WO1990014095A1

WO1990014095A1 - Topical treatment of herpesvirus hominis

Info

Publication number: WO1990014095A1
Application number: PCT/US1990/002943
Authority: WO
Inventors: Lawrence T. Maddren
Original assignee: Maddren Lawrence T
Priority date: 1989-05-26
Filing date: 1990-05-24
Publication date: 1990-11-29
Also published as: CA2056392A1; AU5670990A

Abstract

A method of retarding and reversing the effects of herpesvirus hominis comprises topically applying to human epithelia in an area affected by herpesvirus hominis, hyaluronic acid or its biocompatible salt form having a viscosity greater than about 0.4 Pascal seconds in an amount effective to retard and reverse the effects of herpesvirus hominis.

Description

TOPICAL TREATMENT OF HERPESVIRUS HOMINIS Field of the Invention

The present invention relates to methods of retarding or reversing the effects of herpesvirus hominis using high molecular weight hyaluronic acid or its biocompatible salt form.

Background of the Invention

Herpes or herpes simplex is a recurrent viral infection characterized by the appearance on the epithelium, specifically skin or mucous membrane, of simple or multiple clusters of small vesicles or lesions filled with a clear fluid on slightly raised inflammatory bases. The infective agent in humans is the relatively large herpes simplex virus (HSV) known as herpesvirus hominis. There are two HSV strains: HSV-1 or Type I herpesvirus hominis and HSV-2 or Type II herpesvirus hominis. HSV-l typically causes herpes labalis and keratitis, more commonly called fever blisters or cold sores. HSV-2 typically causes genital herpes.

After initial exposure to the virus and the onset of cutaneous lesions, the HSV remains latent in the skin or nerve ganglia. Recurrent eruptions may be precipitated by various forms of physical and/or emotional stress. After a short prodromal period of tingling discomfort or itching, small vesicles appear on an erythematous base. Single clusters may occur or coalesce to form painful vesicles. These vesicles persist for a few days then begin to dry, forming a thin, yellowish crust. Healing begins in seven to ten days after onset and is generally complete in twenty-one (21) days. Genital herpes is an infection which may be sexually transmitted and may be transmitted by women to an unborn child ^n utero.

There is presently no cure for herpesvirus hominis. Analgesics may be administered to alleviate irritation. However, analgesic administration generally does not help alleviate the outward symptoms of herpesvirus hominis and does not inhibit or prevent the onset of cutaneous lesions. Generally, "hyaluronic acid" (HA) designates an acidic polysaccharide having a molecular weight in a range of about 50,000 to about 8 million Daltons, depending on its source, method of preparation and method of measurement or method of determination. The molecular weight and concentration in solution of hyaluronic acid generally corresponds directly with its viscosity, with a higher molecular weight generally resulting in a higher viscosity.

Hyaluronic acid generally comprises eguimolar parts of d-glucouronic acid and N- acetyl-D-glucosamine and is a naturally occurring compound present on cellulose surfaces, in the basic extracellular substances of the connective tissues of vertebrates, in synovial fluid, in pathologic joints, in group A and C hemolytic streptococci, in Wharton's jelly, in the umbilical cord, in rooster combs, in shark cartilage and in pig snouts.

When dissolved in solution, hyaluronic acid forms random coils which interact with other polysaccharides and achieves an unusually large hydrodynamic volume. Such interaction helps account for its viscous nature in solution. For example, a 1% by weight aqueous solution of certain hyaluronic acids is about 500,000 times more viscous than water alone. At a 10% by weight aqueous solution, hyaluronic acid is so viscous that it may be formed into balls. Commercially available aqueous solutions generally have viscosities of about 0.2 Pascal seconds (Pas) to about 10S Pas (see W.E. Jones, "Viscosupplementation in the Joint" J. Eguine Vet. Sci. 9(2):102-04 (1989)).

Hyaluronic acid is an inhibitor of cell migration, a direct inhibitor of leukocytic activity, prevents the formation of excess fibrous tissue and is an anti-inflammatory agent in many uses. Previously known uses for hyaluronic acid are varied, ranging from its use to replace vitreous humor in opthalmic surgery, as an anti- inflammatory agent in veterinary medicine and as a vehicle in some cosmetic and pharmaceutical preparations.

Summary of the Invention According to the present invention, a method of retarding and reversing the effects of herpesvirus hominis comprises topically applying to human epithelia in an area affected by herpesvirus hominis, hyaluronic acid or its biocompatible salt form having a viscosity greater than about 0.4 Pascal seconds in amount effective to retard and reverse the effects of herpesvirus hominis.

Preferably, hyaluronic acid or its biocompatible salt form has a viscosity in solution of about 23 Pas to about 108 Pas and is present in aqueous solution in an amount of about 10 mg/ml.

Detailed Description of Preferred Embodiments According to the present invention, the effects of herpesvirus hominis may be retarded or reversed by topically applying to human epithelia affected by herpesvirus hominis hyaluronic acid or its biocompatible salt form. Hyaluronic acid or its biocompatible salt form should have a viscosity greater than about 0.4 Pas. It will be appreciated by one skilled in the art in view of this disclosure that viscosity greater than about 0.4 Pas helps facilitate inunction or topical application of hyaluronic acid or its biocompatible salt form according to the present invention.

According to one embodiment of the present invention, for example, hyaluronic acid or its biocompatible salt form has a molecular weight of about 3.8 million Daltons, and has a viscosity in an aqueous solution of about 108 Pas. At this relatively high viscosity, hyaluronic acid or its biocompatible salt may be applied topically without excessive runniness or dripping, thereby allowing the hyaluronic acid or its biocompatible salt to remain in contact with the application area for a period of time (typically about 5 to about 10 minutes) sufficient to provide therapeutic value in retarding and reversing the effects of herpesvirus hominis in accordance with the present invention. Hyaluronic acid or its biocompatible salt in solutions having viscosities less than about 0.4 Pas are generally not desired due to increased inconvenience in topical application.

It is believed that hyaluronic acid or its biocompatible salt form may be derived from any source using conventional processing techniques as long as the resulting hyaluronic acid has a viscosity greater than about 0.4 Pas.

The salt form of hyaluronic acid according to the present invention must be biocompatible, preferably to about the same degree as hyaluronic acid. Thus, the salt form of hyaluronic acid should not cause irritation or discomfort upon application, nor should the salt form of the hyaluronic acid have any other untoward effects whether or not related to the HSV infection. One example of a suitable biocompatible salt form of hyaluronic acid includes sodium salt, forming sodium hyaluronate. One skilled in the art, however, may readily determine, in view of the present specification and without undue experimentation, other biocompatible salt forms of hyaluronic acid which may be used in accordance with the present invention.

Hyaluronic acid or its biocompatible salt form is preferably applied in an aqueous solution. The concentration of hyaluronic acid in such solution must be high enough, given the particular molecular weight of the hyaluronic acid, so that the solution has a viscosity greater than about 0.4 Pas and preferably greater than about 23 Pas for relatively easy topical application. _# In one embodiment of the present invention, for example, hyaluronic acid having a molecular weight of about 500,000 Daltons is present in an aqueous solution in an amount of about 10 mg/ml and has a viscosity of about 0.4 Pas. In another, presently preferred embodiment of the present invention, an aqueous solution of hyaluronic acid or its biocompatible salt having a molecular weight of about 3.8 million Daltons has a concentration of about 10 mg/ l and a viscosity of about 108 Pas.

Where hyaluronic acid or its biocompatible salt is present in an aqueous solution, it may be desired to buffer the solution to a given pH for greater or more consistent biocompatibility. Generally, a pH of about 7.0 to about 7.4 is preferred for good biocompatibility in topical applications to affected epithelia. Such buffers should exhibit good biocompatibility and should not adversely effect the hyaluronic acid or its biocompatible salt form. Examples of suitable buffers include sodium phosphates, such as disodium hydrogen phosphate dihydrate and sodium dihydrogen phosphate hydrate. One skilled in the art will appreciate, however, that other biocompatible buffers may be used in accordance with the present invention.

Hyaluronic acid and its biocompatible salt forms suitable for treating herpesvirus hominis according to the present invention are commercially available from manufactures including Pharmacia AB in Sweden, MedChem Products, Inc., in Woburn, Massachusetts and Trans Bussan, S.A., Geneva, Switzerland. Pharmacia AB manufactures, for example, the Hylartin* V sodium hyaluronate injection compound for American Equine Products, Inc., South Norwalk Connecticut for intra-articular injection in horses. This particular sodium hyaluronate has a molecular weight of about 3.8 million Daltons in a buffered solution with a viscosity of about 108 Pas. This same sodium hyaluronate preparation is also available from Pharmacia AB as the product Healon* for use in opthalmic surgical procedures. This preparation is one example of a suitable biocompatible salt form of hyaluronic acid for use in accordance with the present invention.

Topical application of hyaluronic acid or its biocompatible salt form according to the present invention should be to human epithelia affected by the herpesvirus hominis, such as mucous and skin epithelia in the oral region (e.g., the lip) in the case of HSV-1 infections, for example, and to the mucous and skin epithelia in the genital region in the case of HSV-2 infections, for example. Such application should substantially totally cover the affected area. Those epithelia areas affected by HSV infection are generally readily ascertainable in the precutaneous stage by the infected patient as those areas having a tingling and/or tender sensation or, as in many HSV-2 infections, a tenderness in various muscle groups in the areas surrounding the infection, such as the muscles of the posterior thigh. In the cutaneous stage, affected areas are readily ascertainable as those areas of the epithelia containing HSV induced lesions.

Testing of several HSV-1 infected individuals in an uncontrolled experiment using the Hylartin* V sodium hyaluronate preparation has indicated that frequent and liberal topical applications in accordance with the present invention has several inhibitory effects on the immediate precutaneous and cutaneous stages of the HSV-1 infections. For example, during the completely manifested cutaneous stage of the HSV-1 infection, topical application according to this invention initiates an immediate (within 24 hours) reversal of the painful erythematic lesions. In addition, such application appears to reverse the course of the cutaneous form of the HSV-1 infection and quicken its return to a latent state. Further, topical application according to this invention appears to shorten the cutaneous phase of the infection and dramatically alleviate much of the associated pain and discomfort.

While not wishing to be bound by any particular theory, it is believed that topical application of hyaluronic acid or its biocompatible salt form is best initiated when the HSV infection is in the precutaneous form. While topical application of hyaluronic acid or its biocompatible form at this stage is recommended, topical application at later stages may also be conducted to alleviate discomfort and quicken the return to latency. Topical application to affected epithelia thrice daily is presently believed to be effective to retard and reduce the effects of herpesvirus hominis. Generally, application of hyaluronic acid or its biocompatible salt form should cover the affected area and ensured contact for at least about five to about ten minutes is presently believed to be satisfactory.

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than the specification, as indicating the scope of the invention.

Claims

1. A method of retarding and reversing the effects of herpesvirus hominis, which comprises topically applying to human epithelia in an area affected by herpesvirus hominis, hyaluronic acid or its biocompatible salt form having a viscosity greater than about 0.4 Pascal seconds in an amount effective to retard and reverse the effects of herpesvirus hominis.

2. The method according to claim 1, wherein the epithelia is mucous membrane.

3. The method according to claim 1, wherein the epithelia is lip tissue.

4. The method according to claim 1, wherein the epithelia is genital epithelia.

5. The method according to claim 1, wherein the herpesvirus hominis is Type I herpesvirus hominis.

6. The method according to claim 1, wherein the herpesvirus hominis is Type II herpesvirus hominis.

7. The method according to claim 1, wherein the viscosity of the hyaluronic acid or its biocompatible salt form is greater than about 23 - Pascal seconds.

8. The method according to claim 1, wherein the biocompatible salt form is sodium hyaluronate.

9. The method according to claim 1, wherein the hyaluronic acid or its biocompatible salt form is present in a buffered aqueous solution.

10. The method according to claim 9, wherein the hyaluronic acid or its biocompatible salt form is present in solution in an amount of about 10 mg/ml.

11. The method according to claim 9, wherein the aqueous solution is buffered with a sodium phosphate.

12. The method according to claim 11, wherein the sodium phosphate is selected from the group consisting of disodium hydrogen phosphate and sodium dihydrogen phosphate.

13. The method according to claim 1, wherein the hyaluronic acid or its biocompatible salt form is applied thrice daily in an amount sufficient to substantially totally cover the affected area.