex virus infection or varicella zoster virus infection is disclosed. The method in- eludes topically applying a composition containing an effective amount of one or more macrocyclic lactone compounds, including ¾ avermectin compounds or milbemycin compounds and a pharmaceutically acceptable carrier to the affected area of an individual suffering from herpes simplex virus infection or varicella zoster virus infection. METHOD OF TREATING HERPES VIRUS INFECTION USING MACROCYCLIC LACTONE COMPOUND FIELD OF THE INVENTION [0001] The present invention relates to a method of treating herpes simplex virus and varicella zoster virus infections, more particularly a method of treating herpes simplex virus and varicella zoster virus infections using one or more macrocyclic lactone compounds, more specifically, one or more avermectin compounds or milbemycin compounds. BACKGROUND OF THE INVENTION [0002] Herpes simplex is a viral disease caused by herpes simplex virus 1 (HSV-1) and herpes simplex virus 2 (HSV-2). HSV1 primarily causes mouth, throat, face, eye, and central nervous system infections, while HSV2 primarily causes anogenital infections. However, each may cause infections in all areas of the body. Herpes simplex virus infection causes several distinct medical disorders. Common infection of the skin or mucosa may affect the face and mouth (orofacial herpes), genitalia (genital herpes), or hands (herpes whitlow). [0003] Herpes viruses cycle between periods of active disease, presenting as blisters containing infectious virus particle, lasts for 2-21 days, followed by a remission period, during which the sores disappear. Genital herpes, however, is often asymptomatic, though viral shedding may still occur. In all cases herpes simplex virus is never removed from the body by the immune system. Following a primary infection, the virus enters the nerves at the site of primary infection, migrates to the cell body of the neuron, and becomes latent in the ganglion, and resides as lifelong. Causes of recurrence are uncertain, though some potential triggers have been identified. Herpes simplex is most easily transmitted by direct contact with a lesion or the body fluid of an infected individual, and may also be transmitted through skin-to-skin contact during periods of asymptomatic shedding. [0004] A cure for herpes simplex has not yet been developed. Once infected, the virus remains in the body for life. Vaccines are in clinical trials but have not demonstrated effectiveness. There is no method to eradicate herpes virus from the body, but antiviral medications can reduce viral shedding and can reduce the frequency, duration, and severity of symptomatic episodes. There are several oral antivirals that are effective for treating herpes simplex including acyclovir, valacyclovir, famciclovir, and penciclovir. Known side effects of antiviral medicines, such as Zovirax® or Famvir®, Valtrex ®, include headaches, nausea, vomiting, dizziness, abdominal pain, joint pain, confusion, depression, and cardiac irregularity. Alpha-interferon has shown synergism with other anti-HSV drugs such as caffeine, trifluorothymidine, dimethyl sulfoxide, and nonoxynol- 9 . [0005] Analgesics such as ibuprofen and acetaminophen have been used to reduce pain and fever. Topical anesthetic treatments such as prilocaine, lidocaine, benzocaine or tetracaine have also been used to relieve itching and pain. [0006] Topical antiviral agents have been used to treat herpes simplex, including acyclovir, idoxuridine in dimethyl sulfoxide, and penciclovir. It has been reported that idoxuridine reduced pain duration and decreased time to loss of crust in a study. In a study, application of penciclovir cream, both early and late in the course of HSV infection, decreased the duration of lesions, pain, and viral shedding (Hamuy R . et al, Eur J Dermatol. 1998 Jul-Aug, 8(5):310-9). [0007] Anti-inflammatory agents, often included in the topical formulations, have been used to control the inflammatory process of herpes simplex and herpes zoster. The anti-inflammatory agents include, for example, hydrocortisone, hydrocortisone acetate and dexamethasone sodium phosphate. [0008] Varicella zoster virus is also known as chickenpox virus, varicella virus, zoster virus, and human herpes virus type 3 (HHV-3). Primary varicella zoster virus infection 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. It is reported that throughout the world the incidence rate of herpes zoster every year ranges from 1.2 to 3.4 cases per 1,000 healthy individuals, increasing to 3.9-1 1.8 per year per 1,000 individuals among those older than 65 years. [0009] Herpes zoster or shingles is a viral disease. Years or decades after the initial chickenpox infection, the virus may break out of nerve cell bodies and travel down nerve axons to cause viral infection of the skin in the region of the nerve. The virus may spread from one or more ganglia along nerves of an affected segment and infect the corresponding dermatome (an area of skin supplied by one spinal nerve) causing a painful rash. The earliest symptoms of herpes zoster, including headache, fever, and malaise, are nonspecific. These symptoms are commonly followed by sensations of burning pain, itching, hyperesthesia (oversensitivity), or paresthesia (tingling, pricking, or numbness). The pain may be mild to extreme in the affected dermatome, with sensations that are often described as stinging, tingling, aching, numbing or throbbing, and can be interspersed with quick stabs of agonizing pain. In most cases, after one to two days the initial phase is followed by the appearance of the characteristic skin rash. The pain and rash most commonly occurs on the torso, resulting in a stripe or belt-like pattern that is limited to one side of the body, but can appear on the face, eyes or other parts of the body. Later, the rash becomes vesicular, forming small blisters filled with a serous exudate, as the fever and general malaise continue. The painful vesicles eventually become cloudy or darkened as they fill with blood, crust over within seven to ten days, and usually the crusts fall off and the skin heals; but sometimes, after severe blistering, scarring and discolored skin remain. Although the rash usually heals within two to four weeks, some sufferers experience residual nerve pain for months or years, a condition called postherpetic neuralgia. Herpes zoster oticus is a common complication of shingles; it is a herpes zoster virus infection of the inner, middle, and external ear. Herpes zoster oticus manifests as severe otalgia and associated cutaneous vesicular eruption, usually of the external ear canal and pinna. When associated with facial paralysis, the infection is called Ramsay Hunt syndrome or Ramsay Hunt syndrome type II. [0010] It is until recent years, two vaccines for varicella zoster virus infection, Varivax ® for children and Zostavax ® for older adults, become available. Several oral antiviral drugs have been used to treat varicella zoster virus infection, these include acyclovir for the chicken pox, famciclovir and valaciclovir for the shingles.