Compositions and in Situ Methods for Forming Films on Body Tissue

A composition is prepared by mixing the following components in the indicated proportions:

The composition of Example 1 is tested for pain reduction capability in comparison with the commercially available medication sold under the name "Orabase", a composition containing benzocaine in a sodium carboxymethyl cellulose and pectin base.

Twenty otherwise healthy human subjects who suffer from recurrent aphthous stomatitis are separated into test and control groups of ten members each.

Comparable test sites consisting of an aphthous ulcer and surrounding healthy mucosal tissue is selected in the mouths of each of the subjects. These sites are prepared by irrigating with distilled water and then carefully drying with cotton gauze pads.

The composition prepared according to this example is applied as a thin coating to the prepared aphthous ulcer sites in the mouths of the test group and a similar thin coating of the Orabase control medication is applied to aphthous ulcer sites in the mouths of the control group.

The patients of both the test group and the control group are required to breathe normally through the mouth for a period of two minutes, after which point it is noted that the composition of Example 1 has dried in the mouths of the test group patients to form a film over the aphthous ulcer site.

Observation of the test and control patients demonstrates that the films of the test composition are still present in place in 80% of the test subjects' mouths two hours after application, whereas the control medication completely disappears from the ulcer sites in all subjects in the control group.

The procedure of Example 2 is repeated except that, just prior to the preparation of the ulcer sites, the aphthous ulcers in the mouths of both the test and control patients are insulted by application of orange juice. The incidence of pain is clinically observed for a period of one hour, at which time the treated ulcer sites are once again insulted with orange juice. Pain observation is continued for an additional three hours.

In both the test and control groups, all patients experience a large increase in pain after the first insult, followed by a mild to significant decrease in pain after the immediate application of both the test and control compositions.

At a second insult, the patients in the test group which are treated with the composition of the present invention experience no increase in pain and continue to experience mils to substantial pain reduction for the succeeding three hours. However, the patients in the control group experience a large increase in pain at the second insult which decreases only slightly during the ensuing three hours.

The procedures of Examples 1-2 are repeated except that the compositions contain, respectively, 10% tannic acid, 10% salicylic acid and 7% boric acid. Both of these compositions yield comparable results to those set forth in Examples 2 and 3.

The boric acid cross-linking agent is omitted from the compositions of the preceding Examples. The in situ deposited films formed from these compositions actually comprise two layers which can be mechanically separated. Although these two-layer films are effective in pain treatment, they are less persistent.

Therapeutically effective quantities of various topical medicines are incorporated into the compositions of Example 1. The resulting mixtures are shelf-stable and are topically applied to body tissue and air-dried, forming resilient adherent films containing the medicaments, which migrate to the treatment site to effectively accomplish the desires treatment.

Anesthetics

Benzocaine

Dycloninc hydrochloride

Hexylcaine hydrochloride

Pramoxine hydrochloride

Butamben picrate

Tetracaine hydroiodide

Lidocaine hydrochloride

Dibucaine hydrochloride

Anti-Inflammatory Agents

Hydrocortisone

Hydrocortisone acetate

Betamethasone valerate

Triamcinolone acetonide

Fluocinonide

Dexamethasone

Methylprednisone acetate

Antibiotics

Clindamycin

Erythromycin

Meclocycline sulfosalicylate

Tetracycline

Cholohexidine

Neomycin

Polymixin B sulfate

Bacitracin

Sulfadizine

Antifungal Agents

Clotrimazole

Miconazole

Nystatin

Acyclovis

Interferon

Vidasabine

Betadine

Miscellaneous Topical Agents

Salicylic acid

Isotretinoin

Aloe Vera

Alclomethazone dipropionate

Caprylic acid

Lindane

P.A.B.A.

Interferon

Aluminum Chorhydrate

The method for measuring percutaneous absorption of topical medications, described by McKenzie & Stoughton in Arch. Dermatol 1962; 86: 608-610 and, more recently in Arch. Dermatol 1985; 121: 63-67, was used to assess the clinical effectiveness of various topical medicaments incorporated into the film forming compositions of Example 1.

According to this method, the flexural aspect of a subject's forearms are cleansed and approximately 10 mg of the test material is applied to a clearly marked 8 cm.sup.2 area. Four formulations are evaluated on four different 8 cm.sup.2 areas on each arm, totaling eight formulations per subject. The formulations are applied at 4.00 p.m. and allowed to remain in place overnight. At 8.00 a.m. the test sites are gently washed with soap and water and read two hours after washing. The intensity of blanching is determined on a four-point scale. Twenty subjects were used to evaluate a panel of eight formulations, with a ventilated guard placed over the test sites and ten subjects were used to evaluate the formulations with no guard placed over the test sites. The formulations tested were:

Formulation of

EXAMPLE 1, plus:

1. 1% hydrocortisone

2. 0.5% hydrocortisone

3. 0.05% betamethasone dipropionate

4. 0.1% triamainolone acetonide

Commercial Cream Formulations

5. Aristocort 0.1%

6. Kenalog 0.1%

7. Hytone 1.0%

8. Hytone 0.5%

The 4-point scale utilized is:

No blanching=0

Mild blanching=1

Moderate blanching=2

Intense blanching=3

The subject's test scores for each formulation were summarized to give a total score for that formulation.

A comparison of the scores for each formulation showed that, in all cases the formulations 1, 2, 3 and 4 provided essentially the same skin penetration of the active medicament, with and without the guard. Further, in the case of formulations 5 and 6 the total scores were less than half in subjects without guards than those with guards. In the case of formulations 7 and 8 the total scores with and without guards were approximately equal, but also approximately equal for formulations 1 and 2 with no guard.

These results demonstrated that the in situ films containing the active ingredients (Examples 1-4) were persistent and resisted displacement by abrasion, rubbing, etc., overnight and that the active medicaments therein were effectively transferred to the underlying tissue.

The ability of the film forming compositions of Example 1 to carry and effectively release antibiotics was demonstrated by incorporating 1% neomycin therein. This formulation was compared to a commercial 1% neomycin cream by applying the formulations to hairless mouse skins (10 replications) and agar plates (4 replications) inoculated with staph. aureus. The radius of inhibitions (mm) of each replicate were summed to give a total score for each formulation. The results were:

The following compositions are preferred for use in the oral cavity as topical anesthetics.

When tested as in Example 7, a composition containing hydrocortisone acetate is as effective as those of Example 7 containing hydrocortisone.

The composition consists of:

This composition exhibits satisfactory shelf stability, i.e., one month at room temperature.