WO1998017264A1

WO1998017264A1 - Composition and method for topical treatment of active herpesviral infections

Info

Publication number: WO1998017264A1
Application number: PCT/US1997/019186
Authority: WO
Inventors: Frank L. Greenway
Original assignee: Nextech Enterprises International
Current assignee: Nextech Enterprises International
Priority date: 1996-10-24
Filing date: 1997-10-23
Publication date: 1998-04-30
Anticipated expiration: 1999-04-24
Also published as: AU4915997A

Abstract

It has been discovered that geranium oil, preferably geranium oil bourbon, can treat active herpesviral infections. In labialis and genitalis lesions, the geranium oil treatment can decrease the time of healing, decrease the frequency of recurrent lesions, and can prevent lesion formation when prodromal symptoms are noted. In Bell's palsy, the geranium oil decreased the extent of the unilateral facial paralysis, allowing the eye to close.

Description

COMPOSITION AND METHOD FOR TOPICAL TREATMENT OF ACTIVE HERPESVIRAL INFECTIONS

TECHNICAL FIELD

This invention pertains to the treatment of active heipesviral infections through the topical administration of the compositions described and claimed herein.

BACKGROUND ART

The herpesvirus family is one of four viral families in which the virus contains double- stranded DNA. Examples of herpesviruses include herpes simplex, herpes zoster, the Epstein-Barr virus, and cytomeglovirus. Many herpes viruses are neurotropic; i.e., the virus remains latent in the neurons of sensory ganglia and periodically emerges to cause active skin or nerve infections.

Infection from a herpes simplex virus is generally incurable. Herpes simplex virus Type 1 ("HSV-1 ") causes open lesions to develop generally on or around the mouth, labialis lesions, commonly called cold sores or fever blisters. Herpes simplex virus Type 2 ("HSV-2") causes lesions to develop generally on or around the anogenital region, genitalis lesions. HSV-1 is also thought to cause Bell's palsy, an infection of the motor nerve to the face, the facial nerve. Bell's palsy results in a loss of motor function on one side of the face (unilateral paralysis). The most devastating symptom is the inability to close the eye. The eye often suffers from corneal drying, which can result in ulceration and threaten vision. A related syndrome is Ramsey-Hunt syndrome, which is thought to be caused by herpes zoster virus.

Current treatments for active herpes simplex labialis or genitalis lesions are limited to oral administration of a systemic dose of acyclovir or topical application of acyclovir or allantoin. Oral administration of acyclovir (or famciclovir) is unsatisfactory for many patients because the lesions

SUBSTrrUTE SHEET (RULE 26) still frequently recur and then persist for several days. Topical application of 5% acyclovir is also unsatisfactory for many patients. In HSV-1 lesions, acyclovir improves average healing time by only one day, from six to five days. No effect on recurrence of lesions is reported. See Van Vloten et ah , "Topical Acyclovir Therapy in Patients with Recurrent Orofacial Herpes Simplex Infections," Journal of Antimicrobial Chemotherapy, Vol. 12, Supplement B, pp. 89-93 (1983). In HSV-2 lesions, 5% acyclovir decreases average healing time to eight days from ten days. No change is seen in frequency of recurrence. See Corey et al. , "Double-blind Controlled Trial of Topical Acyclovir in Genital Herpes Simplex Virus Infections," American Journal of Medicine, Vol. 73(1 A), pp. 326-34 (1982). A topical treatment for HSV-1 using an allantoin lip balm has been reported to decrease the frequency of recurrence and to speed the healing of labialis lesions, but the healing time is still several days. See Physician's Desk Reference, p. 779 (1996).

The current recommended treatment for Bell's palsy is oral administration of both acyclovir and the corticosteroid prednisone. These drugs are reported to decrease the extent of the infection and to moderate the nerve damage. Neither directly affects the paralysis of the eye muscles. The current recommended treatment to protect the eye is to wear dark glasses or an eye patch, and to keep the eye moist with drops or ointment. See Rakel, ed., Conn's Current Therapy: Latest Approved Methods of Treatment for the Practicing Physician, pp. 906-07 (1996).

Geranium oil has been used in perfumes and as a food additive since the 1800's. It is on the GRAS (Generally Regarded As Safe) list of the United States Food and Drug Administration. Geranium oil is extracted from plants of the family Geraniaceae, frequently by steam distillation of fresh plants. A variety of species of geranium plants exist throughout the world, with most having approximately the same chemical constituents in the extracted oil. "Geranium oil bourbon," however, derived from Pelargonium graveolens Ait. from Reunion Island off the east African coast, has a unique composition, including a higher level of the semi-volatile alcohol citronellol than geranium oils derived from other species and varieties. U.S. Pat. No. 5,260,342, U.S. Pat. No. 5, 126,376, U.S. Pat. No. 5,086,076, and U.S. Pat. No. 4,983,637 describe a method of treating viral infections with terpenes that have been oxidized with ozone to produce "ozonides of terpenes. " Examples include oxidation products of limonene, citronellol, alpha-carotene, beta-carotene, vitamin A, linalool, linalyl acetate, squalene, and geraniol. U.S. Pat. No. 5,260,313 describes a method to treat neuropathic pain resulting from postherpetic neuralgia with topical application of geranium oil bourbon; i.e., treating the pain that remains after an infection from a reactivation of a latent Herpes zoster viral infection (chicken pox).

U.S. Pat. No. 4,923,685 describes antimicrobial, flavored compositions for use as mouthwashes, and includes geranium oil in a list of possible aromatic, flavoring oils. U.S. Pat. No. 4,832,947 describes a process to incorporate essential oils, such as geranium oil, into hair fibers of freshly permanent waved hair to remove bad odors and to change the consistency of the hair.

Polyphenols isolated from Geranium macrorrhizum L. and G. sanguineum L. have been reported to inhibit the in vitro growth of certain bacteria and fungi. See Ivancheva et al., "Polyphenols from Bulgarian Medicinal Plants with Anti-infectious Activity," in Polyphenols:

Synthesis, Properties, Significance, pp. 717-28 (R.W. Hemingway & P.E. Laks eds., 1992). A polyphenolic complex isolated from G. sanguineum L. in combination with rimantadine has been reported to protect mice from infection of influenza virus. See Gegova et al. , "Combined Effect of Selected Antiviral Substances of Natural and Synthetic Origin. II. Anti-influenza Activity of a Combination of a Polyphenolic Complex Isolated from Geranium sanguineum L. and rimantadine in vivo," Acta Microbiologica Bulgarica, Vol. 30, pp. 37-40 (1993).

It has not previously been suggested that geranium oil might be used as a topical treatment for active heipesviral infections.

DISCLOSURE OF INVENTION

SUBSTΠTJTE SHEET (RULE 26) It has been discovered that geranium oil, preferably geranium oil bourbon, can treat active herpesviral infections. In labialis and genitalis lesions, the novel geranium oil treatment can decrease the time of healing, decrease the frequency of recurrent lesions, and can prevent lesion formation when prodromal symptoms are noted. In Bell's palsy, geranium oil can decrease the extent of unilateral facial paralysis, allowing the eye to close.

Commercially-available, pure geranium oil bourbon has been applied topically to active herpes lesions or to areas beginning to itch, signalling the beginning of an active herpes infection (prodromal symptoms). Topical application of geranium oil bourbon to the lesions of herpes labialis or herpes genitalis accelerated healing by several days, decreased the frequency of recurrent lesions, and prevented lesion formation when prodromal symptoms were felt. These results were seen even with lesions resistant to high dose acyclovir. Topical application of geranium oil bourbon to the facial nerve of patients afflicted with Bell's palsy decreased the unilateral paralysis typical of the disease, especially paralysis of the eye muscles. Geranium oil bourbon has also been diluted with a cream or lip balm and applied to labialis lesions. At a concentration of 80% geranium oil bourbon, the lip balm was as effective as the undiluted oil. At a concentration of 9% , the cream was less effective on labialis lesions than undiluted oil, but still more effective than no treatment. Geranium oil bourbon may also be diluted with creams or balms containing compounds that are currently used to treat labialis lesions, e.g., acyclovir or allantoin.

Geranium oil bourbon has several advantages over prior methods for treating herpes simplex lesions. The novel treatment can decrease healing times to as little as one day, substantially decrease frequency of recurrences, and can even prevent lesions if applied to an area with prodromal symptoms. For Bell's palsy, no effective topical treatment currently exists. Topical application of geranium oil decreases the extent of the paralysis in Bell's palsy, especially of the eye muscles.

In the specification and claims, a concentration or amount of geranium oil or citronellol is considered to be "therapeutically effective" if it accelerates lesion healing, decreases the frequency of recurrent lesions, prevents lesion formation when prodromal symptoms are noted, or decreases the extent of the paralysis due to Bell's palsy.

METHODS FOR CARRYING OUT THE INVENTION Treatment of HSV-2

A 35-year-old female with culture-verified HSV-2 in her genital and anal areas was the subject for a single-patient trial. The patient had a seven-year history of frequently recurring lesions.

During the three-month period prior to initiating treatment with geranium oil and for three months following the initiation of that therapy, the patient kept daily records regarding her antiviral drug dosage and her symptoms.

During the three months prior to treatment with topical geranium oil bourbon, the patient was on a continuous treatment of acyclovir. The acyclovir was taken orally at a dose between 600 mg and 2,000 mg per day, with an average dose of 964 mg per day. Even while taking the acyclovir, the patient experienced symptomatic HSV-2 infection thirty-nine of ninety-four days. Of those thirty- nine days, twenty-eight days included symptoms of open sores, and the remaining eleven days included the burning, itching, and stinging typical of the beginning and end of each outbreak.

On the first day of treatment with geranium oil bourbon, the patient had a 4 cm-long ulcer between her labia minora and labia majora. Geranium oil bourbon, 0.025 cc, was applied to this lesion topically, and the ulcer healed within one day. The patient experienced pain relief almost immediately after the geranium oil bourbon was applied. The patient then stopped taking acyclovir entirely and had no symptoms for forty-eight days.

On the forty-eighth day following geranium oil bourbon treatment, the patient began to experience the prodromal symptoms of an outbreak, including a burning, stinging, and itching sensation in her genital area. She again applied 0.025 cc of geranium oil topically to the area of discomfort. The discomfort went away almost immediately, and the patient had no actual breakout of ulcers. Had the patient not used the geranium oil, she would have predictably (based on her past experience) have suffered a breakout with ulcers requiring about ten days to heal. Thirty-one days after the second treatment, while the patient was on a Christmas holiday, she developed symptoms of genital itching, stinging, and burning. Open lesions appeared two days later.

After two days of lesions in her rectal and vaginal areas, topical geranium oil bourbon was applied and the vaginal lesions resolved in less than one day. She was not able to reach her rectal area well and the anal lesions took three days to heal after initiating the topical treatment.

The patient had thirty-nine days out of ninety-four with symptoms of genital herpes before the geranium oil bourbon treatment but only ten days out of ninety-four after geranium oil bourbon treatment, in spite of being unable to treat one outbreak until after a two-day delay, and in spite of stopping acyclovir treatment at the start of geranium oil bourbon therapy. Geranium oil bourbon is an effective topical treatment for HSV-2 infections. It decreases healing time by several days, decreases the frequency of recurrence, and prevents open lesions from developing when applied to an area with prodromal symptoms.

Treatment of HSV-1

In view of the above success in treating a patient with severe HSV-2 (genital) infection with geranium oil bourbon, a patient with intractable HSV-1 (labialis) infection was also treated with topical geranium oil bourbon.

A 45-year-old female with frequently recurring fever blisters on the vermilion border of the lip was the subject of this single patient trial. The fever blisters were typical of a HSV-1 infection, comprising of a grouped vesicular eruption on an erythematous base. In the month prior to geranium oil treatment, the patient had four episodes of fever blisters on the lip, each lasting six days, for a total of twenty-four out of thirty days with an active lip lesion.

After this thirty-day period, the patient began the geranium oil treatment. She applied one drop of geranium oil bourbon on the first day of the onset of a fever blister on her lip. The sore healed in one day, and she experienced no recurrence in fifteen days of follow-up. Thus, out of seventeen days, she experienced only two days with an active lip lesion.

Geranium oil bourbon is effective in treating active infections of HSV-1. It decreases the healing time to as little as one day and decreases the frequency of recurrence. Treatment of Bell 's Palsy

Two patients with Bell's palsy used geranium oil bourbon to help alleviate paralysis on the affected side of the face, especially the inability to close the eye. The first patient had suffered from Bell's palsy for two weeks and was unable to close her eye on the affected side. Geranium oil bourbon was topically applied to the entire distribution of the facial nerve on the paralyzed side of her face. After three minutes she was able to close her eye on the affected side albeit with some effort.

A second patient developed Bell's palsy, became unable to close the eye on the affected side, and had to wear an eye patch, which made driving an automobile difficult. Geranium oil bourbon was topically applied over the facial nerve on the affected side from the stylomastoid foramen over the distribution of the facial nerve. The patient became able to close his eye and could remove the eye patch. By reapplying the geranium oil every eight to twelve hours, he sustained the ability to close his eye. After several days and several comments about the strong smell of the geranium oil, he stopped applying the geranium oil and the inability to close his eye returned. He resumed the topical application of geranium oil and his ability to close his eye returned.

In both patients, the Bell's palsy resolved after several weeks, and facial nerve function returned, which is typical for the majority of individuals who develop this disease.

Geranium oil bourbon proved effective in decreasing the facial paralysis, especially paralysis of the eye muscles.

Treatment of HSV-1 with Various Concentrations of Geranium Oil

To deliver geranium oil in a more cosmetically acceptable form, a chapstick with 80% geranium oil bourbon in a stearic acid carrier was formulated. A patient who had frequent cold sores that previously took an average of ten days to heal tested the chapstick. This patient had also tried the full strength geranium oil for her fever blisters. Full strength geranium oil bourbon decreased the healing time to an average of three days, with a range of one to five days, from an average of ten days. The 80% geranium oil bourbon in chapstick form gave a similar time for healing, an average of three days. The patient felt the chapstick was a superior delivery system for two reasons. First the chapstick kept the geranium oil in direct contact with the fever blister longer. Full strength geranium oil ran quickly off the lips. Second, the geranium oil in the chapstick was less fragrant than the pure geranium oil, which has a strong odor.

Treatment with a Geranium Oil Mixture

As another means to decrease the odor of geranium oil and to make a more attractive product, geranium oil was mixed with a cream to apply to cold sores. Triad cream is a cream base containing pyruvate and two fat soluble ingredients that may have some healing properties. A cream was prepared of 9% geranium oil bourbon in triad base. (Higher concentrations resulted in separation of the geranium oil from this particular base, and destruction of the cream properties of the carrier.) This geranium oil cream was tried by a patient with frequent cold sores that typically took an average of ten days to heal. This patient had previously used the full strength geranium oil, which reduced healing time to an average of three days. Using the 9% geranium oil cream, the healing time was six to seven days. Although the cream was less fragrant than the full strength geranium oil, it was less effective in decreasing the time to heal. The 9% geranium oil in triad base reduced healing time (from ten days to six or seven days), but was less effective than the full strength geranium oil.

Miscellaneous Although the preferred geranium oil for practicing this invention is commercially available geranium oil bourbon, other geranium oils are expected to work. Geranium oils, especially oils derived from the genus Pelargonium, are comprised chiefly of two alcohols, geraniol and citronellol. The quantities and ratios of these two alcohols vary with variety and place of origin. Oil of geranium Reunion (geranium oil bourbon), the most commercially-available oil, has a high citronellol content, 44 to 52% . See Guenther, "VI. Essential Oils of the Plant Family Geraniaceae, " in The

Essential Oils, Vol. IV, 1950. Without wishing to be bound by this theory, it is believed that citronellol is the active ingredient effective against active heipesviral infections. Because it has been discovered that diluted geranium oil bourbon is therapeutically effective, other geranium oils of lower citronellol content are also expected to be effective. While not limiting the scope of the invention, examples of other geranium oils which may prove especially effective include geranium oil Madagascar (less than 45% citronellol), geranium oil Algerian (26 to 40% citronellol), geranium oil Moroccan (45 % citronellol), geranium oil French (37 to 40% citronellol), geranium oil Spanish (32.9% citronellol), geranium oil Italian (26 to 40% citronellol), geranium oil Egyptian (50% citronellol), geranium oil Congo (34- 48% citronellol), and geranium oil Russian (64% citronellol). Geranium oil or citronellol may be more effective when combined with other ingredients of known anti-herpesviral properties. While not limiting the scope of the invention, examples of other anti-herpesviral compounds which may prove especially effective in combination with either geranium oil or citronellol include acyclovir and allantoin.

The complete disclosures of all references cited in this specification are hereby incorporated by reference. In the event of an otherwise irreconcilable conflict, however, the present specification shall control.

Claims

What is claimed: 1. A method for treating an active herpesviral infection in a human, comprising applying a therapeutically effective amount of geranium oil to the infection.

2. The method of claim 1, wherein the herpesvirus is herpes simplex virus.

3. The method of claim 1 , wherein the herpesvirus is herpes simplex virus Type 1.

4. The method of claim 1, wherein the herpesvirus is herpes simplex virus Type 2.

5. The method of claim 1, wherein the herpesvirus is herpes zoster virus.

6. The method of claim 1 , wherein the herpesvirus is cytomegalovirus.

7. The method of claim 1 , wherein the herpesvirus is Epstein-Barr virus.

8. The method of claim 1 , wherein the the active herpesviral infection results in Bell's palsy.

9. The method of claim 1, wherein the the active heipesviral infection results in Ramsey-Hunt syndrome.

10. The method of claim 1, wherein the geranium oil is applied topically.

11. The method of claim 1, wherein the geranium oil comprises geranium oil bourbon.

12. The method of claim 1 , wherein the geranium oil is in combination with a pharmaceutically acceptable carrier.

13. The method of claim 12, wherein the concentration of geranium oil is greater than about nine percent.

14. The method of claim 12, wherein the concentration of geranium oil is greater than about fifty percent.

15. The method of claim 12, wherein the concentration of geranium oil is greater than about eighty percent.

16. A method for treating an active herpesviral infection in a human, comprising applying a therapeutically effective amount of a combination of geranium oil and a second compound having anti-herpesviral properties.

17. The method of claim 16, wherein the herpesvirus is herpes simplex virus.

18. The method of claim 16, wherein the herpesvirus is herpes simplex virus Type 1.

19. The method of claim 16, wherein the herpesvirus is herpes simplex virus Type 2.

20. The method of claim 16, wherein the herpesvirus is herpes zoster virus.

21. The method of claim 16, wherein the herpesvirus is cytomegalovirus.

22. The method of claim 16, wherein the herpesvirus is Epstein-Barr virus.

23. The method of claim 16, wherein the the active herpesviral infection results in Bell's palsy.

24. The method of claim 16, wherein the the active herpesviral infection results in Ramsey-Hunt syndrome.

25. The method of claim 16, wherein the combination is applied topically.

26. The method of claim 16, wherein the geranium oil comprises geranium oil bourbon.

27. The method of claim 16, wherein the compound is acyclovir.

28. The method of claim 16, wherein the compound is allantoin.

29. A method for treating an active herpesviral infection in a human, comprising applying a therapeutically effective amount of citronellol to the infection.

30. The method of claim 29, wherein the herpesvirus is herpes simplex virus.

31. The method of claim 29, wherein the herpesvirus is herpes simplex virus Type 1.

32. The method of claim 29, wherein the herpesvirus is herpes simplex virus Type 2.

33. The method of claim 29, wherein the herpesvirus is herpes zoster virus.

SUBSTrrUTE SHEET (RULE 26)

34. The method of claim 29, wherein the herpesvirus is cytomegalovirus.

35. The method of claim 29, wherein the herpesvirus is Epstein-Barr virus.

36. The method of claim 29, wherein the the active herpesviral infection results in Bell's palsy.

37. The method of claim 29, wherein the the active herpesviral infection results in Ramsey-Hunt syndrome.

38. The method of claim 29, wherein the citronellol is applied topically.

39. The method of claim 29, wherein the citronellol is in combination with a pharmaceutically acceptable carrier.

40. A method for treating an active herpesviral infection in a human, comprising applying a therapeutically effective amount of a combination of citronellol and a second compound having anti- herpesviral properties.

41. The method of claim 40, wherein the herpesvirus is herpes simplex virus.

42. The method of claim 40, wherein the herpesvirus is herpes simplex virus Type 1.

43. The method of claim 40, wherein the herpesvirus is herpes simplex virus Type 2.

44. The method of claim 40, wherein the herpesvirus is herpes zoster virus.

45. The method of claim 40, wherein the herpesvirus is cytomegalovirus.

46. The method of claim 40, wherein the herpesvirus is Epstein-Barr virus.

47. The method of claim 40, wherein the the active herpesviral infection results in Bell's palsy.

48. The method of claim 40, wherein the the active herpesviral infection results in Ramsey-Hunt syndrome.

49. The method of claim 40, wherein the combination is applied topically.

50. The method of claim 40, wherein the compound is acyclovir.

51. The method of claim 40, wherein the compound is allantoin.

52. A composition of matter comprising a therapeutically effective amount of geranium oil and a second compound having topical anti-herpesviral properties.

53. The composition of claim 52, wherein the compound is acyclovir.

54. The composition of claim 52, wherein the compound is allantoin.

55. A composition of matter comprising a therapeutically effective amount of citronellol and a second compound having topical anti-herpes viral properties.

56. The composition of claim 55, wherein the compound is acyclovir.

57. The composition of claim 55, wherein the compound is allantoin.