WO1985000815A1

WO1985000815A1 - Anti-viral compositions

Info

Publication number: WO1985000815A1
Application number: PCT/US1984/001276
Authority: WO
Inventors: George Blanton
Original assignee: George Blanton
Priority date: 1983-08-12
Filing date: 1984-08-13
Publication date: 1985-02-28
Also published as: AU3220084A; EP0153371A1

Abstract

Pharmaceutical compositions suitable for the treatment of Herpes viral skin infections comprising the combination dimethylsulfoxide, Triamcinolone Acetonide and Vidarabine.

Description

ANTI-VIRAL COMPOSITIONS

The present invention relates to a composition suitable for use in the treatment of viral infections, in particular Herpes Simplex I and II skin infections.

RELATED APPLICATION

The present application is a continuationin-part application of copending application serial number 522,689 filed August 12, 19-83, now abandoned.

BACKGROUND OF THE INVENTION

Society is presently plagued with cutaneous viral manifestations for which no sufficient control or treatment has yet been developed. In particular, many cutaneous viral infections are caused by Herpes Simplex virus and, to date, there have been no cures or adequate treatments developed for viral infections, especially skin infections due to Herpes Simplex I and II.

The compounds Vidarabine (i.e., 9-beta-Earabinofuranosyl-9H-purine-6-amine monohydrate) is Known to have anti -viral activity , but attempts to utilize Vidarabine for the treatment of viral infections, including skin infections due to Herpes Simplex I and II, have been essentially unsuccessful. Vidarabine has been used for the topical treatment of Herpes Simplex virus of the eye, as well as for intravenuous treatment of Herpes encephalitis, but with very little success. It is poorly absorbed by the skin, and the crux of the problem is forcing the infected cells to absorb the medication.

Triamcinolone Acetonide (9-fluoro-11, 21dihydroxy-16-17-[1-methylethylidene bis (oxy)] pregna-1, 4-diene-3, 20-dione is usually in the form of a cream as a topical corticosteroid. It exhibits anti-inflammatory, anti-pruritic and vasocon- strictive actions, and is also indicated for dermatoses that are responsive to corticosteroids. It has been tried as an anti-viral agent, but with essentially no success.

Dimethylsulfoxide is a clear, colorless, liquid used by topical application for the treatment of acute inflammatory conditions involving the musculo-skeletal structures and skin. It is also used for the treatment of interstitial cystitis. It is rapidly absorbed by the skin and this results in a garlic like taste in the mouth. Dimethylsulfoxide has been combined with Zovirax, an anti-viral agent of formula 9-[(2-hydroxethoxy) methyl] quanine sodium for increased absorption, and has been suggested as a treatment agent by Krupp et al-, Current Medical Diagnosis (1982).

SUMMARY OF THE INVENTION

It has now been discovered, unexpectedly and surprisingly, that the formulation of Vidarabine, Triamcinolone Acetonide and dimethylsulfoxide affords a very effective anti-viral agent which is especially efficatious in the treatment of cutaneous viral infections, particularly, but not limited to, those arising from Herpes Simplex I and II. Dimethylsulfoxide is a strong solvent which drives the medication into the cells where it can attack the viral infection.

Thus, according to one aspect of the present invention, there is provided a pharmaceutical composition suitable for the treatment of viral infections in mammals comprising in combination a therapeutically effective amount of dimethylsulfoxide, Triamcinolone Acetonide and Vidarabine.

In the compositions of the present invention, the dimethylsulfoxide is preferably present in an amount of about 23 to 75 percent by weight, especially about 45 percent by weight, the Triamcinolone Acetonide is preferably present in an amount of about 23 to 75 percent by weight, especially about 50 percent by weight, and the Vidarabine is preferably present in an amount of about 2 to 10 percent by weight, especially about 5 percent by weight.

In another aspect of the present invention, there is provided a method of treating viral infections in a patient in need of such treatment, by administering to the patient a therapeutically effective amount of the pharmaceutical composition of the invention.

The oresent invention is further described and illustrated in the following specific, non-limiting examples.

EXAMPLE 1 The composition of the present invention was formulated into a cream utilizing the ingredients set forth in the following Table of Ingredients.

EXPLANATION OF TABLE: 10ml of 90% solution of di methylsulfoxide in water (10%). 20 g of 0.5% of Triamcinolone Acetonide cream. 3.5g of 3% Vidarabine. Quantities and percentages will vary according to the sensitivity of the area of the body being treated and the skin type and sensitivity.

Herein provided is a combination and blend of the above drugs into cream. This cream is used in the rranscuoaneous treatment of viral infections cf the skin, including Herpes Simplex I and II. Also herein provided is the application of this combination biend whicn is most effective and beneficial. Upon occurrence of symptoms, the cream is applied to the infected area four times per day, and up to 24 hours after the symptoms or rash has disappeared. The cream is reapplied for 48 hours when and if next symptoms appear. As indicated earlier, when dimethylsulfoxide is applied to the skin, it is rapidly absorbed and produces a garlic like taste. This has not been reported on application to the skin of the present composition, except when applied to the oral pharynx.

In a further preferred embodiment, the composition of the present comprises Vidarabine 60mg to 500mg in 1ml to 5ml, Dimethylsulfoxide 50% to 100% in 10ml to 50ml, and Triamcinolone Acetonide 0.1% to 0.5% in 10mg to 30mg.

EXAMPLE 2

The following is a description of a study carried out to evaluate the composition of the present invention.

The study consisted of twenty patients ranging in the age from three years to seventy years. Thirteen patients were diagnosed as having Herpes Type I, six as having Herpes Type II, and one patient as having Herpes Zoster. At the time of treatment all but one patient was in good general health. Two patients, both having Herpes Type II, had cultures and titers performed. One patient was immuno-depressed with a history of boreast carcinoma and active Hepatitis. A brief medical history and examination were performed on each patient. The locations of tne skin lesions, the time of their onset, and the date of their resolution were recorded. Patients were categorized according to tne type of Herpes they had contracted. Also they were categorized according to whether treatment was begun on the first day of the onset of the lesions. The lesions were examined daily in regard to the location of the lesions, and the area of involvement. A daily history was taken that included all side effects, any relief of the symptoms, and any comments made by the patients. The date and time that the symptoms abated and the lesions resolved were recorded. Viral cultures were performed on two patients with Herpes Type II. A culture was taken from the same area four days later. A serum Herpes titer was drawn at the same time. The cultures were negative on the fourth day and the titers had remained essentially the same.

Each patient was instructed to apply the cream of the present invention described in Example 1 directly to the lesions with a cotton tip applicator every four hours. They were to continue the treat ment for a period of forty-eight hours after the total resolution of the lesions. They were to report any side effects and any increases or decreases in symptoms during the time they had used the cream.

Eleven patients were treated at initial onset of symptoms. Nine patients were treated one to five days after onset of lesions. As indicated earlier, thirteen oi the patients treated were diagnosed as having Herpes Type I and six patients were diagnosed as having Herpes Type II. One patient had Herpes Zoster.

Tne average time for complete resolution was 2.4 days for the group of patients treated. on initial onset of lesions. The average time for complete resolution was 2.25 days for the group treated twenty-four hours or more after onset of lesions. No side effects were encountered. Relief from pain was immediate in all patients, including the patients with Herpes Zoster. The average time for resolution in the group with Herpes Type I lesions was 2.04 days. The average time for resolution in the group with Herpes Type II was 2.83 days. The lesions were resolved in five days on the patient with Herpes Zoster.

Every patient reported resolution of edema within one to three hours. None of the patients encountered a progression of lesions, nor have any of the patients reported a recurrence of lesions in a period ranging from 120 days to two years. Two patients are currently applying the cream twice a day, every other day, as a prophylaxis. The only unfavorable comment was in relation to the taste of the cream on an oral application. The cream was applied to the oral cavity, face, lips and vagina without urticaria or pain.

The time of resolution and healing for infections treated with the composition of the invention is one third the resolution time for Zovirax. Unlike Zovirax, the composition of the present invention has equal results independent of the clinical stage of the disease. Two tne patients included in tnis study were treaten unsuccessfully witn topical and oral Zovirax. Both patients responded to tne composition. When used as directed, the present composition will prevent recurrence of the disease ana can oe used as a prophylaxis against the disease.

The following further results have been obtained. A 30 year old female was treated successfully with the present composition for Herpes Types I and II. She was treated by topical and oral Zovirax without success. She developed lesions every ten to four teen days. The present composition was applied to her vagina, labia, mouth and tongue and palate. The lesions were healed in three days. She has not had a recurrence in 120 days. A 35 year old male was treated with the present composition for Herpex Type I of the lower lip. He developed several lesions every three months with exposure to the sun. The lesions disappeared in three days. Six months later he developed symptoms and applied the present composition for 48 hours. He has not had another lesion in three years.

Two patients are currently using the present composition as a prophylaxis by applying it twice a day to the areas previously involved.

In-vitro studies with the present composition have not been performed. However, Vidarabine exhibits anti-viral properties in-vivo and in-vitro. Vidarabine, Triamcinolone Acetonide and dlmethylsulfoxide are currently approved for medical use.

The preferred dosage regimen for the present composition is to apply to lesions with a cotton stick applicator every four nours until 48 hours after the lesions have disappeared. The composition is reapplied for 48 hours on initial onset of symptoms (stinging, tingling of the skin.

The present composition is a white cream and preferably contains one milligram of Vidarabine 200mg/ml, 10ml of dimethylsulfoxide 100 percent, and 20 grams of Triamcinalone Acetonide cream 0-5 per cent. It has also been used with 500mg Vidarabine and dimethylsulfoxide 90 percent in 10 percent water with the Triamcinalone cream. However, the present composition is most successful when compounded with 500mg Vidarabine, 20ml 90% dimethylsulfoxide and 20 grams Triamcinalone Acetonide 5% cream.

Generally, the present composition is formulated as a cream under ambient sterile conditions by thoroughly admixing the Vidarabine, dimethylsυlfoxide and Triamcinalone Acetoxide in the above proportions. The cream is thereafter placed in a tube, bottle or other suitable sealable container.

The present composition additionally exhibits strong anti-inflammatory and vasoconstrictive actions, and relief from pain also occurs upon application of the cream. Inflammation and swelling are relieved within one hour. In the treatment of Herpes Type I and II, lesions disappear within one to three days. No reoccurrence at the site of application have been reported. It has prevented the lesions from appearing when applied at the first sign of symptoms. It has equal success on initial and recurrent stages. It has equal success at any anatomical site except of tne eye. It may be used on mncosal surfaces of the moutn or tne vagina. No side effects nave oeen reported. It is not indicated for use in the eye.

Ine present composition is a convenient less costly agent for prescribing. Furthermore, the present composition has proved effective in the treat ment of Herpes Simplex, Types I and II, and of Herpes Zoster.

For the treatment of Herpes viruses, only a small amount of the present composition is required and is applied for only a short period of time. It has proven effective in patients who did not respond to Zovirax. No side effects or drug interactions have been experienced.

For administration to patients, the compositions of the present invention are usually applied topically as an ointment or cream, and suitable dosage rates for administration are in the range of 23 to 75 percent by weight of Triamcinolone Aceto nide, 23 to 75 percent by weight of dimethysulfoxide and 2 to 10 percent by weight of Vidarabine based on the total weight of the composition. Topical administration may be 1 to 4 times per day, provided of course that any dosage level utilized is not harmful to the surrounding skin areas. The preferred dosage rate is every 4 hours until 48 hours after the lesions have disappeared.

Claims

I CLAIM

1. A pharmaceutical composition suitable for the treatment of viral infections in mammalian cells, comprising in combination a therapeutically effective amount of dimethylsulfoxide, Triamcinolone Acetonide and Vidarabine.

2. A composition according to claim 1 wherein the dimethylsulfoxide is present in an amount of about 23 to 75 percent by weight, based on the total weight of the composition.

3. A composition according to claim 1, wherein the Triamcinalone Acetonide is present in an amount of about 23 to 75 percent by weight, based on the total weight of the composition.

4. A composition according to claim 1, wherein the Vidarabine is present in an amount of about 2 to 10 percent by weight, based on the total weight of the composition.

5. A composition according to claim 1, wherein the dimethylsulfoxide is present in an amount of about 45 percent by weight, the Triamcinolone Acetoniαe is present in an amount of about 50 percent by weignt, ana the Vidarabine is present in an amount of about 5 percent by weight, based on the total weight of tne composition.

6. A composition according to claim 1, in the form of a cream suitable for topical application to infected areas of the skin.

7. A method of treating viral infections in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a composition as claimed in claim 1.

8. A method according to claim 7, wherein said viral infection is the result of Herpes Simplex virus infection.

9. A method according to claim 8, wherein said infection is a Herpes Simplex skin infection, and the composition is applied in the form of a cream to infected areas of the skin.

10. A method according to claim 7, wherein said composition comprises about 23 to 75 percent by weight of dimethylsulfoxide, about 23 to 75 percent by weight of Triamcinolone Acetonide, and about 2 to 10 percent by weight of Vidarabine, based on the total weight of the composition.

11. A method according to claim 7, wherein said composition comprises about 45 percent by weight of dimethylsulfoxide, about 50 percent by weight of Triamcinolone Acetonide, and about 5 percent by weight of Vidarabine.