Photodynamic therapy for skin disorders

Abstract

To provide methods for treating facial acne.SOLUTION: A method comprises: (i) administering heat to an affected area of the subject' s skin using a thermal delivery device to achieve a temperature of between about 38 and about 42°C for a suitable time; (ii) incubating a pharmaceutical composition comprising at least one photosensitizing agent for an incubation period of less than about 14 hours to provide an incubated pharmaceutical composition; (iii) administering a therapeutically effective dose of the incubated pharmaceutical composition to the affected area for a suitable time period; and (iii) administering a suitable dose of red light to the affected area, thereby treating the facial acne.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 62 / 533,558, filed July 17, 2017, and U.S. Provisional Patent Application No. 62 / 534,973, filed July 20, 2017, the contents of which are incorporated herein by reference in their entireties.

[0002] The present invention generally relates to methods of treating skin diseases and disorders using red light photodynamic therapy in conjunction with heat. In certain embodiments, the present invention relates to methods of treating acne, non-melanoma skin cancer (NMSC), actinic keratosis (AK), or disseminated superficial actinic porokeratosis (DSAP) using red light photodynamic therapy on heat-treated skin. [Background technology]

[0003] Skin diseases are among the most common human illnesses, affecting 30%-70% of the population, with even higher rates in at-risk subpopulations (Hay RJ et al., J Invest Dermatol. 2014. 134(6):1527-1534). The healthcare burden is similarly significant, with direct medical costs estimated at nearly $27 billion and lost productivity estimated at an additional $11 billion (Lim HW et al. J Am Acad Dermatol. 2017;76:958-972).

[0004] Acne is the most common skin disease. Noninflammatory acne is the most common type and is characterized by milia and blackheads. Inflammatory acne is usually associated with bacterial (P. acnes) infection and is characterized by papules, pustules, nodules, and cysts. The most common trigger for both types of acne is hormonal, and many people experience at least mild forms of acne during adolescence. Other triggers may include diet, stress, and certain medications. Acne can negatively impact quality of life because it often affects appearance at a critical age. (Kligman AM. J Invest Dermatol. 1974;62:268-87).

[0005] Various methods for treating acne are known, including topical medications such as benzoyl peroxide, retinoids, and antibiotics. (Thiboutot D, et al. J Am Acad Dermatol. 2009;60(Suppl 5):S1-50) Systemic medications, such as antibiotics, retinoids, and hormone therapy, can also be used. However, many of these approaches have undesirable side effects and / or fail to produce acceptable results. Antibiotic resistance is on the rise, with many countries reporting that more than 50% of P. acnes strains are resistant to certain topical medications.

[0006] Ultraviolet (UV) / blue light has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of mild to moderate acne due to its anti-inflammatory effects mediated by skin cells. A method combining photosensitizing agents with high-intensity red light has proven effective but is associated with significant side effects. (Hongcharu W, et al., J Invest Dermatol. 2000 Aug;115(2):183-92), Sakamoto FH et al., J Am Acad Dermatol. 2010 Aug;63(2):183-93); (Sakamoto FH et al. J Am Acad Dermatol. 2010 Aug;63(2):195-211). As a result, this approach has been reserved for the most severe cases of acne. [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Hay RJ et al., J Invest Dermatol.2014.134(6):1527-1534 [Non-patent document 2] Lim HW et al. J Am Acad Dermatol.2017;76:958-972 [Non-patent document 3] Kligman AM..J Invest Dermatol.1974;62:268-87 [Non-patent document 4] Thiboutot D, et al.J Am Acad Dermatol.2009;60(Suppl 5):S1-50 [Non-Patent Document 5] Hongcharu W, et al.,.J Invest Dermatol.2000 Aug;115(2):183-92 [Non-patent document 6] Sakamoto FH et al.,J Am Acad Dermatol.2010 Aug;63(2):183-93 [Non-Patent Document 7] Sakamoto FH et al.J Am Acad Dermatol.2010 Aug;63(2):195-211 Summary of the Invention [Problem to be solved by the invention]

[0008] There remains a need for new approaches to the treatment of skin diseases and disorders, including but not limited to acne, that provide improved results and reduce side effects. [Means for solving the problem]

[0009] The present invention provides a method for treating skin diseases or disorders using red light photodynamic therapy on pre-heated skin.

[0010] In a first aspect of embodiment, the present invention is a method of treating facial acne in a subject in need thereof, comprising: (i) applying heat to a lesion area of ​​the subject's skin using a heat delivery device to achieve a skin temperature of about 38°C to about 42°C for a suitable period of time; (ii) incubating a pharmaceutical composition comprising a photoactive agent for a period of less than about 14 hours to provide an incubated pharmaceutical composition; (iii) applying a therapeutically effective amount of the incubated pharmaceutical composition to the lesion area; and (iv) administering an appropriate dose of red light to the lesion area, thereby therapeutically treating the facial acne.

[0011] In one embodiment, the acne is mild acne, moderate acne or severe acne.

[0012] In another embodiment, the acne is comedonal, papulopustular, or nodulocystic.

[0013] In one embodiment, the heat delivery device is a heat mask. In a particular embodiment, the heat delivery device is an acetate mask that heats when crystallized.

[0014] In one embodiment, the lesion area is heated for about 60 minutes. In a specific embodiment, the lesion area is heated to about 40°C.

[0015] In certain embodiments, the incubation period is less than about 14 hours, yet achieves the same effect as if the pharmaceutical composition had been incubated for about 14 hours in the absence of step (i).

[0016] In certain embodiments, the incubation period is less than about 3 hours, yet achieves the same effect as if the pharmaceutical composition had been incubated for about 3 hours in the absence of step (i).

[0017] In certain embodiments, the incubation period is less than about 1 hour, yet achieves the same effect as if the pharmaceutical composition had been incubated for about 1 hour in the absence of step (i).

[0018] In exemplary embodiments, the incubation period is less than about 10 minutes, less than about 5 minutes, or less than about 1 minute.

[0019] In one embodiment, the pharmaceutical composition is a nanoemulsion comprising 10% 5-aminolevulinic acid HCl.

[0020] In another embodiment, the light has a wavelength of about 620 nm to about 640 nm, more specifically, about 630 nm.

[0021] In one embodiment, a suitable dose of light is about 37 J / cm 2 is.

[0022] In exemplary embodiments, treatment results in a reduction in the number of acne lesions in the subject. In certain embodiments, this reduction is sustained for at least three months.

[0023] In exemplary embodiments, treatment results in a reduction in the severity of the subject's acne lesions. In certain embodiments, this reduction persists for at least three months.

[0024] In an exemplary embodiment, the side effects of the treatment are reduced compared to a method that does not include step (i).

[0025] In a second aspect, the present invention is a method of treating facial non-melanoma skin cancer in a subject in need thereof, comprising: (i) applying heat to a lesioned area of ​​the subject's skin using a heat delivery device to achieve a skin temperature of about 38°C to about 42°C for a suitable period of time; (ii) incubating a pharmaceutical composition comprising a photoactive agent for a period of less than about 14 hours to provide an incubated pharmaceutical composition; (iii) applying a therapeutically effective amount of the incubated pharmaceutical composition to the lesioned area; and (iv) administering an appropriate dose of red light to the lesioned area, thereby therapeutically treating the facial non-melanoma skin cancer.

[0026] In certain embodiments, the non-melanoma skin cancer is basal cell carcinoma (BCC). BCC can be primary, recurrent, or previously incompletely excised.

[0027] In another specific embodiment, the non-melanoma skin cancer is squamous cell carcinoma (SCC). The SCC can be primary, recurrent, or previously incompletely resected.

[0028] In one embodiment, the non-melanoma skin cancer is basal cell carcinoma and the heat is applied in (i) for about 30 minutes.

[0029] In another embodiment, the non-melanoma skin cancer is basal cell carcinoma and the heat is applied in (i) for about 20 minutes.

[0030] In an exemplary embodiment, the side effects of the treatment are reduced compared to a method that does not include step (i).

[0031] In certain embodiments, the incubation period is less than about 14 hours, yet achieves the same effect as if the pharmaceutical composition had been incubated for about 14 hours in the absence of step (i).

[0032] In certain embodiments, the incubation period is less than about 3 hours, yet achieves the same effect as if the pharmaceutical composition had been incubated for about 3 hours in the absence of step (i).

[0033] In certain embodiments, the incubation period is less than about 1 hour, yet achieves the same effect as if the pharmaceutical composition had been incubated for about 1 hour in the absence of step (i).

[0034] In exemplary embodiments, the incubation period is less than about 10 minutes, less than about 5 minutes, or less than about 1 minute.

[0035] In a third aspect, the present invention is a method for treating facial actinic keratosis (AK) in a subject in need thereof, comprising: (i) applying heat to a lesioned area of ​​the subject's skin using a heat delivery device to achieve a skin temperature of about 38°C to about 42°C for a suitable period of time; (ii) incubating a pharmaceutical composition comprising a photoactive agent for a period of less than about 14 hours to provide an incubated pharmaceutical composition; (iii) applying a therapeutically effective amount of the incubated pharmaceutical composition to the lesioned area; and (iv) administering an appropriate dose of red light to the lesioned area, therapeutically treating the actinic keratosis.

[0036] In one embodiment, the lesion area is heated for about 30 minutes. In a specific embodiment, the lesion area is heated to about 40°C.

[0037] In an exemplary embodiment, the side effects of the treatment are reduced compared to a method that does not include step (i).

[0038] In certain embodiments, the incubation period is less than about 14 hours, yet achieves the same effect as if the pharmaceutical composition had been incubated for about 14 hours in the absence of step (i).

[0039] In certain embodiments, the incubation period is less than about 3 hours, yet achieves the same effect as if the pharmaceutical composition had been incubated for about 3 hours in the absence of step (i).

[0040] In certain embodiments, the incubation period is less than about 1 hour, yet achieves the same effect as if the pharmaceutical composition had been incubated for about 1 hour in the absence of step (i).

[0041] In exemplary embodiments, the incubation period is less than about 10 minutes, less than about 5 minutes, or less than about 1 minute.

[0042] In a fourth aspect, the present invention is a method of treating disseminated superficial actinic porokeratosis (DSAP) of the face in a subject in need thereof, comprising: (i) applying heat to a lesioned area of ​​the subject's skin using a heat delivery device to achieve a skin temperature of about 38°C to about 42°C for a suitable period of time; (ii) incubating a pharmaceutical composition comprising a photoactive agent for a period of less than about 14 hours to provide an incubated pharmaceutical composition; (iii) applying a therapeutically effective amount of the incubated pharmaceutical composition to the lesioned area; and (iii) administering an appropriate dose of red light to the lesioned area, therapeutically treating the DSAP.

[0043] In an exemplary embodiment, the side effects of the treatment are reduced compared to a method that does not include step (i).

[0044] In certain embodiments, the incubation period is less than about 14 hours, yet achieves the same effect as if the pharmaceutical composition had been incubated for about 14 hours in the absence of step (i).

[0045] In certain embodiments, the incubation period is less than about 3 hours, yet achieves the same effect as if the pharmaceutical composition had been incubated for about 3 hours in the absence of step (i).

[0046] In certain embodiments, the incubation period is less than about 1 hour, yet achieves the same effect as if the pharmaceutical composition had been incubated for about 1 hour in the absence of step (i).

[0047] In exemplary embodiments, the incubation period is less than about 10 minutes, less than about 5 minutes, or less than about 1 minute. [Brief explanation of the drawings]

[0048] [Figure 1] Figure 1 shows the results of treating inflammatory and cystic acne using the method of the present invention described in Example 1. As shown in the figure, subjects remained clear for 3 months (Figure 1B) and at least 6 months. [Figure 2] FIG. 2 shows the results of treating inflammatory and cystic acne using the method of the present invention described in Example 1 at different time intervals and using a porphyrin camera (FIG. 2B). [Figure 3] Figure 3 shows the results of treating a nodular basal cell carcinoma on an extremity according to the method of the present invention described in Example 2. Using a porphyrin camera, a broad rim of porphyrin is shown in the heated area in Figure 3B. [Figure 4] FIG. 4 shows the results of recurrent nodular and invasive basal cell carcinoma on the extremities following the method of the present invention described in Example 3. [Figure 5] FIG. 5 shows the results of treating an infiltrating basal cell carcinoma on the scalp according to the method of the present invention described in Example 4. [Figure 6] FIG. 6 shows the results of treating an invasive basal cell carcinoma on the head according to the methods of the invention described in Example 5, including histology at baseline (FIG. 6A) and one month after treatment (FIG. 6B), demonstrating no residual BCC. [Figure 7] Figure 7 shows the results of treating SCC-IS according to the method of the present invention described in Example 5. Heat is shown to create an increased porphyrin rim around the lesion area, reflecting increased absorption. [Figure 8] FIG. 8 shows the results of treating multifocal basal cell carcinoma using the method of the present invention. [Figure 9] FIG. 9 shows the results of treating refractory disseminated porokeratosis with associated SCC using the method of the present invention described in Example 6. [Figure 10] FIG. 10 shows the results of the treatment described in Example 7, including significant production of porphyrins after 20 minutes of incubation with 20% ALA gel. [Figure 11] FIG. 11 shows the results of the treatment described in Example 8, including greater production of porphyrins after 30 minutes of incubation of the 20% ALA gel. [Figure 12] FIG. 12 shows the results of the treatment described in Example 9 in the absence of heat, demonstrating minimal production of porphyrins after 60 minutes of incubation of the 20% ALA gel. [Figure 13] FIG. 13 shows the porphyrin images during the simultaneous incubation of 20% ALA solution. [Figure 14] Figure 14 shows images of treatment with 20% ALA solution without (Figure 14A) or with (Figure 14B) heat, demonstrating an increased PDT response on the heated side immediately after PDT (Figure 14C). [Figure 15] FIG. 15 shows the various settings when used on a heating pad at 1 minute and measured between about 15 minutes and about 60 minutes. [Figure 16] FIG. 16 shows the results of the method of the present invention using a 17 minute incubation of 20% ALA and using a heater at a temperature of about 38° C. to about 42° C. [Figure 17]17 shows the results of the method of the present invention using 1 hour of incubation with 10% aminolevulinic acid (ALA) along with 37 J / cm2 of 635 nm red light after a sodium acetate warming mask (skin temperature 40° C.) when treating an index patient with moderate inflammatory and pustular acne on the face. As detailed in Example 10, after a single session of thermal PDT, the reduction in lesion count persisted for 9 months. [Figure 18] 18 shows the results of the method of the present invention using a 1-hour incubation with 10% aminolevulinic acid along with 37 J / cm2 of 635 nm red light after a sodium acetate warming mask (skin temperature 40° C.) when treating an index patient with moderate inflammatory and pustular acne on the face. As detailed in Example 11, tissue repair of acne scars is demonstrated 9 months after a single thermal PDT. [Figure 19] Figure 19 shows a porphyrin rim 10 times larger than the size of the original lesion that formed around a basal cell carcinoma (BCC) on the forearm after 1 hour of incubation with 20% ALA under a heating pad set at medium (skin temperature 39°C). The area of ​​the BCC is 3,5802 and the area of ​​the BCC and porphyrin is 36,0822. [Figure 20] Figure 20 shows a porphyrin rim 9 times larger than the original lesion size formed around a squamous cell carcinoma (SCC) on the leg after 30 minutes of incubation with 20% ALA under a sodium acetate warming pouch (skin temperature 42°C). The area of ​​the SCC is 1,0512 and the area of ​​the SCC plus porphyrin is 9,2692. [Figure 21] Figure 21 shows the disappearance of a breast basal cell carcinoma (BCC) 2 months after 30 minutes of incubation with 10% ALA under a sodium acetate warming pouch (skin temperature 42°C), with a porphyrin margin demonstrated using porphyrin imaging. [Figure 22]FIG. 22 shows the results of a split-surface study using porphyrin imaging demonstrating increased porphyrin production on facial skin after incubation with 10% aminolevulinic acid (ALA) for 30 minutes at a skin temperature of 40° C. (using a sodium acetate warming mask) compared to a standard 3-hour incubation at room temperature (skin temperature of 30° C.). [Figure 23] Figure 23 shows increased porphyrin production on facial skin with actinic keratosis after a 30-minute incubation with 20% ALA at 40°C using a sodium acetate warming mask compared to a standard 1-hour incubation at room temperature (room temperature 70°F, skin temperature 30°C). Increased porphyrin production was measured and illustrated as described in Example 12. DETAILED DESCRIPTION OF THE INVENTION

[0049] The present invention is based on the observation that heating the skin increases the efficacy of photodynamic therapy (PDT), allowing for a shorter incubation time for the photosensitizing agent (or pharmaceutical composition comprising the photosensitizing agent) and increased absorption of the photoactive agent (or pharmaceutical composition comprising the photoactive agent). In exemplary embodiments, the methods of the present invention allow for improved outcomes, such as complete disappearance and / or reduced recurrence of the disease or disorder.

[0050] I. Definition As used herein, the term "acne" refers to an inflammatory disease of the pilosebaceous follicles and / or skin glands, and is usually characterized by papules, pustules, cysts, nodules, comedones, and other blemishes or skin lesions.

[0051] As used herein, the term "actinic keratosis" or "AK" refers to a precancerous skin lesion caused by and associated with prolonged exposure to radiant energy, such as sunlight. Actinic keratosis lesions are small, red, rough hyperkeratotic lesions that develop on sun-exposed areas of the skin.

[0052] As used herein, the terms "administer" and "administration" refer to providing or causing the provision of a substance to a subject, such as by topical, subdermal, subcutaneous, intradermal, enteral, parenteral, rectal, nasal, intravenous, intramuscular, intraperitoneal or other route.

[0053] As used herein, the term "basal cell carcinoma" or "BCC" refers to a malignant neoplasia of keratinocytes present in the basal layer of the epidermis. Basal cell carcinoma usually develops in areas exposed to UV rays, particularly the head, face, and neck. BCC typically does not spread beyond the primary site, but can be locally destructive. BCC can be classified as nodular-ulcerative, superficial, pigmented, or patchy sclerodermic.

[0054] As used herein, the term "blue light" refers to light having a wavelength of approximately 380 nm to 500 nm, with visible blue light having a wavelength of approximately 475 nm.

[0055] As used herein, the term "cancer" refers to a disease or disorder characterized by uncontrolled cell division and often by the ability of these cells to invade other tissues, either by direct growth in adjacent tissues through invasion or by implantation at distant sites through metastasis.

[0056] As used herein, the term "drug-light interval" refers to the period of time between administration of a photosensitizer to the lesion area and administration of light to the lesion area.

[0057] As used herein, the term "period of exposure" refers to the time that the skin is continuously exposed to a therapeutic agent (eg, a drug) or other treatment modality (eg, heat, light).

[0058] As used herein, the term "duration of treatment" refers to the time between the start and end of one cycle of treatment.

[0059] As used herein, the term "effective amount" refers to an amount that alone or as part of a treatment regimen will elicit the desired biological or medical response in a tissue, system, animal or human.

[0060] The term "essentially free" as used herein in relation to tolerability refers to minor or insignificant occurrence of skin irritation phenomena manifested during symptoms such as burning or stinging, flushing or redness, or mild, transient phenomena.

[0061] The term "essentially free" as used herein in relation to safety refers to trivial or insignificant occurrence of systemic or serious adverse events.

[0062] As used herein, the term "heat-drug interval" refers to the period of time between the administration of heat to the lesion area and the administration of a photosensitizer to the lesion area.

[0063] As used herein, the term "high rate of clinical response" or "high efficacy" or "substantial reduction" can relate to a reduction of about 45% or more in lesion count, or where subjects meet the success criteria of "clear" or "almost clear," or a "2-grade improvement from baseline."

[0064] The term "high-risk locations" as used herein in relation to non-melanoma skin cancer refers to areas of the face such as the central face, eyelids, eyebrows, periorbital area, nose, lips (skin and vermilion), chin, mandible, pre- and post-auricular skin / sulcus, temples, ears; genitalia; hands and feet.

[0065] As used herein, the term "inhibit" (and / or similar terms such as "reduce," "alleviate," or "suppress," or "avoid," or any variation of these terms) refers to any measurable decrease or complete inhibition of achieving a desired result.

[0066] As used herein, the term "lesion" refers to an affected area of ​​the skin.

[0067] As used herein, the term "lesion count" refers to the number of lesions (e.g., papules and pustules) present in a designated area of ​​the body (e.g., in the case of the face, on the forehead, cheeks, nose, and chin).

[0068] The terms "light" or "radiation" or similar terms used herein include all wavelengths. Preferably, the radiation wavelength is selected to match the wavelength that excites the photosensitizer. Even more preferably, the radiation wavelength matches the excitation wavelength of the photosensitizer compound and has low absorption by non-target tissue. Furthermore, in the present invention, radiation is defined by its intensity, duration, and timing relative to the administration of the photosensitizer. The intensity must be sufficient for the radiation to penetrate the skin and / or reach the target tissue to be treated. The duration must be sufficient to photoactivate the photosensitizer enough to act on the target tissue.

[0069] The term "low dose light" refers to a dose of light of a wavelength that can be absorbed by a photosensitizer that does not cause appreciable cell damage, necrosis, erythema, or inflammation.

[0070] The term "low-risk location" as used herein in relation to non-melanoma skin cancer refers to areas of the trunk or extremities.

[0071] The term "margin" as used herein refers to the area immediately adjacent to or surrounding the tumor site but which does not show any visible signs of carcinoma. Recommended "standard" surgical margins for various malignant lesions of the skin vary.

[0072] The term "moderate risk locations" as used herein in relation to non-melanoma skin cancer includes the cheeks, forehead, scalp and neck.

[0073] As used herein, the term "photodynamic therapy" or "PDT" refers to a technique that involves the administration of a photosensitizer (e.g., to the skin or mucosa) followed by exposure to photoactivating light to activate the photosensitizer and convert it to a cytotoxic form, resulting in cell destruction and thereby treating the disease (see Kennedy JC. et al. J Photochem Photobiol B. 1990).

[0074] As used herein, the terms "photosensitizing agent" or "photosensitizer" or "photoactive" or the like refer to a material, element, chemical, solution, compound, matter, or substance that is sensitive, reactive, receptive, or responsive to light energy. In certain embodiments, the photosensitizer may be activatable, i.e., regulated single O2 production specifically responsive to a certain biomarker.

[0075] The term "porphyrin" as used herein refers to a group of heterocyclic macrocycle organic compounds composed of four modified pyrrole subunits interconnected at their α-carbon atoms through methine bridges (=CH-). Ring-expanded porphyrins result from the extension of φ (phi) electron conjugation by increasing the number of heterocycles or bridging carbons of an existing porphyrin backbone.

[0076] As used herein, the term "red light" refers to light having a wavelength of about 620 nm to about 750 nm.

[0077] As used herein, the term "safe" means free from or essentially free from adverse events (e.g., any undesired or unintended signs, symptoms, or disorders that appear or worsen during the course of treatment).

[0078] The term "scar" as used herein refers to a mark produced during the healing of an injury to the skin or tissue. Scars are permanent and cannot be completely removed. Scars that can be treated according to the methods described herein include, for example, atrophic scars and hypertrophic scars. More specifically, acne scars can be ice pick, boxcar, rolling, bridges and tunnels, gross atrophy, dystrophic, or keloid scars.

[0079] As used herein, the term "target" refers to a cell or tissue of a subject that is intended to be weakened or destroyed by the disclosed methods. The target takes up the photosensitizer, and then, upon application of sufficient radiation, the target tissue is weakened or destroyed.

[0080] Conversely, the term "non-target" as used herein refers to cells or tissues of the subject that are not intended to be impaired or destroyed by the treatment method. These non-target cells include, but are not limited to, non-target cells of other healthy tissues.

[0081] As used herein, the term "therapeutically effective amount" refers to an amount of a therapeutic agent or therapeutic modality that is sufficient to treat a subject. The effective amount of a therapeutic agent and / or therapeutic modality will vary according to factors such as the individual's degree of susceptibility, the individual's age, sex, and weight, and the individual's idiosyncratic response.

[0082] As used herein, the term "topical" refers to laying or spreading directly onto the skin in need of treatment, for example, by hand or by use of an applicator.

[0083] As used herein, the term "skin" refers to the multilayered organ, including the epidermis, dermis, and hypodermis (i.e., subcutaneous tissue), that covers most of the surface of a mammalian subject, such as a human, and also includes the mucous membranes that are in contact with the outer skin.

[0084] As used herein, the term "skin cancer" refers to lentigo, lentigo, maligna, melanoma, keratoacanthoma, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), Merkel cell carcinoma (MCC), sarcoma, angiosarcoma, cutaneous lymphoma, sweat gland carcinoma, and sebaceous gland carcinoma.

[0085] As used herein, the term "squamous cell carcinoma" or "SCC" refers to a form of skin cancer that develops in the squamous cells of the skin and is sometimes referred to as cutaneous squamous cell carcinoma. Like BCC, SCC tends to affect areas of the skin with high levels of UV exposure, such as the head, face, and neck. SCC usually grows rapidly and is prone to metastasis. SCC can arise de novo or from actinic keratosis (with a transformation rate of approximately 0.5-16%). SCC is generally classified as in situ (involving the full thickness of the epidermis) or invasive (penetrating the basement membrane). Invasive SCC can be further classified as well-, moderately, or poorly differentiated.

[0086] As used herein, the term "subject" refers to mammals, such as humans, companion animals (e.g., dogs, cats, birds, etc.), livestock (e.g., cows, sheep, pigs, horses, poultry, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, birds, etc.). In some embodiments, the subject is a human.

[0087] As used herein, the term "thermal treatment device" refers to any device capable of heating the skin, whether directly or indirectly.

[0088] As used herein, the term "treat" or "treating" refers to (i) suppressing or delaying the appearance of clinical symptoms of a disease that develops in a mammal; (ii) inhibiting the disease, i.e., arresting, reducing, or delaying the onset or recurrence of the disease or at least one clinical or subclinical symptom thereof, or (iii) alleviating or attenuating one or more clinical or subclinical symptoms of the disease.

[0089] The term "topical" as used herein relates to the administration of a compound by application onto a body surface, including, but not limited to, transdermal administration and administration through mucous membranes.

[0090] II. Treatment Methods The present invention provides a method of treating a skin disease or disorder using photodynamic therapy (PDT) in conjunction with heat.

[0091] Advantageously, the methods of the present invention allow for a reduction in the incubation time of the photosensitizing agent and / or the duration of treatment compared to methods known in the art, while achieving comparable or superior results. In exemplary embodiments, the methods of the present invention provide improved results compared to conventional treatments. When used to treat skin cancer, the methods of the present invention allow for an increased rate of complete excision, resulting in a reduction in recurrence or a shortened time to recurrence.

[0092] In one embodiment, the present invention is a method of treating a skin disease or disorder in a subject in need thereof, comprising: (i) administering heat to a lesioned area of ​​the subject's skin using a heat delivery device to achieve a suitable temperature for a suitable time; (ii) incubating a pharmaceutical composition comprising a photoactive agent for a period of less than about 14 hours to provide an incubated pharmaceutical composition; (iii) administering a therapeutically effective amount of the incubated pharmaceutical composition to the lesioned area for a suitable period of time; and (iii) administering a dose of light to the lesioned area, thereby treating the skin disease or disorder.

[0093] Skin diseases and disorders The skin diseases or disorders treated by the methods of the present invention can be various. In certain embodiments, the skin disease or disorder is a cancerous lesion, a precancerous lesion, or acne. Areas of the skin that can be treated include parts of the skin on the head, face, neck, arms, legs, and torso, hands, and feet. In certain embodiments, the area to be treated is the head, face, neck, or parts thereof.

[0094] Actinic keratosis. In one embodiment, the skin disorder to be treated according to the method of the present invention is a precancerous lesion. In a specific embodiment, the precancerous lesion is actinic keratosis (AK). AK (also known as actinic keratosis) is the most common precancerous skin lesion and often appears as multiple, crusty, scaly growths. Actinic keratosis lesions generally measure about 2 mm to about 7 mm in diameter. AK lesions can range in color from skin-like to reddish and are often hyperkeratotic.

[0095] AK is typically caused by excessive exposure to ultraviolet (UV) light. In rare cases, AK can be caused by excessive exposure to X-rays. These lesions usually appear on areas exposed to the sun, such as the face, head (hairless scalp), ears, shoulders, neck, arms, forearms and hands. In certain embodiments, the disease or disorder treated according to the method of the present invention is AK on the face, neck or part thereof.

[0096] In one embodiment, the methods of the invention are used to treat precancerous lesions other than actinic keratosis. In certain embodiments, the methods of the invention are used to treat skin diseases or disorders other than actinic keratosis.

[0097] Non-melanoma skin cancer.In another embodiment, the skin disorder treated according to the method of the present invention is a cancerous lesion. In a specific embodiment, the cancerous lesion is non-melanoma skin cancer (NMSC). Non-melanoma skin cancer includes all types of cancer that occur in the skin other than melanoma. The most common types of NMSC are basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC and SCC are sometimes referred to as "keratinocyte carcinomas" to distinguish them from melanoma.

[0098] Basal cell carcinoma arises from the basal keratinocytes of the epidermis, hair follicles, and eccrine sweat glands. Approximately 80% of skin cancers arise from this type of cell, typically on the head and neck (approximately 90%). BCCs usually grow slowly (e.g., 1–2 cm over several years) and rarely spread to other parts of the body (0.0003–0.05%). The tumor invades tissue in a three-dimensional manner through the irregular growth of occult finger-like extensions that remain continuous with the main tumor mass. Actively growing tissue is present at the outer edge of the lesion, with cellular apoptosis and resulting ulceration in the central region.

[0099] The clinical features of BCC depend on the subtype: nodular BCC (also known as "classic basal cell carcinoma") is the most common subtype (more than 60% of cases) and appears as a pink nodule with curled edges, surface telangiectasias, and ulceration or crusting.

[0100] Superficial BCC accounts for up to 20% of cases and is often found on the trunk in sun-protected areas. Appearing as pink, scaly patches or thin plaques, superficial BCC may be mistaken for Bowen's disease, psoriasis, discoid eczema, or tinea corporis. Pigmented BCC occurs more commonly in patients of Far Eastern origin and may be mistaken for nodular melanoma. Morphea (sclerosing) BCC (also known as cicatricial basal cell carcinoma) has the poorest prognosis and appears as faint, scar-like plaques with vague margins.

[0101] Histologically, BCC can be undifferentiated or differentiated. Undifferentiated BCC typically includes pigmented BCC, superficial BCC, sclerosing BCC, and invasive BCC (histological subtypes). Nodular BCC is usually differentiated. Other forms of differentiated BCC include keratinizing BCC, BCC with sebaceous differentiation, and adenoid BCC. Types of biopsy that can be used to confirm the diagnosis and determine the histological subtype of BCC include shave biopsy and punch biopsy.

[0102] In one embodiment, the methods of the invention are used to treat undifferentiated BCC, more particularly superficial BCC.

[0103] In another embodiment, the methods of the present invention are used to treat differentiated BCC, more particularly nodular BCC.

[0104] In an exemplary embodiment, the BCC treated according to the methods of the invention has a mixed histologic pattern, ie, contains two or more major histologic patterns.

[0105] BCC is primarily caused by cumulative exposure to UV light, but can also occur in subjects who have previously been irradiated. Older people and men are at increased risk. Other risk factors include burn scars, smallpox scars, xeroderma pigmentosum, and basal cell nevus syndrome. After developing BCC, patients are at significantly increased risk of developing subsequent BCCs at other sites.

[0106] In one embodiment, the methods of the present invention can be used to treat BCC. In certain embodiments, the methods can be used to treat a BCC selected from the group consisting of nodular, micronodular, cystic, infiltrative, superficial, pigmented, erythematous ulcer (also known as a "Jacobi ulcer"), Pincus-type fibroepithelioma, polyploid, pore-like, or aberrant BCC.

[0107] In exemplary embodiments, the BCC treated in accordance with the present invention is present on the head, neck, or face, hi one embodiment, the BCC is present in a target site selected from the nose, check, periorbital region, auricular region, ear, temple, forehead, or scalp.

[0108] In an exemplary embodiment, the BCC treated in accordance with the invention is present on the trunk, limbs, hands, or feet.

[0109] The size of the lesion can vary. In one embodiment, the BCC is less than about 2 cm. In another embodiment, the BCC is greater than about 2 cm, greater than about 3 cm, greater than about 4 cm, greater than about 5 cm, or greater than about 6 cm. Lateral demarcation of the lesion may be aided by dermoscopy, and deep demarcation can be estimated by biopsy and / or imaging techniques.

[0110] BCC can be primary, incompletely resected, or recurrent. In certain embodiments, BCC is not primary. BCC can, in exemplary embodiments, be nodular or invasive.

[0111] A BCC can be a low-risk, intermediate-risk, or high-risk BCC with respect to recurrence.

[0112] In one embodiment, the BCC treated according to the present invention is a BCC with a low risk of recurrence based on location, size, or both. In certain embodiments, the lesion is in a low-risk location and less than 20 mm in size; in a medium-risk location and less than 10 mm in size; or in a high-risk location and less than 6 mm in size. A lesion may also be considered low risk based on its margins, i.e., if it has well-defined margins.

[0113] In another embodiment, the BCC treated according to the methods of the present invention is a BCC at high (or higher) risk for recurrence based on location, size, or both. In certain embodiments, the lesion is in a low-risk location and is 20 mm or larger; in a medium-risk location and is 10 mm or larger; or in a high-risk location and is 6 mm or larger. A lesion may also be considered high-risk based on its margins, i.e., because it is poorly defined or recurrent.

[0114] About 20% of skin cancers begin in squamous cells - the flat, scale-like cells that make up most of the epidermis. SCC is more likely to spread to other parts of the body than BCC, but much less likely to spread than melanoma.

[0115] The most common risk factor, like BCC, is cumulative exposure to UV radiation. Other risk factors include light skin color (e.g., blue eyes, blond hair), chemical carcinogenesis, chronic radiation dermatitis, HPV, xeroderma pigmentosum, and oculocutaneous albinism.

[0116] SCC can arise de novo or be preceded by actinic keratosis (AK). There is a known transformation rate of approximately 0.0003% to approximately 0.05%. AK involves only a portion of the epidermis, and histologically, AK is distinguished from SCC. SCC in situ involves the full thickness of the epidermis, has a well-defined border, and is characterized by an erythematous, scaly papule or plaque. Invasive SCC further involves penetration of the epidermal basement membrane and is characterized by an indurated, scaly papule or plaque. Invasive SCC may also be classified as moderately or poorly differentiated, with the degree of differentiation correlating with invasiveness.

[0117] In one embodiment, the methods of the present invention can be used to treat SCC. In certain embodiments, SCC is preceded by AK.

[0118] In another specific embodiment, the SCC is de novo, ie, the patient has not been previously diagnosed with AK.

[0119] In one embodiment, the methods of the invention are used to treat SCC in situ.

[0120] In another embodiment, the methods of the invention are used to treat invasive SCC, hi a specific embodiment, the methods are used to treat invasive SCC selected from the group consisting of well-differentiated SCC, moderately differentiated SCC, and poorly differentiated SCC.

[0121] The location of the lesion can vary. In an exemplary embodiment, the SCC treated in accordance with the present invention is present on the head, neck, or face. In one embodiment, the SCC is present in a target site selected from the nose, check, periorbital region, auricular region, ear, temple, forehead, or scalp.

[0122] The size of the lesion can vary. In one embodiment, the SCC is less than about 2 cm in size. In another embodiment, the SCC is greater than about 2 cm, greater than about 3 cm, greater than about 4 cm, greater than about 5 cm, or greater than about 6 cm in size.

[0123] The thickness of the lesion can vary. In one embodiment, the SCC is less than about 2 mm thick. In another embodiment, the SCC is greater than about 2 mm, greater than about 4 mm, greater than about 6 mm, or greater than about 6 mm thick. In exemplary embodiments, the SCC extends beyond the subcutaneous fat or is characterized by perineural invasion (PNI).

[0124] SCC can be primary, incompletely resected, or recurrent. In certain embodiments, the SCC is not primary. In exemplary embodiments, the SCC is loco-regionally recurrent (LRR).

[0125] The SCC may be a low-risk, intermediate-risk, or high-risk SCC with respect to recurrence.

[0126] In one embodiment, the SCC treated according to the present invention is a low-risk SCC for recurrence based on location, size, or both. In certain embodiments, the lesion is in a low-risk location and less than 20 mm in size; in a medium-risk location and less than 10 mm in size; or in a high-risk location and less than 6 mm in size. A lesion may also be considered low-risk based on its margins, i.e., because the margins are well defined, or the lesion is well differentiated, or has a depth of less than 2 mm.

[0127] In another embodiment, the SCC treated according to the present invention is a high-risk (or higher-risk) SCC for recurrence based on location, size, or both. In certain embodiments, the lesion is in a low-risk location and is 20 mm or larger; in a medium-risk location and is 10 mm or larger; or in a high-risk location and is 6 mm or larger. A lesion may also be considered high-risk based on its margin, i.e., because it is poorly defined or recurrent. A lesion may also be considered high-risk because it is poorly differentiated or has a depth greater than 2 mm.

[0128] Other non-melanoma skin cancers that can be treated according to the methods of the present invention include Merkel cell carcinoma, cutaneous lymphoma, Kaposi's sarcoma, skin adnexal tumors and sarcomas, and the like.

[0129] Acne. In a further embodiment, the skin disease or disorder is acne. Acne is a common skin condition that can occur anywhere on the body, but often occurs on the face and back. Acne typically occurs during adolescence, but can occur at any age. Without treatment, dark spots and scars may appear on the skin as the acne clears.

[0130] Acne can be caused by one or a combination of factors, generally including genetic predisposition, excessive production of sebum by the sebaceous glands, altered keratinization with abnormal desquamation of the sebaceous follicular epithelium, proliferation of Propionibacterium acnes, and release of cutaneous inflammatory mediators.

[0131] Acne can be classified as non-inflammatory or inflammatory. Non-inflammatory acne generally includes milia (which are usually small and remain under the skin) and blackheads (which are usually visible).

[0132] Inflammatory acne includes papules (small, usually pink bumps), pustules (red bases with pus on top), nodules (large, solid, painful comedones deeply embedded in the skin), and cysts (painful, pus-filled).Factors that contribute to inflammation include bacterial infection (Propionibacterium acnes), free fatty acids and sebum, pro-inflammatory mediators (IL-1a, IL-b, TNF), and debris.

[0133] Representative, non-limiting types of acne that can be treated by the methods disclosed herein include acne vulgaris, comedonal acne, papular acne, premenstrual acne, prepubertal acne, toxic acne, cosmetic acne, pomade acne, detergent acne, epidermolytic acne, gram negative acne, pseudofolliculitis barbae, folliculitis, perioral dermatitis, hiddradenitis suppurativa, cystic acne, acne atrophica, bromide acne, chloracne, acne conglobata, detergent acne, epidemic acne, and the like. acne), summer acne, fulminant acne, halogen acne, induration acne, iodide acne, keloid acne, mechanical acne, papular acne, pomade acne, premenstral acne, pustular acne, scurvy acne scorbutica), acne scrofulosorum, acne urticata, acne variola, toxic acne, propionic acne acne), exfoliative acne, gram-negative acne, steroid acne, nodular cystic acne, and acne rosacea.

[0134] A grading system can also be used to classify various stages of acne lesions. Grade 1, microcomedones, can appear as milia or blackheads. Grade 2, are papules, i.e., small, pink, inflamed bumps. Grade 3, are pustular lesions with more visible inflammation than papules. Grade 4, are nodular or large, painful, solid lesions that extend deep into the skin. Grade 5, are very large, painful, inflamed lesions.

[0135] In one embodiment, the disease or disorder treated according to the methods of the present invention is acne. In an exemplary embodiment, the disease or disorder is inflammatory acne on the face, neck, or portions thereof. Inflammatory acne can be mildly inflammatory, moderately inflammatory, or severely inflammatory.

[0136] In one embodiment, the disease or disorder treated according to the methods of the invention is mild acne, which is generally categorized by the appearance of blackheads and milia, but can also include papules and pustules.

[0137] In another embodiment, the disease or disorder treated according to the methods of the present invention is moderate acne, which is generally characterized by the appearance of more painful, deeply rooted, inflamed lesions that can lead to scarring.

[0138] In a further embodiment, the disease or disorder treated in accordance with the present invention is severe acne, which is generally characterized by the appearance of deep-seated inflammatory lesions such as cysts and nodules that can be painful and can result in scarring.

[0139] In one embodiment, the disease or disorder treated in accordance with the present invention is not severe acne.

[0140] In one embodiment, the subject treated for acne in accordance with the present invention is an adolescent. In another embodiment, the subject is an adult.

[0141] Sweat pore keratosis. In one embodiment, the methods of the invention are used to treat prokeratosis, a clonal disorder of keratinization characterized by one or more atrophic patches surrounded by a clinically and histologically characteristic hyperkeratotic ridge-like border called a parakeratotic cast.

[0142] The method of the present invention can be used to treat any form of prokeratosis. Various forms are recognized, including classic Mibelli porokeratosis (PM); disseminated superficial porokeratosis (DSAP); disseminated superficial prokeratosis (DSP); linear porokeratosis, disseminated palmoplantar prokeratosis (PPPD; prokeratosis palmaris et plantaris disseminata), and punctate porokeratosis, which may correspond to a variant of PPPD. Other less common forms are also recognized in the literature.

[0143] In an exemplary embodiment, the methods of the invention are used to treat DSAP. In an exemplary embodiment, the methods of the invention are used to treat PM.

[0144] In certain embodiments, the methods of the present invention are used to treat multiple lesions simultaneously.

[0145] heating Heat is administered to the skin by any suitable heat delivery device. The skin should be clean and dry. The device may be configured for direct application to the skin or may be configured to provide heat indirectly. The energy source may be, for example, electrical, chemical, laser, microwave, or radiofrequency. Exemplary, non-limiting heat delivery devices include heating pads, heating masks, space heaters, or infrared heaters.

[0146] In one embodiment, the affected area is the face and the heat delivery device is a heat mask. In an exemplary embodiment, the heat mask is a sodium acetate mask that heats when crystallized. Crystallization is typically induced by bending a small slab of ferrous metal with notches embedded in a liquid of supersaturated sodium acetate. In an exemplary embodiment, the mask is covered with two layers of 2-play polyplastic paper.

[0147] In another embodiment, the affected area is an extremity and the heat delivery device is a heating pad. The heating pad may be positioned in any suitable manner.

[0148] In one embodiment, a heater is used to heat the skin on the face, for example, by placing the heater on a wheeled platform. The subject adjusts the skin heating at an ideal distance (adjusting for comfort) to warm the skin. In this embodiment, the subject should wear protective eyewear (e.g., goggles).

[0149] In one embodiment, the skin is not heated by simply heating the room itself.

[0150] The temperature to which the heat delivery device is heated can vary depending on the disease or disorder and location being treated, hi one embodiment, the heat delivery device is heated to a temperature of about 20°C to 50°C, or more specifically, about 20°C to about 30°C, about 30°C to about 40°C, or about 40°C to about 50°C.

[0151] In one embodiment, the disease or disorder is a precancerous or cancerous lesion on the face and the heat delivery device is heated to a temperature of about 38°C to about 42°C, or more specifically, about 40°C.

[0152] In another embodiment, the disease or disorder is a precancerous or cancerous lesion on an extremity and the heat delivery device is heated to a temperature of about 38°C to about 42°C, or more specifically, about 39°C.

[0153] In an exemplary embodiment, the skin is heated to the temperature of the heat delivery device. In an exemplary embodiment, the temperature of the skin at the surface is lower than the temperature to which the heat delivery device is heated.

[0154] In one embodiment, the skin is heated to a surface temperature of about 20°C to 50°C, or more specifically, about 20°C to about 30°C, about 30°C to about 40°C, or about 40°C to about 50°C.

[0155] In another embodiment, the skin is heated to a surface temperature greater than about 37° C. In certain embodiments, the skin is heated to a surface temperature greater than about 38° C., greater than 39° C., greater than about 40° C., greater than about 41° C., or greater than about 42° C.

[0156] In one embodiment, the skin is heated to a surface temperature of about 38°C to about 42°C, or more specifically, about 40°C.

[0157] In another embodiment, the skin is heated to a surface temperature of about 38°C to about 42°C, or more specifically, about 39°C.

[0158] The duration of exposure to heat can vary, in one embodiment, from about 1 minute to about 90 minutes, or more specifically, from about 1 minute to about 10 minutes, from about 10 minutes to about 20 minutes, from about 20 minutes to about 30 minutes, from about 30 minutes to about 40 minutes, from about 40 minutes to about 50 minutes, from about 60 minutes to about 70 minutes, from about 70 minutes to about 80 minutes, or from about 80 minutes to about 90 minutes or more.

[0159] In another embodiment, the duration of exposure to heat is about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 65 minutes, about 70 minutes, about 75 minutes, or about 80 minutes or more.

[0160] In certain embodiments, the skin disease or disorder is a precancerous lesion and the duration of heat exposure is about, about 20 minutes to about 40 minutes, or, more specifically, about 30 minutes.

[0161] In yet another embodiment, the skin disease or disorder is acne and the duration of exposure to heat is about, about 20 minutes to about 40 minutes, or, more specifically, about 30 minutes.

[0162] Without being bound by any particular theory, it is believed that heating increases one or more of the following: the rate of porphyrin production in the skin, the absorption of the photosensitizing agent, or the area of ​​treatment surrounding the lesion to create a treatment border around the lesion.

[0163] In exemplary embodiments, the rate of porphyrin production in the skin is increased by about 10%, about 20%, about 30%, about 40%, or about 50% or more by heating as disclosed herein.

[0164] In exemplary embodiments, absorption is increased by about 10%, about 20%, about 30%, about 40%, or about 50% or more by heating as disclosed herein. Absorption may reflect an increased ratio of photosensitizing agent absorption to lesion depth, or may reflect an increased ratio of photosensitizing agent absorption to lesion. In certain embodiments, the ratio is about 0.5:1 to about 1:1, more specifically, about 0.5:1, about 0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, or about 1:1 or greater.

[0165] In exemplary embodiments, the area of ​​treatment is increased by about 10%, about 20%, about 30%, about 40%, or about 50% or more by heating as disclosed herein.

[0166] Optionally, the method may include one or more additional pretreatment steps, i.e., before application of the photosensitizing agent. In one embodiment, pretreatment may include scraping, dermabrasion (e.g., with sandpaper), or microporation of the skin.

[0167] Photosensitizers / Compositions The present invention involves the application of a photosensitizer to the skin, which accumulates in the lesion area to a much greater extent than it accumulates in surrounding normal tissue. When the photosensitizer is irradiated with an appropriate dose of light, the activated photosensitizer transfers its energy to surrounding molecular oxygen, generating reactive oxygen species (ROS) in the cells that held the photosensitizer. When an appropriate dose of light is used, the result is cell death.

[0168] The photosensitizer may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.

[0169] Any suitable photosensitizer can be used in the methods of the present invention. Many photosensitizers are known in the art. In one embodiment, the photosensitizer is selected from the group consisting of porphyrins, chlorophylls, and dyes.

[0170] Non-limiting examples of photosensitizers suitable for use in the present invention include phthalocyanines, porphyrins, porphyrin precursors, porphycenes, naphthalocyanines, phenoselenaziniums, hypocrellins, perylenequinones, texaphyrins, benzoporphyrin derivatives, azaporphyrins, purpurins, rose bengal, xanthenes, porphycyanines, isomeric porphyrins, pentaphyrins, sapphyrins, chlorins, benzochlorins, hypericin, anthraquinones, rhodanols, barbituric acid derivatives, ring-expanded porphyrins, dipyrromethenes, coumarins, azo dyes, acridines, rhodamines, azine derivatives, tetrazolium derivatives, safranines, indocyanines, indigo derivatives, indigotriazines, and the like. These include amine derivatives, pyropheophorbides, pyrrole-derived macrocycles, naturally occurring or synthetic porphyrins, naturally occurring or synthetic chlorins, naturally occurring or synthetic bacteriochlorins, naturally occurring or synthetic isobacteriochlorins, naphthalocyanines, phenoxazine derivatives, phenothiazine derivatives, chalcoorganapyryllium derivatives, triarylmethane derivatives, rhodamine derivatives, fluorescein derivatives, verdine derivatives, toluidine blue derivatives, methylene blue derivatives, methylene violet derivatives, Nile blue derivatives, Nile red derivatives, phenazine derivatives, pinacyanol derivatives, plasmocollins derivatives and indigo derivatives, and combinations thereof.

[0171] In one embodiment, the photosensitizer is a porphyrin, hi one embodiment, the porphyrin is selected from the group consisting of hematoporphyrin, metalloporphyrin, porphycene, pheophorbide, purpurin, chlorin, protoporphyrin, and phthalocyanine.

[0172] In certain embodiments, the photosensitizer is 5-aminolevulinic acid (ALA) or a derivative or modification thereof. 5-aminolevulinic acid (also known as 5-aminolevulinic acid, δ-aminolevulinic acid, δ-aminolevulinic acid (delta-aminolaevulinic acid, or 5-amino 4-oxopentanoic acid) is an intermediate in the pathway leading to the production of the photosensitizer protoporphyrin IX (PpIX).

[0173] [ka] 5-Aminolevulinic Acid HCl ALA can be used in the form of a salt, such as HCl, or in a pharmaceutically equivalent form, such as an amide or ester. As used herein, the term "ALA" refers to all of the above compounds.

[0174] In one embodiment, the photosensitizer is a non-porphyrin agent, and in a specific embodiment, the non-porphyrin agent is selected from the group consisting of anthraquinones, phenothiazines, psoraleans, anthracyclines, chalcogenopyrlium dyes, xanthenes, cyanines, and curcuminoid sensitizers.

[0175] The photosensitizer can be administered in pure form, can be dissolved in a non-toxic solvent and then applied, or can be administered in a topical formulation.

[0176] When formulated as a pharmaceutical composition, the composition will contain a pharmaceutically acceptable carrier and may optionally contain one or more of the following agents: buffers, co-solvents, adsorbents, penetration enhancers, surfactants, stabilizers, emulsifiers, preservatives, chelating agents, thickeners, smoothing agents, humectants, or polymers.

[0177] The amount of photosensitizer in a pharmaceutical composition (e.g., a topical dosage form) can vary. In one embodiment, the photosensitizer is present in an amount of about 0.1% to about 75% by weight, more specifically, about 1.0% to about 40% by weight, about 2.0% to about 30% by weight, about 5.0% to about 25% by weight, about 10% to about 20% by weight, about 8% by weight, about 10% by weight, about 12% by weight, about 14% by weight, about 16% by weight, about 18% by weight, about 20% by weight, or about 22% by weight.

[0178] In certain embodiments, the amount of photosensitizer in the pharmaceutical composition is greater than about 10% by weight.

[0179] In certain embodiments, the amount of photosensitizer in the pharmaceutical composition is about 20% by weight.

[0180] In another embodiment, the amount of photosensitizer in the pharmaceutical composition is less than about 20% by weight, more specifically less than about 15% by weight or less than about 10% by weight, but in any case greater than zero.

[0181] In one embodiment, the photosensitizer is formulated for topical delivery. Topical dosage forms can include creams, gels, ointments, pastes, suspensions, lotions, foams, sprays, aerosols, and solutions.

[0182] The term "cream" refers to a semi-solid emulsion system containing both oil and water. Oil-in-water creams are miscible with water and are well absorbed into the skin, e.g., Aqueous Cream BP. Water-in-oil (oily) creams are immiscible with water and are therefore more difficult to remove from the skin. These creams are emollient, lubricating, and moisturizing (e.g., Oily Cream BP). Both systems require the addition of either natural or synthetic surfactants or emulsifiers.

[0183] The term "ointment" refers to a system that has oil or grease as its continuous phase.

[0184] Ointments are semi-solid, anhydrous substances that are occlusive, emollient, and protective. They limit transepithelial water loss and are therefore moisturizing and hydrating. Ointments can be divided into two main groups: fatty, e.g., white petrolatum (mineral oil, petrolatum), and water-soluble, e.g., Macrogol (polyethylene glycol) Ointment BP.

[0185] The term "lotion" refers to a solution typically used in dermatological applications.

[0186] The term "gel" refers to semi-solid permutations gelled with high molecular weight polymers, such as carboxypolymethylene (Carbomer BP) or methylcellulose, and can be considered semi-plastic aqueous lotions. Gels are typically non-greasy, water-miscible, easy to apply and wash off, and are particularly suitable for treating hairy areas of the body.

[0187] In one embodiment, the photosensitizing agent is formulated as a gel. Pharmaceutically acceptable gelling agents suitable for use in topical gel compositions are substances that impart viscosity to the formulation so that it can be effectively applied to the affected area, including, but not limited to, hydroxypropyl cellulose (e.g., Klucel HA), hydroxypropylmethylcellulose carrageenan, microcrystalline cellulose, carbomer, alginate, gellan gum, xanthan gum, veegum, hydroxyethyethyl cellulose, guar gum, and carbomers.

[0188] The gel may further contain local anesthetics and analgesics such as camphor, menthol, lidocaine, dibucaine, and pramoxine; antifungals such as ciclopirox, chloroxylenol, triacetin, sulconazole, nystatin, undecylenic acid, tolnaftate, miconazole, clotrimazole, oxiconazole, griseofulvin, econazole, ketoconazole, and amphotericin B.

[0189] The gel may also include one or more preservatives, such as iodine, povidine-iodine, benzalkonium chloride, benzoic acid, nitroflazine, benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol, resorcinol, and cetylpyridinium chloride.

[0190] The pH of the photosensitizer gel formulation is preferably within a physiologically acceptable pH range, e.g., about 4.5 to about 7.5, more preferably about 5.0 to about 6.5, such as about 5.1, 5.15, 5.2, 5.25, 5.3, 5.35, 5.4, 5.45, 5.5, 5.55, 5.6, 5.65, 5.7, 5.75, 5.8, 5.85, 5.9, 5.95, 6.1, 6.15, 6.2, 6.25, 6.3, 6.35, 6.4, 6.45, or 6.5. An effective amount of a buffer is preferably included to stabilize the pH. Acids or bases can be used to adjust the pH as needed.

[0191] The gel composition can be prepared by mixing the components of the composition according to methods known in the art, for example, as described by standard reference texts such as Remington: The Science and Practice of Pharmacy, 1577-1591, 1672-1673, 866-885 (Alfonso R. Gennaro ed., 19th ed., 1995); Ghosh, TK et al., Transdermal And Topical Drug Delivery Systems (1997), both of which are incorporated herein by reference.

[0192] In an exemplary embodiment, the photosensitizer is formulated as a gel, including 20% ​​aminolevulinic acid hydrochloride gel. In a specific embodiment, the pharmaceutical composition is LEVULAN® KERASTICK®, a topical formulation of 20% 5-aminolevulinic acid hydrochloride. In another specific embodiment, the pharmaceutical composition is not LEVULAN® KERASTICK®.

[0193] In a further embodiment, the photosensitizer is formulated as a gel containing 10% aminolevulinic acid hydrochloride. In a particular embodiment, the pharmaceutical composition is AMULEZ® (available from Biofrontera), a non-sterile topical formulation of 10% 5-aminolevulinic acid hydrochloride (equivalent to 7.8% free acid) in a gel matrix with a nanoemulsion.

[0194] In one embodiment, the photosensitizer is in unit dosage form so that it can be subdivided into unit doses containing appropriate quantities of the compound.

[0195] The amount of photosynthesizing agent to be administered will depend on the choice of photosynthesizing agent, the condition to be treated, the mode of administration, the individual subject, and the judgment of the physician. Depending on the specificity of the preparation, smaller or larger doses may be required. In one embodiment, 1 g (78 mg) of 5-aminolevulinic acid hydrochloride gel (ALA) is administered.

[0196] The time between the application of heat to the affected area and the application of the photosensitizer can vary. This is known as the "heat-to-drug interval" and can be measured in seconds, minutes, hours, or even days.

[0197] In one embodiment, the heat-drug interval is from about 1 second to about 60 seconds, or more specifically, from about 1 second to about 10 seconds, from about 10 seconds to about 20 seconds, from about 20 seconds to about 30 seconds, from about 30 seconds to about 40 seconds, from about 40 seconds to about 50 seconds, or from about 50 seconds to about 60 seconds.

[0198] In another embodiment, the heat-drug interval is about 1 minute to about 60 minutes, more specifically, about 0.1 minutes to about 1 minute, about 1 minute to about 5 minutes, about 5 minutes to about 10 minutes, about 10 minutes to about 20 minutes, about 20 minutes to about 30 minutes, about 30 minutes to about 40 minutes, about 40 minutes to about 50 minutes, or about 50 minutes to about 60 minutes.

[0199] In further embodiments, the heat-drug interval is from about 1 hour to about 24 hours, more specifically, from about 1 hour to about 4 hours, from about 4 hours to about 8 hours, from about 8 hours to 12 hours, from about 12 hours to about 16 hours, from about 16 hours to about 20 hours, or from about 20 hours to about 24 hours.

[0200] The composition can be administered in any suitable manner, preferably topically. Topical compositions can be administered in any suitable manner, such as by rubbing on, pouring on, applying with an applicator (e.g., gauze pad, cotton swab, bandage, etc.). In some cases, the composition can be a liquid, gel, cream, lotion, ointment, solid "stick," etc., that can be applied to the skin by hand, for example, by rubbing or spraying.

[0201] In exemplary embodiments, the lesion area is the site of a precancerous or cancerous lesion, for example, on the face or neck. In some embodiments, the lesion area is an area covering the site of a precancerous or cancerous lesion, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, or 50 cm in diameter. In some embodiments, the suitable location is an area where cancer prevention is desired. In other embodiments, the suitable location is a site where a precancerous or cancerous lesion has previously been removed, and the method is designed to prevent recurrence. In yet another embodiment, the suitable location is a site where a precancerous or cancerous lesion has previously been incompletely removed.

[0202] In exemplary embodiments, the lesion area is, for example, the site of an acne lesion on the face. In some embodiments, the lesion area is an area covering the acne site, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, or 50 cm in diameter. In some embodiments, the appropriate location is an area where acne prevention is desired.

[0203] The duration of exposure to the photosensitizing agent can vary, hi one embodiment, the duration of exposure is from about 1 minute to about 30 minutes, or more specifically, about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, or about 30 minutes.

[0204] In exemplary embodiments, the duration of exposure to the photosensitizing agent can be shorter due to pre-heating of the skin while achieving the same effect, hi one embodiment, the duration of exposure is about 10%, about 30%, about 30, about 40, about 50, or about 60%, about 70%, about 80%, or about 90% while achieving the same effect.

[0205] In certain embodiments, the period of exposure to the photosensitizing agent is about 1 hour, about 45 minutes, about 30 minutes, or less than about 30 minutes.

[0206] Incubation time One advantageous feature of the present invention is the shortened incubation time of the photosensitizer that it allows. FDA approval of PDT for AK requires a 14-hour incubation with ALA before exposure to blue light. However, for many clinicians, this creates a burden, such as an extended treatment period.

[0207] In one embodiment, the incubation time is reduced by more than about 10%, more than about 15%, more than about 20%, more than about 25%, more than about 30%, more than about 35%, more than about 40%, more than about 45%, more than about 50%, more than about 54%, more than about 60%, more than about 65%, more than 70%, more than about 75%, or more than 80%.

[0208] In another embodiment, the incubation time is reduced by about 10% to about 70%, about 20% to about 60%, or about 30% to about 50%.

[0209] In certain embodiments, the incubation time is reduced by more than 30% while achieving results equivalent to photoactivators incubated for about 14 hours.

[0210] In another specific embodiment, the incubation time is reduced by more than 20% while achieving results equivalent to photoactivators incubated for about 5 hours.

[0211] In another specific embodiment, the incubation time is reduced by more than 10% while achieving equivalent results to a photoactivator incubated for about 1 hour to about 3 hours, or more specifically, about 3 hours, about 2 hours, or about 1 hour.

[0212] In another embodiment, the incubation time is less than 14 hours, less than 13 hours, less than 12 hours, less than 11 hours, less than 10 hours, less than 8 hours, less than 7 hours, less than 6 hours, less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, or less than 1 hour.

[0213] In further embodiments, the incubation time is about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, or about 8 hours or more.

[0214] In exemplary embodiments, the incubation time is less than about 1 minute, less than about 45 seconds, less than about 30 seconds, less than about 25 seconds, less than about 20 seconds, less than about 15 seconds, or less than 10 seconds.

[0215] In exemplary embodiments, the incubation time is about 30 seconds, about 25 seconds, about 20 seconds, about 18 seconds, about 16 seconds, about 14 seconds, about 12 seconds, or about 10 seconds, or less.

[0216] In an exemplary embodiment, the photosensitizer is incubated simultaneously with the application of heat to the skin, or within a few seconds or minutes before the heating of the skin, or after the heating of the skin has begun.

[0217] light After the skin is heated and the photosensitizer is applied, the area to be treated is then irradiated with light of an appropriate wavelength and sufficient power in the presence of oxygen to activate the photosensitizer, generating reactive oxygen species that react with biological molecules and cause fatal damage to some of the cells in the treatment area.

[0218] The step of irradiating generally involves providing a light source that is activated to produce light. The light source can be an artificial or natural light source (e.g., sunlight).

[0219] The light can be provided by a laser, a light emitting diode (LED), or other light source known to those skilled in the art (e.g., a chemiluminescent light source). The light can be provided by a single source, or multiple light sources can be used.

[0220] In an exemplary embodiment, the light source is an LED lamp.

[0221] The amount and wavelength of the applied radiation will depend on the nature of the photosensitizer used. Preferably, the wavelength is selected to correspond to or at least overlap with the excitation wavelength of the photosensitizer. Even more preferably, the wavelength matches the excitation wavelength of the photosensitizer and has low absorption by non-target cells or tissues.

[0222] The wavelengths are typically within the visible and near-infrared wavelengths, including wavelengths from about 320 nm to about 780 nm, although specific photosensitizers typically respond to light having specific wavelengths.

[0223] In one embodiment, the light administered to the lesion area is blue light. Blue light has a wavelength of about 380 nm to 500 nm, and visible blue light has a wavelength of about 475 nm. The dominant wavelength of the blue light used in the methods of the present invention can vary. In one embodiment, the dominant wavelength of the blue light used in the methods of the present invention is about 450 nm to about 475 nm. In certain embodiments, the dominant wavelength of the blue light used in the methods of the present invention is about 450 nm, about 455 nm, about 460 nm, about 465 nm, about 470 nm, or about 475 nm. The source of the blue light can vary. In one embodiment, the source of the blue light is Blu-U®, available from DUSA Pharmaceuticals.

[0224] In one embodiment, the light is not blue light. In a specific embodiment, the light is not Blu-U®.

[0225] In another embodiment, the light is not blue light and the photosensitizing agent is not LEVULON® KERASTICK®.

[0226] In another embodiment, the light is red light. The red light has a wavelength of about 620 nm to about 750 nm. The dominant wavelength of the red light used in the methods of the present invention is about 630 nm to about 640 nm, or more specifically, about 635 nm. The source of the red light can vary. In one embodiment, the source of the red light is BF-RhodoLED® (available from BioFrontera).

[0227] In some embodiments, the administration of light is continuous.

[0228] In an exemplary embodiment, the light source is positioned outside the intact skin layer of the subject.

[0229] In other embodiments, two or more separate doses of light can be used within a single treatment, for example, two, three, four or more separate doses. Furthermore, the amount of light applied in the two doses can be the same or different. After the first application of light is applied to the target area, a sufficient time interval should be allowed for an effective amount of photosensitizer to penetrate further into the tissue. The specific layer of the skin that is targeted can vary depending on the disease being treated.

[0230] The duration of exposure to light can vary depending on the power of the radiation source. In one embodiment, the duration of exposure is from about 1 minute to about 30 minutes, or more specifically, from about 1 minute to about 5 minutes, from about 5 minutes to about 10 minutes, from about 10 minutes to about 15 minutes. The time is about 15 to about 20 minutes, about 20 to about 25 minutes, or about 25 to about 30 minutes, or longer.

[0231] In another embodiment, the duration of exposure is about 1 minute, about 3 minutes, about 5 minutes, about 8 minutes, 10 minutes, about 12 minutes, about 15 minutes, about 18 minutes, or about 21 minutes, about 25 minutes, about 28 minutes, or about 31 minutes or more.

[0232] The light should be administered for a sufficient duration and intensity to activate the photosensitizer. The amount of light energy required to achieve effective results can be predetermined by assessing the effective amount for a specific subject, subject type, photosensitizer, and / or formulation. The amount of light energy can also be adjusted according to feedback during treatment. For example, the amount of light being delivered can be adjusted based on simultaneous analysis of the penetration of the photosensitizer, the heat level in the tissue (e.g., skin), or the level of discomfort experienced by the subject.

[0233] In one embodiment, the amount or "dose" is about 5 J / cm 2 ~About 200J / cm 2 , or specifically, about 5 J / cm 2 ~about 10J / cm 2 , about 10J / cm 2 ~About 20J / cm 2 , about 20J / cm 2 ~About 30J / cm 2 , about 30J / cm 2 ~about 40J / cm 2 Or it is in the range of about 40 to about 50.

[0234] In one embodiment, the present invention provides a method of heat-enabled, low-dose PDT. "Low-dose PDT" refers to undergoing full photodynamic therapy using significantly lower levels of radiation intensity and light exposure time (i.e., lower doses of light). In one embodiment, the radiation intensity used is about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, or about 70% lower than prior art methods. In another embodiment, the radiation dose is about 100 J / cm. 2 Less than 80J / cm 2 Less than 70J / cm 2 Less than, or more specifically, about 65 J / cm 2 Less than 60J / cm 2 Less than 55J / cm 2 Less than 50J / cm 2 Less than 45J / cm 2Less than 40J / cm 2 is less than.

[0235] In another embodiment, the amount of radiation is less than about 40 J / cm 2 or more specifically, the dose is less than about 35 J / cm 2 ~about 40J / cm 2 or more specifically, in the range of about 37 J / cm 2 is.

[0236] The fluence rate of the light can vary. In one embodiment, the light source has a fluence rate of about 1 to about 100 mW / cm 2 has a fluence rate of

[0237] In the case of skin tissue, a sufficient time interval is preferably provided to allow the photosensitizer to reach lower levels of the skin, such as the basal epidermis and / or the papillary dermis, which is the upper layer of the dermis immediately below the epidermis. The specific layer of the skin targeted can vary depending on the disease being treated. For example, the time interval can be 1 hour, 30 minutes, 10 minutes, 5 minutes, or any other interval within this range. In addition to providing sufficient time for the photosensitizer to penetrate the skin to the desired level, care should also be taken to avoid providing too long a time, which may result in a significant amount of photosensitizer passing beyond the intended site.

[0238] Typically, administration of photodynamic therapy involves administering one or more sessions of therapy to a subject (e.g., 1, 2, 3, 4, or more sessions of therapy). According to embodiments, a session includes both administration of a photoreactive compound to the treatment area and irradiation of the treatment area, which may occur over a period of several hours or one or more days or weeks. According to other embodiments, a session includes irradiation of only the treatment area. In some embodiments, photodynamic therapy is administered in two sessions. In some embodiments, photodynamic therapy is administered in only one session.

[0239] In exemplary embodiments, the method further comprises monitoring the skin disease or disorder after administration of the photodynamic therapy of the present invention, wherein a lack of clinical response to the method indicates that the method should be repeated and / or the amount of photosensitizing agent and / or the dose of light should be increased. Monitoring may include visual inspection, palpation, diagnostic imaging, assaying for the presence, level, or activity of one or more biomarkers associated with the disease or disorder, and / or the clinical response in a sample obtained from the subject, or a combination of two or more of the above. Monitoring is preferably performed periodically, which in this disclosure means at least several times a week, preferably about daily.

[0240] Where the disease or disorder is non-melanoma skin cancer, monitoring may cover one of more of the following: tumor size, rate of change in tumor size, appearance of new tumors (i.e., recurrence), rate of appearance of new tumors (i.e., recurrence rate), change in symptoms of NMSC, appearance of new symptoms associated with NMSC, quality of life, or a combination of two or more of the above.

[0241] In one embodiment, the method of the present invention reduces the recurrence of NMSC compared to the same method without the preheating step. In specific embodiments, recurrence is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% or more. In another specific embodiment, recurrence is less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%. In another specific embodiment, recurrence is about 10%, about 9.5%, about 9%, about 8.5%, about 8%, about 7.5%, about 7, about 6.5, about 6, about 5.5, about 5, about 4.5, about 4, about 3.5, about 3, about 2.5, about 2, about 1.5, about 1.0, or about 0.5, or less. Recurrence can be measured at any suitable time point, such as, for example, at about 6 months, about 1 year, about 2 years, about 3 years, about 4 years, or about 5 years.

[0242] Without being bound by any particular theory, it is believed that the methods of the present invention allow for improvements in determining tumor margins, hi one embodiment, the ability to determine tumor margins is improved by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or 50% or more using the present methods.

[0243] In another embodiment, the method of the present invention reduces the time to recurrence of NMSC compared to the same method without the preheating step. In specific embodiments, the time to recurrence is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% or more. In another specific embodiment, the average time to recurrence is reduced by about 1 month to about 36 months, or more specifically, by about 1 month, about 3 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about 30 months, about 33 months, or about 36 months or more.

[0244] Advantageously, the methods of the present invention allow for improved determination of tumor margins compared to the same method in the absence of step (i). In exemplary embodiments, the ability to determine tumor margins is improved by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, or about 50% or more.

[0245] In an exemplary embodiment, the method of the present invention allows for marginal precision comparable to conventional surgical procedures.

[0246] When the disease or disorder is acne, monitoring may cover one or more of the following: number of acne lesions, severity of acne lesions.

[0247] In one embodiment, the method of the present invention results in a reduction in the mean number of acne lesions in a subject. In certain embodiments, the percentage reduction is about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, or about 90% or more.

[0248] In certain embodiments, the methods of the present invention result in a reduction in the mean acne lesion count in a subject of about 40% to about 90%, more specifically, about 45% to about 85%, and even more specifically, about 47% to about 80%.

[0249] As the method is performed multiple times, the percentage reduction can increase, for example, the reduction in average acne lesions can be about 30% or more after a first treatment, about 40% or more after a second treatment, and / or about 50% or more after a third treatment.

[0250] The results achieved by the methods of the present invention may be sustained. For example, the reduction in the mean acne lesion count may be sustained for about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, or about 9 months or more. A sustained reduction for about 12 months or more may be considered clinical remission.

[0251] In one embodiment, a population of patients treated according to the methods of the invention has a reduction in the number of acne lesions compared to patients treated according to the same method but in the absence of step (i). In certain embodiments, the number of acne lesions in a population treated according to the methods of the invention is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, or about 90% or more compared to patients treated according to the same method but in the absence of step (i).

[0252] In certain embodiments, the methods reduce the number of acne lesions over a period ranging from 1 week to about 12 weeks. In some embodiments, the methods result in very few instances (e.g., less than 1%) of redness, dryness, and peeling of treated skin.

[0253] In another embodiment, a population of patients treated according to the methods of the invention has a reduction in the severity of acne lesions compared to patients treated according to the same method in the absence of step (i). In certain embodiments, the severity of acne lesions in a population treated according to the methods of the invention is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90% or more compared to patients treated according to the same method in the absence of step (i).

[0254] The methods of the present invention may result in reduced side effects, including, for example, discomfort, scaling, and sterile postulation, compared to the same methods in which there is no preheating step prior to administration of the photosensitizing agent.

[0255] In one embodiment, discomfort is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% or more.

[0256] In another embodiment, desquamation is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% or more.

[0257] In yet another embodiment, sterile postulation is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% or more.

[0258] In certain embodiments, the methods of the present invention provide a statistically significant 2 point reduction in acne severity on the Investigator's Global Assessment (IGA) at weeks 6, 9, or 12 compared to the vehicle control group.

[0259] In another specific embodiment, the methods of the present invention provide an absolute reduction in the number of acne lesions (non-inflammatory, inflammatory, or both) of about 2, about 4, about 6, about 10, about 12, about 14, about 16, about 18, about 20, about 22, or about 24 or more.

[0260] In one embodiment, the method of the present invention reduces the risk of atrophic (depressed) acne scars. In certain embodiments, the risk is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% or more.

[0261] III. Combination Therapy The present invention includes methods of treatment that include the simultaneous administration of one or more therapies in addition to PDT with a pre-thermal treatment as described above. As used herein, the terms "in combination" and "co-administration" can be used interchangeably to refer to the use of more than one therapy (e.g., two or more prophylactic and / or therapeutic agents). The use of these terms does not restrict the order in which the therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject.

[0262] In an exemplary embodiment, the methods of the present invention may be used in combination with one or more agents used to treat actinic keratosis. Non-limiting examples of such agents include 5-fluorouracil (5-FU) and imiquimod (Aldara, Zyclara).

[0263] In an exemplary embodiment, the methods of the present invention may be used in combination with the administration of one or more anti-cancer agents, such as cytotoxic agents, chemotherapeutic agents, anti-signaling agents, and anti-angiogenic agents.

[0264] In one embodiment, the methods of the invention can be used in combination with the administration of one or more drugs used to treat BCC. Non-limiting examples of such drugs include imiquimod (Aldara, Zyclara), topical flurouracil (Efudex, Carac, Fluoroplex), vismodegib, and sonidegib.

[0265] In one embodiment, the methods of the invention can be used in combination with the administration of one or more drugs used to treat SCC. Non-limiting examples of such drugs include imiquimod (Aldara, Zyclara), topical flurouracil (Efudex, Carac, Fluoroplex), and cetuximab (Erbitux).

[0266] In an exemplary embodiment, the methods of the present invention may be used in conjunction with the administration of one or more anti-acne agents. Non-limiting examples of useful anti-acne actives include keratolytics such as salicylic acid (o-hydroxybenzoic acid), derivatives of salicylic acid such as 5-octanoyl salicylic acid and 4-methoxysalicylic acid; retinoids such as retinoic acid and its derivatives (e.g., cis and trans); sulfur-containing D and L-amino acids and their derivatives and salts, particularly their N-acetyl derivatives, a preferred example of which is N-acetyl-L-cysteine; lipoic acid; sebostats such as flavonoids and bioflavonoids; simmonol sulfate and its derivatives, bile salts such as deoxycholate and cholate; abietic acid; adapalene; allantoin; aloe extract; arbietic acid and its salts; aryl-2,4 dioxoxazolidine derivatives; ASEBIOL® (available from the Laboratories of Somerville, NJ) Available from Serobiologiques; azaleic acid; barberry extract; bearberry extract; belamcanda chinensis; benzoquinolinone; benzoyl peroxide; berberine; BIODERMINE® (available from Sederma, Brooklyn, NY); bioflavinoids; bisabolol; S-carboxymethylcysteine; carrot extract; cassin oil; clove oil; citral; citronellal; climazole; CREMOGEN® M82 (available from Dragoco, Totowa, NJ); cucumber extract; dehydroacetic acid and its salts; dehydroeplandersterone salicylate;Dichlorophenylimidazole dioxolane, commercially available as COMPLETECH MBAC-OS® (from Lipo, located in Paterson, NJ); DL-valine and its esters; DMDM ​​hydantoin; Epicutin TT (available from CLR); erythromycin; escinol; ethylhexyl monoglyceryl ether; ethyl 2-hydroxyundecanoate; farnesol; farnesol acetate; geranoil; glabridin; gluconic acid; gluconolactone; glyceryl monocaprate; glycolic acid; grapefruit seed extract; gugulipid lipid); Hederagenin (available from Maruzen); Hesperitin; Hinokitol; Hop extract; Hydrogenated rosin; 10-hydroxydecanoic acid; Ichthyol; Interleukin-1α antagonist; Iodo-2-propynyl butylcarbamate; Kapilarine (available from Greentech); Ketoconazole; Lactic acid; Lemongrass oil; Lichochalcone LR15 (available from Maruzen); linoleic acid; LIPACIDE® C8CO (available from Seppic, located in Paris, France); lovastatin; 4-methoxysalicylic acid; metronidazole; minocycline; soapberry; neem seed oil; vitamin B3 compounds (such as niacinamide and nicotinic acid); nisin; 5-octanolysalicylic acid; octopirox; panthenol; 1-pentadecanol; peonia extract; peppermint extract; Phelladendron extract; 2-phenyl-benzothiophene derivatives; phloretin; PHLOROGINE® (available from Secma); phosphatidylcholine; proteolytic enzymes; quercetin; red sandalwood extract; resorcinol; rosemary extract; rutin; sage extract; salicin; salicylic acid; skullcap cap) extract; Siber Hegner extract; Siberian saxifrage extract; Silicol;Examples of ingredients include sodium lauryl sulfate, sodium sulfoacetamide, Sophora Extract (available from Maruzen), sorbic acid, sulfur, sunder vati extract, tea tree oil, tetracycline, tetrahydroabietic acid, thyme extract, thioxolone, tocopherol, trehalose 6-undecylenate, 3-tridecen-2-ol, triclosan, tropolone, UNITRIENOL® T27 (available from Unichem, Gouda, Netherlands), vitamin D3 and its analogs, white thyme oil, willow bark extract, wogonin, ylang ylang (ylang ylang), zinc glycerolate, zinc linoleate, zinc oxide, zinc pyrithione, zinc sulfate, and mixtures thereof.

[0267] In one embodiment, the methods of the present invention may be used in conjunction with the administration of one or more "anti-inflammatory" compounds. Representative, non-limiting examples of anti-inflammatory compounds include azelaic acid, clindamycin, niacinamide, and tretinoin. [Example]

[0268] [Example 1] Treatment of inflammatory and cystic acne A total of six patients were treated. The affected areas were treated with a heating mask at 40°C for approximately 1 hour, followed by 10% ALA gel and 630 nm red light at 37 J / cm. 2 was applied.

[0269] Results included a mild sunburn-like reaction followed by pustule rupture on day 3 and 95% clearance at 1 month. Results persisted for at least 6 months. See Figure 1, which shows baseline (Figure 1A) and 3-month (healed) results (Figure 1B). See also Figure 2, which shows baseline (Figure 2A), 1-hour (using a poryphorin camera) (Figure 2B), 3-day (Figure 3B), and 6-week results.

[0270] [Example 2] Treatment of basal cell carcinoma on the extremities Patients with nodular basal cell carcinoma were treated. The affected areas were treated with a heating pad at 39°C. Without curettage, each was also treated with 20% ALA gel. 37 J / cm 2 of blue light at 410 nm.

[0271] A broad rim of poryphorins was detected. See Figure 3, including Figure 3B, which shows a broad rim of pophyrins in the heated region.

[0272] [Example 3] Treatment of basal cell carcinoma on the extremities A patient with recurrent nodular and invasive basal cell carcinoma was treated. The affected areas were treated with a 40°C heating pad. Each was also treated with 10% ALA gel for 1 hour, followed by curettage. 37 J / cm 2 The specimen was exposed to 630 nm red light.

[0273] The results show that a single treatment cured the patient for at least six months. See Figure 4, which shows baseline (Figure 4A), one year after curettage alone (Figure 4C), and six months after treatment with PDT (Figure 4D).

[0274] [Example 4] Treatment of BCC on the scalp A patient with invasive basal cell carcinoma of the scalp was treated with heat treatment of the lesion area using a 40°C heating pad. After applying a 20% ALA solution for 1 hour, 10 J / cm 2 The cells were exposed to 417 nm blue light.

[0275] Biopsy showed the absence of lesions one month after treatment (Figure 6B). Further evidence showed that the lesions had healed at one month (Figure 5), which persisted for 16 months after treatment.

[0276] [Example 5] Treatment of SCC-IS Patients with SCC-IS were treated. The lesion areas were thermally treated with a 40°C sodium acetate heating pad. A 20% ALA solution was applied to each for 20 minutes. Blue light was applied at 10 J / cm. 2 The light was irradiated at 417 nm.

[0277] The results show that each was cured one year after a single treatment. See Figure 7.

[0278] [Example 6] Treatment of refractory disseminated porokeratosis with associated SCC A patient with refractory disseminated porokeratosis with associated SCC. The affected area was thermally treated using a 40°C heating pad. 10% ALA gel was applied for 1 hour. 37 J / cm 2 The cells were exposed to red light having an energy of 1000 kJ / cm and a wavelength of 630 nm.

[0279] The results are shown in Figure 9, including baseline (Figure 9A), 1 week (Figure 9B), and 1 month (Figure 9C).

[0280] [Example 7] Treatment of actinic keratosis A patient with actinic keratosis was treated. Heat was applied to the affected area using a 40°C heating mask. After 20 minutes of incubation, a 20% ALA solution was applied. Light was then applied.

[0281] The results are shown in Figure 10, including baseline (Figure 10A), 20 minutes (Figure 10B), 1 day (Figure 10C), 1 week (Figure 10D), and 2 months (Figure 10E). Significant porphyrins are shown.

[0282] [Example 8] Treatment of actinic keratosis Heat was applied to the lesion area using a heating mask at 40° C. After 30 minutes of incubation, a 20% ALA solution was applied, followed by exposure to light.

[0283] The results are shown in Figure 11, including baseline (Figure 11A), 30 minutes (Figure 11B), 1 day (Figure 11C), and 1 week (Figure 11D). Further increases in porphyrins are evident.

[0284] [Example 9] Treatment of actinic keratosis After 60 minutes of incubation, a 20% ALA solution was applied for 1 hour (room temperature 70°F), followed by exposure to light.

[0285] The results are shown in Figure 12, including baseline (Figure 12A) and 1 hour, showing no fever and minimal porphyrins.

[0286] [Example 10] Treatment of moderate inflammatory and pustular acne To treat index patients with moderate inflammatory and pustular acne on the face, 10% aminolevulinic acid (ALA) was administered at 37 J / cm after 1 hour of incubation with a sodium acetate warming mask (skin temperature 40°C). 2 As shown in Figure 17 and Table II, the reduction in lesion counts persisted for 9 months after a single session of thermal PDT.

[0287] [Table 1]

[0288] [Example 11] Treatment of moderate inflammatory and pustular acne 37J / cm after sodium acetate warming mask (skin temperature 40℃) 2 A patient with moderate inflammatory and pustular acne on the face was treated with 10% aminolevulinic acid for 1 hour with 635 nm red light. As shown in Figure 18 and Table II, tissue repair of the acne scar was demonstrated 9 months after a single thermal PDT.

[0289] [Table 2]

[0290] [Example 12] Treatment of actinic keratosis Facial skin with actinic keratosis was treated with a 30-minute incubation with 20% ALA at 40°C using a sodium acetate warming mask, compared with a 1-hour incubation at room temperature (room temperature 70°F, skin temperature 30°C). Increased porphyrins were observed, as shown in Figure 23. Porphyrin images were captured using a VISIA-CR® 4.1 camera system and analyzed using Image-Pro® Plus 7.0 (IPP®, Media Cybernetics Inc.) image analysis software. The intensity of the PpIX fluorescent signal measured within the masked area was quantified on a scale of 0 to 255.

[0291] [Table 3]

Claims

1. 1. A topical composition comprising 10% to 20% 5-aminolevulinic acid HCl for use in a method of treating basal cell carcinoma on an extremity of a patient, the method comprising: (a) incubating the topical composition on a treatment area on a patient's extremity, while optionally heating the treatment area on the patient's extremity; (b) 5 J / cm2 to the treatment area where the topical composition was applied. ２ to 50 J / cm ２ administering a dose of light; and (c) adjusting the amount of light based on a simultaneous analysis of at least one of penetration of 5-aminolevulinic acid HCl or heat level within the treatment area; the light has a wavelength between 320 nm and 780 nm; The topical composition.

2. 10. The topical composition of claim 1, wherein the topical composition comprises 10% 5-aminolevulinic acid HCl or 20% 5-aminolevulinic acid HCl.

3. The topical composition of claim 1 , wherein the light is administered for 5 to 60 minutes.

4. 10. The topical composition of claim 1, wherein the light is blue light having a wavelength between about 380 nm and about 500 nm.

5. 10. The topical composition of claim 1, wherein the light is red light having a wavelength between about 620 nm and about 750 nm.

6. The topical composition of claim 1 , wherein the light is administered by an LED light source.

7. The topical composition of claim 1 , wherein the topical composition is a nanoemulsion.

8. The topical composition of claim 1 , wherein the basal cell carcinoma is nodular or invasive.

9. The light dose is 37 J / cm ２ 2. The topical composition of claim 1, wherein

10. The topical composition of claim 1, wherein the treatment area is heated to a temperature of about 20°C to about 50°C.

11. 10. The topical composition of claim 1, wherein the extremity is the scalp, and step (a) comprises warming the topical composition on the patient's scalp while simultaneously heating the patient's scalp.

12. The topical composition of claim 1 , wherein the extremity is the patient's foot.

13. 1. A topical composition comprising 10% to 20% 5-aminolevulinic acid HCl for use in a method of treating squamous cell carcinoma of the skin in a patient, the method comprising: (a) incubating the topical composition on the treatment area of ​​the patient, while optionally heating the treatment area; (b) 5 J / cm2 to the treatment area where the topical composition was applied. ２ to 50 J / cm ２ administering a dose of light; and (c) adjusting the amount of light based on a simultaneous analysis of at least one of penetration of 5-aminolevulinic acid HCl or heat level within the treatment area; where: the light has a wavelength between 320 nm and 780 nm; The topical composition.

14. The topical composition of claim 13, wherein the squamous cell carcinoma is invasive.

15. The topical composition of claim 13, wherein the light is administered to expose the treatment area to light for about 1 minute to about 30 minutes.

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