WO2009093144A2 - Photodynamic therapy of sebaceous gland disorders - Google Patents

Abstract

The present disclosure includes the use of photodynamic therapy to treat a hyperactive sebaceous gland disorder, such as acne vulgaris. The disclosure includes methods with systemic administration of a photosensitizer to a subject with affected skin and subsequent exposure of that skin to energy of a wavelength capable of activating the photosensitizer.

Description

PHOTODYNAMIC THERAPY OF SEBACEOUS GLAND DISORDERS

RELATED APPLICATIONS

This application claims benefit of priority from U.S. Provisional Patent Applications 61/023,826, filed January 25, 2007, and 61/026,718, filed February 6, 2008, both of which are hereby incorporated by reference as if fully set forth.

FIELD QF THE DISCLOSURE

This disclosure relates to a method of applying photodynamic therapy (PDT) to treat sebaceous glands, including those involved in a hyperactive sebaceous gland disorder such as acne. The use of PDT and one or more appropriate photosensitizers for treating a hyperactive sebaceous gland disorder, including acne such as acne vulgaris, is contemplated and disclosed.

BACKGROUND QF THE DISCLOSURE Hyperactive sebaceous gland disorders such as acne are a common derma tological condition affecting many people. Although often transitory in nature, a condition like acne can be associated with long-term consequences such as psychological and/or physical scarring. Clinical manifestations of acne include comedones for mild lesions, papules, pustules, and nodules for more severe inflammatory lesions. The pathogenesis of acne is multi-factorial. It can involve an increase in keratinocytes, desquamation, hyperactive sebaceous glands with increased sebum production, Propionibacteήum acnes proliferation and local inflammatory responses.

There is an array of therapies for acne targeting different and in some cases multiple pathogenic factors. Topical agents such as retinoids and benzoyl peroxide can be used for treating mild to moderate acne and are known to be able to remove comedones, kill bacteria and reduce inflammation. Antibiotics, given either topically or orally, can be used for treating mild to moderate acne. Light-based treatments such as 420-nm blue light or 1450- nm thermal lasers can also be used to treat mild to moderate acne. Accutane® is an orally administrated retinoic acid that has been approved for treating severe, recalcitrant and nodular acne. It can be efficacious at removing comedones, reducing inflammation and inhibiting proliferation, differentiation and lipogenesis of sebaceous glands. However, there are significant deficiencies associated with currently available therapies. Topical therapies are only marginally effective against mild to moderate acne and can be associated with local irritation. The use of antibiotics is associated with development of drug-resistant bacteria. Accutane is a known teratogenic agent and is associated with multiple significant systemic toxicities including increased risk of depression, increase in blood lipid and significant mucocutaneous adverse effects. Therefore, there is a need for novel therapeutic approaches with good efficacy and safety profiles.

Photodynamic therapy (PDT) has been proposed as a possible treatment for acne. For example, US Patent Number 5,095,030 (Levy) mentions acne as a possible indication which may be treated with PDT. Other disclosures which mention acne as a possible indication for treatment with PDT include WO03/86460 (Geronemus), WO03/39597 (Boch), WO02/13788 (Anderson), US2001 /0023363 (Harth), US6645230 (Whitehurst), US6626932 (Whitehurst), US5955490 (Kennedy), WO 2005/074987 (Curadeau) and WO 2005/120572 (Curadeau). A more detailed discussion can be found in "Topical ALA-Photodynamic Therapy for the Treatment of Acne Vulgaris" J. Invest Dermatol 115:183-192, 2000. This paper discusses the use of the photosensitizer ALA to treat acne vulgaris. However, the paper discusses serious adverse events that occurred during and after the treatment including erythema, edema, and sensations of pain, burning and itching.

Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.

SUMMARY OF THE DISCLOSURE

The disclosure herein relates to a photodynamic method of treating a sebaceous gland disorder. The disclosure includes photoactivating a photosensitizer at a sebaceous gland to treat a disorder thereof, such as a hyperactive sebaceous gland disorder. In many embodiments, the disorder is acne, which has an underlining pathogenesis involving hyperactive sebaceous glands.

In one aspect, the disclosure includes injecting, or systemically administering, a photosensitizer into a subject to allow a sufficient amount to localize in a sebaceous gland of the subject before photoactivation. A sufficient amount is an amount that would be effective upon photoactivation to treat a sebaceous gland disorder. After localization, such as via the passage of sufficient time for accumulation in the sebaceous glands of a subject, the photosensitizer may be photoactivated to provide photodynamic therapy (PDT) to the gland(s) or skin of the subject.

In another aspect, the disclosure includes exposing skin, containing a sebaceous gland with a photosensitizer localized therein, to light energy of a wavelength sufficient to activate the photosensitizer as PDT. The localization to the sebaceous glands of a subject may take place over time after systemic administration, such as by intravenous injection into the subject. In some embodiments, the amount of time post administration is three (3) hours (+ 15 minutes) or longer. In most embodiments, the PDT is applied to an area of skin containing sebaceous glands involved in a disorder, such as a hyperactive sebaceous gland disorder. In some embodiments, the disorder is acne, which has an underlining pathogenesis involving hyperactive sebaceous glands.

So one method of the disclosure includes exposing skin of a subject, after systemic administration of a photosensitizer to the subject and the passage of three or more hours, to light energy at a wavelength capable of activating the photosensitizer. In most embodiments, the treated skin contains areas with a sebaceous gland disorder, such as a hyperactive sebaceous gland disorder. So the method may be used to reduce the severity of, or stem further increases in, the disorder. In some embodiments, the disorder is acne, which has an underlining pathogenesis involving hyperactive sebaceous glands. In many cases, the light energy wavelength for the photosensitizer in the visible range as opposed to the ultraviolet (LTV) range.

In another method, skin of a subject affected by a hyperactive sebaceous gland disorder, such as acne, is treated by

(i) systemically administering a photosensitizer to the subject, and

(ii) exposing affected skin of the subject, after the passage of three or more hours, to light energy at a wavelength capable of activating the photosensitizer. The disclosure herein is based in part on a discovery of significant accumulation and/or retention of photosensitizer in sebaceous glands of a subject's skin after systemic administration to the subject. The application of photoactivating light energy to the skin may thus be considered the application of PDT to the sebaceous glands.

In a further aspect of the disclosure is a method to reduce the size and/or activity of a sebaceous gland in a subject's skin by use of PDT as described herein. So after injection or systemic delivery of a photosensitizer to a subject, and selective localization of the photosensitizer to the sebaceous glands, photoactivating light energy is applied to the skin containing glands to be treated. This method results in a destruction or reduction in the size and/or activity of the treated glands. Alternatively, the method limits or stops further increases in the size and/or activity of the treated glands.

An additional aspect of the disclosure is a method to decrease or reduce sebum production by a sebaceous gland in a subject's skin. In some embodiments, the method decreases or reduces the amount of secreted sebum on the skin surface. In other embodiments, the method is used in cases of unwanted or undesirable levels of sebum production by the subject's skin. The method may include the injection or systemic delivery of a photosensitizer to the subject followed by photoactivation with light energy as PDT after sufficient time has elapsed to allow a selective localization of the photosensitizer to the sebaceous glands. The reduction or decrease in the amount of sebum production may be determined by any suitable quantitative or qualitative means, including the use of Sebutape®, or other transfer medium, or visual and/or tactile inspection.

Thus in combination with the use of a method to decrease sebum production as instantly disclosed herein, a topically applied treatment for treating a skin disorder may have greater efficacy. Another aspect of the disclosure is thus to provide an improvement to a topical agent for treating skin disorder by decreasing sebum production as disclosed herein. In some embodiments, the improvement provides a topical agent with greater access to a hair follicle and/or a sebaceous gland.

While some embodiments of the disclosure are described in terms of animals and other model systems, the application of the disclosure may be made to any animal susceptible to a sebaceous gland disorder. In many embodiments, the disclosed compositions and methods may be applied to a human subject with such a disorder, such as a human patient with acne.

BRIEF DESCRIPTION QF THE FIGURES

Figure 1 shows representative brightfield (upper panels) and fluorescent (lower panels) images of sebaceous glands (axilla) at 3, 6, and 24 hours after LFI infusion in humans.

Figure 2 illustrates the effect of PDT with systemically administered LFI (1 mg/kg) on mouse sebaceous glands. Mean total (open bars) and ORO-positive (closed bars) PSU counts with standard deviations as determined by a human reader for the 72-hour (first pair of bars) and 168-hour (second pair of bars) sampling times are shown.

Figure 3 illustrates effects of PDT with lemuteporfin on mouse sebaceous glands.

DETAILED DESCRIPTION QF MODES QF PRACTICING THE DISCLOSURE

General

The disclosure herein involves the photodynamic treatment of sebaceous gland disorders, including hyperactive sebaceous gland disorders such as acne (including acne vulgaris), seborrhea (or oily skin), seborrheic dermatitis, hidradenitis suppurativa, and sebaceous gland hyperplasia. Aspects of the disclosure include methods involving injection or systemic administration of a photosensitizer to affected skin and subsequent exposure of that skin to energy of a wavelength capable of activating the photosensitizer. The method can also be used as a prophylactic treatment for skin that is suspected of being vulnerable to a sebaceous gland disorders. Therefore, as used herein the reference to "exhibiting symptoms of a sebaceous gland disorder" or "exhibiting symptoms of a hyperactive sebaceous gland disorder" includes skin having symptoms, such as acne lesions, and skin that is thought to be susceptible to developing symptoms. In some embodiments, the disclosed compositions and methods may be used to treat mild, moderate or severe acne and all types of acne lesions. In other embodiments, the disclosed compositions and methods are used to treat moderate or severe acne. In many cases, the acne affected subject receiving treatment is at least 12 years of age. In further embodiments, the disclosed compositions and methods may be used to treat seborrhea, seborrheic dermatitis, hydradenitis suppurativa, or sebaceous gland hyperplasia. In many cases, the affected subject receiving treatment is at least 12 years of age.

The disclosure herein further relates to the use of a hydrophobic or lipophilic photosensitizer composition for the treatment of a sebaceous gland disorder as described herein. In addition, the disclosure relates to the use of a photosensitizer for the manufacture of a hydrophobic or lipophilic photosensitizer composition for use in the treatment of a sebaceous gland disorder as described herein.

Embodiments of the disclosure include a method of treating a sebaceous gland disorder in the skin of a subject. The method may comprise exposing skin of a subject, after injecting or systemically administering a photosensitizer to the subject and the passage of more than three hours, to light energy at a wavelength capable of activating the photosensitizer. In alternative embodiments, the method may be used to abolish or reduce reduce the size and/or activity of a sebaceous gland in a subject's skin, or to decrease or reduce sebum production by a sebaceous gland, all as described herein.

In another embodiment, the method may comprise (i) systemically administering a photosensitizer to the subject, and (ii) exposing skin of the subject, after the passage of more than three hours, to light energy at a wavelength capable of activating the photosensitizer. In many cases, the subject is a human being or patient. In alternative embodiments, the method may be used to abolish or reduce the size and/or activity of a sebaceous gland in a subject's skin, or to decrease or reduce sebum production by a sebaceous gland, all as described herein.

A method of the disclosure may be repeated until a desired level of efficacy is reached. A repeat of a method may be performed at regular or irregular intervals. If repeated, the treatment frequency may vary. For example, the treatments could be daily, every two days, twice weekly, weekly, every two weeks, twice monthly, every four weeks, monthly, every six weeks, every eight weeks, every two months, quarterly, twice annually, or annually, or other suitable time interval. In some cases, the treatment is not repeated more than once per week, or not more than once every two weeks. In other cases, the treatment is repeated at least once every six months, at least once every three months, or at least once every two months. The total number of treatments can range from one to as many as required. The total number of treatments in any 6 month period may be from 1 to 12, from 1 to 6, or from 2 to 3.

In other embodiments, a repeat may be at a periodicity of 7 or about 7 days, 14 or about 14 days, 21 or about 21 days, 28 or about 28 days. Of course an interval of every month, or about every month, may also be used. In other cases, at least two days, at least five days, at least seven days, at least ten days, or at least fourteen days, elapse between treatments.

With reference to treatment of acne as a non-limiting example, a desired level of efficacy may be where the total number of acne lesions has been reduced by 10% or more. In some embodiments, the total number of lesions is reduced by 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more. The total number of lesions may be assessed by predefining one or more test area(s) before commencement of the treatment. Lesion counts (non-inflammatory, inflammatory, and total) are performed within the test area(s). Sizes of the lesions within the test area may also be recorded. The test areas may also be photographed. In some cases, a number of test areas are selected per patient, and these may vary depending on the anatomical distribution of the lesions of that patient. The test areas are reassessed one day, one week, two weeks, one month, two months, and three months or more after completion of the photodynamic therapy. The reduction in lesion count is then calculated.

In additional embodiments, the disclosed methods may be beneficially combined with other therapies for a sebaceous gland disorder. Non-limiting examples of suitable additional therapies for combination with the disclosed methods include tazarotene, isotretinoin, tretinoin, adapalene, clindamycin, erythromycin, dapsone or Aczone ^M (from QLT USA Inc.), benzoyl peroxide, MBI594AN (from Micrologix), Smoothbean 1450 nm Laser therapy, and Blue-light PhotoTherapy.

Using the treatment of acne as a non-limiting example, a disclosed method may be combined with other methods of treating acne. Known acne treatments include but are not limited to topical retinoids or retinoid-like agents, oral retinoids, antibiotics (including topical or oral), oral contraceptives, anti-androgens (including topical or oral), anti-progestins, blue light therapy, laser therapy, and combinations thereof. In some cases, a method of the disclosure is combined with retinoid or retinoid-like treatment, such as topical retinoid treatment. One non-limiting example of a retinoid-like agent is adapalene.

The disclosure is based in part on the surprising discovery that a hydrophobic or lipophilic photosensitizer localizes and/or accumulates in sebaceous glands within skin even as its concentrations decrease in other tissues and fluids of a subject.

Administration of photosensitizer

As described herein, a photosensitizer, optionally in a composition disclosed herein, may be systemically administered by any suitable means. In some embodiments, the administration is by intravenous (IV) injection or by infusion. Thus rapid delivery, such as by IV injection, a bolus, or delivery by infusion over a period of time, such as 5 or about 5, 10 or about 10, 15 or about 15, 20 or about 20, 25 or about 25, 30 or about 30 minutes or longer, may be used.

As used herein, the term "systemic administration" refers to administration through either parenteral or enteral routes of administration. Accordingly, as defined herein "systemic administration" includes but is not limited to intravenous injection, intravenous infusion, intralesional injection, intramuscular injection, subcutaneous injection, mucosal delivery, intranasal administration, transmucosal delivery, pulmonary delivery, oral administration, or rectal administration of an appropriately formulated photosensitizer.

In alternative embodiments, the route of administration is oral or by use of an implant. Additionally, one or more injections into a subject's skin either intramuscularly or subcutaneously may be used to administer or deliver the photosensitizer.

The amount of photosensitizer to administer may vary depending on the nature and knowledge of the photosensitizer. Non-limiting examples of amounts to administer include 1 or more, 2 or more , 3 or more, 4 or more, 5 or more, 10 or more, 15 or more, 20 or more, 25 or more, 30 or more, 40 or more, or 50 or more mg/m² based on a subject's size and weight. The amounts may be determined by use of a standard nomogram. Of course amounts of about 1, about 2, about 3, about 4, about 5, about 10, about 15, about 20, about 25, about 30, about 40, or about 50 or more mg/m ² may also be used. Applied to lemuteporfin as a non-limiting example, a dose of 10 mg/m ² administered via injection or infusion may be used.

After administration, passage of an adequate amount of time is allowed to produce localization and/or accumulation of the photosensitizer in the target sebaceous glands before application of photoactivating light energy. The exact length of time can vary according to the type of photosensitizer. In some embodiments, the elapsed time is about 3 hours (such as within 15 minutes of 3 hours) or longer. Non-limiting examples include the passage of 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, or 26 or more hours. In some cases, passage of 48 or more, 72 or more, 94 or more, or 120 or more hours may be used.

Of course embodiments of the disclosure also include passage of about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, about 24 hours, or about 26 hours or more before application of photoactivating light energy. In some cases, passage of about 48, about 72, about 96 or about 120 hours or more may be used.

Photosensitizers

Any suitable photosensitizing agent or mixture of agents may be in the practice of the disclosed methods. Typically, these agents will absorb radiation in the visible range, such as from about 400nm to about 900nm. In some embodiments, a photosensitizer that absorbs in the range from about 450nm to about 750nm, or from about 500nm to about 700nm, is used.

As used herein, "photosensitizer" or "photosensitizing agent" means a chemical compound that absorbs electromagnetic radiation, most commonly in the visible spectrum, and releases it as energy, most commonly as reactive oxygen species and/or as thermal energy. In most cases, the compound is relatively nontoxic to humans or is capable of being formulated in a nontoxic composition. In many cases, the chemical compound in its photodegraded form is also nontoxic. A non-exhaustive list of photosensitive chemicals may be found in Kreimer- Birnbaum, Sem. Hematol. 26:157-73, 1989 and in Redmond and Gamlin, Photochem. Photbiol. 70 (4): 391-475 (1999) both of which are incorporated herein by reference.

In all aspects of the disclosure, the photosensitizer may be a hydrophobic and/or lipophilic photosensitizer, optionally in a composition suitable for injection or systemic administration into a subject, which localizes to sebaceous glands of the subject's skin.

As used herein the term "hydrophobic photosensitizer" refers to photosensitizers that repel water, have a tendency not to combine with water, or are incapable of being substantially dissolved in water. As used herein the term "lipophilic photosensitizer" refers to photosensitizers that have an affinity for, tend to combine with, or are capable of substantially dissolving in, lipids.

One measure of hydrophobicity is the LogP value. In general, substances having a LogP of 0 or greater are thought to be hydrophobic while those with a negative LogP value are thought to be hydrophilic. In many embodiments of the disclosure, the photosensitizer used herein have a LogP of not less than 0, not less than 0.5, not less than 0.75, or not less than 1.0. In some cases, a photosensitizer has a LogP value of 0 or greater.

As used herein the term "hydrophobic or lipophilic photosensitizer composition" refers to a composition as it is injected or systemically administered to a subject. Therefore, the term encompasses both hydrophobic and lipophilic photosensitizers and hydrophilic photosensitizers that are formulated such that the composition is suitable for administration as disclosed herein. In many embodiments, a lipophilic photosensitizer is used in disclosed embodiments. Additionally, a photosensitizer that strongly absorbs light with extinction coefficients >10,000 M 'cm ¹ may be selected for use in embodiments of the disclosure.

A variety of synthetic and naturally occurring photosensitizers may be used as disclosed herein. Non-limiting examples include, but are not limited to, pro-drugs such as the pro- porphyrin 5 -aminolevulinic acid (ALA) and derivatives thereof, porphyrins and porphyrin derivatives e.g. chlorins, bacteriochlorins, isobacteriochlorins, phthalocyanine and naphthalocyanines and other tetra- and poly-macrocyclic compounds, and related compounds (e.g. pyropheophorbides, sapphyrins and texaphyrins) and metal complexes (such as, but not limited by, tin, aluminum, zinc, lutetium). Use of tetrahydrochlorins, purpurins, porphycenes, and phenothiaziniums is also contemplated. Other suitable photosensitizers include bacteriochlorophyll derivatives such as those described in WO 97/19081, WO 99/45382 and WO 01/40232. One bacteriochlorophyll is palladium- bacteriopheophorbide WST09 (Tookad™). A photosensitizer may be selected from pro- porphyrins, porphyrins, and mixtures thereof. Some examples of pro-drugs include aminolevulinic acid such as Levulan™ and aminolevulinic acid esters such as described in WO 02/10120 and available as Metvix™, Hexvix™ and Benzvix™. Some examples of di- hydro or tetra-hydro porphyrins are described in EP 0337,601 or WO 01/66550 and available as Foscan™ (temoporfin). Combinations of two or more photosensitizers may be used in the disclosed compositions and methods.

In some embodiments of the disclosure, a photosensitizer is selected from those which photobleach upon exposure to activation energy.

A particularly potent group of photosensitizers is known as the green porphyrins, which are described in detail in U.S. Patent No. 5,171,749, which is incorporated herein by reference in its entirety. The term "green porphyrins" refers to porphyrin derivatives obtained by reacting a porphyrin nucleus with an alkyne in a Diels-Alder type reaction to obtain a mono- hydrobenzoporphyrin. Such resultant macropyrrolic compounds are called benzoporphyrin derivatives (BPDs), which is a synthetic chlorin-like porphyrin with various structural analogues, as shown in U.S. Patent 5,171,749.

Typically, green porphyrins are selected from a group of tetrapyrrolic porphyrin derivatives obtained by Diels-Alder reactions of acetylene derivatives with protoporphyrin under conditions that promote reaction at only one of the two available conjugated, nonaromatic diene structures present in the ρrotoρorρhyrin-IX ring systems (rings A and B). Metallated forms of a Gp, in which a metal cation replaces one or two hydrogens in the center of the ring system, may also be used in the practice of the disclosed compositions and methods.

The preparation of the green porphyrin compounds useful in this disclosure is described in detail in U.S. Patent No. 5,095,030, which is incorporated herein by reference in its entirety. Non-limiting examples of green porphyrins include benzoporphyrin derivative diester di-acid (BPD-DA), mono-acid ring A (BPD-MA), mono-acid ring B (BPD-MB), or mixtures thereof. These compounds absorb light at about 692nm wavelength which has good tissue penetration properties. The compounds of formulas BPD-MA and BPD-MB may be homogeneous, in which only the C ring carbalkoxyethyl or only the D ring carbalkoxyethyl would be hydrolyzed, or may be mixtures of the C and D ring substituent hydrolyzates. A number of other BPD B-ring derivatives may also be used in the instant disclosure. These derivatives have the following general formula:

wherein; R⁵ is vinyl, R¹ and R⁶ are methyl, and n is 2. X₁, X₂, and X₃ are listed in the tables below:

Photosensitizers for use as disclosed herein include verteporfin (the benzoporphyrin derivative mono-acid (BPD-MA)), lemuteporfin (as set forth in U.S. Pat. No. 5,929,105 referred to therein as A-EA6), and B3 (as set forth in U.S. Pat. No. 5,990,149). Lemuteporfin has a structure of the formula:

Additionally, the photosensitizers may be conjugated to various ligands to facilitate targeting to sebaceous glands or components thereof. These ligands include receptor- specific peptides and/or ligands as well as immunoglobulins and fragments thereof. Non-limiting ligands include antibodies in general and monoclonal antibodies, as well as immunologically reactive fragments of both.

Dimeric forms of the green porphyrin and dimeric or multimeric forms of green porphyrin/porphyrin combinations may also be used. The dimers and oligomeric compounds of the disclosure can be prepared using reactions analogous to those for dimerization and oligomerization of porphyrins per se. The green porphyrins or green porphyrin/porphyrin linkages can be made directly, or porphyrins may be coupled, followed by a Diels-Alder reaction of either or both terminal porphyrins to convert them to the corresponding green porphyrins.

In addition to the above mentioned photosensitizing agents, other examples of photosensitizers include, but are not limited to, green porphyrins disclosed in US Pat. Nos. 5,283,255, 4,920,143, 4,883,790, 5,095,030, and 5,171,749; and green porphyrin derivatives, discussed in US Pat. Nos. 5,880,145 and 5,990,149. Several structures of typical green porphyrins are shown in the above cited patents, which also provide details for the production of the compounds. Formulations

A photosensitizer may be used alone or as components of a mixture or formulation. A photosensitizer composition or formulation may comprise any component that is suitable for the intended purpose, such as conventional delivery vehicles and excipients including, but not limited to, isotonising agents, pH regulators, solvents, solubilizers, dyes, and buffers and combinations thereof. Pharmaceutical formulations suitable for use with the instant photosensitizers and the disclosed delivery methods can be found, for instance, in Remington's Pharmaceutical Sciences. Non-limiting formulations comprise pharmaceutical excipients or carriers capable of allowing the photosensitizer to localize and/or accumulated in a sebaceous gland. Suitable excipients for use with photosensitizers include water, saline, dextrose, glycerol and the like. Sterile and/or apyrogenic formulations are expressly contemplated for use in the disclosed embodiments.

Typically, the photosensitizer is formulated by mixing it, at an appropriate temperature, e.g., at ambient temperatures, and at appropriate pHs, and the desired degree of purity, with one or more physiologically acceptable carriers, i.e., carriers that are nontoxic at the dosages and concentrations employed.

In many embodiments, the photosensitizer is solubilised, especially when the photosensitizer is hydrophobic or lipophilic. One method of solubilising certain photosensitizers, including green porphyrins, is by formulation in liposomes or other lipid-containing complexes, including microaggregates such as those disclosed in US Patent No. 6,984,395 (the entire contents of which is incorporated herein in its entirety) . An alternative may be to solubilise the photosensitizer in cyclodextrins or cyclodextrin derivatives. Non-limiting examples include partially etherified cyclodextrin, the ether substituents of which are hydroxyethyl, hydroxypropyl or dihydroxypropyl groups. However, appropriate cyclodextrins should be of a size and conformation appropriate for use with the photosensitizing agents disclosed herein..

Other methods suitable for solubilising photosensitizers include the use of a solvent acceptable for use in the treatment of skin tissues and cells such as, but are not limited to, DMSO (dimethylsulfoxide), polyethylene glycol (PEG) or any other solvent. In many embodiments, a disclosed composition or formulations comprises a solubilizer. In some cases, the solubilizer is selected from glycol ethers, polyethylene glycol, polyethylene glycol derivatives, propylene glycol, propylene glycol derivatives, polysorbates (e.g. Tween™), fatty alcohols, aromatic alcohols, propylene glycol, glycerols, oils, surfactants, glucosides, and mixtures thereof.

In some embodiments, a composition or formulation contains one or more PEGs. Non- limiting examples include the presence of at least one PEG of average molecular weight about 2000 or less, about 1500 or less, about 1000 or less, about 800 or less, about 600 or less, about 500 or less, or about 400 or less. A composition or formulation may comprise at least one PEG of average molecular weight about 3000 or more, about 3350 or more, or about 3500 or more. A composition or formulation may also comprise a mixture of PEG's.

Preparation of dry formulations that are reconstituted immediately before use also is contemplated. The preparation of dry or lyophilized formulations can be effected in a known manner, conveniently from a disclosed solutions. A dry formulation is also storable. By conventional techniques, a solution can be evaporated to dryness under mild conditions, especially after the addition of solvents for azeotropic removal of water, such as a mixture of toluene and ethanol as a non-limiting example. The residue is thereafter conveniently dried, e.g. for some hours in a drying oven.

Light energy administration

Application of light energy for photoactivation may be made by any suitable means. Generally, the activation energy is provided by a visible light source although it is contemplated that x-ray, ultraviolet, or ultrasound sources may be used in some cases. Exemplary sources include, but are not limited to, lasers, light emitting diodes (LED), incandescent lamps, arc lamps, standard fluorescent lamps, U.V. lamps, and combinations thereof. Alternatively, any convenient source of activation energy having a component of wavelengths that are absorbed by the photosensitizer may be used, for example, an operating room lamp, or any bright light source, including sunlight. Commercially available activation energy sources include Curelight™ (available from Photocure ASA, Oslo, Norway), BLU- U™ (available from DUSA, Wilmington, MA, USA), PDT Laser (available from Diomed, Andover, MA, USA), Ceralas™ (available from Biolitec AG, Jena, Germany), Omnilux PDT™ (available from PhotoTherapeutics Ltd., Birmingham, UK), and Q-Beam & Quanta- med (Quantum Devices Inc., Barneveld, WI, USA). In some embodiments, it is at least in part supplied by light emitting diodes (LEDs). The LEDs may be arrayed in a manner that somewhat follows the contours of the skin to be treated. IN some embodiments, the arrangement is of multiple flat panels of LEDs that are moveable so that they can be positioned appropriately. As disclosed herein, PDT can be combined with Blue-light Phototherapy in some embodiments of the disclosure. Therefore, some embodiments include the activation energy being delivered by an LED device that supplies both red (e.g. 600-750nm) and blue light (e.g. 390-450nm). In some cases, an embodiment supplies light at about 420nm and at about 690nm.

The activation energy dose administered during the PDT treatment contemplated herein can vary as necessary. For photosensitizers of high potency, such as green porphyrins, the dosage of the light is about 25-100 J/cm² as a non-limiting example. In many cases, the total dose of the irradiation does not exceed 400 J/cm² or 300 J/cm², but in some cases, doses of about 300 or about 400 J/cm² or more may be used. In other cases, a dose of 250 or about 250, 200 or about 200, 150 or about 150, or 100 or about 100 J/cm² may be used. Other non-limiting doses can range between about 0.1 J/cm² to about 200 J/cm² or from about 1 J/cm² to about 100 J/cm². For example, about 25, about 50, about 75, about 100, about 125, about 150, or about 175 J/cm² may be used. Other doses include 25 or more, 50 or more, 75 or more, 100 or more, 125 or more, 150 or more, 175 or more, 200 or more, 225 or more, 250 or more, or 300 or more J/cm².

The activation energy is delivered to the skin over time. The light administration period will vary depending on the rate of delivery, or intensity of the energy source, but may be any length of time that is suitable for the photosensitizer used and the total dosage desired. In many cases, the intensity of the energy source does not exceed about 60OmW/ cm². Non-limiting irradiances of between about 0.1 and about 400 mW/cm² may be used. In some embodiments, the irradiance is between 5 and 100 mW/cm². In other embodiments, the intensity is 10 or about 10, 20 or about 20, 30 or about 30, 40 or about 40, 50 or about 50, 60 or about 60, 70 or about 70, 80 or about 80, 90 or about 90, 100 or about 100, 110 or about 110, 120 or about 120, 130 or about 130, 140 or about 140, 150 or about 150, 160 or about 160, 170 or about 170, 180 or about 180, 190 or about 190, 200 or about 200 mW/cm² or higher. Normally, the irradiation lasts from about 10 seconds to about 4 hours, and may be between about 5 minutes and 1 hour. As non-limiting examples, irradiation times of about 10, about 15, about 20, about 30, about 45, about 60, about 75, about 90, about 105, about 120, about 135, about 150, about 165 and about 180 minutes may be used depending on the energy intensity and the dosage desired. With an intensity of 80 mW/cm², dosages of 50, 100, and 150 J/cm² will take approximately 10 minutes, 25 seconds; 20 minutes, 50 seconds; and 31 minutes, 15 seconds, respectively.

In many embodiments, the activation energy comprises a wavelength close to at least one of the absorption peaks of the photosensitizer. This wavelength differs for different photosensitizers but is readily determined if not previously known. For example, BPD-MA and lemuteporfin have an absorption peak at about 689nm and so, when either is used, the wavelength of the activation energy may be at or close to 689nm. The photosensitizer ALA-methyl ester (available under the tradename Metvix) has an absorption peak at 635nm and so when this photosensitizer is used the activation energy may be at or close to 635nm. ALA (available under the tradename Levulan) has an absorption peak at 417nm and at 630nm so when this photosensitizer is used the activation energy may be at or close to 417nm and/or 630nm.

In many embodiments, the area to be treated has minimal hair coverage when the activation energy is applied. Therefore, if there is significant hair coverage of the area to be treated, the hair is cut short or shaved prior to activation energy application.

The irradiation or light exposure used in the practice of disclosed embodiments may be directed to a small or large area of the body or face depending on the patch to be treated. Any part of the body may be treated, including, but not limited to the face, chest, and/or back. These areas also happen to have significant incidences of acne. Treatment may be preceded with an assessment of the time of light exposure for the patient's minimal erythemal dose (MED) occurrence in order to avoid potential burning of the exposed skin.

To reduce the likelihood of undesirable or unwanted side effects, subjects that receive a disclosed photosensitizer may be protected against temporarily photosensitivity to visible light after administration. Human subjects may be advised to protect their skin and eyes from bright light exposure for a specified period after photosensitizer administration. The length of the photosensitivity protection period depends on the drug dose administered and may be 1, 2, 3, or 4 days in the case of lemuteporfin doses of 2.5, 5, 10, and 20 mg/m², respectively, (as a non- limiting example) based on the white-light photosensitivity. During this period, subjects may avoid exposure of unprotected skin, eyes, or other body organs to direct sunlight or bright indoor light. This includes, but is not limited to, tanning salons, bright halogen lighting, and high power lighting used in surgical operating rooms or dental offices. Prolonged use of noninvasive light-emitting medical devices (e.g., pulse oximeter) should also be avoided during the photosensitivity protection period.

If treated human subjects must go outdoors in daylight during the photosensitivity protection period, they should protect all parts of their skin and eyes by wearing protective clothing and dark sunglasses. UV sunscreens are not effective in protecting against photosensitivity reactions because photoactivation of the residual drug in the skin can be caused by visible light.

In many cases, a subject should not stay in the dark and should be exposed to ambient indoor light, as it may help inactivate the drug in the skin through a process called photobleaching.

Efficacy

The effectiveness of the disclosed compositions and methods may be determined by any suitable means. In many cases, a simple decrease, reduction, or improvement in the sebaceous gland disorder, as recognized by an appropriately skilled clinician, may be used to determine efficacy. Thus an improvement in a hyperactive sebaceous gland disorder, such as an improvement in a subject's acne, seborrhea, seborrheic dermatitis, hydradenitis suppurativa, or sebaceous gland hyperplasia, may be used as an indication of efficacy.

Using acne as a non-limiting example, effectiveness may be determined based upon quantitative and/or qualitative data. Non-limiting examples include a change in the number of acne lesions, whether inflammatory or non-inflammatory. The number of acne lesions (open comedones, closed comedones, papules, pustules and nodules) per area may be counted prior to, and after, treatment over time. Non-limiting examples include counts on Day 0 or 1, Day 13 or 14, Day 27 or 28, Week 6, Week 12, Week 16, and thereafter according to known procedures. Additionally, a global assessment of acne disease may be used to evaluate treatment. As a non-limiting example, assessments before and after treatment in a given area may be made and compared. Non-limiting examples include assessments on Day 0 or 1, Day 13 or 14, Day 27 or 28, Week 6, Week 12, Week 16, and thereafter according to a 5 -point Global Acne Assessment Score (GAAS), as shown in Table 3.

Alternatively, a 5 -point Investigator Global Assessment (IGA) for acne vulgaris, as recommended by the FDA and shown in Table 4 may be used.

Having now generally provided the disclosure, the same will be more readily understood through reference to the following examples which are provided by way of illustration, and are not intended to be limiting of the disclosure, unless specified.

EXAMPLES

The following examples describe experiments involving IV injection of lemuteporphin (also referred to QLT0074) for injection ("LFI"). "LFI" is a lipid based lyophilized formulation as described in Example 1 of U.S. Patent No. 6,984,395 that contains lemuteporfin (QLT0074) along with lactose monohydrate, diolelyl phosphatidylglycerol, and dimyristoyl phosphatidylcholine. Before administration, LFI was reconstituted with sterile water for injection (USP), then diluted to the desired dose with 5% dextrose for injection USP (5DW). To prepare an LFI dose of 1 mg/kg for a mouse with a body weight of approximately 20 grams, 0.1 ml of LFI stock solution was mixed with 0.9 ml of 5DW.

Example 1 : Study of photosensitizer localization in the sebaceous gland

A study was conducted to evaluate the localization of a photosensitizer in the sebaceous, apocrine, and eccrine glands, as well as other skin structures in skin from the axillae and behind the earlobes after intravenous administration to healthy male subjects.

Three subjects (Cohort 1) received a single intravenous (IV) dose of lemuteporfin for injection (LFI) at 15 mg/m² administered as a 10-minute infusion. At 30 minutes (±5 min) after the start of the infusion, a biopsy (3-mm punch) was taken from one axilla and behind one earlobe of each subject. At 3 hours (+10 min) after the start of the infusion, a second set of biopsy samples was taken from the other axilla and behind the other earlobe of each subject.

An additional cohort of 3 subjects (Cohort 2) was treated with a higher LFI dose of 20 mg/ m² and the procedures for Cohort 1 were repeated. The study included a third cohort of 3 subjects to investigate the accumulation of lemuteporfin in sebaceous glands at 6 and 24 hours after LFI infusion. Biopsy samples were examined by a blinded histologist with fluorescence microscopy to evaluate the distribution of lemuteporfin in the skin. Subjects returned on Day 7 for safety evaluation and were contacted on Day 3 and Day 30 for further safety follow-up.

The results show fluorescence (representing lemuteporfin accumulation) in both sweat glands and sebaceous glands of humans following IV infusion of LFI at both doses. Biopsy samples taken at 3, 6, and 24 hours after infusion clearly show selective localization of lemuteporfin in the majority of sebaceous glands sampled (see Figure 1). Furthermore, there is only minimal accumulation of lemuteporfin in other cells or structures in the skin, such as the stratum comeum and epithelium. The localization appears most prominent in the basal cells or sebocytes surrounding the sebaceous glands. Control experiments showed that there is no significant natural fluorescence present in sebaceous glands at the wavelength used for lemuteporfin.

In a previous study, lemuteporfin administered as a single IV dose of 2.5 to 20 mg/m ² and 3 repeated single doses (at 2-week intervals) of 20 mg/m was well tolerated by healthy men and women. There were no clinically significant changes in laboratory results, vital signs, or ECG tracings. Analysis of complement fragment C3A and haptoglobin levels showed no evidence of complement activation or hemolysis, respectively. In another study of 9 subjects, infusion of LFI (15 mg/m² or 20 mg/m²) was also well tolerated.

Example 2: Study of photosensitizer effects in mice

Three individual dose-ranging experiments were performed to assess the sebaceous gland effects of lemuteporfin PDT following IV injection of LFI. Groups of 5 to 10 normal female Balb/c mice of 8 to 12 weeks of age were used. Mice were administered 1 mg/kg LFI IV, followed by 2.5, 5, 10, or 25 J/cm² light-emitting diode (LED) 689 nm (red) light delivered at a fluence rate of 50 mW/cm² to a 2.25 cm² area on the skin of the flank either 1 or 2 hours after injection.

At lower light doses (2.5 or 5 J/cm²), no changes were observed in sebaceous gland counts. Slight increases in sebaceous gland size and interfollicular and hair follicle epithelial layer thickness were observed, suggestive of a mild stimulatory effect. However, at the highest light doses (10 and 25 J/cm²), there was evidence of granulation in the basal/mid regions of sebaceous glands. When 25 or 50 J/cm² light, delivered at an intensity of 50 mW/cm², was administered 1 hour after IV injection of 1, 2.5, or 5 mg/kg of lemuteporfin, mice in the higher PDT dose groups (2.5 mg/kg + 25 J/cm² and 5 mg/kg + 25 J/cm² or 50 J/cm²) experienced severe photodamage to viscera immediately below the irradiation site, and were euthanized.

In skin samples harvested 72 hours following PDT from animals that received lower PDT doses, there was little difference in the appearance of skin substructures, compared to controls. When 50 or 100 J/cm of light was administered at 200 mW/cm to animals that had received IV injections of 1 mg/kg LFI 45 or 60 minutes earlier, several animals in the 100 J/cm groups were lost to analysis due to photodamage, as above. However, in the remaining animals, analysis of skin samples harvested 72 hours post PDT indicated approximately 50% reduction in sebaceous glands, compared to controls. Sebaceous gland counts were also reduced at 72 hours in animals administered 50 J/cm² light. The effect on sebaceous glands was not sustained at 7 days in either group. See Figure 2.

These pilot studies demonstrated transient ablation of mouse sebaceous glands by systemic delivery of LFI followed by LED light treatment. The effect on the sebaceous gland was dependent on the timing of light application, as well as the light intensity and total light dose. Importantly, the effect of PDT was selective towards sebaceous glands. There was no damage to the remaining skin structures.

The effect of PDT on sebaceous glands that was evident 72 hours post-treatment was no longer present in samples harvested at 7 days, likely due to the high tissue regenerative capacity of the mouse.

Example 3: Mouse sebaceous gland PDT efficacy

A study of PDT efficacy with lemuteporfin (QLT0074) in mouse sebaceous glands was conducted. After intravenous administration, photoactivation with red light was used at two dosages and at two time points following administration. The results at 72 hours after PDT are shown in Figure 3. No skin damage or irritation was observed. Example 4: Study of photosensitizer effects in human subjects

Nine (9) human subjects were assessed in a dose escalation evaluation of light doses (5OJ, 10OJ, & 150J/cm²) given 24 hours after a 10 minute IV infusion of LFI (10mg/m²). The results are shown in Table 5.

**Macular blanchable erythema and edema

Localized papular reaction (also known as acneiform eruption) was noted in subjects at various light doses in the dose escalation evaluation studies as noted in Table 4. It has been reported in the literature previously that such papular reaction is indicative of photodynamic therapy- induced destruction of sebaceous gland structure and subsequently of inhibition of sebaceous gland activity (Hongcharu et al., Journal of Investigative Dermatology, 115(2):183-192, 2000; Wiegell et al. J. Am. Acad. Dermatol., 54(4), 647-651 (2006).

Example 5: Clinical Pharmacokinetics and Pharmacodynamics of LFI in Healthy Subjects A phase I, safety, pharmacokinetic, and pharmacodynamic study was conducted on Lemuteporfin in humans, using LFI administered intravenously (40 subjects). In this study, lemuteporfin administered as a single IV dose of 2.5 to 20 mg/m² and 3 repeated single doses (at 2-week intervals) of 20 mg/m² was well tolerated by healthy men and women. There were no clinically significant changes in laboratory results, vital signs, or electrocardiogram (ECG) tracings. Analysis of complement fragment C3A and haptoglobin levels showed no evidence of complement activation or hemolysis, respectively. Lemuteporfin had consistent pharmacokinetics over the range of doses tested. The exposure was dose-proportional and linear, as shown by the area under the curve (AUC) and maximum plasma concentrations (C_1112x). The plasma concentration profiles of lemuteporfin showed a clear bi-exponential decline in plasma concentration across all doses. The apparent elimination half-life, total body clearance, and volume of distribution for lemuteporfin were independent of dose and averaged 10 hours, 2.7 mL/min/kg, and 1 L/kg, respectively. Plasma concentrations of lemuteporfin became undetectable between 24 and 72 hours postdose, in a dose-related fashion, suggesting a short persistence in the body, confirmed by the short mean residence time of about 4 to 7 hours.

Lemuteporfin was marginally metabolized to the 2 monoacid glycol regioisomers (BPD-EMA₀ and BPD-EMA_n), with the C isomer being about twice as abundant in plasma as the D isomer. Lemuteporfin urinary excretion was minimal, indicating that similar to other species, hepatobiliary excretion is the major route of elimination in humans. There was no evidence of accumulation after 3 repeated single doses and the pharmacokinetic parameters were similar for the first and third doses. There were no consistent differences between genders.

Table 6 below shows the mean lemuteporfin plasma concentrations at each time point for the 10 mg/m² dose group.

All references cited herein, including patents, patent applications, and publications, are hereby incorporated by reference in their entireties, whether previously specifically incorporated or not.

Having now fully described the inventive subject matter, it will be appreciated by those skilled in the art that the same can be performed within a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the disclosure and without undue experimentation.

While this disclosure has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications. This application is intended to cover any variations, uses, or adaptations of the disclosure following, in general, the principles of the disclosure and including such departures from the present disclosure as come within known or customary practice within the art to which the disclosure pertains and as may be applied to the essential features hereinbefore set forth.

Claims

We claim:

1. A method of treating a sebaceous gland disorder in the skin of a human subject, said method comprising

(i) systemically administering a photosensitizer to said subject, and (ii) exposing skin of said subject, after the passage of more than three hours, to light energy at a wavelength capable of activating the photosensitizer.

2. A method according to Claim 1 wherein the disorder is a hyperactive sebaceous gland disorder selected from group consisting of acne, seborrhea, seborrheic dermatitis, hydradenitis suppurativa, and sebaceous gland hyperplasia.

3. A method according to Claim 1 wherein the sebaceous gland disorder is acne vulgaris.

4. A method according to Claim 1 wherein the photosensitizer is verteporfin or lemuteporfin or a combination thereof.

5. A method according to Claim 1 wherein the photosensitizer is a hydrophobic and/or lipophilic photosensitizer.

6. The method of claim 5, wherein the photosensitizer is selected from the group consisting of a green porphyrin, 5 -aminolevulinic acid or a derivative thereof, a 5- aminolevulinic acid ester or a derivative thereof, a porphyrin or a derivative thereof, methylene blue or a derivative thereof, a bacteriochlorophyll or a derivative thereof, a chlorin, a bacteriochlorin, an isobacteriochlorin, a phthalocyanine, a naphthalocyanine, a pyropheophorbide, a sapphyrin, a texaphyrin, a tetrahydrochlorin, a purpurin, a porphycene, a phenothiazinium, a pro-porphyrin, and a combination thereof.

7. A method according to any one of Claims 1-6 wherein the photosensitizer is in the form of a composition comprising a pharmaceutically acceptable carrier for systemic administration.

8. A method according to any one of Claims 1-7 wherein said exposing is at 20 hours or more after said administering.

9. A method according to any one of Claims 1-8, wherein said exposing is with a light energy dosage of 10 J/cm² or more.

10. A method according to Claim 9, wherein said dosage is 50 J/cm or more.

11. A method accoring to claim 10, wherein said dosage is 100 J/cm² or more.

12. A method according to Claim 11, wherein said dosage is 150 J/cm² or more.

13. A method according to Claim 11, wherein said dosage is 200 J/cm² or more.

14. A method according to Claim 11, wherein said dosage is 250 J/cm² or more.

15. A method according to Claim 11, wherein said dosage is 300 J/cm² or more.

16. A method according to any one of Claims 1-15 further comprising repeating said administering and exposing one or more times, optionally at an interval of one repeat every seven days or more.

17. A method according to any one of Claims 1-16 wherein the hyperactive sebaceous gland disorder is acne and said method further comprises treatment with at least one other non-photodynamic treatment for acne.

18. A method according to Claim 17 wherein the non-photodynamic treatment is a topical treatment selected from the group consisting of a topical retinoid, a retinoid-like compound, an oral retinoid, a systemic antibiotic, a topical or local antibiotic, an oral contraceptive, a topical anti- androgen, an anti-progestin, and a combination thereof

19. A method according to any one of Claims 1-18 wherein the hyperactive sebaceous gland disorder is acne and said method further comprises treatment with blue light therapy or laser therapy for treating acne.

20. A method according to any one of Claims 1-18 wherein said light energy is provided by a light emitting diode.

21. A composition comprising a photosensitizer for use in treating a hyperactive sebaceous gland disorder in skin by photodynamic, said treating comprising exposing skin of a subject, after systemically administering a photosensitizer to said subject followed by the passage of more than three hours, to light energy at a wavelength capable of activating the photosensitizer.

22. Use of a photosensitizer in the preparation of a medicament for treating a hyperactive sebaceous gland disorder by a method comprising exposing skin of a subject, after systemically administering a photosensitizer to said subject followed by the passage of more than three hours, to light energy at a wavelength capable of activating the photosensitizer.

20. In a method of treating a sebaceous gland disorder in the skin of a human subject, said method comprising systemically administering a photosensitizer to said subject followed by exposing the skin of said subject to light energy at a wavelength capable of activating the photosensitizer, the improvement which comprises exposing the skin of said subject to light energy after the passage of more than three hours from said systemic administration.