Photodynamic therapy compositions and methods of treatment therewith

Abstract

Compositions and methods are provided that are directed to the treatment of sun-exposed skin, wounds and microbial infections.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to PCT Application No. PCT / US2021 / 049928, filed September 10, 2021, and Provisional Application No. 63 / 223,835, filed July 20, 2021, and Provisional Application No. 63 / 223,8359, filed July 20, 2021, the disclosures of which are incorporated herein by reference in their entireties for all purposes. [Background technology]

[0002] Actinic keratosis (AK) is a premalignant skin lesion that typically presents as a lesion on sun-exposed areas such as the face or forearms of affected individuals. Actinic keratosis is common in the United States and worldwide. It is estimated that 60% of predisposed individuals over the age of 40 suffer from at least one AK. If left untreated, AK can develop into a serious disease. For example, it is estimated that AK develops into squamous cell carcinoma in 0.025%-16% of cases. Thus, treatment of AK is recommended if detected.

[0003] Sun-exposed skin can cause additional damaged skin, including pigmented spots, melasma, and general actinic skin damage, which can also be treated. Treatments for AK and sun-exposed skin exist, including ablative procedures (surgery, laser ablation, curettage, cryotherapy) and photodynamic therapy (PDT) using topical aminolauric acid (5-ALA or mel-ALA). Photodynamic therapy (PDT) combines the use of non-toxic photosensitizers (PS) with low-intensity, non-thermal visible light, which results in the generation of cytotoxic species in the presence of oxygen. PDT has long been approved for use in the treatment of certain malignancies and other diseases in the United States (US) and many other countries. Early research led to the development of porfimer sodium (Photofrin®, Concordia Laboratories Inc.), the first FDA-approved PS for clinical use in the US. Since the development of this treatment, many uses of PDT have been proposed and evaluated. Although the combination of dye and light activation has been applied to bacteria, viruses, and fungi in vitro, this technique has been difficult to reproduce in vivo and therefore is not currently approved in the United States for use in treating bacteria, viruses, and fungi in vitro, or other indications such as damaged skin caused by sun exposure, particularly for treating sun-exposed skin.

[0004] Thus, there remains a need to develop compositions and methods of use for effective photodynamic treatment of damaged skin caused by sun exposure. Summary of the Invention

[0005] In one aspect, the present disclosure provides a pharmaceutical composition comprising a photosensitizer and one or more gelling agents.

[0006] In some embodiments, the present disclosure provides a pharmaceutical topical formulation comprising porfimer sodium and one or more pharma- ceutical acceptable excipients.

[0007] In some embodiments, the present disclosure provides a method for treating damaged skin, such as damaged skin caused by sun exposure in a subject, the method comprises administering any pharmaceutical composition or pharmaceutical preparation disclosed herein to a subject in need thereof, the composition is applied to the damaged skin or chronic sun-exposed skin, and light is applied to the damaged skin or chronic sun-exposed skin. In certain embodiments, the sun-exposed skin to be treated is selected from one or more of the group consisting of chronic sun-exposed skin, wrinkles, pigmented spots, melasma, actinic keratosis, seborrheic keratosis, photodamaged skin, acne, warts, and psoriasis. In certain embodiments, the sun-exposed skin to be treated is actinic keratosis.

[0008] In another embodiment, the subject does not experience pain when light is applied to sun-exposed skin. In another embodiment, the subject does not experience pain according to a visual analog scale of pain when light is applied to sun-exposed skin.

[0009] In another embodiment, the subject does not develop edema or pruritus from treatment on sun-exposed skin, hi another embodiment, the subject does not develop erythema lesions from treatment on sun-exposed skin. [Brief description of the drawings]

[0010] [Figure 1] 1 shows accumulation of porfimer sodium in the epidermis for each formulation, Formulation 2, Formulation 3, Formulation 4, and Formulation 5, in the stability study outlined in Example 3. [Diagram 2] The wavelength activity ranges of porfimer sodium, PpIX and mTHPC are shown. [Diagram 3] 1 shows the results of stability testing of formulations 7A, 7B, and 7C at 25° C. / 60% RH. [Figure 4] 1 shows the results of stability testing of formulations 7A, 7B, and 7C at 40° C. / 75% RH. [Diagram 5] 1 shows the results of stability studies of formulations 7A, 7B, and 7C at 5° C. [Figure 6] 1 shows the results of stability testing of formulations 7D, 7E, and 7F at 25° C. / 60% RH. [Figure 7] 1 shows the results of stability testing of formulations 7D, 7E, and 7F at 40° C. / 75% RH. [Figure 8] 1 shows the results of stability testing of formulations 7D, 7E, and 7F at 5° C. [Figure 9] 1 shows the study design described in Example 6. [Figure 10] 1 shows the study design described in Example 7. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] In one aspect, the present disclosure provides compositions and methods for photodynamic treatment of damaged skin caused by chronic sun exposure in a subject, including treatment of actinic keratosis with minimization of adverse side effects, such as minimization of pain, edema, pruritus and / or erythema.

[0012] definition Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by those skilled in the art of the present disclosure. The following references provide those skilled in the art with general definitions for many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994), The Cambridge Dictionary of Science and Technology (Walker ed., 1988), The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991), and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings given to them below, unless otherwise specified.

[0013] As used herein, the verb "comprise" and variations thereof as used in the description and claims are used in their open-ended sense, meaning that the items that follow the word are included, but not the exclusion of items not specifically mentioned. The present disclosure may suitably "comprise", "consist of", or "consist essentially of" the steps, elements, and / or reagents recited in the claims.

[0014] As used herein, the term "or" is understood to be inclusive unless specifically stated or clear from context. As used herein, the terms "a," "an," and "the" are understood to be singular or plural unless specifically stated or clear from context.

[0015] Throughout this specification, the terms "about" and / or "approximately" may be used in conjunction with numerical values ​​and / or ranges. The term "about" is understood to mean a value close to the stated value. Additionally, the phrases "less than about [value]" or "greater than about [value]" should be understood in light of the definition of the term "about" provided herein. The terms "about" and "approximately" may be used interchangeably.

[0016] As disclosed herein, "photodynamic therapy" or "PDT" involves the use of chemical photosensitizers or non-toxic photoactivatable dyes, non-thermal visible light, and reactive oxygen species. The therapy is based on the transfer of energy (absorbed as light via the photosensitizer) to oxygen molecules, resulting in their intermediate conversion to highly reactive forms such as singlet oxygen and superoxide, which are harmful to cells. Photodynamic therapy requires a light source to trigger the photosensitizer with low-power visible light of a specific wavelength. Most optical photosensitizers are powered by light with wavelengths between 380 nm and 850 nm, which corresponds to a light penetration depth of 0.2 cm to 2.5 cm.

[0017] As disclosed herein, PDT uses "photosensitizers" or "PS" that are activated by absorption of visible or near-infrared light to form an initial excited singlet state, which then transitions to a long-lived excited triplet state. This triplet state can undergo a photochemical reaction in the presence of oxygen to form reactive oxygen species (including singlet oxygen) that can destroy pathogenic microorganisms and / or treat damaged skin. The bispecificity of PDT relies on the accumulation of PS in infected tissues and also on localized light delivery. As disclosed herein, PS includes porphyrin-based photosensitizers and tetrapyrrole structures, such as porphyrins, chlorins (HPPH; NPe6; Temoporfrin (Foscan), mTHPC), and porphysomes, such as those found in pyropheophorbide nanovesicles, such as bacteriochlorophyll porphysomes, zinc pyropheophorbide porphysomes, and pyropheophyorbide porphysomes, as well as chlorin-like compounds (benzoporphyrins; verteporfin, bacteriochlorins and phthalocyanines, purpurins (ethyl etiopurpurin tin); metalloporphyrins (texaphyrins); pheophorbides (TOOKAD); protoporphyrins (Levulan, Metvix, 5-ALA (PpIX)), and the like. The PS may include, but are not limited to, non-porphyrin photosensitizers such as phenothiazinium salts, e.g., methylene blue, toluidine blue, nile blue, cyanine, hypericin, and chalcogen pyrylium dyes; PPA904; the benzophenothiazinium dye EtNBS; and the PS may also include fluorescent dyes of the xanthene class, including fluorescein and rose bengal; fullerenes (C60 fullerenes attached to polar diserinol groups or quaternary pyrrolidinium groups), as well as squaraogenine, BODIPY (boron-dipyrromethene) dyes, phenalenone; hypericin, hypocrellin, riboflavin, curcumin, and titanium dioxide. As used herein, the preferred PS is porfimer sodium (Photofrin®).

[0018] As disclosed herein, "PDT enhancer" refers to, for example, potassium iodide (KI), which has an enhancing effect on PDT. For example, adding KI to a mixture of microbial cells and PS that is subsequently excited with light can result in many log units of additional microbial kill. Adding KI to porfimer sodium allows for broad spectrum PDT. As disclosed herein, PDT enhancers can include inorganic salts such as sodium azide, sodium thiocyanate, sodium bromide and potassium iodide, sodium and iodide, and potassium selenocyanate (KSeCN). In some embodiments, the PDT enhancer is potassium iodide (KI).

[0019] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cows, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. A preferred subject is a human.

[0020] The term "treating" refers to one or more of relieving, alleviating, delaying, reducing, improving, or managing at least one symptom of a condition in a subject. The term "treating" can also refer to one or more of halting a condition, delaying the onset of a condition (i.e., the period before clinical symptoms of a condition), or reducing the risk of onset or worsening of a condition.

[0021] The term "managing" includes therapeutic treatment as defined above. Managing includes achieving a steady state level of infection as determined by methods known in the art. Steady state may include assessment of one or more of the following: severity of infection(s), size and location of infection(s), number of different microbial pathogens present in the infection(s), amount of microbial pathogens that are tolerant or resistant to antibiotics, degree of response to treatment such as with the PS compositions disclosed herein, degree of biofilm formation and reduction, and side effects experienced by the subject. During management of an infection, the infection may fluctuate from increasing to decreasing in severity, amount or extent of infection, amount of side effects experienced by the subject, or other indicia of the subject's outcome. The degree of management of an infection can be determined by evaluation of the above factors to assess whether the clinical course of the infection has improved, is bacteriostatic, or worsened over a period of time, such as days, months, or years. In some embodiments, managing an infection includes successful treatment of a microbial pathogen(s) that is otherwise drug tolerant or resistant.

[0022] As disclosed herein, "sun-exposed skin" refers to any skin or body area of ​​a subject having significant chronic sun exposure, wrinkles, pigmented spots, sun-induced moles, seborrheic keratoses, and / or sun-damaged skin such as actinic keratoses.

[0023] The term "reducing the severity" of damage refers to an improvement in the clinical course of damaged or chronic sun-exposed skin based on any measurable criteria. Such criteria can include measurable indicators such as reducing the extent of damaged skin, such as actinic keratosis or photodamaged skin. In some embodiments, reducing the severity of damaged skin, such as actinic keratosis, or photodamaged or sun-exposed skin, is determined by measuring the improvement of clinical signs and symptoms. For example, reducing the severity of actinic keratosis can reduce, for example, rough and / or scaly skin patches. In some embodiments, for example, reducing the severity involves stopping the steady decline of symptoms such that the subject enters into successful management of the condition. In other embodiments, reducing the severity can result in substantial to complete treatment of sun-exposed skin.

[0024] "Effective amount" as used herein refers to an amount that is sufficient to achieve a desired biological effect. "Therapeutically effective amount" as used herein refers to an amount that is sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of damaged skin or sun-exposed skin.

[0025] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0026] A "response" to a treatment method can include, inter alia, a decrease or amelioration of undesirable signs and symptoms, a reduction in the progression of an infection or its symptoms, an increase in beneficial symptoms or clinical outcomes, a reduction in side effects, a stabilization of the disease or indication, and a partial or complete cure of the disease or indication.

[0027] "Antibiotic susceptibility or sensitivity" refers to whether a bacterium is successfully treated by a given antibiotic. Similarly, "antifungal susceptibility or sensitivity" refers to whether a fungus is successfully treated by a given antibiotic. Susceptibility testing can be performed by methods known in the art, such as the Kirby-Bauer method, the Stokes method, and the agar broth dilution method. The effectiveness of an antibiotic in killing bacteria or preventing bacteria from growing can be observed as areas of decreasing or stable amounts of bacterial growth on media such as wafers, agar, or broth cultures, respectively.

[0028] "Antimicrobial resistance" refers to the ability of a microorganism to resist the action of drugs that once successfully treated that microorganism. Microorganisms that are resistant to multiple antimicrobial drugs are called multidrug resistant (MDR). Resistance occurs through one of three mechanisms: natural resistance in certain types of bacteria, genetic mutations, or one species acquires resistance from another. Mutations can result in inactivation of the drug, changes in the drug's binding site, altered metabolic pathways, and reduced drug permeability.

[0029] As used herein, the terms "antibacterial activity," "antifungal activity," and "antimicrobial activity" with reference to the PS compositions of the present disclosure refer to the ability to kill and / or inhibit the growth or reproduction of a particular microorganism. In certain embodiments, antibacterial or antimicrobial activity is assessed by culturing bacteria, such as gram-positive bacteria (e.g., S. aureus), gram-negative bacteria (e.g., Moraxella catarrhalis), or atypical bacteria not classified as gram-positive or gram-negative, or fungi (e.g., C. albicans), according to standard techniques (e.g., in liquid culture or agar plate), contacting the culture with a PS composition of the present disclosure, and monitoring cell growth after said contacting. For example, in liquid culture, bacteria may be grown to an optical density ("OD") representative of the midpoint of exponential growth of the culture, and the culture is exposed to one or more concentrations of one or more PS compounds of the present disclosure or variants thereof, and the OD relative to a control culture is monitored. A decrease in OD relative to the control culture represents antibacterial activity (e.g., indicative of lytic killing activity). Similarly, bacterial colonies can be allowed to form on agar plates, the plates exposed to the disclosed PS compositions or variants thereof, and the subsequent growth of the colonies assessed against control plates. A reduction in colony size, or total number of colonies, indicates antibacterial activity.

[0030] "Biofilm" refers to any symbiotic community of microorganisms in which cells adhere to each other and often to surfaces. These adherent cells are embedded within a slimy extracellular matrix composed of extracellular polymeric substances (EPS). During biofilm formation, the resistance of microorganisms to antibiotics is up to 1000 times higher compared to that of planktonic bacteria. Bacterial aggregates are clusters of laterally aligned cells that can initiate the development of biofilms with more complex and dense 3D structures. In some embodiments, biofilms can include one or more species of bacteria (e.g., Moraxella catarrhalis and Staphylococcus aureus) and / or one or more different phyla (e.g., bacteria and fungi).

[0031] The term "infectious disease" is used herein in its broadest sense and refers to any infectious disease, such as that caused by microbial bacterial or fungal infection. Examples of such infectious diseases can be found in many well-known textbooks, such as, for example, "Medical Microbiology" (Greenwood, D., Slack, R., Peutherer, J., Churchill Livingstone Press, 2002); "Mims' Pathogenesis of Infectious Disease" (Minis, C., Nash, A., Stephen, J., Academic Press, 2000); "Fields" Virology. (Fields, BN, Knipe DM, Howley, PM, Lippincott Williams and Wilkins, 2001); and "The Sanford Guide To Antimicrobial Therapy," 26th Edition, JP Sanford et al. (Antimicrobial Therapy, Inc., 1996), which are incorporated herein by reference.

[0032] As used herein, the terms "prophylactic agent" and "prophylactic agents" refer to an agent, such as the PS composition of the present disclosure, that can be used to prevent, manage, or control one or more signs and symptoms of a disease or disorder, particularly a damaged area, including a disease or disorder associated with sun-exposed skin, such as actinic keratosis.

[0033] As used herein, "substantially" or "substantially" refers to the complete or nearly complete extent or degree of an action, characteristic, property, state, structure, item, or result. For example, in the case of an object that is "substantially" sealed, it means that the object is completely sealed or nearly completely sealed. The exact degree of acceptable deviation from absolute perfection may depend on the particular situation in some cases. Generally speaking, however, the closeness of perfection is such that the overall result is the same as if absolute and total perfection had been obtained. The use of "substantially" also applies when used in a negative sense to refer to the complete or nearly complete lack of an action, characteristic, property, state, structure, item, or result. For example, in the case of a composition that is "substantially free" of other active substances, the complete lack or nearly complete lack of other active substances results in the same effect as if the compound were completely devoid of other active substances. In other words, a composition that is "substantially free" of an ingredient or component or another active agent may still contain such item so long as there is no measurable effect thereof.

[0034] "Weight per weight" or "weight by weight" or "w / w" refers to the proportion of a particular substance in a mixture, measured by weight or mass. As used herein, "wt %" refers to the percent of the total weight of the composition.

[0035] Throughout this specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges include all subranges within that range. Thus, a range of "50 to 80" includes all possible ranges within that range (e.g., 51 to 79, 52 to 78, 53 to 77, 54 to 76, 55 to 75, 60 to 70, etc.). Furthermore, all values ​​within a given range may be endpoints of a range subsumed within that range (e.g., a range of 50 to 80 includes ranges with endpoints such as 55 to 80, 50 to 75, etc.).

[0036] Moreover, it should be noted that the claims may be drafted to exclude any element, and thus, this statement is intended to serve as a predicate for the use of exclusive terminology such as "only," "solely," and the like, or the use of a "negative" limitation in connection with the recitation of claim elements.

[0037] The present invention relates to compositions, such as pharmaceutical compositions, comprising a photosensitizer and one or more pharma- ceutically acceptable excipients, and methods involving administering said compositions to a subject to treat damaged skin caused by sun exposure in the subject.

[0038] Pharmaceutical Compositions In some embodiments, the present disclosure provides a pharmaceutical composition comprising a photosensitizer, one or more gelling agents, and one or more pharma- ceutically acceptable excipients or carriers. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises a photosensitizer, a gelling agent, one or more permeation enhancers, humectants, stabilizers, solubilizers, and / or preservatives. In some embodiments, the pharmaceutical composition may also comprise one or more solvents, buffers, bodifying agents, antioxidants, stabilizers, and surfactants. In another embodiment, the pharmaceutical composition comprises one or more photosensitizers, gelling agents, one or more permeation enhancers, humectants, solubilizers, preservatives, and / or enhancers.

[0039] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a photosensitizer, one or more gelling agents, and one or more pharma- ceutically acceptable excipients or carriers. In some embodiments of the pharmaceutical compositions disclosed herein, the pharmaceutical composition comprises a photosensitizer, a gelling agent, one or more permeation enhancers, humectants, stabilizers, solubilizers, and / or preservatives. In some embodiments, the pharmaceutical composition may also include one or more solvents, buffers, bodifying agents, antioxidants, and surfactants.

[0040] In some embodiments of the pharmaceutical compositions disclosed herein, the photosensitizer is a porphyrin-based photosensitizer and a tetrapyrrole structure, e.g., porphyrins, chlorins (HPPH; NPe6; temoporphrin (Foscan), mTHPC)), and porphysomes, such as in pyropheophorbide nanovesicles, such as bacteriochlorophyll porphysomes, zinc pyropheophorbide porphysomes, and pyropheophiorbide porphysomes, and chlorin-like compounds (benzoporphyrins; verteporfin, bacteriochlorins, and phthalocyanines, purpurins (ethyl etiopurpurin tin); metalloporphyrins (texaphyrins); pheophorbides (TOOKAD); protoporphyrins (Levulan, Metvix, 5-ALA (PpIX)), and Non-porphyrin photosensitizers, such as phenothiazinium salts, such as methylene blue, toluidine blue, nile blue, cyanine, hypericin, and chalcogen pyrylium dyes; PPA904; benzophenothiazinium dye EtNBS; and PS may also include fluorescent dyes of the xanthene class, including fluorescein and rose bengal; fullerenes (C60 fullerenes attached to polar diserinol groups or quaternary pyrrolidinium groups), as well as squalaogenin, BODIPY (boron-dipyrromethene) dyes, phenalenone; hypericin, hypocrellin, riboflavin, curcumin, titanium dioxide. As used herein, the preferred PS is porfimer sodium (Photofrin®).

[0041] In some embodiments of the pharmaceutical compositions disclosed herein, porfimer sodium is in an amount ranging from about 0.01% to about 1.0% by weight, or from about 0.05% to about 0.7% by weight, or from about 0.1% to about 0.5% by weight, or from about 0.15% to about 0.3% by weight. In some embodiments, porfimer sodium is in an amount ranging from 0.01% to 1.0% by weight, or from 0.05% to 0.7% by weight, or from 0.1% to 0.5% by weight, or from 0.15% to 0.3% by weight. In some embodiments of the pharmaceutical compositions disclosed herein, porfimer sodium is present in an amount ranging from about 0.01%, about 0.02%, 0.03%, 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% to about 1.0% by weight, including all values ​​and subranges therebetween. In some embodiments, porfimer sodium is in an amount ranging from about 0.01% to about 1.0% by weight, or from about 0.05% to about 0.7% by weight, or from about 0.1% to about 0.5% by weight. In some embodiments, porfimer sodium is in an amount ranging from 0.01% to 1.0% by weight, or 0.05% to 0.7% by weight, or 0.1% to 0.5% by weight, In some embodiments, porfimer sodium is in an amount ranging from about 0.05% to about 0.15% by weight, or about 0.15% to 0.25% by weight, or 0.4% to 0.6% by weight.

[0042] A gelling agent may be added to the pharmaceutical composition of the present invention. The gelling agent is any suitable substance used to modify the viscosity of the composition. For example, the gelling agent may be highly cross-linked or otherwise have strong intermolecular interactions to enhance the cohesion of the composition. A variety of gelling agents can be used, including, for example, but not limited to, sugars or alcohols derived from sugars, such as mannitol, sorbitol, and the like, starch and starch derivatives, cellulose derivatives, such as microcrystalline cellulose, sodium cahoxymethyl cellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose, attapulgite, bentonite, dextrin, alginates, carrageenan, tragacanth gum, acacia gum, guar gum, xanthan gum, pectin, gelatin, kaolin, lecithin, magnesium aluminum silicate, carbomer and carbopol, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, silicon dioxide, surfactants, surfactant / wetting agent mixtures, emulsifiers, other polymeric materials, and mixtures thereof, etc. Examples of suitable gelling agents include hydroxypropyl cellulose, acrylic acids, such as Carbopol 980, and lecithins, such as lecithin-PLO.

[0043] For topical application to the skin, the pharmaceutical compositions of the present disclosure may be combined with one or a combination of gelling agents for topical formulations, which may include, but are not limited to, aqueous liquids, alcohol-based liquids, water-soluble gels, lotions, ointments, non-aqueous liquid bases, mineral oil bases, blends of mineral oil and petrolatum, lanolin, liposomes, protein carriers such as serum albumin or gelatin, powdered cellulose carmel, carbomer polymers, such as carbomer homopolymers, carbomer copolymers, such as Carbopol® polymers, and combinations thereof. Carbopol® polymers are crosslinked acrylic acid polymers, for example with polyalkenyl ethers or divinyl glycol. In some embodiments, the Carbopol® polymer is Carbopol® 71G, Carbopol® 971P, Carbopol® 974P, Carbopol® 980, Carbopol® 981, Carbopol® 5984, Carbopol® 934, Carbopol® 934P, Carbopol® 940, Carbopol® 941, and Carbopol® 1342. The compositions of the present invention comprise a semi-solid and gel-like medium that includes a polymeric thickener, water, a preservative, an active surfactant or emulsifier, an antioxidant, and a solvent or mixed solvent system. The solvent or mixed solvent system is important for the formation of microparticles that are in proportion to the dissolved pharmaceutical agent. However, the formation of microparticles must not interfere with the ability of the polymeric thickener or preservative system to perform their function.

[0044] Polymeric thickeners that may be used include those known to those skilled in the art, such as hydrophilic and hydroalcoholic gelling agents frequently used in the cosmetic and pharmaceutical industries. Preferably, the hydrophilic or hydroalcoholic gelling agent includes "CARBOPOL®" (BFGoodrich, Cleveland, Ohio), "HYPAN®" (Kingston Technologies, Dayton, NJ), "NATROSOL®" (Aqualon, Wilmington, Del.), "KLUCEL®" (Aqualon, Wilmington, Del.), or "STABILEZE®" (ISP Technologies, Wayne, NJ).

[0045] In some embodiments of the pharmaceutical compositions disclosed herein, the gelling agent is selected from one or more of the group consisting of carbomer, crosslinked, polyacrylic acid, lecithin, hydroxyethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. In some embodiments, the gelling agent is a polymer of acrylic acid crosslinked with a polyalkenyl ether or divinyl glycol. In some embodiments, the gelling agent is a carbomer. In some embodiments, the carbomer is Carbopol® 71G, Carbopol® 971P, Carbopol® 974P, Carbopol® 980, Carbopol® 981, Carbopol® 5984, Carbopol® 934, Carbopol® 934P, Carbopol® 940, Carbopol® 941, and / or Carbopol® 1342.

[0046] In some embodiments of the pharmaceutical compositions disclosed herein, the gelling agent is in an amount ranging from about 0.5% to about 3.0% by weight, or from about 0.7% to about 2.0% by weight, or from about 1.0% to about 1.75% by weight. In some embodiments, the gelling agent is in an amount ranging from 0.5% to 3.0% by weight, or from 0.7% to 2.0% by weight, or from 1.0% to 1.75% by weight, or from 1.1% to 1.6% by weight, or from 1.2% to 1.5% by weight, including all values ​​and subranges therebetween. In some embodiments, the gelling agent is in an amount ranging from about 0.5% to about 3.0% by weight, or from about 0.7% to about 2.0% by weight, or from about 0.5% to about 1.5% by weight. In some embodiments, the gelling agent is in an amount ranging from 0.5% to 3.0% by weight, or from 0.7% to 2.0% by weight, or from 0.5% to 1.5% by weight.

[0047] In some embodiments, the pharmaceutical composition or pharmaceutical topical formulation further comprises one or more permeation enhancers.

[0048] As defined herein, a "permeation enhancer" is understood to mean any substance that acts as a skin penetrant and enhances the ability of an active agent to pass through the epidermal tissue into or through the dermal tissue. Thus, the permeation enhancer may be, for example, a penetration enhancer. In some embodiments, the permeation enhancer may be one or more of an alcohol, an amide, a fatty acid, an ester, an ether alcohol, a surfactant, a phospholipid, a pyrrolidone, or a terpene. In certain embodiments, the permeation enhancer is ethanol, isopropyl alcohol, decanol, octanol, propylene glycol, polyethylene glycol, transcutol such as Azone® (1-dodecylazacycloheptan-2-one) or laurocapram, lauric acid, oleic acid, linoleic acid, ethyl acetate, butyl acetate, methyl acetate, isopropyl myristate, isopropyl palmitate, diethylene glycol monoethyl ether (DEGEE), sodium lauryl sulfate, benzalkonium chloride, cetylpyridinium chloride, etc. The antioxidant may be one or more of: cetearyl alcohol, cetyltrimethylammonium bromide; polysorbates (such as Tween® 20, Tween® 80, etc.), dodecyl betaine, dimethyl sulfoxide (DMSO), decyl methyl sulfoxide (DCMS), d-limonene, l-menthol, 1,8-cineole, N-methyl-1-2-pyrrolidone (NMP), 2-pyrrolidone (2P), N-methyl-1-2-pyrrolidone (NMP), 4-decyl oxazolidin-2-one, phosphatidylcholine, acid phosphatase, papain, and phospholipase C.

[0049] Permeation enhancers may also act as solvents or have a solvating effect, act as surface surfactant enhancers, and / or act as emulsifiers. Permeation enhancers that may be used include those known to those skilled in the art, such as polyols and esters, such as glycol esters (e.g., polyethylene glycol, polyethylene glycol monolaurate) and butanediol; sulfoxides, such as dimethyl sulfoxide and decyl methyl sulfoxide; ethers, such as diethylene glycol monoethyl ether (e.g., Transcutol® P); fatty acids, such as lauric acid, oleic acid, and valeric acid; fatty acid esters, such as isopropyl myristate, isopropyl palmitate, methyl propionate, and ethyl oleate; nitrogen compounds, such as urea, dimethylacetamide, dimethylformamide 2-pyrrolidone, ethanolamine, methyl-2-pyrrolidone, diethanolamine, and triethanolamine; terpenes; alkanones; organic acids, such as salicylic acid, citric acid, and succinic acid; azones, polysorbates, alcohols, and any mixtures thereof. In addition, one or more surfactants may be used as permeation agents or permeation enhancers. In some embodiments, the permeation enhancer is selected from one or more of the group consisting of propylene glycol, polyethylene glycol having an average molecular weight of 200-4000, diethylene glycol monoethyl ether, Transcutol P, polysorbate 80, polyoxyglycerides, Labrasol®, diethyl sebacate, diisopropyl adipate, dimethyl isosorbide, dimethyl sulfoxide, ethanol, Tween 80, laureth-4, butanediol, polyethylene glycol monolaurate, diethylene glycol monoethyl ether, dimethyl sulfoxide, decyl methyl sulfoxide, lauric acid, oleic acid, valeric acid, isopropyl myristate, isopropyl palmitate, methyl propionate, ethyl oleate, and oleic acid.Suitable examples of permeation enhancers include hexylene glycol, propylene glycol SR, polyethylene glycol 400SR, polyethylene glycol 300LA, diethylene glycol monoethyl ether, and polysorbate 80SR.

[0050] In some embodiments, the permeation enhancer is selected from one or more of the group consisting of diethylene glycol monoethyl ether, dimethyl sulfoxide, propylene glycol, polyethylene glycol, and various forms, molecular weights, and grades thereof. In certain embodiments, the permeation enhancer is selected from one or more of the group consisting of propylene glycol SR, polyethylene glycol 400SR, polyethylene glycol 300LA, diethylene glycol monoethyl ether, dimethyl sulfoxide, and polysorbate 80SR. In some embodiments, the permeation enhancer is selected from one of propylene glycol SR, dimethyl sulfoxide, and diethylene glycol monoethyl ether.

[0051] In some embodiments of the pharmaceutical compositions disclosed herein, the one or more permeation enhancers are in an amount ranging from about 0.5% to about 90% by weight, from about 0.5% to about 80% by weight, from about 0.5% to about 70% by weight, or from about 1% to about 60% by weight, or from about 10% to about 60% by weight, or from about 5% to about 30% by weight, or from about 15% to about 30% by weight. In some embodiments, the permeation enhancer is in an amount ranging from 0.5% to 50% by weight, or from 10% to 40% by weight, or from 15% to 30% by weight.

[0052] In one embodiment, two or more permeation enhancers are provided in a single composition having the ranges disclosed immediately above. In a particular embodiment, four permeation enhancers are provided in a single composition. In another embodiment, three permeation enhancers are provided in a single composition. In another embodiment, two permeation enhancers are provided in a single composition. In a particular embodiment, the two or more permeation enhancers can range from about 55% to about 85% by weight, about 65% to about 80% by weight, or about 70% to about 80% by weight. In another embodiment, the single composition can include a single permeation enhancer. In one embodiment, the single permeation enhancer can range from about 0.5% to about 60% by weight, about 10% to about 50% by weight, about 15% to about 45% by weight, or about 20% to about 40% by weight, or about 25% to about 40% by weight. In one embodiment, at least one of the permeation enhancers is DMSO.

[0053] In some embodiments, the compositions disclosed herein include a solubilizer. In some embodiments of the pharmaceutical compositions disclosed herein, the solubilizer is in the range of 1.0% to about 5% by weight, or about 1% to about 3% by weight, or in an amount of about 2% by weight. In some embodiments, the solubilizer is in an amount of about 1.0% by weight, or about 2% by weight, or about 3% by weight, or about 4% by weight, or about 5% by weight.

[0054] In some embodiments of the compositions disclosed herein, the permeation enhancer is about 0.5%, about 1%, about 5%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%, about 101%, about 102%, about 103%, about 104%, about %, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70% by weight, including all subranges therebetween. In some embodiments, the permeation enhancer is in an amount ranging from about 1.0% to about 80% by weight, or from about 15% to about 75% by weight. In some embodiments, a pharmaceutical composition or formulation disclosed herein comprises dimethyl sulfoxide in an amount in the range of 1.0% to about 60% by weight, including about 1.0% by weight, about 5.0% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, or any subranges and values ​​therebetween. In some embodiments, a pharmaceutical composition or formulation disclosed herein comprises diethylene glycol monoethyl ether in an amount ranging from 1.0% to about 60% by weight, including about 1.0% by weight, about 5.0% by weight, about 10% by weight, about 15% by weight, about 20% by weight, about 25% by weight, about 30% by weight, about 35% by weight, about 40% by weight, about 45% by weight, about 50% by weight, about 55% by weight, about 60% by weight, or any subranges and values ​​therebetween.In some embodiments, the pharmaceutical compositions or formulations disclosed herein comprise diethylene glycol monoethyl ether in an amount ranging from 1.0% to about 60% by weight and dimethyl sulfoxide in an amount ranging from 1.0% to about 60% by weight. In some embodiments, the pharmaceutical compositions or formulations disclosed herein comprise diethylene glycol monoethyl ether in an amount ranging from about 20% to about 40% by weight and dimethyl sulfoxide in an amount ranging from about 10% to about 50% by weight. In some embodiments, the pharmaceutical compositions or formulations disclosed herein comprise about 30% by weight of diethylene glycol monoethyl ether and about 20% or about 40% by weight of dimethyl sulfoxide.

[0055] In some embodiments, the compositions disclosed herein include a PDT enhancer. In certain embodiments, the PDT enhancer can be one or more inorganic salts, such as sodium azide, sodium thiocyanate, sodium bromide, potassium iodide (KI), sodium iodide, and potassium selenocyanate (KSeCN). In certain embodiments, the PDT enhancer is potassium iodide (KI). In some embodiments of the pharmaceutical compositions disclosed herein, the concentration of the PDT enhancer (e.g., KI) is in an amount ranging from about 0.1 mM to about 1 M. In some embodiments, the PDT enhancer (e.g., KI) is in an amount ranging from about 10 mM to about 100 mM. For example, in some embodiments, the PDT enhancer (e.g., KI) is at about 10 mM, or about 20 mM, or about 30 mM, or about 40 mM, or about 50 mM, or about 60 mM, or about 70 mM, or about 80 mM, or about 90 mM, or about 100 mM, or about 110 mM, or about 120 mM, or about 130 mM, or about 140 mM, or about 150 mM, or about 160 mM, or about 170 mM, or about 180 mM, or about 190 mM, or about 200 mM, or about 210 mM, or about 220 mM, or about 230 mM, or about 240 mM, or about 250 mM, or about 260 mM, or about 270 mM, or about 280 mM, or about 290 mM, or about 300 mM, or about 310 mM, or about 320 mM, or about 330 mM, or about 340 mM, or about 350 mM, or about 360 mM, or about 370 mM, or about 380 mM, or about 390 mM, or about 400 mM, or about 410 mM, or about 420 mM, or about 430 mM, or about 440 mM, or about 450 mM, or about 460 mM, or about 470 mM, or about 480 mM, or about 490 mM, or about 500 mM, or about 510 mM, or about 520 mM, or about 530 mM, or about 540 mM, or about 550 mM, or about 560 mM, or about 570 mM, or about 580 mM, or about 590 mM, or about 600 mM, or about 610 mM, or about 620 mM, or about 500 mM, or about 100 mM, or about 270 mM, or about 280 mM, or about 290 mM, or about 300 mM, or about 310 mM, or about 320 mM, or about 330 mM, or about 340 mM, or about 350 mM, or about 360 mM, or about 370 mM, or about 380 mM, or about 390 mM, or about 400 mM, or about 410 mM, or about 420 mM, or about 430 mM, or about 440 mM, or about 450 mM, or about 460 mM, or about 470 mM, or about 480 mM, or about 490 mM, or about 500 mM, including all subranges and values ​​therebetween. In some embodiments, the PDT enhancer (e.g., KI) is in an amount of about 100 mM. In certain embodiments, the augmentation agent for PDT in the amounts or ranges herein is a KI.

[0056] In some embodiments, the PDT enhancer (e.g., KI) is in an amount ranging from about 0.01% to about 5% by weight. For example, in some embodiments, the PDT enhancer (e.g., KI) is in an amount ranging from about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9 ... %, approximately 1.6% by weight, approximately 1.7% by weight, approximately 1.8% by weight, approximately 1.9% by weight, approximately 2.0% by weight, approximately 2.1% by weight, approximately 2.2% by weight, approximately 2.3% by weight, approximately 2.4% by weight, approximately 2.5% by weight, approximately 2.6% by weight, approximately 2.7% by weight, approximately 2.8% by weight, approximately 2.9% by weight, approximately 3.0% by weight, approximately 3.1% by weight, approximately 3.2% by weight, approximately 3.3% by weight, approximately 3.4 Weight%, about 3.5% by weight, about 3.6% by weight, about 3.7% by weight, about 3.8% by weight, about 3.9% by weight, about 4.0% by weight, about 4.2% by weight, about 4.4% by weight, about 4.6% by weight , about 4.8% by weight, about 5.0% by weight, about 5.5% by weight, about 6.0% by weight, about 6.5% by weight, about 7.0% by weight, about 7.5% by weight, about 8.0% by weight, about 8.5% by weight, about 9 In some embodiments, the PDT enhancer is in an amount ranging from about 0.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%, about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about 14.5%, to about 15.0% by weight, including all subranges and values ​​therebetween. In some embodiments, the PDT enhancer (e.g., KI) is in an amount ranging from about 0.5% to about 5% by weight, or from about 1% to about 2% by weight. In certain embodiments, the PDT enhancer in the amounts or ranges herein is KI.

[0057] In some embodiments of the pharmaceutical compositions disclosed herein, the enhancer of PDT is selected from the group consisting of sodium azide, sodium thiocyanate, sodium bromide, potassium iodide, and sodium iodide, hi some embodiments, the enhancer of PDT is potassium iodide (KI).

[0058] In some embodiments, the pharmaceutical composition or pharmaceutical topical formulation further comprises one or more surfactants. In some embodiments, the surfactant is a polysorbate, such as polysorbate 80. In addition, other surfactants may be used instead of polysorbate 80, such as sodium lauryl sulfate and related alkyl ether sulfates, sodium lauryl ether sulfate, and sulfates, such as sodium myreth sulfate; polyethylene glycol, and the fraction size of polyethylene glycol may vary. Other suitable surfactants include alkylaryl ether phosphates, alkyl ether phosphates, and carboxylates, such as sodium stearate, or non-ionic surfactants, such as ethoxylates, fatty acid esters of polyhydroxy compounds, fatty acid esters of sorbitol, fatty acid esters of sucrose, and alkyl polyglucosides.

[0059] In some embodiments of the pharmaceutical compositions disclosed herein, the surfactant is in an amount ranging from 0.01% to about 5% by weight, including about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, or about 2.5% by weight. %, about 2.1 wt%, about 2.2 wt%, about 2.3 wt%, about 2.4 wt%, about 2.5 wt%, about 2.6 wt%, about 2.7 wt%, about 2.8 wt%, about 2.9 wt%, about 3.0 wt%, about 3.1 wt%, about 3.2 wt%, about 3.3 wt%, about 3.4 wt%, about 3.5 wt%, about 3.6 wt%, about 3.7 wt%, about 3.8 wt%, about 3.9 wt%, about 4.0 wt%, about 4.2 wt%, about 4.4 wt%, about 4.6 wt%, about 4.8 wt%, to about 5.0 wt%, including all subranges and values ​​therebetween. In some embodiments, the solvent is in an amount ranging from about 0.5 wt% to about 1.5 wt%, or about 1 wt%.

[0060] In some embodiments, the pharmaceutical composition or topical formulation further comprises one or more solvents. Among the acceptable solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, non-aqueous solvents may be used. Examples of non-aqueous solvents suitable for use in this application include propylene glycol. In some embodiments, the solvent is hexylene glycol.

[0061] In some embodiments of the pharmaceutical compositions disclosed herein, the solvent is in an amount ranging from 0.01% to about 5% by weight, including about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about In some embodiments, the surfactant is in an amount ranging from about 1% to about 3% by weight, or about 2% by weight, including about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4.0%, about 4.2%, about 4.4%, about 4.6%, about 4.8%, to about 5.0% by weight, including all subranges and values ​​therebetween. In some embodiments, the surfactant is in an amount ranging from about 1% to about 3% by weight, or about 2% by weight.

[0062] In some embodiments of the pharmaceutical composition disclosed herein, the pharmaceutical composition is a topical formulation. In some embodiments, the topical formulation comprises porfimer sodium, and when applied to the skin, provides at least 0.01% of porfimer sodium to the epidermis to dermis layer of a subject. In some embodiments, at least 0.03% of porfimer sodium is retained. In some embodiments, at least 0.04% of porfimer sodium is retained.

[0063] In some embodiments of the pharmaceutical compositions disclosed herein, the topical formulation is applied under the following conditions, such as those described in Example 7. In some embodiments, at least 0.03% of porfimer sodium is retained in the epidermis. In some embodiments, at least 0.04% of porfimer sodium is retained in the epidermis under the conditions, such as those described in Example 7.

[0064] In some embodiments, the present disclosure provides a pharmaceutical topical formulation containing porfimer sodium and one or more pharma- ceutical acceptable excipients that, when applied to the skin of a subject, provides at least 0.01% of the porfimer to the epidermis-to-dermis layer of a subject. In some embodiments, the present disclosure provides a pharmaceutical topical formulation containing porfimer sodium and one or more pharma-ceutical acceptable excipients that, when applied to the skin of a subject, provides at least 0.03% of the porfimer to the epidermis-to-dermis layer of a subject. In some embodiments, the pharmaceutical topical formulation, when applied to the skin of a subject, provides at least 0.04% of the porfimer to the epidermis-to-dermis layer of a subject.

[0065] In one embodiment, the pharmaceutical composition of the present invention is comprised of porfimer sodium, which is a stable composition compared to the prior art. In some embodiments of the pharmaceutical topical formulations disclosed herein, the composition has less than 20% total impurities by HPLC after 4 weeks at 40° C. / 75% RH. In some embodiments of the pharmaceutical composition of the present disclosure, the pharmaceutical composition is a topical formulation. In some embodiments, the composition of the present disclosure has less than 20% total impurities by HPLC after 4 weeks at 40° C. / 75% RH. In some embodiments, the composition of the present disclosure has less than 19% total impurities by HPLC after 4 weeks at 40° C. / 75% RH. In some embodiments, the composition of the present disclosure has less than 18% total impurities by HPLC after 4 weeks at 40° C. / 75% RH. In some embodiments, the composition of the present disclosure has less than 17% total impurities by HPLC after 4 weeks at 40° C. / 75% RH. In some embodiments, the composition of the present disclosure has less than 16% total impurities by HPLC after 4 weeks at 40° C. / 75% RH. In some embodiments, compositions of the present disclosure have less than 15% total impurities by HPLC after 4 weeks at 40° C. / 75% RH. In some embodiments, compositions of the present disclosure have less than 14% total impurities by HPLC after 4 weeks at 40° C. / 75% RH. In some embodiments, compositions of the present disclosure have less than 13% total impurities by HPLC after 4 weeks at 40° C. / 75% RH. In some embodiments, compositions of the present disclosure have less than 12% total impurities by HPLC after 4 weeks at 40° C. / 75% RH.

[0066] In some embodiments, compositions of the present disclosure have less than 20% total impurities by HPLC after 4 weeks at 25° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 19% total impurities by HPLC after 4 weeks at 25° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 18% total impurities by HPLC after 4 weeks at 25° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 17% total impurities by HPLC after 4 weeks at 25° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 16% total impurities by HPLC after 4 weeks at 25° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 15% total impurities by HPLC after 4 weeks at 25° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 14% total impurities by HPLC after 4 weeks at 25° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 13% total impurities by HPLC after 4 weeks at 25° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 12% total impurities by HPLC after 4 weeks at 25° C. / 60% RH.

[0067] In some embodiments, compositions of the present disclosure have less than 20% total impurities by HPLC after 4 weeks at 5° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 19% total impurities by HPLC after 4 weeks at 5° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 18% total impurities by HPLC after 4 weeks at 5° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 17% total impurities by HPLC after 4 weeks at 5° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 16% total impurities by HPLC after 4 weeks at 5° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 5% total impurities by HPLC after 4 weeks at 5° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 14% total impurities by HPLC after 4 weeks at 5° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 13% total impurities by HPLC after 4 weeks at 5° C. / 60% RH. In some embodiments, compositions of the present disclosure have less than 12% total impurities by HPLC after 4 weeks at 5° C. / 60% RH.

[0068] In other embodiments, compositions of the present disclosure have less than 5%, 4%, 3%, or 2% hematoporphyrin (HP) impurities by HPLC after 4 weeks at 5° C. / 60% RH. In other embodiments, compositions of the present disclosure have less than 5%, 4%, 3%, or 2% hematoporphyrin (HP) impurities by HPLC after 4 weeks at 25° C. / 60% RH. In other embodiments, compositions of the present disclosure have less than 5%, 4%, 3%, or 2% hematoporphyrin (HP) impurities by HPLC after 4 weeks at 40° C. / 75% RH.

[0069] In other embodiments, the compositions of the present disclosure have less than 10%, 9%, 8%, 7%, 6%, or 5% total hydroxyvinyldeuteroporphyrin (HVD) (isomers 1 and 2) impurities by HPLC after 4 weeks at 5° C. / 60% RH. In other embodiments, the compositions of the present disclosure have less than 10%, 9%, 8%, 7%, 6%, or 5% total hydroxyvinyldeuteroporphyrin (HVD) (isomers 1 and 2) impurities by HPLC after 4 weeks at 25° C. / 60% RH. In other embodiments, the compositions of the present disclosure have less than 10%, 9%, 8%, 7%, 6%, or 5% total hydroxyvinyldeuteroporphyrin (HVD) (isomers 1 and 2) impurities by HPLC after 4 weeks at 40° C. / 75% RH.

[0070] In other embodiments, the compositions of the present disclosure have less than 5%, 4%, 3%, or 2% protoporphyrin (PP) impurities by HPLC after 4 weeks at 5° C. / 60% RH. In other embodiments, the compositions of the present disclosure have less than 5%, 4%, 3%, or 2% protoporphyrin (PP) impurities by HPLC after 4 weeks at 25° C. / 60% RH. In other embodiments, the compositions of the present disclosure have less than 5%, 4%, 3%, or 2% protoporphyrin (PP) impurities by HPLC after 4 weeks at 40° C. / 75% RH.

[0071] The compositions of the present disclosure can be utilized to treat a subject in need of treatment. In certain embodiments, the subject is a mammal, such as a human, or a non-human mammal. When administered to a subject, such as a human, the composition or compound can be administered, for example, as a pharmaceutical composition comprising a compound of the present disclosure and a pharma- ceutically acceptable carrier. Some examples of materials that can serve as pharma- ceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, methylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycosaminoglycans; (11) glycerol; (12) glycerol; (13) glycerol; (14) glycerol; (15) glycerol; (16) glycerol; (17) glycerol; (18) glycerol; (19) glycerol; (20) glycerol; (21) glycerol; (22) glycerol; (23) glycerol; (24) glycerol; (25) glycerol; (26) glycerol; (27) glycerol; (28) glycerol; (29) glycerol; (30) glycerol; (31) glycerol; (32) glycerol; (33) glycerol; (34) glycerol; (35) glycerol; (36) glycerol; (37 Examples of suitable non-toxic, compatible substances include ethanol, e.g., propylene glycol, (11) polyols and sugar alcohols, e.g., glycerin, sorbitol, mannitol, xylitol, erythritol, and polyethylene glycol, (12) esters, e.g., ethyl oleate and ethyl laurate, (13) agar, (14) buffers, e.g., magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffers; and (21) other non-toxic, compatible substances used in pharmaceutical formulations, including salts such as sodium chloride. In some embodiments, when such pharmaceutical compositions are for human administration, the aqueous solution is pyrogen-free or substantially pyrogen-free. Additives can be selected, for example, to provide delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition can be in unit dosage form, such as a lyophilizate, powder, solution, syrup, injectable solution, etc., for reconstitution. The composition may also be in a solution suitable for topical administration.

[0072] In some embodiments, the pharmaceutical compositions of the present disclosure are formulated for topical administration. In some embodiments, the compositions of the present disclosure are formulated for topical administration to areas of broken skin. Broken skin can include, but is not limited to, skin and soft tissue infections, skin lesions, vesicles, chronic ulcers, cysts, blisters, blisters, open ulcers such as decubitus ulcers (bedsores) and other pressure ulcers, cellulitis ulcers, erysipelas lesions, wounds, burns, furuncles, skin ulcers, or other conditions in which the skin is damaged, injured, cracked, split, and / or affected by other conditions. Topical formulations generally include a sterile buffer, such as sterile PBS, water, or saline buffer, or sterile SM buffer. A variety of buffers may be used in conjunction with the present disclosure and will be readily apparent to one of skill in the art. For example, in some embodiments, suitable buffers include sodium or potassium citrate, citric acid, phosphate buffers such as sodium phosphate, boric acid, sodium bicarbonate, and various mixed phosphate buffers including combinations of Na2HPO4, NaH2PO4, and KH2PO4. In some embodiments, sodium phosphate buffers are used. In some embodiments, sodium citrate buffers are used. Thus, the pH of the formulation may vary from about 5 to about 10. In some embodiments, the pH of the formulation is about 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or about 10. In some embodiments, the pH of the formulation is about 7.4.

[0073] For topical application to the skin, the pharmaceutical composition of the present disclosure may be used with one or a combination of carriers for topical formulations. Carriers for topical formulations may include semi-solid and / or gel-like vehicles, which may include polymeric thickeners, water, preservatives, active surfactants, emulsifiers, and / or solvents or mixed solvent systems. U.S. Patent No. 5,863,560 discloses many different carrier combinations that may aid in skin exposure to drugs, the contents of which are incorporated herein by reference. The carrier may or may not be accompanied by a controlled release formulation, as disclosed, for example, in U.S. Patent No. 2008 / 0260697, the contents of which are incorporated herein by reference. In some embodiments, the carrier may or may not be accompanied by a viscous formulation, such as a gel, as disclosed, for example, in U.S. Patent No. 2009 / 0191254, the contents of which are incorporated herein by reference.

[0074] In some embodiments, the topical pharmaceutical composition of the present disclosure is provided in a sealed container. The container may be a vial, syringe, tube, bottle, ampoule (e.g., blow-fill-seal polypropylene ampoule), sachet, etc., and may comprise or consist of glass, plastic, or other suitable material. For example, ampoules are generally manufactured industrially from short lengths of glass tubing, which are formed by heating with a gas torch and gravity. Computer vision techniques are often used, for example, for quality control. Filling and sealing of ampoules may be performed by automated machines. Blank ampoules may be purchased from scientific glass suppliers and sealed, for example, with a small gas torch, preferably under an inert atmosphere. In some embodiments, the container may also be filled with an inert gas in addition to the pharmaceutical composition. In some embodiments, the composition is provided in an ampoule or other suitable container, and transferred for use to a medium suitable for direct contact with injured skin, such as a patch, wipe, bandage, dressing, as described below.

[0075] In some embodiments, topical administration of the pharmaceutical composition of the present disclosure includes the use of a dressing. The pharmaceutical composition of the present disclosure may be incorporated into a dressing and / or applied separately in conjunction with the use of a dressing. The dressing promotes healing by keeping the wound moist, forming a barrier against infection, and / or keeping the surrounding skin dry, and limiting exposure of the PDT active ingredient to light. When treating local wounds (e.g., skin and soft tissue infections), the degree of moisture in the wound should be considered. Heavy exudates necessitate the selection of moisture-absorbing materials, including, but not limited to, alginates, foams, collagen-alginate combinations, carboxymethylcellulose materials, or gauze. Dry wounds with little exudate generally respond well to hydrogels. Hydrogel sheets often contain a three-dimensional network of cross-linked hydrophilic polymers. Amorphous hydrogels are similar in composition to hydrogel sheets, but lack cross-linking. Gels may also include additional components, such as collagen, alginates, or complex carbohydrates. Alginate dressings often contain calcium or calcium-sodium salts of natural polysaccharides derived from wakame seaweed. When the alginate material comes into contact with sodium-rich wound exudate, ion exchange occurs, producing a hydrophilic gel. Additional dressing options include, but are not limited to, films, such as adhesive backing films, gels, and foams, such as silicone-coated foams, hydrocolloids, collagen-based dressings, absorbent polymers, and the like. Hydrocolloid dressings often contain an adhesive component, an absorbent component, and an elastomeric component. For example, carboxymethylcellulose is a common absorbent component. Hydrofiber dressings also often contain carboxymethylcellulose, such as sodium carboxymethylcellulose. Foam dressings often contain a polymer, often polyurethane, with small open cells that can hold liquid. Some types of foam dressings have a waterproof film covering the top surface and may have an adhesive coating on the wound contact surface or wound border.Film dressings often contain a thin, transparent polyurethane sheet coated on one side with an adhesive. The sheet is permeable to gas and water vapor, but impermeable to wound fluids. Hydrofiber dressings often contain sodium carboxymethylcellulose fibers. Collagen-based dressings often contain purified collagen, derived from bovine, porcine, equine, or avian sources. Collagen-based dressings are believed to aid in wound healing, for example, by stimulating fibroblast production.

[0076] In some embodiments, the topical administration of the pharmaceutical composition of the present disclosure comprises instillation. The pharmaceutical composition of the present disclosure may be incorporated into an instillation and / or may be applied separately in conjunction with the use of instillation. Instillation refers to the administration of a liquid pharmaceutical composition by gradually introducing, for example, a liquid drop by drop. A typical instillation therapy instills a fluid into a wound under low positive pressure. Devices for use in instillation include, for example, Kritter-type instillation catheters (see, for example, Brent H. et al. 2005. Wounds 17(2):37-48). Techniques known in the art for improving instillation and distribution of liquid include, but are not limited to, filling the wound with instillation liquid, applying a porous wound filler, and / or combining with negative pressure wound therapy.

[0077] To deliver the compositions of the present disclosure at the desired dosage and according to a suitable dosage regimen, the administration methods described herein and / or known in the art may be used. Dosage and administration regimen may vary depending on the specific formulation, route of administration, condition being treated, and other factors. Animal experiments may provide reliable guidance for determining effective dosages in human treatment, which is within the skill of ordinary physicians. Interspecies scaling of effective dosages may be performed by those skilled in the art, for example, according to the principles described by Mordenti, J. et al. "The use of interspecies scaling in toxicokinetics" in Toxicokinetics and New Drug Development, Yacobi et al., Eds., Pergamon Press, New York 1989, pp42-96.

[0078] The preparation can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical arts.The amount of active ingredient that can be combined with carrier material to produce a single dosage form varies according to the subject to be treated and specific method of administration.The amount of active ingredient that can be combined with carrier material to produce a single dosage form is generally the amount of compound that produces therapeutic effect.

[0079] The compositions can also be formulated for sustained or controlled release of the active ingredient therein, for example, using hydroxypropylmethylcellulose, other polymer matrices, liposomes, porphysomes, nanoparticles and / or microspheres, etc., with the percentages varied to obtain the desired release profile. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately prior to use.

[0080] Liquids useful for topical administration include pharma- ceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, gels, syrups and elixirs. In addition to the active ingredient, liquids can contain inert diluents commonly used in the art, such as water or other solvents, cyclodextrin and its derivatives, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil, etc.), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, topical compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, and preservatives.

[0081] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0082] Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound can be mixed under sterile conditions with a pharma- ceutically acceptable carrier, and any preservatives or buffers that may be required. Ointments, pastes, creams, and gels can contain, in addition to the active compound, one or more excipients or carriers, such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, polymers, salts, and zinc oxide, or mixtures thereof. In some embodiments, the PS composition is in the form of an aqueous solution. In some embodiments, the excipient comprises a salt selected from sodium chloride. In some embodiments, the excipient comprises sodium chloride.

[0083] In some cases, it is desirable to slow the absorption of a drug to prolong its effect. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. Therefore, the absorption rate of a drug depends on its dissolution rate, which may vary depending on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle.

[0084] Actual dosage levels of the active ingredients in pharmaceutical compositions can be varied to provide an amount of the active ingredient effective to achieve the desired therapeutic effect for a particular patient, composition, and method of administration without causing toxicity to the patient.

[0085] The selected dosage level will depend on a variety of factors, such as the activity of the particular compound or combination of compounds or their esters, salts or amides used, the route of administration, the time of administration, the rate of excretion of the particular compound(s) used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) used, the age, sex, weight, condition, overall health and prior medical history of the subject being treated, and similar factors well known in the medical arts.

[0086] A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian could begin administration of the pharmaceutical composition or compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved. By "therapeutically effective amount" is meant the concentration of the compound sufficient to induce the desired therapeutic effect, or the frequency with which the patient is treated. It is generally understood that the effective amount of the compound will vary depending on the subject's weight, sex, age, and medical history. Other factors that affect the effective amount can include, but are not limited to, the severity of the subject's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent administered together with the compound of the present disclosure. A larger total dose can be delivered by multiple administrations of the drug. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison's Principles of Internal Medicine 13 ed., 1814-1882, incorporated herein by reference).

[0087] In general, a suitable dosage of an active compound used in the compositions and methods of the present disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dosage will generally vary, depending on the factors described above.

[0088] Wetting agents, emulsifying agents and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives, and antioxidants can also be present in the composition.

[0089] Examples of pharma- ceutically acceptable antioxidants include (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, etc., (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc., and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc. In some embodiments, the antioxidant is phenoxyethanol.

[0090] In some embodiments of the pharmaceutical compositions disclosed herein, the antioxidant is in an amount ranging from 0.01% to about 5% by weight, including about 0.01%, about 0.05%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9 ... In some embodiments, the antioxidant is in an amount ranging from about 0.5% to about 1.5% by weight, or about 1.0% by weight.

[0091] Topical delivery methods may include application (e.g., by finger wipe or with an applicator), spray, foam, bandage, sustained release patch, liquid-absorbed wipe, and combinations thereof. In some embodiments, the compositions of the present disclosure are provided directly or in a carrier(s) or patch, wipe, bandage, dressing, or other vehicle suitable for direct contact with the skin, particularly SSTIs.

[0092] Without wishing to be bound by theory, this success is believed to be due to the composition in combination with the photodynamic agent porfimer sodium. The composition can stabilize porfimer sodium. Furthermore, the inclusion of skin penetrants and other solvents allows for controlled release and penetration of porfimer sodium. Furthermore, the drying of the composition on the tissue surface is improved by selecting certain compositions, especially those that contain humectants. Furthermore, the selection of the appropriate viscosity of the composition allows for effective skin contact, enhancing spreading and thereby localizing the active agent to the site of infection.

[0093] How to use In some embodiments, the present disclosure provides a method for treating damaged skin, such as damaged skin caused by sun exposure, in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a composition containing porfimer sodium, where the composition is applied to the skin, such as sun-exposed skin. In certain embodiments, the damaged skin that may be treated may include chronic sun-exposed skin, wrinkled skin, pigmented skin, melasma, actinic keratosis, seborrheic keratosis, photodamaged skin, acne, warts, and / or psoriasis, and may be treated with a pharmaceutical composition containing porfimer sodium, where the composition is applied to the skin, such as sun-exposed skin.

[0094] In some embodiments, the present disclosure provides a method for treating damaged skin caused by sun exposure in a subject, the method comprising administering to a subject in need thereof any pharmaceutical composition or pharmaceutical formulation of the present disclosure, wherein the composition is applied to the damaged skin (e.g., applied to sun-exposed skin) and light is applied to the damaged skin. In some embodiments, the light has a wavelength in the range of about 380 nm to about 850 nm. In some embodiments, the light has a wavelength in the range of about 400 nm to about 700 nm. In some embodiments, the light has a wavelength of about 630 nm.

[0095] In some embodiments, the present disclosure provides a method for treating chronic sun-exposed skin, wrinkles, pigmented spots, melasma, actinic keratosis, seborrheic keratosis, photodamaged skin, acne, warts, and psoriasis, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition or formulation of the present disclosure, the composition or formulation being applied to the photodamaged skin, and light being applied to the damaged skin. In some embodiments, the light has a wavelength ranging from about 380 nm to about 850 nm. In some embodiments, the light has a wavelength ranging from about 400 nm to about 700 nm. In some embodiments, the light has a wavelength of about 630 nm. In some embodiments, the treatment is for actinic keratosis. In some embodiments, the treatment is for seborrheic keratosis.

[0096] In some embodiments, the method for photodynamic therapy includes treating damaged skin due to sun exposure or treating chronic sun-exposed skin, wrinkles, pigmented spots, melasma, actinic keratosis, seborrheic keratosis, photodamaged skin, acne, warts, and psoriasis with no or minimal adverse reactions or side effects due to photodynamic therapy. In certain embodiments, the present disclosure provides a method for treating actinic keratosis, comprising administering to a subject in need thereof a therapeutically effective amount of a composition or formulation of the present disclosure, the composition or formulation being applied to the damaged skin, and light being applied to the damaged skin, and adverse side effects are minimized, such as minimizing pain, edema, pruritus, and / or erythema. In certain embodiments, the photodynamic agent is porfimer sodium. In another particular embodiment, adverse side effects are minimized more than other photodynamic agents when applied topically to a subject. In fact, one of the most significant drawbacks of topical use of photodynamic agents is the significant pain during light application. For example, topical application of both 5-ALA and methyl-ALA is known to cause specific pain during photoirradiation, likely due to the fact that the drugs are localized in hair follicles, nerve endings, epidermal cells and sebaceous glands. Thus, the field is in need of new methods to reduce pain during treatment.

[0097] Thus, embodiments of the present invention include a method for treating damaged skin caused by sun exposure in a subject, the method comprising administering to a subject in need thereof any pharmaceutical composition or formulation described herein, wherein the composition is applied to the sun-exposed skin and light is applied to the sun-exposed skin to minimize adverse side effects, such as minimizing pain, edema, pruritus and / or erythema. In certain embodiments, the pharmaceutical composition comprises a photosensitizer and one or more gelling agents. In certain embodiments, the photosensitizer is porfimer sodium (Photofrin®).

[0098] In another specific embodiment of the method herein, the sun-exposed skin treated with no or minimal adverse side effects is selected from one or more of the group consisting of chronic sun-exposed skin, wrinkles, pigmented spots, melasma, actinic keratosis, photodamaged skin, acne, warts, and psoriasis.In a specific embodiment, the present invention includes a method for treating sun-exposed damaged skin in a subject, the method includes administering to a subject in need thereof any pharmaceutical composition or pharmaceutical formulation described herein, the composition or formulation includes porfimer sodium, the composition is applied to the sun-exposed skin, and light is applied to the sun-exposed skin.In a specific embodiment, the subject does not suffer from pain when light is applied to the sun-exposed skin.In another embodiment, the subject does not suffer from pain according to a visual analog scale of pain when light is applied to the sun-exposed skin. See, for example, Bodian CA, Freedman G, Hossain S, Eisenkraft JB, Beilin Y. The Visual Analog Scale for Pain. Anesthesiology 2001:95:1356-61. In certain embodiments, the subject suffers from pain on the visual analog scale of 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or less when light is applied to sun-exposed skin. In certain embodiments, the subject suffers from pain on the visual analog scale of 5, 4, 3, 2, 1, or less when light is applied to sun-exposed skin. In certain embodiments, the subject suffers from pain on the visual analog scale of 3, 2, 1, or less when light is applied to sun-exposed skin. In certain embodiments, the subject experiences pain at a level of 2, 1, or lower according to a visual analog scale of pain when light is applied to sun-exposed skin.

[0099] In another aspect, the present disclosure also provides a method for treating a topical skin infection, comprising administering to a subject in need thereof a therapeutically effective amount of a porfimer sodium-containing composition, wherein the composition is applied to the skin infection (e.g., applied to the infected surface). In some embodiments, the skin infection is a skin and soft tissue infection (SSTI), acute bacterial skin and skin structure infection (ABSSSI), both complicated and uncomplicated.

[0100] In some embodiments, the disclosure provides a method for treating an infected area, comprising administering to a subject in need thereof any pharmaceutical composition or formulation of the disclosure, wherein the composition is applied to the infected area (e.g., applied to the surface of a wound) and light is applied to the infected area. In some embodiments, the light has a wavelength in the range of about 380 nm to about 850 nm. In some embodiments, the light has a wavelength in the range of about 400 nm to about 700 nm. In some embodiments, the light has a wavelength of about 630 nm. In some embodiments, the disclosure provides a method for treating a microbial infection, comprising administering to a subject in need thereof a therapeutically effective amount of a composition or formulation of the disclosure, wherein the composition or formulation is applied to the infection and light is applied to the infected area. In some embodiments, the light has a wavelength in the range of about 380 nm to about 850 nm. In some embodiments, the light has a wavelength in the range of about 400 nm to about 700 nm. In some embodiments, the light has a wavelength of about 630 nm. In some embodiments, the infected area is a wound. In certain embodiments, the wound is a local wound. In some embodiments, the area or local wound is infected with one or more bacterial and / or fungal pathogens. In some embodiments, the area or local wound is infected with an antibiotic-resistant bacterial pathogen.

[0101] Localized treatment offers the advantages of avoiding systemic adverse effects, providing increased concentrations at the target site, and allowing the use of drugs that are not available for systemic therapy, avoiding microbial resistance mechanisms associated with systemic therapy, such as, but not limited to, biofilms. In some embodiments, mechanical debridement may be used to improve localized treatment by reducing the existing bacterial bioburden and opening up a time-dependent therapeutic window for topical antimicrobial therapy (TAT) (Wolcott RD, et al. 2010. J. Wound Care, 19:320-328).

[0102] In some embodiments, the infected area is infected with one or more Gram-positive bacteria. In some embodiments, the infected area is infected with one or more Gram-negative bacteria. In some embodiments, the infected area is infected with one or more fungal pathogens. In some embodiments, the infected area is infected with the gram-positive bacteria Staphylococcus aureus(+), Staphylococcus aureus MRSA(+), Peptostreptococcus anaerobius(+), Proprionibacterium acnes(+) (now called Cutibacterium acnes), Bacillus thuringiensis(+), Bacillus atrophaeus(+), Streptococcus mutans(+), Streptococcus pneumoniae(+), or the gram-negative bacteria Prevotella(-), Porphyromonas gingivalis(-), Salmonella enterica(-), Escherichia coli(-), Yersinia intermedia(-), Acinetobacter baumannii(-), Neisseria gonorrhea(-), Haemophilus influenza(-), Fusobacterium nucleatum(-), or Moraxella.Catarrhalis(-). In some embodiments, the infected area is infected with Candida spp. Candida albicans, Candida glabrata, Candida parasilosis, Candida krusei, Candida tropicalis, and / or Candida.Guilliermondi.In some embodiments, the infected area is infected with the following gram-positive bacterial pathogens: Staphylococcus aureus(+), Staphylococcus aureus MRSA(+), Peptostreptococcus anaerobius(+), Proprionibacterium acnes(+) (now called Cutibacterium acnes), Bacillus thuringiensis(+), Bacillus atrophaeus(+), Streptococcus mutans(+), Streptococcus pneumoniae(+), or the gram-negative bacteria Prevotella(-), Porphyromonas gingivalis(-), Salmonella enterica(-), Escherichia coli(-), Yersinia intermedia(-), Acinetobacter baumannii(-), Neisseria gonorrhea(-), Haemophilus influenza(-), Fusobacterium nucleatum(-), or Moraxella.Catarrhalis(-). In some embodiments, the infected area is infected with one or more of the following fungal pathogens: Candida C.albicans, C.glabrata, C.parasilosis, C.krusei, C.tropicalis, C.guilliermondi. In some embodiments, the infected area is a wound. In certain embodiments, the wound is a topical wound.

[0103] In some embodiments, the porfimer sodium compositions of the present disclosure have activity against bacterial flora found in chronic sinusitis of adult bacterial sinusitis, such as Streptococcus pneumonia (gram-positive facultative anaerobe), Moraxella catarrhalis (gram-negative, aerobic), Staphylococcus aureus (gram-positive, facultative anaerobe), Methicillin-resistant Staphylococcus aureus (MRSA) (gram-positive facultative anaerobe), Prevotella spp. (gram-negative, obligate anaerobe), Peptostreptococcus spp. (gram-positive, anaerobic), Fusobacterium nucleatum (gram-negative, anaerobic), Porphyromonas gingivalis (gram-negative, anaerobic), S. pneumoniae (gram-positive facultative anaerobe), and propionibacterium acnes (gram-positive, anaerobic).

[0104] Biofilms of S. aureus and other bacteria present in infections such as SSTIs make successful management and reduction of infections more difficult. Combinations of SSTI-associated bacteria that form multi-species biofilms, including S. aureus, have shown greater resistance, virulence and pathogenicity than comparable single-species biofilms. The presence of such complex biofilms in SSTI patients is considered to be a major contributor to the chronic and persistent nature of these infections.

[0105] In some embodiments, the bacterial pathogen is resistant to one or more antibiotics. Of particular concern are methicillin-resistant Staphylococcus aureus strains (MRSA). MRSA was a rare occurrence in hospital environments until the 1990s, when MRSA prevalence in hospitals exploded. MRSA is now considered endemic to hospitals, especially in the UK (Johnson AP et al. 2001 J. Antimicrobial Chemotherapy 48(1):143-144). In addition, MRSA poses an emerging threat in diabetic foot infections (Retrieved January 17, 2009 from the CDC: Centers for Disease Control and Prevention website).

[0106] The porfimer sodium compositions of the present disclosure have activity against multiple bacterial and fungal strains. In some embodiments, the porfimer sodium compositions are used to treat patients infected with the gram-positive bacteria Staphylococcus aureus(+), Staphylococcus aureus MRSA(+), Peptostreptococcus anaerobius(+), Proprionibacterium acnes(+) (now called Cutibacterium acnes), Bacillus thuringiensis(+), Bacillus atrophaeus(+), Streptococcus mutans(+), Streptococcus pneumoniae(+), or the gram-negative bacteria Prevotella(-), Porphyromonas gingivalis(-), Salmonella enterica(-), Escherichia coli(-), Yersinia intermedia(-), Acinetobacter baumannii(-), Neisseria gonorrhea(-), Haemophilus influenza(-), Fusobacterium nucleatum(-), or Moraxella catarrhalis(-), and multiple strains of the fungal pathogens Candida, including, but not limited to, C. albicans, C. glabrata, C. parasilosis, C. krusei, C. tropicalis, and C. guilliermondi, in vitro and in vivo.

[0107] Thus, in some embodiments of the present disclosure, the present invention is directed to a method for treating a bacterial infection in a patient infected with the gram-positive bacteria Staphylococcus aureus(+), Staphylococcus aureus MRSA(+), Peptostreptococcus anaerobius(+), Proprionibacterium acnes(+) (now called Cutibacterium acnes), Bacillus thuringiensis(+), Bacillus atrophaeus(+), Streptococcus mutans(+), Streptococcus pneumoniae(+), or the gram-negative bacteria Prevotella(-), Porphyromonas gingivalis(-), Salmonella enterica(-), Escherichia coli(-), Yersinia intermedia(-), Acinetobacter baumannii(-), Neisseria gonorrhea(-), Haemophilus influenza(-), Fusobacterium The present invention provides a method for treating and / or preventing infections and wounds associated with Candida spp. Candida albicans, Candida glabrata, Candida parasilosis, Candida krusei, Candida tropicalis, and / or Candida Guilliermondi.

[0108] In some specific embodiments, methods of treating and / or preventing infections or wounds associated with one or more of Staphylococcus aureus, Staphylococcus aureus MRSA, P. anaerobius, P. acnes, B. thuringiensis, Bacillus atrophaeus, S. mutans, S. pneumoniae, Prevotella, P. gingivalis, S. enterica, E. coli, Y. intermedia, A. baumannii, N. gonorrhoea, H. influenza, F. nucleatum, M. catarrhalis, or the fungal pathogens Candida spp. C. albicans, C. glabrata, C. parasilosis, C. krusei, C. tropicalis, C. guilliermondi, both in humans and animals, using porfimer sodium compositions. In other aspects, the disclosure provides methods of treating and / or preventing infections associated with species or strains related to these bacteria. In some embodiments, the bacterial infection is a SSTI. Staphylococcus aureus, Staphylococcus aureus MRSA, P.anaerobius, P.acnes, B.thuringiensis, B.atrophaeus, S.mutans, S.pneumoniae, Prevotella, P.gingivalis, S.enterica, E.coli, Y.intermedia, A.baumannii, N.gonorrhoea, H.influenza, F.nucleatum, M.catarrhalis are the cause of many severe opportunistic infections, especially in individuals with SSTI.

[0109] In some embodiments, the pharmaceutical compositions of the present disclosure are intended for treating and / or preventing wounds associated with Staphylococcus aureus, Staphylococcus aureus MRSA, P. anaerobius, P. acnes, B. thuringiensis, B. atrophaeus, S. mutans, S. pneumoniae, Prevotella spp., P. gingivalis, S. enterica, E. coli, Y. intermedia, A. baumannii, N. gonorrhoea, H. influenza, F. nucleatum, M. catarrhalis. In some embodiments, the wound is infected with one or more of the fungal pathogens Candida spp. C. albicans, C. glabrata, C. parasilosis, C. krusei, C. tropicalis, C. guilliermondi, or is associated with other bacterial species or strains, including, but not limited to, infected areas such as skin infections, infections in and around the wound, chronic ulcers, ulcers associated with burns, post-operative infections, infections associated with catheters and surgical drains, and blood infections.

[0110] PDT using the porfimer sodium compositions of the present disclosure finds application as a non- or minimally invasive effective treatment for oral infections, head and neck infections, superficial and / or subcutaneous infections (e.g., bacterial and / or fungal infections), including, but not limited to, infections resulting from sinusitis, wounds, open fractures, surgical implants, and surgical procedures. In some embodiments, the compositions are used in the treatment and / or prevention of bacterial infections associated with areas of broken skin, including, but not limited to, infections associated with skin ulcers, skin lesions, vesicles, cysts, blisters, blisters, open ulcers such as decubitus ulcers (bedsores) and other pressure ulcers, chronic ulcers, cellulitis, impetigo and ulcers associated therewith, erysipelas and lesions associated therewith, wounds, burns and wounds associated therewith, furuncles, or other conditions where the skin is damaged, cracked, broken, cracked, and / or affected by other conditions.

[0111] In any of the embodiments described herein, the porfimer sodium compositions may be used to treat infections (e.g., SSTIs, ABSSSIs) with one or more of the fungal pathogens Candida spp. C. albicans, C. glabrata, C. parasilosis, C. krusei, C. tropicalis, C. guilliermondi.

[0112] In some embodiments of the method for treating an infected area, administration of the porfimer sodium composition results in one or more of the following: (i) reducing and / or dispersing microbial (e.g., bacterial and / or fungal) biofilms, (ii) attenuating the growth or formation of microbial (e.g., bacterial and / or fungal) biofilms, and (iii) preventing the reformation or spread of microbial (e.g., bacterial and / or fungal) biofilms. In some embodiments, the porfimer sodium composition treats, manages, and / or reduces the severity of bacterial or fungal infections of the skin and soft tissues by one or both of: (i) preventing infection by bacterial or fungal pathogens, and / or (ii) reducing bacterial or fungal pathogens. In some embodiments, the porfimer sodium compositions treat, manage, or reduce the severity of an infection by one or more of: (i) preventing the production or secretion of exotoxins from bacterial or fungal pathogens; (ii) inhibiting cell viability or cell proliferation of planktonic cells of bacterial or fungal pathogens; (iii) inhibiting biofilm formation by bacterial or fungal pathogens; (iv) inhibiting the invasiveness of biofilms or microbial pathogens to underlying tissues (e.g., subcutaneous tissue); (v) inhibiting the virulence of biofilms or microbial pathogens to underlying tissues (e.g., subcutaneous tissue); (vi) inhibiting biofilm viability or growth of biofilm-forming cells of bacterial or fungal pathogens; and / or (vii) preventing biofilm reformation after debridement. In some embodiments, the subject experiences two or more of the enumerated outcomes. In some embodiments, the subject experiences three or more of the enumerated results. In some embodiments, the subject experiences four or more of the enumerated results. In some embodiments, the subject experiences all of the outcomes recited.

[0113] In some embodiments of the disclosed method, after administration of the composition or formulation, one or more of the following occurs: (i) bacterial and / or fungal biofilm is reduced and / or dispersed; (ii) bacterial and / or fungal biofilm growth or formation is attenuated; and (iii) bacterial and / or fungal biofilm reformation or spread is prevented. In some embodiments, the subject experiences at least one of the outcomes listed. In some embodiments, the subject experiences at least two of the outcomes listed. In some embodiments, the subject experiences all of the results listed. In some embodiments of the method for treating an infected area, the subject experiences one or more of the following outcomes after completion of dosing: reduction in reinfection / recurrence; elimination or improvement of signs and / or symptoms of infection, including redness, swelling, induration, exudation, pain, warmth (at the site of infection) or fever; improved quality of life; eradication of invasive pathogens and / or biofilm; reduced need for concurrent systemic antibiotics.

[0114] In some embodiments, the method for photodynamic therapy includes treating infections without or with minimal adverse reactions or side effects from photodynamic therapy. In certain embodiments, when the composition and then light are applied to the infection, skin or wound of a subject, adverse side effects are minimized, such as minimizing pain, edema, pruritus and / or erythema. In certain embodiments, the photodynamic agent is porfimer sodium. In another particular embodiment, adverse side effects are minimized more than other photodynamic agents when applied topically to a subject. In fact, one of the most significant drawbacks of topical use of photodynamic agents is the significant pain during light application. For example, topical application of both 5-ALA and methyl-ALA is known to cause specific pain during light application, likely due to the fact that the drugs are localized in hair follicles, nerve endings, epidermal cells and sebaceous glands. Thus, there is a need in the field for novel methods to reduce pain during treatment.

[0115] Thus, embodiments of the present invention include a method for treating a wound in a subject, comprising administering to a subject in need thereof any pharmaceutical composition or formulation described herein, wherein the composition is applied to the subject and light is applied to the subject, minimizing adverse side effects, such as minimizing pain, edema, pruritus and / or erythema. In certain embodiments, the pharmaceutical composition comprises a photosensitizer and one or more gelling agents. In certain embodiments, the photosensitizer is porfimer sodium (Photofrin®).

[0116] In certain embodiments, the subject does not suffer pain when light is applied to the subject's infection, wound or skin. In another embodiment, the subject does not suffer pain according to the visual analog scale of pain when light is applied to the subject's infection, wound or skin. See, for example, Bodian CA, Freedman G, Hossain S, Eisenkraft JB, Beilin Y. The Visual Analog Scale for Pain. Anesthesiology 2001:95:1356-61. In certain embodiments, the subject suffers pain according to the visual analog scale of pain at a level of 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or less when light is applied to the subject. In certain embodiments, the subject suffers pain according to the visual analog scale of pain at a level of 5, 4, 3, 2, 1 or less when light is applied to the subject. In certain embodiments, the subject experiences pain at a level of 3, 2, 1, or lower on the visual analog scale when light is applied to the subject. In certain embodiments, the subject experiences pain at a level of 2, 1, or lower on the visual analog scale when light is applied to the subject.

[0117] In certain embodiments of the methods herein, the pharmaceutical composition is applied to the infection and / or skin of the subject for about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 12 minutes, 14 minutes, 14 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, or 120 minutes. In another embodiment, the light is applied to the subject for about 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 12 minutes, 14 minutes, 14 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 60 minutes, or 120 minutes.

[0118] In certain embodiments, the composition is applied to the subject for about 15 minutes to about 60 minutes, and the light is applied for about 5 minutes to about 25 minutes. In certain embodiments, the composition is applied to the subject for about 15 minutes to about 30 minutes, and the light is applied for about 5 minutes to about 25 minutes. In another embodiment, the subject does not develop erythema lesions. In another embodiment, the subject does not develop erythema lesions of greater than 1 or 2 according to the erythema scale due to the treatment of the subject.

[0119] In certain embodiments, the composition is applied to the subject for about 15 minutes to 60 minutes and the light is applied for about 5 minutes. In certain embodiments, the composition is applied to the subject for about 15 minutes to 30 minutes and the light is applied for about 5 minutes. In certain embodiments, the light is applied for 5 to 25 minutes. In certain embodiments, the composition is applied to the subject as provided in any one of Examples 7-11 provided herein. In another embodiment, the subject does not develop edema and / or pruritus from treatment on sun-exposed or damaged skin. In another embodiment, the subject does not develop erythema lesions from treatment on damaged or sun-exposed skin. In another embodiment, the subject does not develop erythema lesions of greater than 1 or 2 increase according to the erythema scale from treatment on sun-exposed skin.

[0120] In some embodiments of the methods disclosed herein, the porfimer sodium composition is administered three times a day, twice a day, once a day, once every 2 days, once every 3 days, three times a week, once a week, once every 2 weeks, once a month, or once every 2 months. In some embodiments, the composition is administered once a day or three times a week. In some embodiments, the subject is administered multiple doses of the porfimer sodium composition daily or weekly for a time ranging from about 1 week to about 12 weeks. In some embodiments, the subject is administered multiple doses of the porfimer sodium composition daily or weekly for a time ranging from about 1 week to about 12 weeks. For example, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 1 year. In some embodiments, the subject is administered multiple doses of the porfimer sodium composition daily or weekly for about 4 weeks to about 10 weeks. In some embodiments, the pharmaceutical composition is administered for the first 24 hours, every 4 hours, or every 6 hours. In some embodiments, the pharmaceutical composition is administered every 12 hours or every 24 hours after the first 24 hours for at least an additional 3 days, hi some embodiments, the pharmaceutical composition is administered every 12 hours or every 24 hours for at least an additional 4 days.

[0121] In some embodiments of the methods disclosed herein, the porfimer sodium composition is administered three times a day, twice a day, once a day, once every 2 days, once every 3 days, three times a week, once a week, once every 2 weeks, once a month, or once every 2 months. In some embodiments, the composition is administered once a day or three times a week. In some embodiments, the subject is administered multiple doses of the porfimer sodium composition daily or weekly for a time ranging from about 1 week to about 12 weeks. In some embodiments, the subject is administered multiple doses of the porfimer sodium composition daily or weekly for a time ranging from about 1 week to about 12 weeks. For example, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, or about 1 year. In some embodiments, the subject is administered multiple doses of the porfimer sodium composition daily or weekly for about 4 weeks to about 10 weeks. In some embodiments, the pharmaceutical composition is administered for the first 24 hours, every 4 hours, or every 6 hours. In some embodiments, the pharmaceutical composition is administered every 12 hours or every 24 hours after the first 24 hours for at least an additional 3 days, hi some embodiments, the pharmaceutical composition is administered every 12 hours or every 24 hours for at least an additional 4 days.

[0122] Embodiment 1. A pharmaceutical composition comprising a photosensitizer and one or more gelling agents.

[0123] 2. The photosensitizer is selected from the group consisting of porphyrins, chlorins (HPPH; NPe6; temoporphyrin (Foscan), mTHPC), and porphysomes such as those found in pyropheophorbide nanovesicles, such as bacteriochlorophyll porphysomes, zinc pyropheophorbide porphysomes, and pyropheophiorbide porphysomes, as well as chlorin-like compounds (benzoporphyrins; verteporfin, bacteriochlorins, and phthalocyanines, purpurins (ethyl etiopurpurin tin); metalloporphyrins (texaphyrins); pheophorbides (TOOKAD); protoporphyrins (Levulan, Metvix, 5-ALA (PpIX)), and non-porphyrin photosensitizers, such as phenotypic The pharmaceutical composition of embodiment 1, wherein the dye is selected from one or more of the group consisting of: azinium salts, such as methylene blue, toluidine blue, Nile blue, cyanine, hypericin and chalcogen pyrylium dyes; PPA904; the benzophenothiazinium dye EtNBS; fluorescent dyes of the xanthene class, including fluorescein and rose bengal; fullerenes (C60 fullerenes attached to polar diserinol groups or quaternary pyrrolidinium groups); squaraogenine, BODIPY (boron-dipyrromethene) dyes, phenalenone; hypericin, hypocrellin, riboflavin, curcumin, titanium dioxide and porfimer sodium (Photofrin®).

[0124] 3. The pharmaceutical composition of embodiment 1, wherein the photosensitizer is porfimer sodium.

[0125] 4. The pharmaceutical composition of embodiment 3, wherein the porfimer sodium is in an amount ranging from about 0.01% to about 1.0% by weight, or from about 0.05% to about 0.7% by weight, or from about 0.1% to about 0.5% by weight, or from about 0.15% to about 0.3% by weight.

[0126] 5. The pharmaceutical composition of embodiment 3, wherein the porfimer sodium is in an amount ranging from 0.01% to 1.0% by weight, or from 0.05% to 0.7% by weight, or from 0.1% to 0.5% by weight, or from 0.15% to 0.3% by weight.

[0127] 6. The pharmaceutical composition of any one of embodiments 1-5, wherein the gelling agent is selected from one or more of the group consisting of Carbopol polymers, carbomers, crosslinked polyacrylic acid, lecithin such as lecithin-PLO, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose.

[0128] 7. The pharmaceutical composition according to embodiment 6, wherein at least one gelling agent is a carbomer.

[0129] 8. The pharmaceutical composition according to embodiment 7, wherein the gelling agent is a polymer of acrylic acid crosslinked with a polyalkenyl ether or divinyl glycol.

[0130] 9. The pharmaceutical composition of embodiment 7, wherein the carbomer is the Carbopol polymer Carbopol® 71G, Carbopol® 971P, Carbopol® 974P, Carbopol® 980, Carbopol® 981, Carbopol® 5984, Carbopol® 934, Carbopol® 934P, Carbopol® 940, Carbopol® 941, and / or Carbopol® 1342.

[0131] 10. The pharmaceutical composition according to any one of embodiments 1 to 9, wherein the gelling agent is in an amount ranging from about 0.5% to about 3.0% by weight, or from about 0.7% to about 2.0% by weight, or from about 1.0% to about 1.75% by weight.

[0132] 11. The pharmaceutical composition according to any one of the preceding embodiments, wherein the gelling agent is in an amount ranging from 0.5% to 3.0% by weight, or from 0.7% to 2.0% by weight, or from 1.0% to 1.75% by weight.

[0133] 12. The pharmaceutical composition of any one of embodiments 1-10, wherein the pharmaceutical composition further comprises one or more permeation enhancers.

[0134] 13. The pharmaceutical composition of embodiment 7, wherein the permeation enhancer is selected from one or more of the group consisting of propylene glycol SR, polyethylene glycol 400SR, polyethylene glycol 300LA, diethylene glycol monoethyl ether, dimethylsulfoxide (DMSO), and polysorbate 80SR.

[0135] 14. The pharmaceutical composition of embodiment 13, wherein the permeation enhancer is selected from one of propylene glycol SR and diethylene glycol monoethyl ether.

[0136] 15. The pharmaceutical composition of any one of embodiments 12-14, wherein the permeation enhancer is in an amount ranging from about 1.0% to about 60%, or from about 5% to about 30%.

[0137] 16. The pharmaceutical composition of any one of embodiments 12-15, wherein the pharmaceutical composition comprises a photosensitizer, a gelling agent, one or more permeation enhancers, a humectant, a solubilizer, and a preservative.

[0138] 17. i) the water retention agent is in an amount ranging from about 10% by weight to about 20% by weight, or about 15% by weight; ii) the solubilizer is in an amount ranging from 1.0% by weight to about 5% by weight, or from about 1% to about 3%, or about 2%; and / or iii) The pharmaceutical composition of embodiment 16, wherein the preservative is in an amount ranging from 0.5% to about 5% by weight, or from about 0.5% to about 2% by weight, or from about 1% to about 3% by weight.

[0139] 18. The pharmaceutical composition according to any one of the preceding embodiments, wherein the pharmaceutical composition is a topical formulation.

[0140] 19. The pharmaceutical composition of embodiment 18, wherein the topical formulation comprises porfimer sodium and, when applied to human skin under conditions such as those described in Example 7, provides at least 0.03% (percent) of the porfimer to the epidermis of the subject.

[0141] 20. The pharmaceutical composition of embodiment 18, wherein the topical formulation comprises porfimer sodium and, when applied to intact human skin of a subject, provides at least 0.03% (percent) of the porfimer to the epidermal to dermal layer of the subject.

[0142] 21. The pharmaceutical composition according to embodiment 19 or 20, wherein the composition has less than 20% total impurities by HPLC after 4 weeks at 40° C. / 75% RH.

[0143] 22. A medicinal topical formulation comprising porfimer sodium and one or more pharma- ceutical acceptable excipients, the formulation providing at least 0.03% (percent) of the porfimer to the dermis of a subject when applied to an infected area or wound of the subject.

[0144] 23. The pharmaceutical topical formulation of embodiment 19, wherein the topical formulation provides at least 0.04% (percent) of the porfimer to the epidermis of the subject.

[0145] 24. The pharmaceutical topical formulation of embodiment 22 or 23, wherein the composition has less than 20% total impurities by HPLC after 4 weeks at 40° C. / 75% RH.

[0146] 25. The pharmaceutical topical formulation of any one of embodiments 22-24, wherein the pharmaceutical topical formulation further comprises a gelling agent, one or more permeation enhancers.

[0147] 26. A method for treating sun-exposed skin in a subject, the method comprising administering to the subject in need thereof any pharmaceutical composition described in any one of embodiments 1-25, wherein the composition is applied to the sun-exposed skin and light is applied to the sun-exposed skin.

[0148] 27. The method of embodiment 26, wherein the light has a wavelength in the range of about 380 nm to about 850 nm.

[0149] 28. The method of embodiment 27, wherein the light has a wavelength of about 630 nm.

[0150] 29. The method of any one of embodiments 26-28, wherein the sun-exposed skin being treated is selected from one or more of the group consisting of chronic sun-exposed skin, wrinkles, pigmented spots, melasma, actinic keratosis, seborrheic keratosis, photodamaged skin, acne, warts, and psoriasis.

[0151] 30. The method of any one of embodiments 26-29, wherein the subject does not experience pain when the light is applied to the sun-exposed skin.

[0152] 31. The method of embodiment 30, wherein the subject does not experience pain according to a visual analog scale of pain when the light is applied to the sun-exposed skin.

[0153] 32. The method of embodiment 31, wherein the subject experiences a level of pain of 5, 4, 3, 2, 1, or lower according to a visual analog scale of pain when the light is applied to the sun-exposed skin.

[0154] 33. The method of any one of embodiments 26-32, wherein the composition is applied to the skin or wound of the subject for 15 to 60 minutes and light is applied for 5 to 25 minutes.

[0155] 34. The method of any one of embodiments 26-33, wherein the composition is applied to the subject as provided in any one of Examples 4-14 herein.

[0156] 35. The method of any one of embodiments 26-34, wherein the subject does not develop treatment-induced swelling or pruritus on the sun-exposed skin.

[0157] 36. The method of any one of embodiments 26-35, wherein the subject does not develop erythema lesions due to the treatment on the sun-exposed skin.

[0158] 37. The method of any one of embodiments 26-36, wherein the subject does not develop erythema lesions higher than 1 or 2 according to the erythema scale upon treatment of the sun-exposed skin.

[0159] 38. The method of embodiment 37, wherein the composition is applied to the skin or wound of the subject for 15 to 60 minutes and light is applied for 5 to 25 minutes.

[0160] 39. The method according to embodiment 38, wherein the composition is applied to the subject as provided in any one of Examples 6 to 14 herein.

[0161] 40. The method of any one of embodiments 26-39, wherein the subject is treated for actinic keratosis and / or seborrheic keratosis.

[0162] 41. A pharmaceutical composition according to any one of Table 1 or Table 5.

[0163] 42. A method for treating sun-exposed skin in a subject, the method comprising administering to the subject in need thereof any of the pharmaceutical compositions of embodiment 41, wherein the composition is applied to the sun-exposed skin and light is applied to the sun-exposed skin.

[0164] 43. A method for treating an infected area, the method comprising administering to a subject in need thereof a topical pharmaceutical composition according to embodiment 41, wherein the pharmaceutical composition is applied to the infected area.

[0165] 44. The method of embodiment 42 or 43, wherein the subject is administered light having a wavelength of about 630 nm that is applied to the infected area.

[0166] 45. The method of embodiment 43 or 44, wherein the infected area results from a microbial infection.

[0167] 46. ​​The infected area is: Infection with the gram-positive bacteria Staphylococcus aureus(+), Staphylococcus aureus MRSA(+), Peptostreptococcus anaerobius(+), Proprionibacterium acnes(+) (now called Cutibacterium acnes), Bacillus thuringiensis(+), Bacillus atrophaeus(+), Streptococcus mutans(+), Streptococcus pneumoniae(+) and / or the gram-negative bacteria Prevotella(-), Porphyromonas gingivalis(-), Salmonella enterica(-), Escherichia coli(-), Yersinia intermedia(-), Acinetobacter baumannii(-), Neisseria gonorrhea(-), Haemophilus influenza(-), Fusobacterium nucleatum(-), or Moraxella.Catarrhalis(-), and / or infected with Candida spp. Candida albicans, Candida glabrata, Candida parasilosis, Candida krusei, Candida tropicalis, and / or Candida.Guilliermondi. EXAMPLES

[0168] The following examples are provided to illustrate the disclosure and should not be construed as limiting thereof.

[0169] Example 1: Porfimer Sodium Formulations 1-6 The translation of successful in vitro studies using conventional porfimer sodium solutions to in vivo studies is extremely challenging. For example, in vivo studies describing antimicrobial photodynamic therapy using conventional FDA-approved porfimer sodium preparations have yielded negative or mixed results in models of abrasion wounds despite promising results in vitro. Similarly, formulations containing conventional reconstituted porfimer sodium, such as those mixed with thickening agents, have not improved efficacy in vivo due to the poor skin penetration ability of porfimer sodium in saline. Conventional FDA-approved porfimer sodium preparations have poor stability when reconstituted in solution. Thus, reconstituted porfimer sodium must be used immediately or within 24 hours upon reconstitution. The compositions of the more complex and advanced porfimer sodium (0.2 w / w%) formulations that were prepared, Formulations 1 to 6, are outlined below in Table 1. [Table 1-1] [Table 1-2]

[0170] Example 2: Stability and skin permeability studies for formulations 1-5. Stability testing

[0171] The stability of porfimer sodium formulations 1-5 was tested. Each formulation was tested for physical and chemical stability. Physical testing included appearance (visual description and color of the product), pH and microscopy. Chemical testing included assay (LC%) and looking for impurities, specifically degradation products of porfimer sodium. Specific impurities / degradation products analyzed for detection by HPLC retention time include the hydrolysis products of porfimer sodium, hematoporphyrin (HP) and hydroxyvinyldeuteroporphyrin (HVD) (isomers 1 and 2), as well as the dehydration product, protoporphyrin (PP). The total amount of impurities is the accumulation of these impurities.

[0172] The environmental chambers are maintained at the following temperature (C) and relative humidity (RH) conditions: Long Term Storage: 25±2° C. / 60±5% RH. Refrigerated: 5±3° C. Accelerated Storage: 40±2° C. / 75±5% RH. The results are summarized in Figure 1 and Table 2 below. [Table 2-1] [Table 2-2]

[0173] As shown in Table 2, except for formulation 1, which showed greater than 24% impurities at 40° C., formulations 3 and 5 were physically and chemically stable for 4 weeks at 5° C., 25° C. / 60% RH and 40° C. / 75% RH. This was a surprising and unexpected result considering that porfimer sodium is only stable for 24 hours when reconstituted in saline.

[0174] Example 3: Skin permeability test Studies have been completed that have demonstrated the ability of the formulation to deliver drug into human skin in an in vitro environment, as well as retain the API within the appropriate skin layers. The study design parameters are shown in Table 3 below. [Table 3]

[0175] In this experiment, the TEWL of each diffusion cell was measured and recorded before the application of the test substance. A range of 25 g / m2 / h or less is acceptable for this study. An automated in-line flow-through diffusion cell system (PermeGear Collector FC 33, version 3.1) was used to evaluate drugs in skin permeation experiments. A positive displacement pipette set to deliver 7.8 μL was used to evenly dispense the test substance onto the skin tissue surface. The study was performed under light-tight and closed conditions. Fractions were taken at intervals indicated in the protocol with a maximum of 24 hours. Precautions should be taken to prevent light exposure on the samples. Fractions were taken and immediately capped and stored in aluminum foil at -20°C. At the end of the test period, the tissue surface was washed once with a dry cotton swab, once with a cotton swab wetted with a cleaning solvent (hexane:acetonitrile = 1:9 (v / v)), and once with a dry cotton swab in a light-proof environment, followed by three consecutive tape strips. Swabs and tape strips were analyzed upon request. The washed and tape-striped skin was placed dermis side down on aluminum foil and processed in a light-proof environment. The samples were placed in an oven set at 60 °C for approximately 2.0 minutes. The epidermis was separated from the dermis using tweezers. The separated samples were placed into their respective labeled weighed vials, and the weight of the tissue was recorded.

[0176] The epidermis and dermis samples were processed and homogenized using the following protocol while maintaining a light-tight environment: 500 μL of homogenization mixture (water:acetonitrile = 1:1 (v / v)) was added to the labeled tube containing the skin sample. The dermis was homogenized at 10,000 RPM for 30 seconds four times with a 45 second pause period. The epidermis was then homogenized at 10,000 RPM for 30 seconds two times with a 45 second pause period. After homogenization was completed, 1000 μL of acetonitrile was added and vortexed briefly before sonicating in a water bath for 10 minutes. The vials were centrifuged and the supernatant was used for mass spectrometry. The following samples were analyzed for drug content: receptor fluid samples at different time points; skin samples (epidermis and dermis of each cell at the final time point), tape strips, and swabs were analyzed for mass balance determination. The permeation profile of each formulation into the receiving fluid at the end of the time point, as well as the permeation of each formulation into the epidermis and dermis, were calculated.

[0177] result Skin retention studies showed that 24 hours after application, permeation of porfimer sodium was primarily seen in the epidermal layer of the skin (see Figure 1 and Table 4). None of the formulations demonstrated permeation of porfimer sodium into the receptor fluid. [Table 4]

[0178] Of the formulations tested, formulation 3 showed higher epidermal retention at 0.0481%, followed by formulations 2, 5 and 4 at 0.0218%, 0.0218% and 0.0183%, respectively.

[0179] Example 4: Topical porfimer sodium formulations 7A-7J with and without KI Sodium porfimer formulations 7A-7J, with or without KI, were prepared according to Table 5 below. [Table 5-1] [Table 5-2]

[0180] Example 5: Stability test of porfimer sodium formulations 7A to 7F Stability studies were performed on porfimer sodium formulations 7A, 7B, and 7C (0.1, 0.2, 0.5 w / w%) without KI, and porfimer sodium formulations 7D, 7E, and 7F (0.1, 0.2, 0.5 w / w%) with KI (100 mM).

[0181] The environmental chambers are maintained at the following temperature (C) and relative humidity (RH) conditions: Long Term Storage: 25±2°C / 60±5% RH. Refrigerated: 5±3°C. Accelerated Storage: 40±2°C / 75±5% RH.

[0182] Prototypes of each formulation were tested for physical and chemical stability. Physical tests typically include appearance (visual description and color of the product), pH, and microscopy. Chemical tests include assay (% of label) and impurities.

[0183] result: The results of stability tests of porfimer sodium formulations 7A-7F stored for 2 weeks and 1 month at 25° C. / 60% RH, 40° C. / 75% RH, and 5° C. are shown in Figures 3-8. As shown in Figures 3-8, the assay values ​​of all samples at 2 and 4 weeks were within approximately 93-105% of the labeled amount of sodium porfimer.

[0184] Example 6: Study to evaluate the potential duration and intensity of skin reactions in subjects receiving topical administration of formulations for the delivery of porfimer sodium with or without potassium iodide This study was designed to evaluate skin irritation in healthy volunteers following a single topical application of gel formulation variations containing porfimer sodium with or without potassium iodide.

[0185] Study Group As shown in Figure 9, in the first set of subjects, two of the variations used were application of Formulation 3 containing the drug porfimer sodium in two concentrations (0.2% and 0.5%). In the second set of subjects, two of the variations used were a second gel formulation containing two different concentrations of the drug porfimer sodium, 0.2% (Formulation 7B) and 0.5% (Formulation 7C). In the third set of subjects, two of the variations used were formulations containing porfimer sodium 0.2% + 100 mM potassium iodide (Formulation 7E) and porfimer sodium (0.5%) + 100 mM potassium iodide (Formulation 7F). The study consisted of formulation application, either a 15 or 30 minute incubation period, followed by approximately 50 J / cm2. 2 The skin irritation after exposure to 630 nm light was evaluated.

[0186] Procedure / Method Photosensitivity treatments were typically performed on the inside of each forearm. An adhesive-sided exposure cuff was placed on the skin, avoiding cuts, bruises, lesions, freckles, moles, or scars whenever possible. After placement of a disposable dose patch, a marker was used to identify the coordinates for cuff placement for future follow-up studies. The formulation was applied to the opening of the cuff and incubated for 30 minutes. Each of the areas was then dosed (50 J / cm2). 2 Subjects were exposed to the topical formulation for approximately 5 minutes. Sensations felt and described by the subject were recorded. After exposure was complete, the area that received the topical formulation was wiped with saline soaked gauze to clean any residual or excess formulation. Photographic documentation and documentation of any visible reactions in the treated area was completed. Data collected consisted of the subject's skin coloration based on an erythema scale and photo documentation. A visual analog scale was used to collect information regarding pain associated with the test. The level and duration of the patient's skin reactions and symptoms (if any) were recorded immediately after treatment, 48 hours, 1 week, and 2 weeks after treatment.

[0187] result: There were no reports of pain, swelling, or pruritus (itching) across all 72 lesions.

[0188] Erythema was reported. No erythema lesions were observed at any of the 72 treatment sites across all samples prior to treatment. Additionally, no erythema was reported 48 hours, 1 week, or 2 weeks after treatment. Any erythema observed was only immediately after exposure (i.e., transient) (see Tables 6-9) and was not associated with discomfort (itch or pain). As shown in Table 6, no ratings above 2 (pink) were observed across all groups, and when reported, the most common report was slight pinkness (61%). [Table 6] [Table 7] [Table 8] [Table 9]

[0189] Example 7: Study to evaluate the potential duration and intensity of skin reactions in subjects receiving topical administration of formulations for the delivery of porfimer sodium with or without potassium iodide This study was designed to evaluate skin irritation in healthy volunteers following a single topical application of gel formulation variations containing porfimer sodium with or without potassium iodide.

[0190] The test consisted of formulation application, a 30 minute incubation period, followed by approximately 50 J / cm 2 Skin irritation after exposure to 630 nm light was evaluated for 100 mg of ...

[0191] Procedure / Method The photosensitivity procedure was performed on various locations of the body where evidence of chronic sun exposure was present, such as wrinkles, pigmented spots, and / or seborrheic and chemical keratoses. An adhesive-sided exposure cuff was placed on the skin, avoiding cuts, bruises, lesions, freckles, moles, or scars whenever possible. After placement of the disposable dose patch, a marker was used to identify the coordinates for cuff placement for future follow-up. The formulation was applied to the opening of the cuff and incubated for 30 minutes. Each of the areas was dosed (50 J / cm2). 2 Subjects were exposed to the topical formulation for approximately 5 minutes. Sensations felt and described by the subject were recorded. After exposure was complete, the area that received the topical formulation was wiped with saline soaked gauze to clean any residual or excess formulation. Photographic documentation and documentation of any visible reactions in the treated area was completed. Data collected consisted of the subject's skin coloration based on an erythema scale and photo documentation. A visual analog scale was used to collect information regarding pain associated with the test. The level and duration of the patient's skin reactions and symptoms (if any) were recorded immediately after treatment, 48 hours, 1 week, and 2 weeks after treatment.

[0192] Specifically, 24 areas of 6 subjects were included in this study. Of these 19 areas, the areas received the formulations and 630 nm light as follows: 4 areas 0.2% PS (Formulation 7B), 6 areas 0.2% PS+KI (Formulation 7E), 4 areas 0.5% PS (Formulation 7C), and 5 areas 0.5% PS+KI (Formulation 7F). A total of 5 areas received only light (630 nm) as a control. Of the non-control areas for treatment, 6 areas had seborrheic keratosis, 10 areas had actinic keratosis, 2 areas had evidence of sun-exposed skin, and 1 area had small pigmented spots (lentigines). [Table 10]

[0193] As shown above, subjects had minimal or no adverse side effects of itching, pain or swelling.Of the six subjects, only one subject experienced very mild pain in three different treatment areas.One subject had transient swelling in one treatment site of actinic keratosis.

[0194] Its administration subsequently increased the erythema over the pre-treatment wound or lesion area. [Table 11]

[0195] As shown above, all lesional and non-lesional erythema subsided after 48 hours. result:

[0196] All subjects completed the study. It is important to note that in particular in the evaluation of the treated areas in the patients, the erythema that appeared was primarily confined to lesions within the treated areas (except for one lesion in a single subject). This was the case for lesions described as actinic keratosis and seborrheic keratosis lesions. This demonstrates that for what is believed to be a combination of subthreshold light and drug doses, there is a somewhat selective effect on lesions within the treated areas, with little adverse side effects outside of the lesions or treated areas.

[0197] Furthermore, except for one subject (one of six subjects), no treatment-related pain was reported in this study. When added to the first 18 patients in Example 6, this supports the hypothesis that the formulations of the two tested porfimer sodium concentrations (0.2% and 0.5%), with or without the addition of potassium iodide, do not cause pain at the treatment site. In subjects who reported pain in three of the four treated sites, in the chronic sun exposure group, the VAS score during therapy was 1 in (2) lesions and 2 in (1) lesion. Immediately after treatment, the subject reported pain in two lesions with a score of 1, and the pain in the third lesion disappeared immediately after the light was removed. Thus, in this case, the pain sensation was tolerable and did not prevent the exposure from being performed. Conclusion:

[0198] Very few, if any, subjects had sensitivity from the study parameters used: one subject perceived very mild pain and one subject had transient swelling at the treatment site of one of the actinic keratoses.

[0199] Additionally, all lesional and non-lesional erythema increases subsided over the 48 hour period. Additionally, there was evidence of rapid treatment, as one pigmented lesion was resolved by 50% and one actinic keratosis was completely cleared at the three week follow-up visit. Thus, Examples 6 and 7 demonstrate the ability to treat chronically exposed skin with no or only minor adverse side effects, such as increased pain and erythema.

[0200] Example 8: Study to evaluate the treatment of actinic keratosis in subjects receiving topical administration of a formulation for the delivery of porfimer sodium Two concentrations of porfimer sodium (0.2% and 0.5%) of drugs 7B and 7C are applied to a set of subjects with actinic keratosis. The study included application of the formulation, a 30 minute incubation period, followed by approximately 50 J / cm2 for 5 minutes. 2 The intensity of actinic keratosis skin reactions after irradiation with 630 nm light was evaluated.

[0201] Procedure / Method Generally, a procedure is performed to expose actinic keratosis in a subject to photodynamic therapy using formulations 7B or 7C with topical porfimer sodium. Photodynamic therapy is performed to treat lesions on the upper extremities, including the arms, chest, or head. The formulations are applied to selected areas and incubated for 30 minutes. Each of the areas is then treated with a dose (50 J / cm 2 Subjects were exposed to the topical formulation for approximately 5 minutes. Sensations felt and described by the subject were recorded. After exposure was completed, the area that received the topical formulation was wiped with saline-soaked gauze to clean any residual or excess formulation, and an erythema score was recorded. Photographic sampling and recording of any visible reaction and symptomatic improvement in the treated area was completed after treatment.

[0202] result: Resolution of actinic keratosis or reduction in the appearance of actinic keratosis is achieved by subjects receiving formulations 7B and 7C with a porfimer drug. Furthermore, there is no difference in pain, edema, erythema and / or pruritus between subjects receiving formulations with a porfimer drug and subjects not receiving a porfimer drug. Thus, the present disclosure provides a method for treating actinic keratosis without the adverse side effects commonly known in the art.

[0203] Example 9: Study to evaluate the treatment of chronic sun-exposed skin and seborrheic keratosis with topical administration of a formulation for the delivery of porfimer sodium without potassium iodide Applications of two concentrations of porfimer sodium (0.2% and 0.5%), drugs 7B and 7C, are applied to a set of subjects with chronic sun-exposed skin and photodamaged skin such as seborrheic keratosis. The study involves formulation application, a 30 minute incubation period, followed by approximately 50 J / cm2 for 5 minutes. 2 The treatment of photodamaged skin following irradiation with 630 nm laser light was evaluated.

[0204] Procedure / Method The procedure is generally performed to treat photodamaged skin of a subject. Photodynamic therapy with formulation 7B or 7C containing sodium polyacrylate is performed to treat photodamaged skin on the upper extremities of a patient with mild to moderate photodamaged skin due to chronic sun exposure, such as wrinkles or pigmented spots, or seborrheic keratosis. The formulations were applied and incubated for 30 minutes. Each of the areas was treated with a dose (50 J / cm2) of 1000 mg / mL. 2 The subjects were exposed to a 500 nm (630 nm) light source for approximately 5 minutes. Sensations felt and described by the subjects were recorded. After exposure was completed, the areas that received the topical formulation were wiped with saline soaked gauze to clean any residual or excess formulation. Photographic sampling and recording of any visible reaction and symptomatic improvement in the treated areas was completed after treatment.

[0205] result: Treated areas of pigmented lesions in chronic sun-exposed skin show at least 50% lightening of the lesions (seborrheic keratosis) at follow-up. The lesions also generally show an increase in erythema score 1, which disappeared within 48 hours after exposure. Reduction of photodamaged skin such as pigmented spots or wrinkles was also achieved in subjects who received the formulation containing the porfimer drug. Furthermore, there is no difference in pain, edema, erythema and / or pruritus between subjects who received the formulation and those who did not. Thus, the present disclosure provides a method for treating photodamaged skin and seborrheic keratosis without the adverse side effects commonly known in the art.

[0206] Example 10: Study to evaluate the treatment of actinic keratosis in subjects receiving topical administration of porfimer sodium containing potassium iodide and a formulation for delivering A set of subjects with actinic keratosis is administered a formulation containing porfimer sodium 0.2% + 100 mM potassium iodide (Formulation 7E) and porfimer sodium (0.5%) + 100 mM potassium iodide (Formulation 7F). The study consisted of formulation application, a 30 minute incubation period, followed by approximately 50 J / cm2 for 5 minutes. 2 The exposure of actinic keratosis after 630 nm light exposure was evaluated.

[0207] Procedure / Method This procedure is typically performed to treat actinic keratosis in subjects. Photodynamic therapy with formulation 7E or F is performed to treat upper extremity lesions with actinic keratosis. The formulations are applied and incubated for 30 minutes. Each of the areas is then treated with a dose (50 J / cm 2 Subjects were exposed to the topical formulation for approximately 5-12 minutes. Sensations felt and described by the subject were recorded. After exposure was completed, the area that received the topical formulation was wiped with saline-soaked gauze to clean any residual or excess formulation. Photographic sampling and documentation of any erythema or symptomatic improvement in the treated areas at subsequent follow-up was completed after each treatment session.

[0208] result: Resolution of actinic keratosis or reduction in the appearance of actinic keratosis is achieved by subjects receiving formulations 7E and 7F with a porfimer drug. Furthermore, there is no difference in pain, edema, erythema and / or pruritus between subjects receiving formulations with a porfimer drug and those not receiving the same. Thus, the present disclosure provides a method for treating actinic keratosis without the adverse side effects commonly known in the art.

[0209] Example 11: Study to evaluate the treatment of chronic sun-exposed skin and seborrheic keratosis with topical administration of a formulation for the delivery of porfimer sodium containing potassium iodide A set of subjects with photodamaged skin is administered a formulation containing porfimer sodium 0.2% + 100 mM potassium iodide (Formulation 7E) and porfimer sodium (0.5%) + 100 mM potassium iodide (Formulation 7F). The study consisted of formulation application, a 30 minute incubation period, followed by approximately 50 J / cm2 for 5 minutes. 2 The treatment of photodamaged skin following 630 nm light exposure was evaluated.

[0210] Procedure / Method The procedure is generally performed to treat photodamaged skin of a subject. Photodynamic therapy with formulation 7E or 7F, which contains porfimer and potassium iodide, is performed to treat photodamaged skin of the upper extremities having wrinkles or pigmented spots, or mild to moderate photodamaged skin such as seborrheic keratosis. The formulations were applied and incubated for 30 minutes. Each of the areas was treated with a dose (50 J / cm2) of 1000 mg / mL. 2 Subjects were exposed to the topical formulation for approximately 5 minutes. Sensations felt and described by the subject were recorded. After exposure was completed, the area that received the topical formulation was wiped with saline soaked gauze to clean any residual or excess formulation. Photographic samples and records of any visible reaction and symptomatic improvement in the treated areas were completed after each treatment.

[0211] result: Treated areas of pigmented lesions in chronic sun-exposed skin show at least 50% lightening of the lesions (seborrheic keratoses) at follow-up. The lesions also generally show an increase in erythema score of 1, which disappeared within 48 hours after exposure. Reduction of photodamaged skin such as pigmented spots or wrinkles was also achieved in subjects who received the formulation containing the porfimer drug. Furthermore, there is no difference in pain, edema, erythema and / or pruritus between subjects who received the formulation and those who did not.

[0212] Thus, the present disclosure provides methods for treating photodamaged skin and seborrheic keratosis without the adverse side effects commonly known in the art.

[0213] Example 12: Study to evaluate the potential duration and intensity of skin reactions in subjects receiving topical administration of formulations for the delivery of porfimer sodium with DMSO, with and without potassium iodide This study was designed to evaluate skin irritation in healthy volunteers following a single topical application of gel formulation variations containing porfimer sodium with DMSO and with or without potassium iodide.

[0214] Study Group The potential duration and intensity of skin reactions of porfimer sodium formulations (Formulations 7I and 7J in Example 4, Table 5) are tested. Subjects in the test group receive (i) a formulation containing 0.5% by weight porfimer sodium + 40% by weight dimethyl sulfoxide (DMSO) + 30% by weight diethylene glycol monoethyl ether (DEGEE) (Formulation 7I); or (ii) a formulation containing 0.5% by weight porfimer sodium + 40% by weight DMSO + 30% by weight DEGEE + 1.66% by weight 100 mM potassium iodide (Formulation 7J). The formulations are applied to various locations on the subject's body where evidence of chronic sun exposure exists. Subjects in the placebo group receive a gel formulation without porfimer sodium. The test involves application of the formulation, an incubation period of either 15 or 30 or 60 minutes, followed by approximately 50 J / cm2. 2 or 100 J / cm 2 The skin irritation after exposure to 630 nm light was evaluated.

[0215] Procedure / Method Photosensitivity treatments were typically performed on the inside of each forearm. An adhesive-sided exposure cuff was placed on the skin, avoiding cuts, bruises, lesions, freckles, moles, or scars whenever possible. After placement of a disposable dose patch, a marker was used to identify the coordinates for cuff placement for future follow-up studies. The formulation was applied to the opening of the cuff and incubated for 30 minutes. Each of the areas was then dosed (50 J / cm2). 2 or 100 J / cm 2 Subjects were exposed to the topical formulation for approximately 6-12 minutes. Sensations felt and described by the subject were recorded. After exposure was completed, the area that received the topical formulation was wiped with saline-soaked gauze to clean any residual or excess formulation. Photographic documentation and documentation of any visible reactions in the treated area were completed. Data collected consisted of the subject's skin coloration based on an erythema scale and photographic documentation. A visual analog scale was used to collect information regarding pain associated with the study. Patients' level and duration of skin reactions and symptoms, as well as safety data, were recorded immediately after treatment, 48 hours, 1 week, and 2 weeks after treatment.

[0216] Inclusion criteria Subjects must meet all of the following criteria: Female and male healthy volunteers, 18-75 years of age; able to understand and communicate effectively in English and able to provide written consent; Fitzpatrick skin types I-IV; with healthy and chronically sun-exposed skin (with or without evidence of actinic keratosis) over the areas to be tested, with a minimum number of areas or sites to accommodate each formulation and dose; and able to give written informed consent, including accepting the requirements and limitations listed in the consent form.

[0217] Exclusion criteria A subject will be excluded from the study for any of the following reasons: current use of commercial tanning devices; having Fitzpatrick skin type V to VI; having skin wounds or lesions at the planned exposure site; having current skin cancer or a personal history of skin cancer; having diabetes, psoriasis, or other inflammatory skin conditions; current use of steroids, corticosteroids, or inhaled steroids for asthma; being under 18 years of age or over 75 years of age; being unable to provide informed consent; having a history of porphyria or other intrinsic photosensitive disease; having a tattoo on the inner forearm.

[0218] Example 13: In vivo evaluation of the ability of porfimer sodium gel formulations with or without DMSO, with or without 100 mM KI to reduce / eliminate microbial colonization in a partial thickness wound healing model. This study evaluated the ability of three different concentrations of porfimer sodium (0.1%, 0.2%, and 0.5%) gel formulations with (formulations 7D-F, 7H) or without (formulations 7A-C, 7G) 100 mM KI to reduce / eliminate microbial colonization from surgical sites in a partial thickness wound healing model. This study also evaluates the ability of porfimer sodium in gel formulations containing a 20% concentration of DMSO (formulations 7G-H containing 20% ​​DMSO by weight).

[0219] The study was conducted in female Yorkshire pigs over a 4 day period. A dermatome was used to create partial thickness wounds approximately 2.0 cm (width) x 2.0 cm (length) and 0.5 mm deep parallel to the spine of the animals, with one row of five wounds on each side for animals treated with test article, and / or one row of eight wounds on one side and a second row of seven wounds on the other side for animals in the control group.

[0220] After wounding, the designated wound on each animal was infected with Methicillin-resistant Staphylococcus aureus (MRSA-ATCC 1768). Three wounds on the control animals served as uninfected controls and were not inoculated. The wounds were dressed and bacterial colonization was allowed to occur overnight. A single course of treatment was administered to the designated infected wounds in the test article treatment group. Treatment consisted of application of the test article, followed by a 30 minute incubation period, followed by 200 J / cm2. 2 The treatment consisted of 20 minutes of photoactivation at 37 °C for 20 min. Designated infected wounds in the control group received application of the test article but were not subjected to photoactivation. Microbial load was determined from wound swabs taken immediately before treatment, 1 hour and 24 hours after treatment, and tissue biopsies taken 24 hours after treatment. The experiments were performed under dim light (<200 lux). The treatment groups are summarized in Table 13 below. [Table 12]

[0221] Example 14: Study to evaluate porfimer sodium with or without potassium iodide, with or without DMSO to reduce / eliminate microbial colonization and biofilm in partial thickness wounds Sodium porfimer formulations 7I and 7J, with or without KI, were prepared according to Table 5 in Example 4.

[0222] A total of 28 partial thickness wounds were made in parallel on the spine of porcine subjects and all partial thickness wounds were infected with methicillin resistant S. aureus ATCC BAA 1768 with untreated or differently treated treatment groups as described in Table 13 below. [Table 13]

[0223] 100 microliters (100 μL), 10 7 ~10 8 Freshly cultured methicillin-resistant Staphylococcus aureus (ATCC BAA 1768) at a concentration of CFU / mL was spotted into the center of each wound for all wounds using a sterile pipette. The bacterial inoculum was gently rubbed into the test site using a sterile spatula for 10 seconds (always taking care to confine exposure to infectious material to the wound and not to exposed intact skin adjacent to the wound) and allowed to dry for 3 minutes. The treatment procedure for the study is further described in Table 14 below.

[0224] Application of the formulation is to a specific legion followed by 5 days of phototherapy. Swab samples are taken before application of the formulation, 1 hour after phototherapy, and 24 hours after phototherapy. The 24 hour swab samples also serve as pre-treatment swab samples on days 2, 3, 4, and 5. 24 hours after treatment on day 5, swab samples are taken followed by biopsy samples of each lesion. [Table 14-1] [Table 14-2]

[0225] Each Photofrin formulation (7I-7J) was applied to the wound bed and incubated for the time indicated in Table 14. The formulation was then irradiated with 200 J / cm using a fiber optic lens attached to a 630 nm emitting laser. 2 Following application (approximately 20-25 minutes) of 100 mL of 1000 mL of 100% ethanol was administered to each wound. The wounds were then swabbed and re-bandaged 1 hour after treatment.

[0226] 24 hours after treatment, animals were euthanized, dressings were removed, and wounds were swabbed for microbial load determination as per Table 14. Wound tissue was harvested and half of the harvested tissue was placed in 10% formalin for histological examination and the other half was placed in a pre-weighed culture tube containing sterile PBS for microbial load determination.

[0227] Wounds were treated, surgical sites examined, and dressings changed on the treatment days indicated in Table 14. All treatments were performed under ABSL-2 conditions. On each treatment day, the outer dressing was removed using sterile scissors and the bandages were removed using sterile forceps. Prior to treatment, each wound was swabbed with a sterile cotton swab in a serpentine motion starting at the upper left wound edge (against the spine) and ending at the lower right wound edge. Swabs were placed into sterile culture tubes containing 1-2 mL of sterile PBS for determination of microbial load.

[0228] For microbial load determination, tubes containing PBS and wounds were vortexed and serial dilutions of the eluted bacteria were prepared in sterile PBS and plated in duplicate on oxacillin screen agar (Mueller-Hinton agar containing 6 μg / mL oxacillin and 4% NaCl). Colonies on the plates were counted after incubation at 37°C and bacterial load was reported as colony forming units per milliliter of wound fluid (CFU / mL).

[0229] Tubes containing tissue specimens were weighed to determine tissue mass. Wound tissue was homogenized and serial dilutions of the homogenate were prepared in PBS and plated in duplicate on oxacillin screen agar. Colonies on the plates were counted after incubation at 37°C and bacterial load is reported as colony forming units per milligram of wound tissue (CFU / mg). Incorporation by Reference

[0230] All publications and patents mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. Equivalent

[0231] Although specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification and the following claims. The full scope of the present disclosure should be determined by reference to the claims and their full scope of equivalents, as well as the specification and such variations.

Claims

A pharmaceutical composition comprising sodium porfimer for use in a method for treating sun-exposed skin in a subject in need thereof, said method comprising administering said pharmaceutical composition to said subject, said pharmaceutical composition being applied to said sun-exposed skin and light being applied to said sun-exposed skin.

2. The pharmaceutical composition according to claim 1, wherein the light has a wavelength in the range of about 380 nm to about 850 nm.

3. The pharmaceutical composition according to claim 2, wherein the light has a wavelength of about 630 nm.

4. The sun-exposed skin to be treated is selected from one or more of the group consisting of chronically sun-exposed skin, wrinkles, pigmented spots, melasma, actinic keratosis, seborrheic keratosis, photo-damaged skin, acne, warts, and psoriasis. The pharmaceutical composition according to any one of claims 1 to 3.

5. The pharmaceutical composition according to claim 1, wherein the subject does not experience pain when the light is applied to the sun-exposed skin.

6. The pharmaceutical composition according to claim 1, wherein the subject does not experience pain according to a visual analog scale of pain when the light is applied to the sun-exposed skin.

7. The pharmaceutical composition according to claim 1, wherein the subject experiences pain at a level of 2, 1, or lower according to a visual analog scale of pain when the light is applied to the sun-exposed skin.

8. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is applied to the subject's skin or wound for 15 minutes or 30 minutes, and light is applied for 5 to 25 minutes.

9. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is applied to the subject as provided in any one of Examples 6 to 11.

10. The pharmaceutical composition according to claim 4, wherein the subject does not develop edema or pruritus due to the treatment of the sun-exposed skin.

11. The pharmaceutical composition according to claim 4, wherein the subject does not develop erythema lesions greater than a pretreatment erythema scale score of 1 due to the treatment of the sun-exposed skin.

12. The pharmaceutical composition according to claim 4, wherein the subject does not develop erythema lesions higher than 1 or 2 according to an erythema scale score due to the treatment of the sun-exposed skin.

13. [[ID=2,4]]The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is applied to the subject's skin or wound for 15 minutes or 60 minutes, and light is applied for 5 minutes to 25 minutes.

14. The pharmaceutical composition according to any one of claims 1 to 3, wherein the subject is treated for actinic keratosis.

15. The pharmaceutical composition according to any one of claims 1 to 3, wherein the subject is treated for seborrheic keratosis.

16. The pharmaceutical composition according to claim 1, wherein the method comprises administering to the subject a pharmaceutical composition comprising sodium porfimer, one or more gelling agents, one or more penetration enhancers, polysorbate 80, glycerin, benzyl alcohol, phenoxyethanol, and hexylene glycol, and wherein the gelling agent is hydroxypropyl cellulose.

17. The pharmaceutical composition according to claim 1, wherein sodium porfimer is present in the pharmaceutical composition in an amount in the range of about 0.4% to about 0.6% by weight.

18. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises one or more penetration enhancers selected from the group consisting of propylene glycol SR, diethylene glycol monoethyl ether, and dimethyl sulfoxide (DMSO) in an amount in the range of about 65% to about 75% by weight.

19. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises an enhancer for PDT selected from the group consisting of sodium azide, sodium thiocyanate, sodium bromide and potassium iodide (KI), sodium iodide and potassium selenosulfocyanate (KSeCN) in an amount in the range of about 1.3% to about 2% by weight.

20. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is applied to the skin or wound of the subject for 15 minutes or 30 minutes, and the light having a wavelength of about 630 nm is applied for 5 to 25 minutes.

21. The pharmaceutical composition according to claim 20, wherein the subject does not experience pain according to a visual analog scale of pain when the light is applied to the sun-exposed skin.

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