Combination Of Local And Systemic Therapies For Enhanced Treatment of Dermatologic Conditions

Abstract

A treatment for inflammatory dermatoses, such as psoriasis and atopic dermatitis (eczema), is disclosed that utilizes topical administration of a halogenated xanthene, such as rose bengal, together with administration of one or more complementary targeted systemic dermatology therapies, preferably a therapy that addresses the inflammatory pathway and is other than an NSAID that is a COX-1 and / or COX-2 inhibitor. Examples of complementary targeted systemic therapeutic ingredients include: corticosteroids, including betamethasone dipropionate and fluocinonide; dithranol; vitamin D analogs, including calcipotriol; and retinoids, non-biologics including methotrexate, ciclosporin, hydroxycarbamide, and fumarates including dimethyl fumarate; as well as one or more biologics, including antibodies or paratope-containing antibody portions to TNF-α, antibodies to pro-inflammatory cytokines interleukin-12, interleukin-23 and interleukin-17, and TNF inhibitors. Treatment of other epithelial tissue, such as the lining of the gut, is also disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATION[0001]This application is a continuation of copending U.S. application Ser. No. 16 / 204,832, filed on Nov. 29, 2018 which claims priority to U.S. provisional application Ser. No. 62 / 592,086, filed on Nov. 29, 2017, whose disclosures are incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention relates to the fields of dermatology and improved therapeutic regimens therefore.BACKGROUND OF THE INVENTION[0003]Pharmacologic approaches for treating hyperproliferative or inflammatory dermatologic conditions have traditionally relied on the use of various single agent systemic therapies, single agent topical therapies (monotherapies), or other locally administered modalities like light therapy, all in a rotation to avoid toxicity or intermittently to reduce inflammation and address symptoms which appear often sporadically. These diseases are chronic, lifelong and are difficult to manage.[0004]The underlying disease triggers are difficul...

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Benefits of technology

[0023]The present invention is the result of unanticipated and unpredicted synergy resulting upon combination of certain local therapeutic modalities, and in particular certain local immunomodulative therapies such as antimicrobial- or keratinocyte-directed treatment using a halogenated xanthene agent such as that referred to under the name PH-10, with an effective amount of one or more certain systemic therapeutic modalities. This combination can boost the therapeutic activity of both therapeutic modalities with the potential for no significant increase, or even an overall decrease, in morbidity relative to that typically achieved using the component therapies separately.

[0025]However, for usual usage, as well as for cases where disease is widely disseminated, severe, or presents in a form difficult to fully cover with a topical agent, use of a complementary therapeutic modality offers synergistic benefit, particularly when it contributes anti-inflammatory activity that complements the activity afforded through topical application of halogenated xanthenes. The use of such complementary therapies can have further advantage in terms of synergistic interactions that permit one or both therapies to be used at reduced doses or shorter in duration (relative to that needed when used individually as monotherapies), while retaining high efficacy, thereby reducing undesirable adverse effects.

[0026]In particular, the use of a potent topical therapy directed toward the autoimmune response-causing hyperproliferation of skin cells, such as topical application with, for example, PH-10 or another halogenated xanthene-containing composition, in conjunction with one or more systemic dermatology therapies (especially those that address one or more inflammatory pathway) is highly attractive because this combination yields a uniquely salubrious combination: exposure of the patient's skin disease to a halogenated xanthene's antimicrobial effects in addition to keratinocyte modulatory effects in the presence of systemic anti-inflammatory or biologic targeted to an anti-inflammatory pathway. The effects of such combination can be heightened before, at the time of administration of the halogenated xanthene or subsequent to topical administration.

[0028]The benefits of combining local skin therapy with a systemic anti-inflammatory therapy regimen can make otherwise undesirable systemic therapies viable. Thus, because of the resultant augmentation in potency of the systemic component of the combination therapy, reduced systemic dose regimens can be possible with commensurate reduction in adverse effects from the systemic therapy. Further, because the adverse effect profile of the local therapy (i.e., topical xanthene) is non-overlapping to that of most systemic therapies, a combined local and systemic dermatologic therapy is inherently safer and more attractive compared with prior combinations that can produce undesirable synergistic adverse effects.

Problems solved by technology

These diseases are chronic, lifelong and are difficult to manage.

The underlying disease triggers are difficult to predict and address and lead to a challenge for interventions prior to manifestation of widespread symptoms.

Topical steroids are the most common prescribed treatment for hyperproliferative skin disorders; however, extended use of topical corticosteroid creams may cause thinning of the skin, stretch marks and have systemic effects.

This treatment has the drawback of increasing aging of the skin and susceptibility to skin cancer as well as inconvenience for the patient to attend multiple light therapy sessions in the physician's office.

Newer biologic agents like adalimumab, guselkumab, efalizumab, etanercept, infliximab, abatacept, golimumab and ustekinumab are expensive and have different sets of side effects, notably latent tuberculosis reactivation, increase risk of infection, exacerbation of demyelinating conditions, liver toxicity and cardiovascular complications.

More skin conditions may not be completely responsive to such monotherapy, either due to systemic toxicity necessitating lower dosages or development of resistance that circumvents the activity of the monotherapy agent.

This is further complicated by the lack of clinical studies in children's AD as they are often prescribed medicines approved initially in adults whose underlying disease is potentially driven by other inflammatory markers.

2016 March-April; 29(2):120-125), and combinations are often used in psoriasis (Feldman et al., Am Health Drug Benefits 2016 Dec. 9(9):504-513); however, many of these combinations do not achieve a satisfactory response.

Regardless of the cause, once an aberrant immune-inflammatory response starts, it is difficult to stop with conventional therapies.

Additionally, intradermal injection of rose bengal in the presence of light led to polymorphonuclear leukocyte accumulation and histamine release with accompanying increased erythema in rabbit skin.

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