Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1997-11-10
2002-05-21
Levy, Neil S. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S400000, C424S401000, C514S357000, C514S862000
Reexamination Certificate
active
06391282
ABSTRACT:
FIELD OF THE INVENTION
Anti histamine compositions for relief of delayed contact dermatites,
BACKGROUND OF THE INVENTION
Allergies are divided into four types as discussed in Goodman & Gilman, “The Pharmacological Basis of Therapeutics” as follows:
Allergic responses have been divided into four general categories, based on the mechanism of immunological involvement (Coombs and Gell, in Gell, Coombs and Lachmann, eds.,
Clinical Aspects of Immunology
, Blackwell, Oxford, p 761, 1975).
Type I, or anaphylactic, reactions in human beings are mediated by IgE antibodies. The Fc portion of IgE can bind to receptors on mast cells and basophils. If the Fab portion of the antibody molecule then binds antigen, various mediators (histamine, leukotrienes, prostaglandins) are released and cause vasodilatation, edema, and an inflammatory response. The main targets of this type of reaction are the gastrointestinal tract (food allergies), the skin (urticaria and a topic dermatitis), the respiratory system (rhinitis and asthma), and the vasculature (anaphylactic shock). These responses tend to occur quickly after challenge with an antigen to which the individual has been sensitized and are termed immediate hypersensitivity reactions.
Type II, or cytolytic, reactions are mediated by both IgG and IgM antibodies and usually are attributed to their ability to activate the complement system. The major target tissues for cytolytic reactions are the cells in the circulatory system. Examples of type II allergic responses include penicillin-induced hemolytic anemia, methyldopa-induced autoimmune hemolytic anemia, quinidine-induced thrombocytopenic purpura, sulfonamide-induced granulocytopenia, and hydralazine- or procainamide-induced systemic lupus erythematosus. Fortunately, these autoimmune reactions to drugs usually subside within several months after removal of the offending agent.
Type III, or Arthus, reactions are mediated predominantly by IgG; the mechanism involves the generation of antigen-antibody complexes that subsequently fix complement. The complexes are deposited in the vascular endothelium, where a destructive inflammatory response called serum sickness occurs. This phenomenon contrasts with the type II reaction, in which the inflammatory response is induced by antibodies directed against tissue antigens. The clinical symptoms of serum sickness include urticarial skin eruptions, arthralgia or arthritis, lymphadenopathy, and fever. These reactions usually last for 6 to 12 days and then subside after the offending agent is eliminated. Several drugs, such as sulfonamides, penicillins, certain anticonvulsants, and iodides, can induce serum sickness. Stevens-Johnson syndrome, such as that caused by sulfonamides, is a more severe form of immune vasculitis. Symptoms of this reaction include erythema multiform, arthritis, nephritis, CNS abnormalities, and myocarditis.
Type IV, or delayed-hypersensitivity, reactions are mediated by sensitized T lymphocytes and macrophages. When sensitized cells come in contact with antigen, an inflammatory reaction is generated by the production of lymphokines and the subsequent influx of neutrophils and macrophages. An example of type IV or delayed hypersensitivity is the contact dermatitis caused by poison ivy.
DISCUSSION OF THE PRIOR ART
Most treatments for the delayed allergic reaction, as opposed to palliative treatment for itching and drying of the secretions from the lesion, are hormonal or anti-inflammatory in nature. Examples are cortisone, chloroxine, coal tar, dexamethasone, neomycin, hydrocortisone, ketoconizole. High potency fluorinated corticosteroids if applied in the earlier stages of the rash where the skin is red but not yet blistered can be useful in limited areas to materially decrease the evolution of the dermatitis and prevent the apparent spread of the disease. The use of these preparations is limited because of their high potency and the real possibility of systemic effects especially if used on large areas where the skin is broken or ulcerative. Systemic corticosteroids and andrenocorticotropic hormone work well but must be given by injection. The use of these agents is usually limited to those cases that are in stage 5-7 (see below).
The reaction to delayed hypersensitivity such as poison ivy can be broken down into several stages. The following is the system used to grade the response:
Stage of
reaction
1
Erythema with itching
2
Erythema with edema and itching
3
Erythema with edema and beginning vesiculation involving
less than 25% of the site
4
Same as 3 but involving 25-50% of the site
5
Same as 3 but involving 50-75% of the site
6
Same as 3 but vesicles confluent in a circular pattern on the
site
7
Erythema, edema, vesiculation and evidence of ulcerative
breakdown
Only one preparation, Caladryl® for the treatment of poison ivy, poison oak and poison sumac containing an antihistamine, diphenhydramine hydrochloride, as one of its components has been marketed in the USA to date. This product is ineffective because of the weak antihistaminic effect in the treatment of these irritations except for some relief of itching and as a drying agent due to the presence of Calamine in the formulation. Several ointments are on the market in Europe, but they are not indicated for the treatment of poison ivy, poison oak or poison sumac as these plants are not found in Europe. From their formulations (usually contain 0.05% antihistamine), as found on their package inserts, they would be no more effective in the treatment of poison ivy, poison oak and poison sumac than Caladryl®. To have the desired effect one needs to deliver a very active antihistamine at a high concentration to a local area.
SUMMARY OF THE INVENTION
Contrary to the above teachings that the Type IV or delayed hypersensitivity is mediated by sensitized T lymphocytes and macrophages, that it has been found an antihistamine and in particular clemastine or chlorpheniramine can mediate the delayed dermatitis and in particular that caused by poison ivy and poison sumac or poison oak. Especially useful are antihistamines having a high degree of intrinsic activity as shown by their low oral dosage as antihistamine (0.1-10, suitably 1-2 mg), which can be topically administered at a sufficiently high active concentration to be effective in the treatment of delayed allergic reactions. Applied in this manner in the early stages of the irritation to the developing delayed reaction, these products have the property, in the correct formulation, of stopping the reaction to poison ivy, poison oak and poison sumac.
The early stage of the irritation is characterized by the beginning of itching, appearance of redness and of small red welts. After application of the preparation the itching stops and the redness recedes. The skin returns to its nearly normal condition within 12-36 hours.
Even if applied after major blisters appear, the reaction to the allergen stops—the blisters collapse and the itching stops. Some time is still required for the healing of the skin after the reaction to the allergen stops.
Poison ivy treatments to be effective must be a massive intervention because by the time the rash is apparent the allergic response because of the delayed reaction is well on the way to being a major problem. This massive intervention in our case is a very potent antihistamine as judged by the oral dose given in a large amount (0.5% ointment or 1-2 mg in a spray) to a local area.
The effective antihistamines, most suitably, clemastine or chlorpheniramine can be delivered to the site of the lesion either as an ointment to be massaged into the skin by hand, or as a spray also to be massaged into the skin by hand. If the fumarate or other salt is to be used, a pump spray and polar solvents would be preferred. If the free base should be used as the active ingredient, either a pump spray, or an aerosol spray using a propellant can be employed. After applying the spray, the resulting fine layer of liquid can be massaged into the skin by hand.
The only limit on the solvent to be used for the spray or ointment
Flemington Pharmaceutical Corp.
Levy Neil S.
Selitto Behr & Kim
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