Photodynamic therapy method for skin disorders

Abstract

To provide a treatment of skin diseases and disorders, including but not limited to acne, with reduced side effects.SOLUTION: Provided is a method for treating facial acne in a subject in need thereof. The method comprises: (i) administering heat to a lesion area of subject's skin by using a heat-delivery device to achieve, for an appropriate period of time, a temperature of about 38°C to about 42°C; (ii) incubating a pharmaceutical composition comprising at least one photosensitizer 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 lesion area for an appropriate period of time; and (iii) administering an appropriate dose of red light to the lesion area, thereby treating the facial acne.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 533,558, filed July 17, 2017. and the benefit of U.S. Provisional Patent Application No. 62 / 534,973, filed July 20, 2017. No. 60 / 699,999, filed on Dec. 1, 2003, the contents of which are incorporated herein by reference in their entirety. do.

[0002] The present invention generally relates to the treatment of skin diseases and disorders using red light photodynamic therapy in conjunction with heat. In certain embodiments, the present invention relates to a method for treating skin damage caused by heat treatment. Red light photodynamic therapy is used to treat acne, non-melanoma skin cancer (NMSC), and actinic keratoconjunctivitis. The present invention relates to a method for treating disseminated superficial actinic porokeratosis (AK) or disseminated superficial actinic porokeratosis (DSAP). [Background technology]

[0003] Skin diseases are the most common human illnesses, affecting 30% to 70% of the population and potentially The rates are even higher in high-risk subpopulations (Hay RJ et al., J Invest Dermatol.2014.134(6):1527-1534) The medical burden was similarly significant, with direct medical costs estimated at nearly $27 million and lost An additional $11 billion in productivity is estimated. (Lim HW et al. J Am Acad Dermatol.2017;76:958-972).

[0004] Acne is the most common skin disease. Non-inflammatory acne is the most common type, and milia Inflammatory acne is usually caused by bacteria (P. acnes ( It is associated with P. acnes infection and is characterized by papules, pustules, nodules, and cysts. The most common triggers for both types of acne are hormonal, and many Many people experience at least a mild form of acne during adolescence. Other triggers include diet, smoking, and Treatments may include stress and certain medications. Acne often affects appearance at a critical age. This can have a negative impact on quality of life. (Kligman AM. J Invest Dermatol.1974;62:268-87).

[0005] topical medications for treating acne, such as benzoyl peroxide, retinoids, and antibiotics; Various methods are known. (Thiboutot D, et al. J Am Acad Dermatol.2009;60(Suppl 5):S1-50). Antibiotics, Systemic medications, such as thrombocytopenic and hormonal therapy, may also be used, although these approaches Many of these have undesirable side effects and / or do not produce acceptable results. Antibiotic resistance is on the rise, with over 50% of P. acnes Many countries have reported that strains of B. nescifera are resistant to certain topical medications.

[0006] Ultraviolet (UV) / blue light is mildly effective due to its anti-inflammatory effects mediated on skin cells. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of mild to moderate acne. The combination of photoactivators and high-intensity red light has proven effective, but (Hongcharu W, et al., J Invest D ermatol.2000 Aug;115(2):183-92),Sakamoto FH et al.,J Am Acad Dermatol.2010 Aug;6 3(2):183-93);(Sakamoto FH et al.J Am Aca d 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] Skin conditions, including but not limited to acne, that provide improved results and reduced side effects There remains a need for novel approaches to the treatment of cancer and disorders. [Means for solving the problem]

[0009] The present invention uses red light photodynamic therapy on pre-heated skin to treat skin disorders or Methods for treating disorders are provided.

[0010] In a first aspect of the embodiment, the present invention relates to a method for treating facial acne. 1. A method of treating facial acne in a subject, comprising: (i) heating a skin treatment solution at about 38°C to about 42°C for a suitable period of time; Applying heat to the affected area of ​​the subject's skin using a heat delivery device to achieve a skin temperature. (ii) incubating the photoactivator for a period of less than about 14 hours to provide an incubated pharmaceutical composition; (iii) administering to the lesion area a therapeutically effective amount of a pharmaceutical composition comprising: (iv) applying an appropriate dose of red light to the affected area; and therapeutically treating said 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. ystic).

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

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

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

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

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

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

[0019] In one embodiment, the pharmaceutical composition comprises nanoparticles containing 10% 5-aminolevulinic acid HCl. It is an emulsion.

[0020] In another embodiment, the light is from about 620 nm to about 640 nm, more specifically from about 63 It has a wavelength of 0 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 some cases, this reduction persists for at least three months.

[0023] In an exemplary embodiment, treatment results in a decrease in the severity of the subject's acne lesions. In 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). will be done.

[0025] In a second embodiment, the present invention involves treating non-melanoma skin cancer of the face. 1. A method for treating facial non-melanoma skin cancer in a subject, comprising: (i) treating the skin with acetaminophen at a temperature of about 38°C for a suitable period of time; A heat delivery device is used to heat the affected area of ​​the subject's skin to achieve a skin temperature of about 42°C. (ii) applying heat to the area for less than about 14 hours to provide an incubated pharmaceutical composition; (iii) incubating the pharmaceutical composition containing the photoactive agent in the affected area for a period of time; (iv) applying an effective amount of the incubated pharmaceutical composition to the affected area; administering an appropriate dose to therapeutically treat said non-melanoma skin cancer of said face. , method.

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

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

[0028] In one embodiment, the non-melanoma skin cancer is basal cell carcinoma and the heat is caused by: Add for about 30 minutes.

[0029] In another embodiment, the non-melanoma skin cancer is basal cell carcinoma and the heat is , is added 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). will be done.

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

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

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

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

[0035] In a third aspect, the present invention relates to a method for treating actinic keratosis (AK) on the face. 1. A method for treating facial actinic keratosis (AK) in a subject, the method comprising: (i) administering for an appropriate period of time; A heat delivery device is used to heat the skin of the subject to achieve a skin temperature of about 38°C to about 42°C. (ii) applying heat to the affected area of ​​the patient for about 14 hours to provide an incubated pharmaceutical composition; (iii) incubating the pharmaceutical composition comprising the photoactive agent in the lesion area for a period of less than 10 minutes; (iv) applying a therapeutically effective amount of the incubated pharmaceutical composition to the affected area; administering an appropriate dose of red light to therapeutically treat said actinic keratosis. It is the law.

[0036] In one embodiment, the lesion area is heated for about 30 minutes. The lesion area is heated to approximately 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). will be done.

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

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

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

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

[0042] In a fourth aspect, the present invention provides a method for treating disseminated superficial actinic porokeratosis (DSAP) of the face. Disseminated superficial actinic porokeratosis (DSAP) of the face in subjects requiring placement 2. A method of treating a patient with rheumatoid arthritis, comprising: (ii) applying heat to the affected area of ​​the subject's skin using a heat delivery device; The pharmaceutical composition containing the photoactive agent is incubated for a period of less than about 14 hours to provide a pharmaceutical composition containing the photoactive agent. (iii) applying a therapeutically effective amount of the incubated pharmaceutical composition to the affected area. (iii) administering an appropriate dose of red light to the affected area; therapeutically treating the AP.

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

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

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

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

[0047] In exemplary embodiments, the incubation period is less than about 10 minutes, less than about 5 minutes, or less than about 1 minute. be. [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 relates to the heating of the skin, which increases the efficacy of photodynamic therapy (PDT) and A pharmaceutical composition containing a photosensitizing agent) and a pharmaceutical composition containing a photoactivator (or a pharmaceutical composition containing a photoactivator) This is based on the observation that the use of hydroxybenzoates allows for increased absorption of the pharmaceutical composition. In some embodiments, the methods of the present invention may result in a complete disappearance and / or reduced recurrence of the disease or disorder. , allowing for improved results.

[0050] I. Definition As used herein, the term "acne" refers to the secretion of sebaceous glands in the pilosebaceous hair follicle. Inflammation of the ceous follicles and / or skin glands It refers to sexually transmitted diseases, usually consisting of papules, pustules, cysts, nodules, comedones, or other blemishes. s) or characterized by skin lesions.

[0051] As used herein, the term "actinic keratosis" or "AK" refers to skin irritation caused by sun exposure or other factors. caused by prolonged exposure to radiant energy, such as sunlight Actinic keratosis represents a precancerous skin lesion associated with long-term exposure. These are small, red, rough hyperkeratotic lesions that occur on irritated areas.

[0052] As used herein, the terms "administer" and "administration" include topical, subdermal ( subdermal, subcutaneous, intradermal, enteral, parenteral, rectal, nasal, intravenous, intramuscular, intraperitoneal Providing or causing to be provided with any substance to a subject, including by any other route Represents.

[0053] As used herein, the term "basal cell carcinoma" or "BCC" refers to a tumor that develops at the base of the epidermis. Basal cell carcinoma is a malignant neoplasm of keratinocytes present in the basal layer of the skin. Basal cell carcinoma is usually caused by exposure to UV rays. BCC usually does not spread beyond the primary site, but BCC may be nodular-ulcerative, superficial, pigmented, or patchy. It can be classified as a peel type.

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

[0055] The term "cancer" as used herein refers to cancer characterized by uncontrolled cell division. These cells often spread to adjacent tissues through invasion. colonization at distant sites by direct proliferation at the site of implantation or through metastasis n) refers to a disease or disorder characterized by the ability to invade other tissues.

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

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

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

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

[0060] The term "essentially free" as used herein in relation to tolerance means that the or skin irritation occurring during symptoms, such as stinging, flushing or redness, or mild, transient symptoms represents a trivial or insignificant occurrence of

[0061] The term "essentially free" as used herein in relation to safety means that the represents a trivial or insignificant occurrence of a minor or serious adverse event.

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

[0063] As used herein, "high rate of clinical response" or "high efficacy" or "substantial reduction" The term "clear" refers to a reduction of about 45% or more in lesion counts, or when the subject is "clear" or "almost clear." " or related to a "2-grade improvement from baseline." It is possible.

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

[0065] As used herein, the term "inhibit" (and / or "reduce," "alleviate") "to prevent" or "to inhibit" or "to avoid" or any variation of these terms The term) refers to any measurable reduction 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., ulcers) in a designated area of ​​the body. For example, on the face, lesions (e.g., papules and rashes) present on the forehead, cheeks, nose, and chin This represents the number of pustules.

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

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

[0070] The term "low-risk location" as used herein in relation to non-melanoma skin cancer represents the trunk or limb region.

[0071] As used herein, the term "margin" refers to the area immediately adjacent to or surrounding the tumor site. It refers to an area surrounding the site of the tumor but showing no visible signs of carcinoma. The "standard" surgical margins recommended for various malignant lesions ns) vary.

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

[0073] As used herein, the term "photodynamic therapy" or "PDT" refers to a After administration of the photosensitizer (e.g., to the skin or mucosa), the photosensitizer is activated and converted into a cytotoxic to convert the cytoplasmic ... This technique involves exposing the cells to photoactivating light. (Kennedy JC, et al. (See J Photochem Photobiol B. 1990).

[0074] As used herein, a "photosensitizing agent" refers to a "NT" or "photosensitizer" or "photoactive (PH Terms such as "photoactive" and "photoactive" refer to sensitivity, responsiveness, or receptivity to light energy. A material, element, chemical substance, solution, compound, matter, or thing that is reactive or responsive In certain embodiments, the photosensitizer may be activatable, i.e., There may be a single regulated O2 production that responds specifically to the biomarker.

[0075] As used herein, the term "porphyrin" refers to a porphyrin having a methine bridge (=CH-) Four modified pyrrole subunits interconnected at their α-carbon atoms via Expanded porphyrins represent a group of heterocyclic macrocyclic organic compounds consisting of: By increasing the number of heterocycles or bridging carbons in the existing porphyrin skeleton, , φ (phi) arises from the expansion of electron conjugation.

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

[0077] As used herein, the term "safe" refers to the absence of adverse events (e.g., during the course of treatment). any undesired or unintended sign, symptom or disease that manifests or worsens with means not having or essentially not having

[0078] As used herein, the term "scar" refers to the healing of an injury to the skin or tissue. This refers to the scars that are created during the process. Scars are permanent and cannot be completely removed. Scars that may be treated in accordance with the methods described herein include, for example, atrophic scars and hypertrophic scars. More specifically, acne scars include ice pick, boxcar, and roll-on scars. bridges and tunnels, gross atrophy may be atrophic, dystrophic or keloid scars .

[0079] As used herein, the term "target" refers to a molecule that is attenuated by the disclosed methods. A target refers to a cell or tissue of interest that is intended to be treated or destroyed. When the photosensitizer is incorporated and then exposed to sufficient radiation, the target tissue is weakened or destroyed. will be done.

[0080] Conversely, the term "non-targeted" as used herein refers to a substance that is not weakened by the treatment method. These refer to cells or tissues of interest that are not intended to be removed or destroyed. 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 sufficient to treat a subject. An effective amount of a therapeutic agent and / or therapeutic modality refers to an amount of a therapeutic agent or therapeutic modality that is sufficient to treat an individual. The degree of sensitivity of the individual, the age, sex and weight of the individual, and the individual's idiosyncratic response will determine the risk of developing a serious illness. It will fluctuate.

[0082] As used herein, the term "topical" refers to any application, e.g., by hand or applicator. By using a dermatologist, the device is laid directly on the skin that needs treatment. Or it means spreading.

[0083] As used herein, the term "skin" refers to the surface of a mammalian subject, such as a human. The epidermis, dermis, and hypodermis (i.e., the subcutaneous tissue) that cover most of the It is a multi-layered organ, including the mucous membrane that is in contact with the outer skin.

[0084] As used herein, the term "skin cancer" includes lentigo, malignant , maligna), melanoma, keratoacanthoma, basal cell carcinoma (BCC), squamous cell carcinoma (SC C), Merkel cell carcinoma (MCC), sarcoma, angiosarcoma, cutaneous lymphoma, sweat gland carcinoma It represents sebaceous gland carcinoma and sebaceous gland carcinoma.

[0085] As used herein, the term "squamous cell carcinoma" or "SCC" refers to a flat cell carcinoma of the skin. It refers to a form of skin cancer that develops in epithelial cells and is sometimes called cutaneous squamous cell carcinoma. Like BCC, SCC affects areas of the skin with high levels of UV exposure, such as the head, face, and neck. SCCs usually grow quickly and tend to metastasize. SCCs can develop de novo or SCC can arise from linear keratosis (approximately 0.5-16% conversion rate). SCC generally develops in situ ( SCCs are classified as either full-thickness (involving the full thickness of the epidermis) or invasive (penetrating the basement membrane). SCCs can be further classified as well-, moderately, or poorly differentiated. .

[0086] As used herein, the term "subject" refers to a mammal, e.g., a human, a pet animal, animals (e.g., dogs, cats, birds, etc.), livestock (e.g., cattle, sheep, pigs, horses, poultry, etc.) Some animals are categorized as: In an embodiment, the subject is a human.

[0087] As used herein, the term "thermal treatment device" refers to a device that is either direct or indirect. This refers to any device capable of heating the skin, whether or not it is a medical device.

[0088] As used herein, the term "treat" or "treating" means (i) (ii) inhibiting or delaying the onset of clinical symptoms of a disease occurring in a mammal; inhibiting the onset of the disease or its recurrence or at least one of them; (iii) arresting, reducing or delaying the clinical or subclinical symptoms of ) refers to the alleviation or attenuation of one or more clinical or subclinical symptoms of a disease.

[0089] As used herein, the term "topical" refers to the administration of a compound by application onto a body surface. With respect to administration, the present invention includes, but is not limited to, transdermal administration and administration through mucous membranes.

[0090] II. Treatment Methods The present invention uses photodynamic therapy (PDT) in conjunction with heat to treat skin diseases or disorders. This provides a way to

[0091] Advantageously, the method of the present invention achieves comparable or better results while reducing the It is possible to shorten the incubation time of the photosensitizing agent and / or the duration of treatment compared to methods known in the field. In an exemplary embodiment, the method of the present invention provides improved When used to treat skin cancer, the method of the present invention provides a complete incision This allows for an increased rate of recurrence, resulting in a reduction in recurrence or a shortened time to recurrence.

[0092] In one embodiment, the present invention provides a method for treating a skin disease or disorder. 1. A method of treating a skin disease or disorder in an elephant, comprising: (i) achieving an appropriate temperature for an appropriate time; administering heat to the affected area of ​​the subject's skin using a heat delivery device to i) adding a pharmaceutical composition containing a photoactive agent for a period of less than about 14 hours to provide an incubated pharmaceutical composition (iii) incubating the composition; and (iv) administering a therapeutically effective amount of the composition to the affected area for a suitable period of time. (iii) administering a dose of light to the affected area; Thereby, the method comprises 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 vary. In some embodiments, the skin disease or disorder is a cancerous lesion, a precancerous lesion, or acne. Areas of skin that can be treated include the head, face, neck, arms, legs and torso, hands and feet ( In certain embodiments, the area to be treated includes a portion of skin on the skin of the feet. , head, face, neck or parts thereof.

[0094] Actinic keratosis. In one embodiment, the skin disorder to be treated according to the methods of the present invention is In certain embodiments, the precancerous lesion is actinic keratosis (AK). AK (also known as actinic keratosis) is the most common precancerous skin lesion. Actinic keratosis lesions are often multifocal, appearing as crusty, scaly growths. Generally, they are about 2mm to 7mm in diameter. AK lesions range in color from skin-like to reddish. The color may vary from pale to pale and is often hyperkeratotic.

[0095] AK is typically caused by excessive exposure to ultraviolet (UV) light. In the United States, AK can be caused by overexposure to X-rays. These lesions can be: Typically 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 methods of the present invention is AK on the face, neck or parts of these.

[0096] In one embodiment, the methods of the present invention are used to treat precancerous lesions other than actinic keratosis. In certain embodiments, the methods of the present invention are used to treat skin conditions other than actinic keratosis. It is used to treat a disease or disorder.

[0097] Non-melanoma skin cancer. In another embodiment, a skin disorder treated according to the methods of the present invention is a cancerous lesion. In certain embodiments, the cancerous lesion is a non-melanoma skin cancer (NMSC). Non-melanoma skin cancer includes all types of cancer that occur within the skin and are not 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 "keratinocytes" to distinguish them from melanoma. It is also called "keratinocyte carcinoma."

[0098] Basal cell carcinoma arises from the basal keratinocytes of the epidermis, hair follicles, and eccrine sweat glands. 80% of cases develop from this type of cell, usually on the head and neck (approximately 90%). They usually grow slowly (e.g., 1–2 cm over several years) and cannot spread to other parts of the body. These are rare (0.0003-0.05%). Through the irregular growth of sexual, finger-like extensions, the tumor invades tissue in a three-dimensional manner. Proliferating tissue is present at the outer edge of the lesion, while in the central region, cell apoptosis and subsequent regeneration occur. It is accompanied by ulceration.

[0099] The clinical features of BCC depend on the subtype: nodular BCC ("classical basal cell carcinoma"); ), is the most common subtype (more than 60% of cases), Appears as a dark brown nodule with curled edges, superficial telangiectasias, and ulceration or crusting .

[0100] Superficial BCC accounts for up to 20% of cases and occurs on the trunk in sun-protected areas. It appears as pink scaly patches or thin plaques, so it is considered superficial BC. C is Bowen's disease, psoriasis, discoid eczema, or tinea corporis Pigmented BCC occurs more commonly in patients of Far Eastern origin and can result in It may be mistaken for nodal melanoma. Morphea (sclerosing) BCC (cicatricial basal cell (also known as carcinoma) has the poorest prognosis and appears as subtle, scar-like plaques and vague Has a margin.

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

[0102] In one embodiment, the method of the present invention is directed to undifferentiated BCC, more particularly superficial BCC. It is used to treat

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

[0104] In an exemplary embodiment, the BCC treated according to the methods of the present invention is a mixed histology BCC. have a histological pattern, i.e., contain two or more major histological patterns.

[0105] BCC is primarily caused by cumulative exposure to UV light, although it may also occur if the patient has not previously been exposed to radiation. It can also occur in subjects who have had previous exposure. Elderly people and men are at increased risk. Other risk factors include burn scars, smallpox scars, xeroderma pigmentosum, and basal cell nevi. After developing a BCC, patients are at risk for developing subsequent BCCs at other sites. increases significantly.

[0106] In one embodiment, the methods of the present invention can be used to treat BCC. In embodiments, the method is for the treatment of nodular, micronodular, cystic, invasive, superficial, pigmented , erythroderma ulcer (also known as "Jacobi ulcer"), Pi Concussive fibroepithelioma, polyploid, pore-like or aberrant The present invention can be used to treat BCC selected from the group consisting of: ant) ​​BCC.

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

[0108] In an exemplary embodiment, the BCC treated in accordance with the present invention is a tumor of the trunk, extremities, hands, or feet. exists above.

[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, or greater than about 4 cm. The lateral delimitation of the lesion is greater than about 5 cm, or greater than about 6 cm. Deep demarcation may be aided by biopsy and / or imaging techniques. It can be estimated by surgery.

[0110] BCC can be primary, incompletely resected, or recurrent. Therefore, BCC is not primary. BCC, in an exemplary embodiment, is a nodular or invasive It could be.

[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 tumor in location or size or both. Based on this, the BCC is at low risk for recurrence. Located in a risk location and less than 20mm in size; Located in a medium risk location and less than 10m or are in a high-risk location and are less than 6 mm in size. In addition, lesions were considered low risk according to their borders, i.e., well-defined. It can be done.

[0113] In another embodiment, the BCC treated according to the methods of the present invention may be characterized by its location, size, or Based on both, BCCs are at high (or higher) risk for recurrence. In an embodiment, the lesion is in a low-risk location and is 20 mm or larger in size; Located in a medium risk location and measuring 10 mm or more; or Located in a high risk location and and 6 mm or more in size. Also, in terms of the boundary, i.e., the boundary is well defined. Lesions may be considered high risk because they are not recurrent or are recurrent.

[0114] About 20% of skin cancers are caused by 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 less likely to spread than melanoma. It's much less propagable.

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

[0116] SCC may arise de novo or may be preceded by actinic keratosis (AK) There is a known conversion rate of about 0.0003% to about 0.05%. AK is present only in a portion of the epidermis. Histologically, AK is distinguished from SCC. SCC in situ is a full-thickness epidermal tumor. It is characterized by sharply demarcated, erythematous, scaly papules or plaques. Invasive SCC also involves penetration of the epidermal basement membrane, resulting in an indurated, scaly papule. Invasive SCC is characterized by moderately or poorly differentiated tumors or plaques. They may be classified, and the degree of differentiation correlates with invasiveness.

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

[0118] In another specific embodiment, the SCC is de novo, i.e., the patient has previously undergone AK therapy. I have never been diagnosed with it.

[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. In certain embodiments, the method is for the treatment of well-differentiated SCC, moderately differentiated SCC and and poorly differentiated SCC. can be.

[0121] The location of the lesion can vary. In an exemplary embodiment, the lesion treated in accordance with the present invention The SCC is located on the head, neck, or face. Check, periorbital area, auricular area, ear, temple, forehead or scalp The target site is selected from the group consisting of:

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

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

[0124] SCC can be primary, incompletely resected, or recurrent. In an exemplary embodiment, the SCC is a locoregionally recurrent SCC. It 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 tumor in location or size or both. In certain embodiments, the lesion is a SCC with a low risk of recurrence based on the Located in a risk location and less than 20mm in size; Located in a medium risk location and less than 10m or are in a high-risk location and are less than 6 mm in size. In addition, the lesions are considered to be well demarcated, i.e., well demarcated or well-defined. These tumors are differentiated into small tumors or have a depth of less than 2 mm and therefore may be considered low risk.

[0127] In another embodiment, the SCC treated according to the present invention may be characterized by location, size, or both. Based on the above, the SCC is at high (or higher) risk for recurrence. In terms of morphology, the lesions are in low-risk locations and are 20 mm or larger; medium-risk lesions or in a high-risk location and is 6 mm or larger; The size is more than 100 m. Also, in terms of boundaries, i.e., boundaries are not well defined. Lesions may be considered high risk because they are persistent or recurrent. Lesions may be considered high risk because they are thick or have 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. These include cutaneous lymphoma, cutaneous adnexal tumor, Kaposi's sarcoma, skin adnexal tumor and sarcoma.

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

[0130] Acne can be caused by one factor or a combination of factors, commonly genetics Predisposing factors, excessive production of sebum by the sebaceous glands, sebaceous follicle epithelium Changes in the keratinization process with abnormal desquamation of the icular epithelium, propionyl Proliferation of Propionibacterium acnes These include the release of inflammatory mediators and inflammatory substances in the skin.

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

[0132] Inflammatory acne includes papules (small, usually pink bumps), pustules (red at the base and red at the top), containing pus), nodules (large, solid, painful comedones deeply embedded in the skin) and cysts ( Painful and 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 This includes dead tissue and debris.

[0133] Representative, non-limiting examples of acne that can be treated by the methods disclosed herein include: Types include acne vulgaris, comedonal acne, papular acne, and premenstrual acne. l acne), prepubescent acne, toxic acne, cosmetic acne, pomade acne (poma de acne, detergent acne, exfoliative acne, gram negative acne tive acne), pseudofolliculitis, folliculitis, perioral dermatitis, and hidradenitis suppurativa (hidradenitis suppurativa). dradenitis suppurativa), cystic acne, atrophic acne (acne atrophica), bromide acne, chloracne, acne conglobata, detergent acne, epidemic acne (epidemic acne), summer acne, fulminant acne, halogen acne, induration acne, Iodide acne, keloid acne, mechanical acne, papular acne, pomade acne, premenstrual acne ( Premenstral acne, pustular acne, scurvy acne butica), acne scrofulosorum, urticarial acne (acne urticata), variatiform acne, toxic acne, propionic acid acne (pro pionic acne), epidermolytic acne, gram-negative acne, steroid acne, nodules and cysts Includes acne cystic and acne rosacea.

[0134] A grading system may also be used to classify the various stages of acne lesions. Grade 1, Microcomedones can appear as milia or blackheads. Grade 2 is a papule, a small, pink, inflamed bump. Grade 3 is a papule. Grade 4 is a nodular or pustular lesion that extends deep into the skin. Grade 5 is a very large, painful, solid lesion. be.

[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 part 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 present invention is mild acne. Mild acne is commonly classified by the appearance of blackheads and milia, but may also include papules and It may also contain pustules.

[0137] In another embodiment, the disease or disorder treated in accordance with the methods of the present invention is moderate acne. Moderate acne is characterized by more painful, deep-seated inflammation that can lead to scarring. It is generally characterized by the appearance of lesions that cause

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

[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 being treated for acne in accordance with the present invention is an adolescent. In embodiments, the subject is an adult.

[0141] Sweat pore keratosis. In one embodiment, the method of the present invention is directed to prokeratosis. It is used to treat porokeratosis. One or more atrophies surrounded by a characteristic hyperkeratotic ridge border, both clinically and histologically It is a crohn's disease of keratinization characterized by ectopic plaques.

[0142] The methods of the present invention treat all forms of prokeratosis. It can be used to treat: Classical porokeratosis of Mibelli (PM); Disseminated superficial porokeratosis disseminated superficial prokeratosis (DSP); linear pore keratosis, disseminated Palmar prokeratosis (PPPD) plantaris disseminata) and a variant of PPPD Various forms are recognized, including porokeratosis globosa. Other less common forms are also found in the literature. can be done.

[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 some embodiments, the methods of the present invention are used to treat multiple lesions simultaneously. do.

[0145] heating Heat is administered to the skin by any suitable heat delivery device. The skin is clean, dry, and The device may be adapted for direct application to the skin, or The energy source may be, for example, electrical, chemical, or other suitable means. Chemical, laser, microwave or radiofrequency Exemplary, non-limiting heat delivery devices include heating pads, heating masks, and This includes a hair dryer or infrared heater.

[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 heated when crystallized. The crystallization is typically performed in a liquid of supersaturated sodium acetate. caused by bending a small plate of ferrous metal with a notch embedded in it. In an exemplary embodiment, the mask is made of 2-play polyplastic. It is covered with two layers of paper.

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

[0148] In some embodiments, the heater can be placed on the face, for example, by placing the heater on a wheeled platform. Used to heat the skin. The subject is asked to choose the ideal temperature for skin heating (adjusted for comfort). In this embodiment, the subject is wearing protective eyewear. Protective gear (e.g., goggles) should be worn.

[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 may vary depending on the disease or disorder and location being treated. In one embodiment, the heat delivery device provides a temperature of about 20°C to 50°C, or more specifically, about 2 The mixture is heated to a temperature of 0°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 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; 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 this 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 maintained at a temperature of about 20°C to 50°C, or more specifically, about 20°C to about The surface temperature is heated to 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 this embodiment, the skin is heated to a temperature of greater than about 38°C, greater than 39°C, greater than about 40°C, or greater than about 41°C. The heating step is performed at a temperature above about 42°C, or above about 42°C.

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

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

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

[0159] In another embodiment, the period 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 is a condition that develops during exposure to heat. The time 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 period of exposure to heat is: About, about 20 minutes to about 40 minutes, or more specifically, about 30 minutes.

[0162] Without being bound to any particular theory, heating may increase one or more of the following: The rate of porphyrin production in the skin, absorption of the photosensitizer, or the amount of porphyrin in the surrounding area may be affected. The area of ​​treatment surrounding the lesion to generate a treatment margin.

[0163] In an exemplary embodiment, the rate of porphyrin production in the skin is measured using the methods disclosed herein. By heating as described above, the amount of hydroxybenzoates can be reduced by about 10%, about 20%, about 30%, about 40% or about It will be increased by more than 50%.

[0164] In an exemplary embodiment, absorption is achieved by heating as disclosed herein. Thus, the absorption may be increased by about 10%, about 20%, about 30%, about 40%, or about 50% or more. may reflect an increased ratio of photosensitizer uptake:lesion depth, or In certain embodiments, the ratio may be about 0.5:1 to about 1. 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 an exemplary embodiment, the area of ​​treatment is heated as disclosed herein. By doing so, the amount of the ion exchange reaction is increased by about 10%, about 20%, about 30%, about 40%, or about 50% or more. .

[0166] Optionally, the method may include one or more further pretreatment steps, i.e., before application of the photosensitizing agent: In one embodiment, the pretreatment may include scraping the skin (e.g., using sandpaper). The procedure may involve dermabrasion or microporation (used in the past).

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

[0168] The photosensitizer may be administered orally or parenterally, neat or with a conventional pharmaceutical carrier. They can be administered in combination.

[0169] Any suitable photosensitizer may be used in the method of the present invention. are known in the art. In one embodiment, the photosensitizer is a porphyrin, The fluororesin is selected from the group consisting of chlorophylls and dyes.

[0170] Non-limiting examples of photosensitizers suitable for use in the present invention include phthalocyanines, polyisocyanines, and the like. Porphyrin, porphyrin precursor, porphycene, naphthalocyanine, phenoselenazine um, hypocrellin, perylenequinone, texaphyrin, benzoporphyrin derivatives, porphyrin, purpurin, rose bengal, xanthene, porphycyanin (por phycyanines), isomeric porphyrins, pentaphyrins, sapphyrins, and chlorophyrins. Phosphorus, benzochlorin, hypericin, anthraquinone, rhodanols ), barbituric acid derivatives, ring-expanded porphyrins, dipyrromethenes, coumarins, azo dyes, Clidine, rhodamine, azine derivatives, tetrazolium derivatives, safranine, indocya Nin, indigo derivatives, indigo triazine derivatives, pyropheophorbide, pyrrole derivatives macrocyclic compounds, naturally occurring or synthetic porphyrins, naturally occurring or synthetic Chlorins, naturally occurring or synthetic bacteriochlorins, naturally occurring or synthetic isochlorins Sobacteriochlorin, naphthalocyanine, phenoxazine derivatives, phenothiazine derivatives Chalcoorganapyryllium derivatives , triarylmethane derivatives, rhodamine derivatives, fluorescein derivatives, verudin derivatives Toluidine blue derivatives, methylene blue derivatives, methylene violet derivatives, Nile Blue derivatives, Nile Red derivatives, phenazine derivatives, pinacyanol derivatives, Included are rasmocollins derivatives and indigo derivatives, and combinations thereof.

[0171] In one embodiment, the photosensitizer is a porphyrin. Phosphorus is a compound found in hematoporphyrin, metalloporphyrin, porphycene, pheophorbide, purpurins, chlorins, protoporphyrins, and phthalocyanines. do.

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

[0173] [ka] 5-Aminolevulinic Acid HCl ALA may be present in the form of a salt, such as HCl, or in a pharmaceutically acceptable salt, such as an amide or ester. As used herein, the term "ALA" can be used in any useful form. , represents all of the above compounds.

[0174] In one embodiment, the photosensitizer is a non-porphyrin agent. Non-porphyrin agents include anthraquinones, phenothiazines, and psoralens. ans), anthracycline, chalcogenopyrlium ium) dyes, xanthene, cyanine and curcuminoid sensitizers. do.

[0175] The photosensitizer may be administered in pure form or may be dissolved in a non-toxic solvent prior to application. The compound may be administered intravenously or in a topical formulation.

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

[0177] The amount of photosensitizer in a pharmaceutical composition (e.g., a topical dosage form) can vary. In the composition, the photosensitizer is about 0.1% by weight to about 75% by weight, more specifically, about 1.0% by weight. ~40% by weight, approximately 2.0% by weight ~ 30% by weight, approximately 5.0% by weight ~ 25% by weight, approximately 1 0% to approximately 20% by weight, approximately 8% by weight, approximately 10% by weight, approximately 12% by weight, approximately 14% by weight, approximately It is present in an amount of about 16%, about 18%, about 20% 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, preferably More specifically, less than about 15% by weight or less than about 10% by weight, but in either case Also, more than zero.

[0181] In one embodiment, the photosensitizer is formulated for topical delivery. , creams, gels, ointments, pastes, suspensions, lotions, foams, sprays, aerosols and and a solution.

[0182] The term "cream" refers to a semi-solid emulsion system containing both oil and water. Aqueous Cream is a medium-oil cream that is miscible with water and easily absorbed into the skin. BP. Water-in-oil (oily) creams are immiscible with water and therefore difficult to remove from the skin. These creams are emollients, lubricating, and moisturizing. (e.g. Oily Cream BP). Both systems contain natural or synthetic surfactants or emulsions. This requires the addition of either a stabilizer or a stabilizer.

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

[0184] Ointments are semi-solid, anhydrous substances that are occlusive, emollient, and protective. It limits the loss of water from the epidermis and is therefore moisturizing and hydrating. For example, white petrolatum (mineral oil, petrolatum) and water-soluble, for example, Macrogol (poly Ethylene Glycol Ointment BP can be divided into two major groups: do.

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

[0186] The term "gel" refers to a high molecular weight polymer, such as carboxypolymethylene (Carbohydrate). Permuta BP) or a semi-solid substitute gelled with methylcellulose tions) and can be considered as semi-plastic aqueous lotions. Gels are usually It is non-greasy, water-miscible, easy to apply and wash off, and is ideal for treating hairy areas of the body. Particularly suitable.

[0187] In one embodiment, the photosensitizing agent is formulated as a gel. Suitable pharmaceutically acceptable gelling agents for use in the gelation of the present invention include hydroxypropyl cellulose (e.g., Klucel HA), hydroxypropyl methylcellulose carrageenan, microcrystalline cellulose Lullose, carbomer, alginate, gellan gum, xanthan gum, veegum gum), hydroxyethyl cellulose formulations including, but not limited to, guar gum and carbomers is a substance that gives viscosity to the formulation so that it can be effectively applied to the affected area. .

[0188] The gel contains local anesthetics such as camphor, menthol, lidocaine, dibucaine, and pramoxine. drugs and analgesics; ciclopirox, chloroxylenol, triacetin, sulconazole, Nystatin, undecylenic acid, tolnaftate, miconazole, clotrimazole, Xiconazole, griseofulvin, econazole, ketoconazole and amphotericin It may further comprise an antifungal agent such as B.

[0189] The gel contains iodine, povidine-iodine, benzalkonium chloride, and sodium chloride. Benzoic acid, nitroflazine, benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenoxyethanol may also contain one or more preservatives, such as ethanol, resorcinol, and cetylpyridinium chloride. can be done.

[0190] The pH of the photosensitizer gel formulation is preferably within a physiologically acceptable pH range, e.g. For example, it is within the range of about 4.5 to about 7.5, more preferably about 5.0 to about 6.5, and more preferably 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 etc. To stabilize the pH, an effective amount of a buffer is preferably included. To adjust the pH, an acid or a base can be used.

[0191] The gel composition can be prepared by methods known in the art, for example, by the method described in Remington: The S Science and Practice of Pharmacy,1577-159 1,1672-1673,866-885(Alfonso R. Gennaro ed. .,19th ed.,1995);Ghosh,TKet al.,Transd. ermal And Topical Drug Delivery Systems( of composition according to the methods described by standard reference texts such as (1997). The composition can be prepared by mixing the ingredients, both of which are incorporated herein by reference. will be incorporated into

[0192] In an exemplary embodiment, the photosensitizer is a gel comprising 20% ​​aminolevulinic acid hydrochloride gel. In certain embodiments, the pharmaceutical composition is formulated as a 20% 5-aminolevulinic acid solution. LEVULAN® KERASTICK®, a topical formulation of phosphate hydrochloride In another specific embodiment, the pharmaceutical composition comprises LEVULAN® KERASTIC Not K(R).

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

[0194] In one embodiment, the photosensitizer is subdivided into unit doses containing appropriate amounts of the compound. The dosage form is a unit dosage form so that the

[0195] The amount of photosynthesizing agent to be administered is The choice of photosynthetic agent, the condition to be treated, the mode of administration, the individual subject, and the judgment of the practitioner will all play a role. Depending on the specificity of the preparation, smaller or larger doses may be required. In this dosage form, 1g (78mg) of 5-aminolevulinic acid hydrochloride gel (ALA) is administered. do.

[0196] The time between the application of heat to the lesion area and the application of the photosensitizer can vary. This is known as the "heat-to-drug interval" It may 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 seconds to approx. 10 seconds, approx. 10 seconds to approx. 20 seconds, approx. 20 seconds to approx. 30 seconds, approx. 30 seconds to approx. 40 seconds, approx. 40 The time is from about 50 seconds to about 50 seconds or from about 50 seconds to about 60 seconds.

[0198] In another embodiment, the heat-drug interval is from about 1 minute to about 60 minutes, more specifically, from about 0. 1 minute 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 The time is 30 minutes, about 30 to about 40 minutes, about 40 to about 50 minutes, or about 50 to about 60 minutes.

[0199] In further embodiments, the heat-drug interval is from about 1 hour to about 24 hours, more preferably Specifically, about 1 hour to about 4 hours, about 4 hours to about 8 hours, about 8 hours to 12 hours, about 12 hours The time is from about 1 hour 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. It may be applied in any suitable manner, for example, rubbed on, poured on, etc. ed on), application using an applicator (e.g., gauze pad, cotton swab, bandage, etc.), etc. In some cases, the composition may be applied by hand, for example, by rubbing or spraying. It can be applied to the skin in the form of a liquid, gel, cream, lotion, ointment, or solid. Stick" and the like.

[0201] In an exemplary embodiment, the lesion area is a precancerous lesion or lesions, for example, on the face or neck. In some embodiments, the lesion area is a site of a precancerous lesion or An area covering the site of a cancerous lesion, e.g., approximately 1, 2, 3, 4, 5, 6, 7, 8, In some embodiments, the distance is 9, 10, 15, 20, 25, 30, 40, or 50 cm. In another embodiment, the suitable location is an area where cancer prevention is desired. The location is a site where a precancerous or cancerous lesion was previously removed, and the method prevents recurrence. In yet another embodiment, the appropriate location is designed to prevent precancerous The lesion or cancerous lesion was previously incompletely removed.

[0202] In an exemplary embodiment, 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 site of acne, for example, an area about 10 mm in diameter. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40 or 50c In some embodiments, the suitable location is an area where acne prevention is desired. do.

[0203] The duration of exposure to the photosensitizing agent can vary. In one embodiment, the duration of exposure is 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 an exemplary embodiment, the duration of exposure to the photosensitizing agent is the same as that of the previous exposure to the photosensitizing agent due to pre-heating of the skin. In one embodiment, the duration of exposure may be shorter while still achieving the same effect. While achieving the effect of about 10, about 30, about 30, about 40, about 50 or about 60%, about 70 %, about 80% or about 90%.

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

[0206] Incubation time One advantageous feature of the present invention is the reduced incubation time of the photosensitizer that it allows. FDA approval of PDT for AK requires 14 hours of treatment with ALA before exposure to blue light. Incubation is required, although for many clinicians this is considered to be an extended period of treatment. What burden does this cause?

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

[0208] In another embodiment, the incubation time is about 10% to about 70%, about 20% to about 60%, about 30% to about 70%, about 80% to about 85%, about 90% to about 95%, about 10% to about 105%, about 10% to about 125%, about 125% to about 145%, about 145% to about 165%, about 165% to about 185%, about 185% to about 195%, about 20% to about 225%, about 225% to about 245%, about 245% to about 265%, about 265% to about 285%, about 285% to about 30 ... It is reduced by 0% to approximately 50%.

[0209] In certain embodiments, the incubation time is set to produce results equivalent to a photoactivator incubated for about 14 hours. While achieving this, it will be shortened by more than 30%.

[0210] In another specific embodiment, the incubation time is approximately 5 hours, resulting in results equivalent to a photoactivator incubated for approximately 5 hours. This is achieved by shortening the time by more than 20%.

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

[0212] In another embodiment, the incubation time is less than 14 hours, less than 13 hours, less than 12 hours, less than 1 hour, Less than 1 hour, Less than 10 hours, Less than 8 hours, Less than 7 hours, Less than 6 hours, Less than 5 hours, 4 hours less than, 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, It is 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, It may be about 16 seconds, about 14 seconds, about 12 seconds, or about 10 seconds, or less.

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

[0217] light After the photosensitizer is applied, the skin is heated and then heated to activate the photosensitizer. In the presence of oxygen, light of the appropriate wavelength and sufficient power is directed to the area to be treated to produce a reaction. These reactive oxygen species react with biomolecules and destroy cells in the treatment area. causing fatal damage to some of them.

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

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

[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. The wavelength is selected to correspond to or at least overlap with the excitation wavelength of the photosensitizer. More preferably, the wavelength matches the excitation wavelength of the photosensitizer and is resistant to degradation by non-target cells or tissues. It has good absorption.

[0222] The wavelengths are typically in the visible and near-infrared range, including wavelengths of about 320 nm to about 780 nm. However, specific photosensitizers usually respond to light with specific wavelengths. do.

[0223] In one embodiment, the light administered to the affected area is blue light. Visible blue light has a wavelength of about 475 nm. The dominant wavelength of the blue light used in the present invention may vary. The dominant wavelength of the blue light used in the method is about 450 nm to about 475 nm. In an embodiment, the dominant wavelength of the blue light used in the method 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 colored light can vary. In one embodiment, the source of blue light is DUSA Phar Blu-U(R) is obtained from maceuticals.

[0224] In one embodiment, the light is not blue light. In a particular embodiment, the light is Blu-U ( R).

[0225] In another embodiment, the light is not blue light and the photosensitizing agent is LEVULON® KER Not ASTICK(R).

[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 method of the present invention is about 630 nm to about 6 40 nm, or more specifically, about 635 nm. Sources of red light are varied. In one embodiment, the source of red light is BF-RhodoLED® (BioFr (obtained from ontera).

[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, more than one administration of light, e.g., 2, 3, 4 or more, is administered within a single treatment. Separate doses can be used. Furthermore, the amount of light applied in the two doses can be the same. Once the first application of light is applied to the effective area, the light A sufficient time interval should elapse to allow an effective amount of the sensitizer to penetrate further into the tissue. The specific layer of skin targeted can vary depending on the disease being treated. .

[0230] The duration of exposure to light may vary depending on the power of the radiation source. The period is about 1 minute to about 30 minutes, or more specifically, about 1 minute to about 5 minutes, about 5 minutes to about 10 minutes. , about 10 minutes to about 15 minutes minutes, about 15 to about 20 minutes, about 20 to about 25 minutes, or about 25 to about 30 minutes, Or longer than this.

[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, 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 satisfactory results will vary depending on the specific subject, type of subject, and photosensitivity. The effective amount can be predetermined by assessing the quality and / or composition of the compound. The amount of light energy can also be adjusted according to feedback during the treatment. The amount of light being delivered can be measured with simultaneous analysis of the penetration of the photosensitizer, the thermal radiation in the tissue (e.g., skin). The amount of time spent in the ventilator may be adjusted based on the level of discomfort being experienced by the ventilator or subject.

[0233] In one embodiment, the amount or "dose" is about 5 J / cm 2 ~About 200J / cm 2 , or Specifically, about 5J / 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 The range is about 40 to about 50.

[0234] In one embodiment, the present invention provides a method for the treatment of cancer using heat-assisted, low-dose PDT (heat-assisted, low-dose PDT). We provide a method for low-dose PDT (low-dose PDT). This means that the radiation intensity and exposure time used are at significantly lower levels (i.e., lower In one embodiment, the use of The intensity of the emitted radiation is about 10%, about 20%, about 30%, about 40%, or less than that of the prior art method. In another embodiment, the amount of radiation is about 100 J. / cm 2 Less than 80J / cm 2 Less than 70J / cm 2 Less than, or more specifically, about 65J / cm 2 Less than 60J / cm 2 Less than 55J / cm 2 Less than 50J / cm 2 Less than 45J / cm 2 Less than 40J / cm 2 is less than.

[0235] In another embodiment, the amount of radiation is less than about 40 J / cm 2 Less than or more than Specifically, the dose is about 35 J / cm 2 ~about 40J / cm 2 or more specifically In terms of energy, it is approximately 37J / cm 2 is.

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

[0237] In the case of skin tissue, the basal epidermis and / or epidermis Photosensitizers are applied to lower levels of the skin, such as the papillary dermis, the upper layer of the dermis just below the A sufficient time interval is preferably provided for the targeted skin material to reach the target area. The physical interval can vary depending on the condition being treated. For example, the time interval can be: It can be 1 hour, 30 minutes, 10 minutes, 5 minutes or any other interval within this range. In addition to allowing sufficient time for the photosensitizer to penetrate the skin to the desired level, Care should also be taken to avoid giving too much time, which can lead to the intention being overwhelmed. This can result in the passage of a significant amount of the photosensitizer beyond the site of administration.

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

[0239] In an exemplary embodiment, the method comprises administering a photodynamic therapy of the present invention to the skin. and further comprising monitoring the disease or disorder, wherein lack of clinical response to the method is indicative of a clinically significant improvement in the ability of the subject to be treated with the method. The method should be repeated and / or the amount of photosensitizer and / or the dose of light increased. Monitoring should be done by visual inspection, palpation, imaging, or other means related to the disease or disorder. The presence, level or activity of one or more biomarkers associated with a subject, and / or and assaying a clinical response in a sample obtained from the study, or a combination of two or more of the above. The monitoring is preferably performed periodically, which in this disclosure means: At least several times a week, preferably about every day.

[0240] If the disease or disorder is non-melanoma skin cancer, surveillance may include monitoring the following: tumor size; The rate of change in tumor size, the appearance of new tumors (i.e., recurrence), the rate of appearance of new tumors (i.e., (i.e., recurrence rate), changes in NMSC symptoms, emergence of new symptoms associated with NMSC, lifestyle changes, one of more qualities or a combination of two or more of the above It can be targeted.

[0241] In one embodiment, the method of the present invention has the following advantages over the same method in which the preheating step is absent: In certain embodiments, recurrence is reduced by about 5%, about 10%, or About 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% In another specific embodiment, the recurrence is reduced by less than about 10%, less than about 8%, less than about 6% In another specific embodiment, recurrence is less than about 1%, less than about 4%, or less than about 2%. 0, approx. 9.5, approx. 9, approx. 8.5, approx. 8, approx. 7.5, approx. 7, approx. 6.5, approx. 6, approx. 5.5, approx. 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. Recurrence may occur, for example, within about 6 months, about 1 year, about 2 years, about 3 years, or less. Measurements may be taken at any suitable time point, such as at 4 years or about 5 years.

[0242] Without being bound to any particular theory, the method of the present invention is useful in determining tumor margins. In one embodiment, the ability to determine tumor margins is believed to allow for improvements in Using the method, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35% , about 40%, about 45%, or 50% or more improvement.

[0243] In another embodiment, the method of the present invention provides a method for reducing the amount of heat generated by heating the product compared to the same method in which the preheating step is not present. In certain embodiments, the time to recurrence of NMSC is reduced. is approximately 5%, approximately 10%, approximately 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40% In another specific embodiment, the mean time to recurrence is reduced by about 45% or about 50% or more. The time period may be from about 1 month to about 36 months, or more specifically, about 1 month, about 3 months, about 6 months, Approximately 9 months, approximately 12 months, approximately 15 months, approximately 18 months, approximately 21 months, approximately 24 months, approximately 27 months , approximately 30 months, approximately 33 months, or approximately 36 months or more.

[0244] Advantageously, the method of the present invention reduces tumor margins compared to the same method in the absence of step (i). In an exemplary embodiment, 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 5 0% or more improvement.

[0245] In an exemplary embodiment, the method of the present invention provides a marginal graft that is no different from a conventional surgical procedure. This allows for precise treatment.

[0246] If the disease or disorder is acne, monitoring may include: number of acne lesions, severity of acne lesions, It may be of one or more degrees.

[0247] In one embodiment, the methods of the present invention result in a decrease in the mean number of acne lesions in a subject. In certain embodiments, the percentage decrease 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 90% That's all.

[0248] In certain embodiments, the methods of the present invention provide a method for reducing the oxidative stress of about 40% to about 90%, more particularly, about 45% to about 85%, and even more specifically, about 47% to about 80% of subjects have an average acne risk. This results in a reduction in the number of lesions.

[0249] As the method is performed multiple times, the percentage reduction may increase. For example, The reduction may be greater than or equal to about 30% after the first treatment, greater than or equal to about 40% after the second treatment, and / or greater than or equal to about 40% after the third treatment. After placement, the reduction may be about 50% or more.

[0250] The results achieved by the methods of the present invention can be sustained, for example, a reduction in the mean number of acne lesions. is about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months Duration of about 12 months or more may be considered clinical remission. do.

[0251] In one embodiment, the patient population treated according to the method of the present invention comprises the inclusion of step (i). In particular, patients treated according to the same method in the presence of In certain embodiments, the number of acne lesions in a population treated according to the methods of the present invention is determined by measuring the number of acne lesions in the population treated according to the method of the present invention. about 5%, about 10%, about 15%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately It may be reduced by 60%, about 70%, about 80%, or about 90% or more.

[0252] In one embodiment, the method reduces acne lesion counts over a period ranging from 1 week to about 12 weeks. In some embodiments, the method reduces redness, dryness, and irritation of the treated skin. This results in very few cases of delamination (eg, less than 1%).

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

[0254] The method of the present invention is compared to the same method in which there is no preheating step prior to administration of the photosensitizing agent. These side effects include, for example, discomfort, scaling, and rash. Fungal postulation is included.

[0255] In one embodiment, the discomfort is 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 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, the sterile postulation is about 10% About 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% It will be reduced by more than this.

[0258] In certain embodiments, the methods of the present invention provide a therapeutic effect of 50 mg / kg / day on a 6-week, 9-week, or 12-week treatment compared to a vehicle control group. A statistically significant 2-point decrease in Investigator Global Assessment (IGA) acne severity was observed at week 1 This gives a decrease in the concentration.

[0259] In another specific embodiment, the method of the present invention comprises administering a 2, 4, 6, 10, 12, 24, 36, 38, 40, 42, 44, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96 About 14, about 16, about 18, about 20, about 22, or about 24 or more acne lesions (non-inflammatory, inflammatory or both).

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

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

[0262] In an exemplary embodiment, the methods of the invention are used to treat actinic keratosis. Non-limiting examples of such agents include: - Contains fluorouracil (5-FU) and imiquimod (Aldara, Zyclara) It can be enjoyed.

[0263] In an exemplary embodiment, the method of the present invention involves administering to a subject a cytotoxic agent, a chemotherapeutic agent, a signal transduction agent, or a combination thereof. anti-signaling agents and anti-angiogenic agents, It may be used in combination with the administration of the above anti-cancer drugs.

[0264] In one embodiment, the methods of the present invention comprise one or more of the following: Non-limiting examples of such drugs include imiquimod ( Aldara, Zyclara), flurouracil - topical ( Efudex, Carac, Fluoroplex), vismodegib, and sonidegib It can be enjoyed.

[0265] In one embodiment, the methods of the present invention comprise one or more of the following: Non-limiting examples of such drugs include imiquimod ( Aldara, Zyclara), flurouracil - topical ( Efudex, Carac, Fluoroplex) and cetuximab (Erbitux ) is included.

[0266] In an exemplary embodiment, the methods of the invention are administered in combination with the administration of one or more anti-acne agents. Non-limiting examples of useful anti-acne actives include salicylic acid (o-hydroxybenzoates), salicylic acids such as benzoic acid, 5-octanoyl salicylic acid and 4-methoxysalicylic acid keratolytic agents such as derivatives of; retinoic acid and its derivatives (e.g., cis and trans) retinoids, such as sulfur-containing D and L-amino acids and their derivatives and salts, in particular those N-acetyl derivatives, a preferred example of which is N-acetyl-L-cysteine; lipoic acid anti-seborrheic substances (sebostats) such as flavonoids and bioflavonoids; Mucor sulfate and its derivatives, deoxycholate and cholesteryl Bile salts such as cholate; abietic acid; adapalene; allantoin Aloe extract; Arbietic acid and its salts; Aryl -2,4 dioxooxazolidine derivative; ASEBIOL® (Somerville, New Zealand) Laboratories located in Somerville, NJ available from Serobiologiques); azaleic acid (azaleic acid id); barberry extract; bearberry extract ;Belamcanda sinensis(belamcanda chinensis);Benzoki Norinone; Benzoyl peroxide; Berberine; BIODERMINE® (Brooklyn , obtained from Sederma, located in Brooklyn, NY Bioflavinoids; Bisabolol; S-Cal Carboxymethylcysteine; carrot extract; cassin oil; Clove oil; Citral; Citronellal; Climazole CREMOGEN® M82 (Totowa, New Jersey) .J.); Cucumber Extract; Dehydroacetic Acid and and its salts; Dehydroeplanderosterone salicylate rsterone salicylate);COMPLETECH MBAC-OS( R) (located in Paterson, NJ) Dichlorophenylimidazole dioxolane (DL-Ba), commercially available from Lipo Phosphorus and its esters; DMDM ​​hydantoin; Epicutin TT (imported from CLR) Available); Erythromycin; Ethynol; Ethylhexyl monoglyceryl ether; 2 -Hydroxyundecanoic acid ethyl ester;Farnesol;Farnesol acetate;Geranoyl ( geranoil); glabridin; gluconic acid; gluconolactone; monocapric acid gluconate Lyceryl; Glycolic Acid; Grapefruit Seed Extract; Gugulipid (Gugu Li pid); Hederagenin (available from Maruzen); Hesperitin; Hinokitol; Hop extract; Hydrogenated rosin; 10 hydroxydecanoate Canic acid; Ichthyol; Interleukin-1α antagonist; Iodo-2-propynyl Butyl carbamate; Kapilarine (available from Greentech); Keto Conazole; Lactic acid; Lemongrass oil; Lichochalcone LR15 (Maru available from Zen); linoleic acid; LIPACIDE® C8CO (Paris, France) available from Seppic); lovastatin; 4-methoxysalicylic acid; meth Ronidazole; Minocycline; Soapberry; Neem seed oil; Vitamin Niacin B3 compounds (such as niacinamide and nicotinic acid); nisin; 5-octanol (o ctanoly) salicylic acid; octopirox; panthenol ;1-Pentadecanol;Peonia extract;Peppermint extract;Phenoxyethanol Phelladendron extract; 2-phenyl-benzothiophene Derivatives; Phloretin; PHLOROGINE® (available from Secma); Phosph Antidyslipidylcholine; proteolytic enzymes; quercetin; red sandalwood d) Extract; Resorcinol; Rosemary extract; Rutin; Sage extract; Salicin; Salicylic acid; skullcap extract; Sib Hegner er hegner) extract; Siberian saxifrage (Siberian saxifraga) ge) extract; silicol; sodium lauryl sulfate; sulfoacetate Sodium Amide;Sophora Extract (available from Maruzen); Sorbic acid; sulfur; sunder vati extract; tea tree -(tea tree) oil; tetracycline; tetrahydroabietic acid; thyme (t hyme) extract; thioxolone; tocopherol; 6-undecylenate trehalose; 3-Tridecen-2-ol; Triclosan; Tropolone; UNITRIENOL(R)T Located at 27 Gouda, Netherlands, Unic available from hem); Vitamin D3 and its analogs; White thyme oil; Willow bark ( Willow bark extract; Wogonin; Ylang Ylang ); Zinc glycerolate; Zinc linoleate; Oxidized Includes zinc; zinc pyrithione; zinc sulfate, and mixtures thereof.

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

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

[0269] The results showed that after a mild sunburn-like reaction, the pustules burst on the third day and disappeared by 95% within one month. The results were sustained for at least 6 months. See Figure 1, which shows the baseline (A) and 3-month results (healed) (Figure 1B). in (Figure 2A), 1 h (using a poryphorin camera) (Figure 2 See also Figure 2, which shows the results at 3 days (Figure 3B), and 6 weeks.

[0270] [Example 2] Treatment of basal cell carcinoma on the extremities A patient with nodular basal cell carcinoma was treated. The affected area was treated with a heating pad at 39°C. Without curettage, each was also treated with 20% ALA gel. 37 J / cm 2 4 blue lights It hit at 10nm.

[0271] A broad rim of poryphorins was detected. See Figure 3, including Figure 3B, which shows the broad margins of pophyrins in sea ​​bream.

[0272] [Example 3] Treatment of basal cell carcinoma on the extremities A patient with recurrent nodular and invasive basal cell carcinoma was treated with a 40°C heating pad. The lesion areas were treated. Each was also treated with 10% ALA gel for 1 hour and then scraped. 7J / cm 2 The specimen was exposed to 630 nm red light.

[0273] Results show that a single treatment cured patients for at least six months. Sline (Figure 4A), 1 year after curettage alone (Figure 4C), and 6 months after treatment with PDT. See FIG. 4 showing (FIG. 4D).

[0274] [Example 4] Treatment of BCC on the scalp A patient with invasive basal cell carcinoma of the scalp was treated. The lesion was heated to 40°C using a heating pad. The area was heat treated with 20% ALA solution for 1 hour followed by 10 J / cm 2 4 of 4 Illuminated with 17 nm blue light.

[0275] Biopsy showed the absence of lesions one month after treatment (Figure 6B). However, the lesions were cured within 1 month (Figure 5), which persisted for 16 months after treatment. It continued.

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

[0277] The results show that one year after a single treatment, each patient was cured. See Figure 7. I want to be.

[0278] [Example 6] Treatment of refractory disseminated porokeratosis with associated SCC Patient with refractory disseminated porokeratosis with associated SCC. The lesion area was then heat treated. 10% ALA gel was applied for 1 hour. 37 J / cm 2 NoE The cells were exposed to red light having a wavelength of 630 nm and 1000 keV.

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

[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, followed by exposure to light.

[0281] Baseline (Figure 10A), 20 min (Figure 10B), 1 day (Figure 10C), 1 week (Figure 10D) The results are shown in Figure 10, including 1 month (Fig. 10E) and 2 months (Fig. 10F). is 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, 20% AL Solution A was applied and then exposed to light.

[0283] Baseline (Figure 11A), 30 min (Figure 11B), 1 day (Figure 11C) and 1 week (Figure 11 The results are shown in Figure 11, including the results for the porphyrins in Figure 11.

[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). He guessed right.

[0285] The results are shown in Figure 12, including baseline (Figure 12A) and 1 hour. , minimal porphyrin is shown.

[0286] [Example 10] Treatment of moderate inflammatory and pustular acne Index patients with moderate inflammatory and pustular acne on the face To treat the ulcers, a 10% sodium acetate warming mask (skin temperature 40°C) was used. After 1 hour of incubation with minolevulinic acid (ALA), 37 J / cm 2 Using 635nm red light As shown in Figure 17 and Table II, the reduction in lesion count was greater after a single thermal PDT. It lasted for nine months after that.

[0287] [Table 1]

[0288] [Example 11] Treatment of moderate inflammatory and pustular acne 37J / cm after sodium acetate warming mask (skin temperature 40℃) 2 635nm red Mild inflammatory lesions on the face with 10% aminolevulinic acid for 1 hour incubation with light and patients with pustular acne. As shown in Figure 18 and Table II, a single thermal PD Tissue repair of acne scars is shown 9 months after T.

[0289] [Table 2]

[0290] [Example 12] Treatment of actinic keratosis Sodium acetate compared to 1 hour incubation at room temperature (70°F, skin temperature 30°C). Incubation with 20% ALA at 40°C for 30 minutes using a heating mask resulted in the reduction of actinic keratosis. As shown in Figure 23, the increased porphyrin Porphyrin images were obtained using the VISIA-CR(R) 4.1 camera system. Shooting and Image-Pro(R)Plus7.0(IPP(R), Media Cy The images were analyzed using image analysis software (Bernetics Inc.). The intensity of the PpIX fluorescence signal measured within the region was quantified on a scale of 0–255.

[0291] [Table 3]

Claims

1. 1. A pharmaceutical composition comprising at least 5-ALA for use in a therapeutic method for treating facial acne in a patient in need thereof, the method comprising: (i) administering heat to the affected area of ​​the patient's skin using a heat delivery device to achieve a temperature of about 38°C to about 42°C for a suitable period of time while simultaneously incubating the pharmaceutical composition; and (ii) applying an appropriate dose of light to the affected area, thereby treating facial acne; Pharmaceutical compositions.

2. 1. A non-therapeutic method of treating facial acne in a patient in need thereof, the method comprising: (i) administering heat to the affected area of ​​the patient's skin using a heat delivery device to achieve a temperature of about 38°C to about 42°C for a suitable period of time while simultaneously incubating a pharmaceutical composition comprising at least 5-ALA; and (ii) irradiating the affected area with an appropriate dose of light, thereby treating facial acne.

3. 3. A pharmaceutical composition for use in a therapeutic method according to claim 1 or a non-therapeutic method according to claim 2, wherein the incubation time is less than about 10 hours, or less than about 5 hours, or less than about 3 hours.

4. 10. A pharmaceutical composition for use in a therapeutic method according to claim 1 or a non-therapeutic method according to claim 2, wherein heat is applied using a sodium acetate mask.

5. 3. The pharmaceutical composition for use in the therapeutic method of claim 1 or the non-therapeutic method of claim 2, wherein the heat is administered in (i) for about 60 minutes.

6. 3. The pharmaceutical composition for use in the therapeutic method of claim 1 or the non-therapeutic method of claim 2, wherein the pharmaceutical composition is a gel or a nanoemulsion.

7. 5-ALA is present in an amount of about 20% by weight of the pharmaceutical composition, or 5-ALA is present in an amount of about 10% by weight of the pharmaceutical composition.

8. The pharmaceutical composition for use in the therapeutic method of claim 1 or the non-therapeutic method of claim 2, wherein the wavelength of the light is from about 320 nm to about 780 nm.

9. The light dose is about 5 J / cm ２ ~200 J / cm ２ 3. A pharmaceutical composition for use in the therapeutic method of claim 1 or the non-therapeutic method of claim 2, wherein

10. 3. The pharmaceutical composition for use in the therapeutic method according to claim 1 or the non-therapeutic method according to claim 2, wherein the acne is mild acne, moderate acne, severe acne or inflammatory acne.

11. 1. Use of a pharmaceutical composition comprising at least 5-ALA for the preparation of a medicament for the therapeutic treatment of facial acne, comprising: When applied, (i) administering heat to the affected area of ​​the patient's skin using a heat delivery device to achieve a temperature of about 38°C to about 42°C for a suitable period of time while simultaneously incubating the pharmaceutical composition; and (ii) applying an appropriate dose of light to the affected area, thereby treating facial acne.

12. 1. Use of a pharmaceutical composition comprising at least 5-ALA for the preparation of a medicament for the non-therapeutic treatment of facial acne, comprising: When applied, (i) administering heat to the affected area of ​​the patient's skin using a heat delivery device to achieve a temperature of about 38°C to about 42°C for a suitable period of time while simultaneously incubating the pharmaceutical composition; and (ii) applying an appropriate dose of light to the affected area, thereby treating facial acne.

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