Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-11-19
2002-06-04
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S859000
Reexamination Certificate
active
06399652
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for treating acne vulgaris, particularly with topical treatment using avermectin compound.
BACKGROUND OF THE INVENTION
Acne vulgaris, known as acne by the general public, is a common and multifaceted skin disorder of the hair follicles and sebaceous glands. Although it affects almost 100% of adolescents to varying degrees and generally wanes as adolescence ends, the disease may persist into adulthood. Adult women, in particular, may be affected and may experience premenstrual flares. However, severe acne vulgaris tends to be more common in adolescent males than in people of other age-groups.
At least four factors contribute to the development of acne: follicular plugging, increased sebum production by the sebaceous glands, colonization of the sebaceous follicles with Propionibacterium acnes, and inflammation. Propionibacterium acnes is the most common gram-positive, non-spore forming bacteria, a common resident of the pilosebaceous glands of the human skin. It is the causative agent of acne vulgaris.
Follicular plugging occurs when desquamating cells lining the follicular lumen stick together, rather than flowing to the surface with sebum. This occurs because of abnormal keratinization, components of which are increased cell division and increased cohesiveness of cells lining the follicular lumen. These cells mix with sebum, plug the opening of the hair follicle, and form a closed comedo (commonly called whitehead). If this mixture protrudes from the follicular opening, it turns a dark color (blackheads).
During adolescence, when sebum production increases, the sebaceous follicles become colonized with Propionibacterium acnes. This anaerobic diphtheroid hydrolyzes sebum into free fatty acids, which serve as the primary proinflammatory substances of acne vulgaris. Propionibacterium acnes also secrete chemotactic factors that attract neutrophils. Lysosomal enzyme released from the neutrophils rupture the follicle wall releasing proinflammatory mediators including keratin and lipids into the surrounding dermis. The resulting inflammation forms erythematous papules or pustules, nodules, cysts, or abscesses. If the inflammation is severe, as in cystic acne, the skin may eventually scar.
Therefore, the key features of the pathogenesis of acne vulgaris can be characterized as 1) increased sebum production, 2) hyperkeratinization of the neck of the follicles, 3) bacterial proliferation, and 4) inflammation.
Acne vulgaris can be classified into three categories: comedonal, inflammatory, and nodulocystic. Within each category, acne vulgaris can be further divided into mild, moderate, or severe, based on the number of lesions and the amount of skin involved.
Comedonal acne consists predominantly of open or dosed comedones with generally few, if any, inflammatory lesions. Comedonal acne generally responds to existing topical keratolytic agents, which decrease the adhesiveness of follicular cells. Inflammatory acne consists of comedonal lesions plus inflammatory lesions, such as erythematous papules and pustules. It generally requires treatment with both topical agents and systemic antibiotics. By comparison, nodulocystic acne comprises extensive comedonal lesions and inflammatory papules and pustules, plus nodules and cysts or abscesses. Existing topical agents are not effective for initial treatment of these lesions.
Effective management of acne vulgaris can be accomplished by addressing the four key features of the pathogenesis. Topical therapy is usually the first choice for patients with mild-to-moderate inflammatory acne. The use of topical therapy minimizes potential side effects associated with the use of systemic agents. Topical therapies include benzoyl peroxide, which is the most commonly used non-prescription acne medication. It is an important antibacterial oxidizing agent that can decrease the number of Propionibacterium acnes and frequently the amount of free fatty acids. Benzoyl peroxide is the first line monotherapy for mild acne vulgaris and it is available in over-the-counter preparations. Benzoyl peroxide is applied once or twice daily and patients often experience mild redness and scaling of the skin during the first week of usage.
Tretinoin is the most effective topical comedolytic agent currently, decreasing the cohesiveness of follicular epithelial cells, and thereby inhibiting the formation of microcomedones and increasing cell turnover resulting in expulsion of existing comedones. This agent also decreases the thickness of the stratum corneum and potentiates the penetration of topical antibiotic agents. Tretinoin therapy comprises once daily application. Mild redness and peeling are a part of the therapeutic effect of the medication but can result in reduced patient compliance. The improvement may take as long as 6 to 12 weeks, and flare-ups of acne vulgaris can occur during the first few weeks of therapy.
Mild inflammatory acne vulgaris lesions can also be treated with topical antibiotics including erythromycin ointment, clindamycin solution, and meclocylcine cream. The primary action of the antibiotics is to reduce the population of Propionibacterium acnes in the sebaceous follicle and thereby suppress the free fatty acid production. The effectiveness of topical antibiotics in the treatment of acne is limited by their low lipid solubility and subsequent difficulty in penetrating sebum-filled follicles. Topical antibiotics are applied twice daily.
Patients with moderate to severe inflammatory acne often require oral antibiotics in addition to topical therapy. The most commonly prescribed agents include tetracycline, erythromycin, minocycline, and doxycycline. Treatment is usually maintained for several months. Side effects include the overgrowth of nonsusceptible organisms, including Candida, which can produce vaginal and oral yeast infections.
Patients with severe inflammatory acne vulgaris unresponsive to other therapy may require treatment with oral isotretinoin. Isotretinoin is a compound related to vitamin A, and is the only agent that decreases sebum production and reverses the abnormal epithelial formation process. This agent can also decrease number of Propionibacternum acnes in the sebaceous follicle. Duration of therapy is usually 20 weeks, and the satisfactory response rate is quite high. However, treatment is often accompanied by many side effects, including dry skin, pruritus, epistaxis, and photosensitivity, as well as hypertriglyceridemia, abnormal liver function tests, electrolyte imbalances, and elevated platelet counts. Most serious though, is the teratogeric effect of isotretinoin. Use of isotretinoin during pregnancy is absolutely contraindicated. So serious is the potential for death or teratogenic effects to a fetus, isotretinoin is practically contraindicated in women of child-bearing age. Use of isotretinoin must be accompanied by a guarantee by the patient that conception will be avoided at any and all costs.
Because acne vulgaris is a multifactorial disease which is manifest to varying degrees, it is important for the physician to assess the patient to attempt to find therapies which will be helpful to the patient without causing major side effects. All of the current conventional treatments are associated with some degree of adverse side effects that limit their usefulness. Consequently, there is a need for a drug that can effectively treat acne vulgaris without side effects.
The preferred compound that is used to illustrate the present invention is ivermectin. Ivermectin is a semi-synthetic derivative of avermectin and is generally produced as a mixture of at least 80% 22,23-dihydroavermectin B
1a
and less than 20% 22,23-dihydroavermectin B
1b
. The following molecular structure represents the avermectin series of compounds, which can be chemically converted to useful derivatives as discussed below.
wherein R is the 4′-(alpha-L-oleandrosyl)-alpha-L-oleandrose group of the structure:
wherein the broken line indicates a single or double bond; R
1
is hydroxy and is
Jarvis William R. A.
Kim Vickie
Li Yi
Silverman M. K.
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