Medical composition and uses thereof

Details Medical composition and uses thereof Medical composition and uses thereof

1999-06-16

2003-05-13

Jarvis, William R. A. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S055000, C424S059000

Reexamination Certificate

active

06562802

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to a medical composition and use thereof for the manufacture of a topical barrier formulation, an UV-radiation absorbing formulation, or an antiviral, antifungal, or antiinflammatory formulation.
Since the first epidemiological data on allergic contact dermatitis reported in the thirties, nickel has been the most frequent allergen in women. The primary site for sensitization has changed, from suspenders to metal buttons in jeans to pierced ear lobes. Sensitization may also occur from occupational contact with objects like electrical assembly, cuff links, locksmith tools, dental equipment, scissors, knitting equipment, chemical reagents etc.
In the following, the focus is on the severe condition of hand eczema, but obviously, eczema on other sites like the stomach caused by nickel containing jeans buttons or on ear lobes caused by contact with earrings is a big problem.
The sources of primary sensitization resulting in hand eczema are either occupational or environmental. Occupations include platers, metal workers, cashiers, hairdressers or office workers. Environmental primary sensitization include housewives, environment and hobbies with nickel exposure. In patients already sensitized to nickel, the risk of acquiring hand eczema is far greater, especially when the skin is damaged. In many cases a multifactorial situation, including nickel exposure, exposure to irritants, atopic constitution and other factors plays a role. Investigations in the USA, Finland and Denmark have shown that the number of nickel sensitive women in the general population approximates 10% (1,2,3).
However, a higher frequency of nickel allergy (15-18%) is found in the age groups where hand eczema commonly develops (4). When hand dermatitis develops in the nickel sensitized subjects, the condition becomes a definite threat to the individual's working ability. In a study from Denmark it was shown that nickel hand eczema is the most common skin disease which leads to permanent disability (5). This results in huge costs for the social welfare system and in personal suffering for the patients. In another Danish study (6) based on a questionnaire sent to a stratified sample (2500) of the female population, it was concluded that 43% of the nickel sensitive subjects reported hand eczema. The study also demonstrated that women who were nickel sensitive ran an increased risk of developing hand eczema compared to non-nickel-sensitive women. Also, those who already had a hand eczema were more likely to develop nickel allergy. As pointed out earlier, the risk of developing nickel allergy increases when the skin is injured as is the case in e.g. irritant contact dermatitis caused by exposure to irritants like detergents in working or home environment. A study investigating the bioavailability of nickel from consumer products was made (7) and the provocation threshold in nickel sensitive patients varied from 0.47 &mgr;g to 5.2 mg.
The current method for treating nickel dermatitis is basically to treat the acute eczema with corticosteroid creams and advise the patients to avoid nickel containing objects, which is obviously a difficult task. Another method that has been used experimentally is to administer nickel chelating agents like disulfiram (8). Although some improvement of the patients' eczema was achieved, side effects in the form of flare-up reactions and hepatotoxicity was noted. Triethylenetetramine has been used in the same manner, however without resulting in any significant improvement (9). In addition, reports of teratogenicity in rats by triethylenetetramine indicated a limited value of the method.
A recent review of the use of binding agents and barrier creams (10) showed that the most effective nickel chelating substance is 3% clioquinol applied topically in a cream in combination with 1% hydrocortisone. The method used was patch testing with cream-coated 20 pence coins in 26 nickel-sensitive subjects (11).
However, clioquinol toxicity has been found in dogs treated daily with 5 g of a 3% preparation for a month, and there may be a risk of toxicity in infants and children from its topical use. Also, clioquinol is a known contact allergen and is present in the European Standard Series for the detection of contact hypersensitivity. It is therefore considered unsuitable for the purpose of preventing nickel dermatitis. A certain effect, expressed as decreased patch test reactivity, was found for EDTA in combination with 1% hydrocortisone, where only 40% of the subjects showed reduced nickel patch test reactivity (11). The purpose of using an active barrier cream is to prevent nickel from coming into contact with the epidermis of the skin, and to avoid use of corticosteroid topical treatment on the inflammation of the skin. The negative effects of prolonged use of corticosteroids is well known.
In another study (12), where pretreatment of a cream containing 10% Na
2
H
2
EDTA was used, somewhat better results were achieved in reducing patch test reactivity (76%). The maximum challenge concentration in this study was however only 1% of nickel sulfate, compared to 5% which is normally used in patch testing. A patch test study (13) in 21 nickel sensitive individuals where nickel discs were applied on top of Carbopol barrier gels containing 10% CaNa
2
EDTA showed that the discs without pretreatment gave a positive reaction in 11 out of the 21 subjects. All of the subjects showed a positive reaction to 5% nickel sulfate. Since only 11 out of 21 subjects reacted to the discs, it seems that the release of nickel ions from the discs was insufficient for inducing a positive reaction. The 11 subjects positive to the challenge by the disc did not react when the disc was applied on top of the barrier gel. A blank gel without CaNa
2
EDTA also showed a reduction in sensitivity where 3 out of 11 showed a positive reaction on challenge to the disc and 7 patients showed a reduced reaction when treated with the vehicle.
From an experiment in vitro it was shown that the gels caused an increase in the release of nickel ions from the alloys. This is considered as an unwanted effect since it counteracts the barrier effect of the formulation.
Studies using tin complexes with EDTA, cyclohexane-1,2-diaminetetraacetic acid (CDTA) and diethylenetri-aminepentaacetic acid showed only poor results in chelating nickel, chromium and cobalt (14). The fact that none of the above mentioned creams have resulted in any commercially used product further underlines the need for developing an effective active nickel barrier cream.
Cobalt allergy is often associated with nickel allergy because the metals are often associated with each other. A positive test to cobalt occurs 20 times more frequently in those allergic to nickel than in those not allergic. The frequency of cobalt patch test positive patients is around 7%, and of-these around 50% are isolated reactions. However cobalt also occurs isolated in various products such as printing inks, paints, polyester resins, electroplating, wet alkaline clay in pottery, porcelain dyes, animal feeds.
Trivalent chromium penetrates the skin very poorly, binding to proteins on the surface of the skin, whereas hexavalent chromium penetrates the skin easily but binds poorly to proteins on the surface of the skin. It is thought that hexavalent chromium penetrates the epidermis and is then reduced by enzymes to the trivalent form which combines with proteins to form the allergenic compound.
The true frequency of patch test positive patients to chromate is probably in the range of 2-4%. The most common cause of chromate allergy is contact with cement. Other sources are from chrome-tanned leather, antirust paint, timber preservatives, matches with chromate in the match head, coolants and machine oil and many other sources.
Dermatitis from chromate sensitivity is normally quite severe and has a poor prognosis.
Allergic reactions on the skin and oral mucosa induced by gold, i.e. the Au
+
and Au
3+
ions, have also been encountered an

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