Anti-Infective Methods and Compositions

The following ingredients were admixed to form homogenous gels containing from 0.5 to 5.0% by weight of antihistamine (all percentages given are w/w):

The following ingredients were admixed to form homogeneous creams containing from 0.5 to 5.0% by weight of antihistamine:

The following ingredients were admixed to form homogeneous lotions containing from 0.5 to 5.0% by weight of antihistamines:

An isotonic solution of sodium chloride in sterile preserved water was prepared containing 2% diphenhydramine hydrochloride by weight.

Gels, creams, lotions and solutions may be prepared in accordance with Examples 1-16, substituting in place of diphenhydramine hydrochloride the following antihistaminic agents:

0.5-5% dimenhydrinate hydrochloride

0.5-5% tripelennamine citrate

0.5-5% brompheniramine maleate

0.5-5% chlorpheniramine maleate

0.5-5% triprolidine hydrochloride

Suitable minor changes in the nature and quantities of the inactive ingredients comprising the gel, cream and lotion vehicles may be required in certain cases with the above substitute active ingredients. In general, the vehicles set forth in Examples 1-16 are suitable for most of the antibacterially active antihistaminic agents.

A sufficient quantity of a gel, cream or lotion according to Examples 1-15 to coat a skin area requiring anti-infective treatment is applied directly to the skin area and gently spread until a thin, uniform coating over the affected area is achieved. This treatment can be repeated from 1-5 times daily, as required.

30 ml. of an isotonic solution prepared according to Example 16 are placed in a squeezable spray bottle with a nebulizer tip. The solution is then sprayed directly onto an inflamed nasal passages by inserting the tip of the container into the nostrils and squeezing the container, or sprayed onto inflamed throat area by inserting the tip into the mouth, directed toward the throat, and squeezing the container. This treatment can be repeated from 1-5 times daily as required.

One or two drops of a sterile isotonic solution prepared according to Example 16 are administered directly into the eye with an eyedropper for treatment of conjunctivitis.

The following antihistamines in liquid solution were screened for in vitro antibacterial activity:

Ethanolamine Derivatives

(a) Diphenhydramine 2% aqueous solution

(b) Dimenhydrinate 2% aqueous solution

(c) Doxylamine 2% aqueous solution

Ethylenediamine Derivatives

(a) Pyrilamine 2% aqueous solution

(b) Tripelennamine 2% aqueous solution

Alkylamine Derivatives

(a) Brompheniramine 2% aqueous solution

(b) Chlorpheniramine 2% aqueous solution

(c) Triprolidine 2% aqueous solution

The 2% solutions listed above were diluted further with sterile water, using serial half-step dilutions. Forty lambda of each were then pipetted onto seeded Mueller-Hinton agar plates. The agar plates were then incubated for 24 hours at 35.degree. C. and zones of inhibition were then recorded. The Minimum Inhibitory Concentration (MIC) was the lowest concentration of the test material which produced a zone of inhibition against the organism. The MIC for each test material (antihistamine), using each organism, is listed in Table 1.

Stock cutaneous strains of each organism were grown in Mueller-Hinton broth for 18 hours at 35.degree. C. Plates were seeded with the 18 hour broth culture, allowed to air dry at room temperature (about 10 minutes) and then used for determination of zones of inhibition as outlined above.

A laboratory propagated strain of C. albicans, originally isolated from an infected skin lesion of a patient, was grown in Mueller-Hinton broth for 18 hours at 35.degree. C. Plates were then seeded with the broth culture and allowed to air-dry at room temperature (22.degree. C.) for about 10-15 minutes. Forty lambda of the 2% aqueous solutions or of serial half-step dilutions in water were then pipetted onto the seeded Mueller-Hinton agar plates. The plates were then incubated for 24 hours at 35.degree. C. and zones of inhibition were then recorded. The Minimum Inhibitory Concentration (MIC) was the lowest concentration of the test material which produced a zone of inhibition against the organism. The MIC for each test material (antihistamine) is listed in the enclosed table. Table 2 lists the MIC's against C. albicans while Table 3 lists the MIC's against in vitro-grown spores of the human pathogen T. mentagrophytes. This strain was isolated from a human infection and was grown on Sabourand-Dextrose agar for 2 weeks. The spores were collected by flooding the agar plates after the 2 week growth period with a 0.01% solution of Tween-80 (sorbitol ester) and then filtering the Tween solution through gauze mesh to collect the suspension of spores. Sabourand-Dextrose agar plates are then seeded with the spore suspension. After air-drying, 40 lambda of each test solution is pipetted onto the plates and the plates left to incubate for 4 days at 22.degree. C.

Test materials A & B (both gels) were prepared with the following ingredients:

As indicated, the only difference between the two test materials was that Material A contained about 60% ethyl alcohol by weight and Material B contained no alcohol but about 2% diphenhydramine by weight.

The floral expansion was carried out by translocating cutaneous microflora from the perineal region to the forearms of 10 subjects and then expanding them by covering the forearm sites occlusively under chambers for 24 hours. After that, materials A and B were applied in duplicate to designated test sites and the sites cultured at (i) 5 minutes and (ii) 10 minutes for quantitative bacteriology. A control (untreated site) was included at each time-point.

The findings are summarized in Table 4. There was a highly significant killing effect by both the alcohol gel (A) and the diphenhydramine gel (B) at both time-points. There were no apparent significant differences in bactericidal activity between A and B, however, either at 5 or at 10 minutes. On the average, both treatments (A and B) produced two to three orders of magnitude reduction in bacterial counts (e.g., from 10.sup.6 organisms per cm.sup.2 to 10.sup.3.5 organisms per cm.sup.2).

The method described above was repeated on 6 new subjects with test materials A and B, but quantitative bacterial values were taken after 24 hours on the treated or control sites to assay for bacteriostatic activity. Additional test materials C, D, E and F were also applied to the forearms of these subjects for comparative purposes. These materials comprised the following:

Material C The same ingredients as material A with the addition of 2% diphenhydramine in place of

2% purified water--i.e., this gel contained both 60% ethyl alcohol and 2% diphenhydramine.

Material D Bacitracin ointment U.S.P. (500 units per gram).

Material E 60% ethyl alcohol (liquid).

Material F Povidone iodine ointment U.S.P. 10%.

As a control, a material designated "base" containing the same ingredients as materials A, B and C but no alcohol or diphenhydramine was applied to the patient's forearms as well. In addition, an untreated site was cultured for control purposes.

The findings are summarized in Table 5. There was a highly significant bacteriostatic effect observed with both materials A and B, considerably superior to the effect achieved with bacitracin (material D) or ethyl alcohol (material E). But a substantially greater bacteriostatic effect was observed with material C, close to that of povidone iodine (material F), indicating a synergistic interaction between the antihistamine and alcohol components of material C.

It should be noted that the antimicrobial treatment methods of the present invention utilizing antihistamine-containing compositions are not limited to the treatment of conditions where both antihistaminic and antibacterial or antimycotic treatment are required. The compositions and methods of the invention are useful in treating any tissue areas where topical antibacterial or antimycotic agents would normally be applied for anti-infective purposes, whether or not pruritus, erythema or edema are present. In fact, as demonstrated by the in vivo data set forth above, the compositions utilized in the subject methods are better and more potent antibacterial agents than many drugs commonly used as the principal active ingredients in commercially available topical anti-infective products which have no antihistaminic components.

As further demonstrated by the clinical data, the methods of the invention provide not merely a short-term bactericidal effect to the treated tissue areas, but also a long-term bacteriostatic effect, thus inhibiting re-infection of the treated areas.

It has thus been shown that there are provided compositions and methods which achieve the various objects of the invention and which are well adapted to meet the conditions of practical use.

As various possible embodiments might be made of the above invention, and as various changes might be made in the embodiments set forth above, it is to be understood that all matters herein described are to be interpreted as illustrative and not in a limiting sense.