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

RELATED APPLICATION

The present application is a continuation- in-part application of copending application serial number 522,689 filed August 12, 19-33, now abandoned.

BACKGROUND OF THE INVENTION

Society is presently plagued with cutane¬ ous viral mani estations for which no sufficient con¬ trol or treatment has yet been developed. In particu¬ lar, 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.

TiiB compounds Vidarabine (i.e., 9-beta-Z- arabinofura_nσsyl-9H--pu ine--o-amine monoiiyαrat.e, is Know r_o nave .anr-i ^** -viral ac"civiτ_y, out, -&τ>τ,emτ>zs .: utilize Vidarabine for e treatment of viral infec¬ tions, including skin infections due to Herpes Sim- plex 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, 21— dihydroxy-l6-17-[l-methylethylidene bis (oxy)] preg- na-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 mus- culo-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-C (2-hydroxethoxy) methyl] quanine sodium for increased absorption, and has been suggested as a treatment agent by Krupp et al-, Current Medical Diagnosis (1922 .

SUMMARY OF THE INvΞHTIO::

IT. r-as now ueen αiscover-en., unexpecceάly ana surprisingly, τ_naτ_- τ_-ne lormulation of Vidarabine, Triamcinolone Acetonide and dimethylsulfoxide affords a very effective anti-viral agent which is especially efficatious in the treatment of cutaneous viral in¬ fections, particularly, but not limited to, those arising from Herpes Simplex I and II. Dimethylsulfox- ide is a strong solvent which drives the medication

O

1 into the cells where it can attack the viral infec¬ tion.

Thus, according to one aspect of the pre¬ sent invention, there is provided a pharmaceutical composition suitable for the treatment of viral in¬ fections in mammals comprising in combination a ther- apeutically effective amount of dimethylsulfoxide, Triamcinolone Acetonide and Vidarabine.

10

In the compositions of the present inven¬ tion, the dimethylsulfoxide is preferably present in an amount of about 23 to 75 percent by weight,

15 especially about 45 percent by weight, the Triamcin- - olone 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 prefer-

20 ably 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 tr-eating viral infec- 2 tions in a patient in need of such treatment, by ad¬ ministering to the patient a therapeutically effect¬ ive amount of the pharmaceutical composition c ,r.e . invention.

^0 The oresent invention is furtner descrioe- ^* . and illustrated in the following specific, non-Iir._- ^~ - ing exampleε.

EXAMPLE 1

35

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

- TABLE OF INGREDIENTS Ingredients Quantity

Dimethysulfoxide 90$ 10ml

Triamcinolone

Acetonide 0.5$ 20g

Vidarabine 3$ 3.5g

EXPLANATION OF TABLE: 10ml of 90$ solution of di methylsulfoxide in water (10 ). 20 g of 0.5$ of Tri- amcinolone 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 blenc ox τ_ne aoove drugs into cream. Ihis cream is used ir. τ_-ne rranscuoaneous treatment of viral infections cf the skin, including Herpes Simplex I and II. Alεc herein provided is zne -application of τ-his combina¬ tion biend whicn is mo-st effective and βeneficiaL. upon occurrence oi symptoms, ne cream is appiieα tc tne iniec -eα area four times per αay, and up to 2_ _* hours after the symptoms or rash has disappeared. The cream is reapplied for 4S hours when and if next symptoms appear. As indicated earlier, when dimethyl¬ sulfoxide is applied to the skin, it is rapidly ab- sorbed and produces a garlic like taste.This has not

-BTJRE

OMPI

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 6θmg to 500mg in 1ml to 5ml, Dimethylsulfoxide 50$ to 100$ in 10ml to 50ml, and Triamcinolone Acetonide 0.1$ to 0.5$ in lOmg to 30mg.

EXAMPLE 2

The following is a description of a study carried out to evaluate the composition of the pre- sent 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. Twc patients, both having Herpes Type II, had cultures and titers performed. One patient was immuno-depreεε- ed with a history of ioreast carcinoma and active Hep¬ atitis. A brief jmedical history and examination were performed on each pa isnt. The locations of tne skin lesions, the time of tneir onset, and tne date cf tneir resolution were recorded. Patients were cate- gorized acco.rding to tne type of Herpes they had con¬ tracted. 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

-βU EΛ^ OMPI " . "

- -

1 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

5 performed on two patients with Herpes Type II. A cul¬ ture 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.

10

Each patient was instructed to apply the cream of the present invention described in Example 1 directly to the lesions with a cotton tip applica¬ tor every four hours. They were to continue the treat

15 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.

20 Eleven patients were treated at initial on¬ set of symptoms. Nine patients were treated one to five days after onset of lesions. As indicated earli¬ er, thirteen oi the patients treated were diagnosed as having Herpes Type 1 and six patients were diag-

~ nosed 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 treateα. en

-5-~ initial onset of lesions. Tne average time for corr- plete 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

35 with Herpes Zoster.

1ϊΛ3 RE.A £ ^ ^fAPl

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.S3 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 en¬ countered a progression of lesions, nor have any of

10 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 un¬ favorable comment was in relation to the taste of the - ^■ -5 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 in¬

20 fections treated with the composition of the inven¬ tion is one third the resolution time for Zovirax. Unlike Zovirax, the composition of the present inven¬ tion has equal results independent of the clinical stage of the disease. Two tne patients included in tnis study were trea en unsuccessfully witn topical and oral Zovirax. Botn patients responded to tne compo.siti.on. Wnen used as directed, tne present, composition will prevent recurrence of tne disease ana can oe used as a prophylaxis against the disease.

The following further results have been ob¬ tained. 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 with¬

35 out 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 le¬ sions 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 pre¬ sent composition as a prophylaxis by applying it twice a day to the areas previously involved.

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

The preferred dosage regimen for the pre¬ sent composition is to apply to lesions with a cotton stick applicator every four nours until A-S nours af¬ ter the lesions have disappeared. The composition iε reapplied for 4δ nours on initial onset of symptoms (.stinging, tingling of tne s_cir_..

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 compo¬ sition is most successful when compounded with 500mg Vidarabine, 20ml 90$ dimethylsulfoxide and 20 grams Triamcinalone Acetonide 5$ cream.

Generally, the present composition is form¬ ulated as a cream under ambient sterile conditions by thoroughly admixing the Vidarabine, dimethylsυl- foxide and Triamcinalone Acetoxide in the above pro- portions. The cream is thereafter placed in a tube, bottle or other suitable sealable container.

The present composition additionally exhi¬ bits strong anti-inflammatory and vasoconstrictive actions, and relief from pain also occurs upon appli¬ cation 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 ana omical site except of tne eye. It may be used on mncosal surfaces of the moutn or tne vagina. k,o side effects nave oeen re¬ ported. It is not indicated for use in tne eye.

Ine present composition i≤ a convenien . less costly agent ϊor prescribing. Furtnermore, tnε 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 compo¬ sitions 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 admini¬ stration may be 1 to 4 times per day, provided of course that any dosage level utilized is not harmful

-i-

^'" to the surrounding skin areas. The preferred dosage "rate is every 4 hours until 48 hours after the lesions have disappeared.