Link:  Pharm/Biotech Resources

Title:  Topical aminolevulinic acid-photodynamic therapy for the treatment of acne vulgaris

United States Patent:  6,897,238

Issued:  May 24, 2005

Inventors:  Anderson; Richard Rox (Lexington, MA)

Assignee:  General Hospital Corporation (Boston, MA)

Appl. No.:  929384

Filed:  August 14, 2001

Light treatments of sebaceous gland disorders with 5-aminolevulinic acid and photodynamic therapy are disclosed. A preferred treatment includes topical application of 5-aminolevulinic acid to the skin followed by light exposures with repeated treatment at various intervals. At low doses of ALA and photodynamic therapy (PDT) in single or multiple treatments, improvement in the sebaceous gland disorder, e.g., acne, provides the discovery that diminishment in sebum secretion and the eradication of bacteria occurs. At high doses of ALA and a single high energy PDT treatment, permanent changes to the sebaceous gland and sebum secretion have been discovered.

BACKGROUND OF THE INVENTION

Skin disorders, such as acne, can be irritating and embarrassing. The major disease of skin associated with sebaceous follicles, is acne vulgaris. This is also the most common reason for visiting a dermatologist in the United States. There are many treatments, but no cures for acne. These include antibiotics (which inhibit growth of p. acnes bacteria which play a role in acne), retinoids such as Accutane® (isotetinoin, which reduces sebaceous gland output of sebum), and antimicrobials such as benzoyl peroxide. Acne lesions result from the rupture of a sebaceous follicle, followed by inflammation and pus (a "whitehead"), or by accumulation of plugged material in the sebaceous follicle (a "blackhead"). This pathophysiology has two major requirements: (1) plugging of the upper portion of the follicle, and (2) an increase in sebum production. The upper portion of the follicle, i.e., the "pore" into which sebum is secreted and which is directly in communication with the skin surface, is called the infundibulum. A plug forms in the infundibulum from cells, sebum, bacteria, and other debris. The sebaceous gland continues to produce sebum (an oily fluid), stretching the infundibulum until either it or some lower portion of the follicles ruptures.

Generally, only a minority of sebaceous hair follicles on the face and upper back develop acne lesions. Therefore, it is likely that some structural differentiation predisposes a fraction of the follicles to develop acne. In most males, acne is worst in the teenage years and then subsides, suggesting that a subpopulation of follicles may be present which ultimately self-destruct. In women, teenage acne is often followed by menstrual acne flares well into adulthood. Since both plugging of the infundibulum and high sebaceous gland activity are necessary for an acne lesion to develop, it is likely that two of the predisposing factors for the follicles which become infected are (1) an infundibulum shape which is easily plugged, and/or (2) a hyperactive sebaceous gland.

Unlike medical dermatology, most laser dermatology treatments are actually "cures"-producing a permanent anatomic, microsurgical effect on the skin. This includes skin resurfacing, portwine stain treatment, tattoo and pigmented lesion removal, and hair removal. Selective photothermolysis or controlled skin ablation with lasers or other extremely intense light sources, might therefore be capable of curing skin disorders, such as acne, if appropriately targeted to the primary site(s) of pathophysiology.

Therefore a need exists which circumvents and provides a solution to the above-described shortcomings of the presently known treatments.

SUMMARY OF THE INVENTION

The present invention is based, at least in part, on the discovery that 5-aminolevulinic acid (ALA) described infra, in combination with an energy source, e.g., photo (light) therapy, can be used to modulate, e.g., treat, sebaceous gland disorders, e.g., eliminate, inhibit, or prevent occurrence or reoccurrence of the skin disorder. Topically-applied ALA is taken up by epithelial cells and metabolized via the porphyrin pathway to protoporphyrin IX (PpIX), the precursor of heme. PpIX is a photosensitizer that accumulates not only in the epidermal cells, but also the pilosebaceous units. When intense light, e.g., visible light, red light, light with a wavelength range of between about 320 and 700 nm, is delivered to the ALA-treated skin, PpIX is excited into a triplet state, which reacts with oxygen to produce singlet oxygen, causing membrane damage and cell destruction. Topical ALA may directly enter hair follicles, where sebaceous glands actively synthesize and retain PpIX.

The present treatment protocol is efficient, is topical, and provides relief of the sebaceous gland disorder for at least 20 weeks. Moreover, the present invention provides optimized conditions for treatment of skin, such that the therapeutic treatment is non-irritating, long lasting (greater than 20 weeks) and can be accomplished in one or more applications. A preferred example of such a sebaceous gland disorder is acne.

The present invention pertains to methods for treating skin disorders associated with sebaceous follicles by topically applying 5-aminolevulinic acid (ALA) to a section of skin afflicted with a sebaceous gland disorder, wherein the ALA is converted into PpIX which is then activated by energy that penetrates outer layers of epidermis. A sufficient amount of the ALA infiltrates the afflicted section of skin, is converted into PpIX, and is exposed to sufficient energy to cause the PpIX to become photodynamically activated, thereby treating the sebaceous gland disorder. In one embodiment, the sebaceous gland disorder is acne. Suitable energy sources for photodynamic treatment include flash lamp based sources and lasers, such as Nd: YAG, Alexandrite, flash lamp-pumped dyes and diodes. Alternatively, the energy source can also be a continuous wave energy source. In preferred embodiments, the ALA is dissolved in an aqueous/alcoholic solution in concentrations between about 10% and 20% by weight.

The present invention also pertains to methods for modifying the opening to the infundibulum by topically applying ALA to the opening to the infundibulum, wherein the ALA is converted into PpIX, that is then photodynamically activated by energy which penetrates outer layers of epidermis. A sufficient amount of the ALA infiltrates spaces about the infundibulum and the infundibulum is exposed to sufficient energy to cause the converted ALA to become photodynamically activated, thereby modifying the opening to the infundibulum. In one embodiment, the opening to the infundibulum is increased. In still another embodiment, the opening to the infundibulum is altered such that pore pluggage will not occur, e.g., the infundibulum is reshaped such that excess sebum, oils, dirt and bacteria will not cause pore pluggage to occur, resulting in a black head (comedon) or white head (milium).

The present invention also pertains to methods for suppressing, e.g., decreasing, the oil/lipid output production of the sebaceous gland. Application of ALA to the pilosebaceous unit, e.g., the sebaceous gland, followed by photodynamic stimulation of the resultant PpIX by an energy source can cause selective permanent physical alteration to the sebaceous gland and/or follicle such that surrounding tissue remains unaffected. The physical alteration to the sebaceous gland and/or follicle results in diminished production of sebum and the size of the sebaceous gland is decreased.

The present invention further pertains to methods for modifying the pilosebaceous unit by topically applying ALA to the pilosebaceous unit, wherein the resultant PpIX is photodynamically activated by energy which penetrates into the dermis and into the outer layers of epidermis. A sufficient amount of ALA infiltrates the pilosebaceous unit and the pilosebaceous unit is exposed to sufficient energy to cause the increased levels of PpIX to become photodynamically activated, thereby modifying the pilosebaceous unit. In one embodiment, the pilosebaceous unit is treated such that sebum production is diminished. A decrease in pore pluggage can occur, as a result of the diminishment of sebum production. In one preferred embodiment, treatment of the pilosebaceous unit by the present invention results in elimination of pore pluggage, e.g., the pilosebaceous unit is treated such that excess sebum, oils, dirt and bacteria will not cause pore pluggage to occur, resulting in a black or white head.

DETAILED DESCRIPTION OF THE INVENTION

The features and other details of the invention will now be more particularly described and pointed out in the claims. It will be understood that the particular embodiments of the invention are shown by way of illustration and not as limitations of the invention. The principle features of this invention can be employed in various embodiments without departing from the scope of the invention.

5-Aminolevulinic acid, also known as 5-aminolaevulinic acid, delta-aminolevulinic acid, delta-aminolaevulinic acid, or 5-amino4-oxopentanoic acid, is an intermediate in the pathway to the production of the photosensitizer, proptoporphyrin IX (PpIX). In the present invention, 5-Aminolevulinic acid can be used as a salt, such as the hydrochloride salt. 5-Aminolevulinic acid can also be used in a pharmacologically equivalent form, such as an amide or ester. Examples of precursors and products of 5-aminolevulinic acid and pharmacologically equivalent forms of 5-aminolevulinic acid that can be used in the present invention are described in J. Kloek et al., Prodrugs of 5-Aminolevulinic Acid for Photodynamic Therapy, Photochemistry and Photobiology, Vol. 64 No. 6, December 1996, pages 994-1000; WO 95/07077; Q. Peng et al., Build-Up of Esterified Aminolevulinic-Acid-Derivative-Induced Porphyrin Fluorescence in Normal Mouse Skin, Journal of Photochemistry and Photobiology B: Biology, Vol. 34, No. 1, June 1996; and WO 94/06424. These references are incorporated herein in their entirety. The term "ALA" refers to all of the above-referenced compounds as described herein.

The present invention is based, at least in part, on the discovery that ALA leads to increased concentration of PpIX in epithelial cells, hair follicles, the pilosebaceous unit, the infundibulum and/or sebaceous glands, and in combination with an energy source, photodynamic therapy can be used to treat sebaceous gland disorders, e.g., eliminate, remove, or prevent occurrence or reoccurrence of the sebaceous gland disorder. Examples of such sebaceous gland disorders include sebaceous gland hyperplasia, acne vulgaris and acne rosacea. A preferred example of such a sebaceous gland disorder is acne.

The term "photodynamic" refers to the administration of a photosensitizing agent to a subject, including administration of a precursor of a photosensitizing agent such as ALA, and subsequent irradiation with energy, e.g., light, of the target cells or tissue of the subject. It is believed that ALA and hence, the photosensitizing agent preferentially accumulate in the target cells, because they are of an infective origin, e.g., bacteria. It has now been surprisingly discovered that the administration of ALA, as a result of their more rapid proliferation, causes the target cells or tissue contain relatively greater concentrations of light sensitive porphyrins, e.g., PpIX, and thus are more sensitive to light. Thus, the targeted tissue (hair follicles, infundibulum, sebaceous gland, pilosebaceous unit) containing sufficiently high concentrations of the photosensitizing agent, including the metabolites of ALA, selectively absorb greater amounts of energy and can be selectively localized and distinguished from the adjacent cells or tissues. Photodynamic activation of the photosensitizing agent destroys the cells/tissue with increased concentrations of the photosensitizing agent. In particularly preferred embodiments, bacteria present in the sebaceous gland are eradicated. The effect of the light is dependent upon the photosensitizer selected wavelength or range of wavelengths, as well as the intensity and duration of administration of the energy, e.g., light.

In one aspect, the present invention is drawn to methods for treating sebaceous gland disorders by topically applying ALA to a section of skin afflicted with a sebaceous gland disorder. The ALA is converted in PpIX via the protoporphyrin pathway, and the resultant photosensitizer PpIX is energetically stimulated by an energy source. A sufficient amount of ALA infiltrates the skin and the section of skin is exposed to at least one frequency band of energy so as to impart, to the converted ALA, sufficient energy to cause the resultant PpIX to become photodynamically activated resulting in a physiological change, thereby treating the sebaceous gland disorder. In one embodiment, the sebaceous gland disorder is acne. Suitable energy sources include a wide range of pulsed or continuous electromagnetic sources including, optical energy emitted by the sun, ultraviolet light generators, flash lamp based sources and lasers, such as Nd: YAG, Alexandrite, and flash lamp-pumped dye lasers and diode lasers. Alternatively, the energy source can be a continuous wave energy source, such as arc lamps, tungsten-halogen lamps and light-emitting diodes.

In preferred embodiments, the energy source emits visible light, especially red visible light. Generally, the range of energy applied to the skin surface ranges from 1 J/cm² to about 200 J/cm², preferably from about 25 J/cm² to about 200 J/cm², and most preferably about 100 J/cm².

In general, the wavelength range for therapeutic treatment is from about 320 nm to about 700 nm, preferably from about 550 to about 700 nm, more preferably from about 550 to about 600 nm.

For example, in one embodiment, the skin is treated with a low dose of ALA and low dose of energy to provide relief from acne. This can be considered a therapeutic treatment in which occasional multiple treatments are required to alleviate the sebaceous gland disorder, e.g., acne. The procedure can be repeated daily, monthly, bimonthly, every three months or as required to maintain the diminishment of the sebaceous gland disorder. A suitable treatment includes topical application of about 0.1 to about 10 weight percent of ALA, preferably between about 0.1 to about 5 weight percent, most preferably between about 0.1 to 1 weight percent of ALA followed by a low dosage of energy, e.g., a range of between about 1 J/cm² and about 20 J/cm², preferably between about 1 J/cm² and about 10 J/cm², and most preferably between about 1 J/cm² and 5 J/cm², e.g., 1 J/cm². This therapeutic treatment is of great interest in that these lower levels of ALA are effect to destroy the bacteria associated with acne; the bacteria is very sensitive to the ALA-photodynamic therapy. This therapy offers the advantage of utilizing low levels of ALA and energy, such that the patient does not feel discomfort and that the skin becomes hyperpigmented. The individual can undergo treatments on a regular basis to prevent or alleviate the sebaceous gland disorder. In general, the energy utilized has a wavelength range of between about 330 nm and about 650 nm to about 700 nm.

In another embodiment, the skin is treated with a high dose of ALA and a high dose of energy to provide a permanent improvement in the sebaceous gland disorder, e.g., acne. This can be viewed as a permanent therapeutic cure for the affliction in that the sebaceous gland is diminished in size and microscarring occurs to and about the sebaceous gland, thereby decreasing or eliminating the secretion of sebum. It is believed that the microscarring from the ALA-PDT therapy fixes the size of the sebaceous gland so that it cannot expand to once again produce large quantities, relatively, of sebum. The microscarring and the reduction of sebaceous gland size and sebum production has been 6 months after a single treatment. A suitable permanent treatment includes topical application of about 10 to about 30 weight percent of ALA, preferably between about 10 and about 20 weight percent ALA, and most preferably about 20 weight percent ALA followed by a high dose of energy, e.g., a range of between about 50 J/cm² and about 200 J/cm², preferably between about 100 J/cm² and about 150 J/cm², and most preferably between about 125 J/cm² and 175 J/cm². In this embodiment, the optimal wavelength range is between about 550 nm and about 650 nm.

Typically, ALA is administered topically as a solution. The concentration of the ALA can be in the range from about 0.1 to about 30 percent by weight, preferably from about 0.1 to about 20 percent by weight, and most preferably from about 10 to about 20 percent by weight. The ALA can be formulated into various creams and emulsions that can penetrate into the skin. A preferred solution is a combination of alcohol, ethyl alcohol and water. Generally, ALA is applied topically in an appropriate carrier and permitted to permeate into the skin over a period of about 1 to about 12 hours, preferably from about 2 to about 5 hours, and most preferably about 3 hours. As a general practice, the treated area is covered with material, such as a plastic, which helps to slow evaporation of the solvent of the carrier system. The individual is then subjected to photodynamic therapy to treat the sebaceous gland disorder. In one embodiment, the individual is treated with a 20% ALA in a hydroalcoholic vehicle (Levulan, provided by DUSA Pharmaceuticals) for 3 hours under occlusion with plastic film and 150 J/cm² of broad band light (550-700 nm).

The present invention also pertains to methods for modifying the opening to the infundibulum by topically applying ALA to the opening to the infundibulum, wherein the ALA is converted into PpIX, and is treated with at least one frequency band of energy which penetrates outer layers of epidermis. A sufficient amount of ALA infiltrates spaces about the infundibulum and the section of skin is exposed to at least one frequency band of energy so as to impart to the converted ALA, PpIX, sufficient energy to cause the PpIX to become photodynamically activated, thereby modifying the opening to the infundibulum. In one embodiment, the opening to the infundibulum is altered such that pore pluggage will not occur, e.g., the infundibulum is reshaped such that excess sebum, oils, dirt and bacteria will not cause pore pluggage to occur, resulting in a blackhead (comedon) or white head (milium). In a preferred embodiment, the opening to the infundibulum is opened.

The present invention further pertains to methods for modifying the pilosebaceous unit by topically applying ALA to the pilosebaceous unit, wherein the resultant PpIX absorbs at least one frequency band of energy which penetrates outer layers of epidermis. A sufficient amount of the ALA infiltrates the pilosebaceous unit and the section of skin is exposed to at least one frequency band of energy so as to impart to the resulting increased concentration of PpIX, sufficient energy to cause the PpIX to become photodynamically activated, thereby modifying the pilosebaceous unit. In one embodiment, the pilosebaceous unit is treated such that sebum production is diminished, thereby resulting in decreased pore pluggage. In one preferred embodiment, treatment of the pilosebaceous unit by the present invention results in elimination of pore pluggage, e.g., the pilosebaceous unit is treated such that excess sebum, oils, dirt and bacteria will not cause pore pluggage to occur, resulting in a black or white head.

In another aspect, the invention includes the combination of ALA with UVA and/or UVB absorbing substances. The combination can be applied topically and is useful in the treatment of sebaceous gland disorders, such as acne. Application of the ALA with the UVA and/or UVB absorbing substance followed by PDT causes the converted ALA to eradicate bacteria associated with acne. Generally, sunlight is the energy source for PDT stimulation and the total fluence of energy is between about 1 and about 100 J/cm², preferably between about 1 and about 50 J/cm² and most preferably between about 10 and about 40 J/cm². Typically the ALA concentration is in the range of between about 0.1 to about 10 percent by weight, preferably between about 0.1 and about 5 percent by weight and most preferably between about 0.1 and 1 percent by weight. In general the UVA and/or UVB filter substances are included in the composition in a range of between about 0.1 to about 30% by weight, preferably from about 0.1 to about 10% by weight and most preferably from about 0.1 to about 5% by weight.

Suitable UVB filters include those which absorb energy between about 290 nm and 320 nm, the so-called UVB range, and are generally derivatives of 3-benzylidene camphor, 4-aminobenzoic acid, cinnamic acid, salicylic acid, benzophenone and 2-phenylbenzimidazole. Examples of oil soluble UVB filters include 3-benzylidene camphor derivatives, e.g., 3-(4-methylbenzylidene)camphor, 3-benzylidene-camphor; 4-aminobenzoic acid derivatives, e.g., 4-(dimethylamino)-benzoic-acid (2-ethylhexyl)ester, 4-(dimethylamino)benzoic-acid-amylester; esters of cinnamic acid, e.g., 4-methoxycinnamic-acid-(2-ethylhexyl)ester, 4-methoxycinnamic-acid-isopentylester; esters of salicylic acids, e.g., salicylic acid(2-ethylhexyl)ester, salicylic acid(4-isopropylbenzyl)ester, salicylic acid-homomenthylester; derivatives of benzophenone, e.g., 2-hydroxy4-methoxybenzophenone, 2-hydroxy-4-methoxy-4′-methylbenzophenone, 2,2′-dihydroxy-4-methoxybenzophenone; esters of benzalmalonic acids, e.g., 4-methoxybenzalmalonic-acid-di(2-ethylhexyl)ester; 2,4,6-trianilino-(p-carbo-2′-ethyl-1′-hexyloxy)-1,3,5-triazin. Examples of water-soluble UVB filter substances include salts of 2-phenylbenzimidazol-5-sulphonic acid including the sodium, potassium or triethanolammonium salt and sulphonic acid; sulphonic acid derivatives of benzophenones, e.g., 2-hydroxy-4-methoxybenzophenon-5-sulphonic acid and its salts; sulphonic acid derivatives of 3-benzylidene camphor such as 4-(2-oxo-3-bornylidene methyl)benzolsulphonic acid, 2-methyl-5-(2-oxo-3-bornylidenemethyl)sulphonic acid and its salts.

UVA substances filter radiation in the range between 320 nm and about. 400 nm, the co-alled UVA range. Derivatives of dibenzoylmethane are predominantly used to protect against rays in the UVA range and include, for example, 1-(4′-tert.butylphenyl)-3-(4′-methoxyphenyl)propane-1,3-dione and 1-phenyl-3-(4′-iso-propylphenyl)propane-1,3-dione.

Sebaceous glands are components of the pilosebaceous unit. They are located throughout the body, especially on the face and upper trunk, and produce sebum, a lipid-rich secretion that coats the hair and the epidermal surface. Sebaceous glands are involved in the pathogenesis of several diseases, the most frequent one being acne vulgaris. Acne is a multifactorial disease characterized by the occlusion of follicles by plugs made out of abnormally shed keratinocytes of the infundibulum (upper portion of the hair follicle) in the setting of excess sebum production by hyperactive sebaceous glands. Various treatment modalities for acne exist that aim in modifying the rate of sebum secretion by the sebaceous glands (e.g., retinoids), inhibiting the bacterial overgrowth in the follicular duct (antibiotics), or decreasing the inflammation of acne lesions (anti-inflammatory agents). Most of these agents are not curative of acne and simply control the disease by affecting one of the aforementioned pathogenic factors. Oral retinoids are a notable exception: they are potent drugs that can achieve a significant cure rate for acne, but their side effect profile often limits their use. Advantages of the present invention include that treatment can permanently alter the pilosebaceous unit, rendering it no longer susceptible to pore pluggage without the side effects associated with oral retinoids.

The term "sebaceous gland disorders" is intended to include those sebaceous gland disorders which can be treated by a photosensitized material, such as PpIX that is converted from ALA. The PpIX can be photodynamically activated, e.g., reactive, such that it is susceptible to photoactivation or stimulation, e.g., light, i.e., laser stimulation. The activation or excitation of the material generates reactive species, such as a triplet state, which can interact with oxygen to produce singlet oxygen, causing membrane damage and cell destruction. The singlet oxygen can interact with the site of pore pluggage, inflammation, bacteria, viruses, etc. and promote, for example, oxidation of those agents which are associated with the disorder. Examples of sebaceous gland disorders which can be treated by the methods of the invention include sebaceous gland hyperplasia, acne vulgaris and acne rosacea. Of particular importance is treatment of acne by the method of the invention.

The term "pluggage" is intended to obstruction of the pores by the buildup of sebum, dirt, bacteria, mites, oils, and/or cosmetics in the pore, e.g., about the infundibulum.

The term "acne" is art recognized and is intended to include acne vulgaris and acne rosacea. Acne vulgaris the most common skin disease seen in dermatologic practice which affects approximately 17 million people in the United States. Its precise cause is unknown, although abnormal keratin production with obstruction of the follicular opening, increased production of sebum (lipids secreted by the androgen-sensitive sebaceous glands), proliferation of Propionibacterium acnes (anaerobic follicular diphtheroids), follicular rupture and follicular mites (demodex) are commonly associated with acne.

Skin conditions such as acne are believed to be caused or exacerbated by excessive sebum flow produced by sebaceous glands most of which are adjacent to and discharge sebum into, hair follicles. Sebum is composed of keratin, fat, wax and cellular debris. Sebum forms a moist, oily, acidic film that is mildly antibacterial and antifungal and may to some extent protect the skin against drying. It is known that the bacteria which contribute to acne, Propionibacterium acnes or (P-acnes), grows in sebum. Significant sebum flow in humans begins at puberty. This is when acne problems generally arise. The methods of the present invention decrease or eliminate the overproduction of sebum and thereby eliminates acne.

Not to be limited by theory, photodynamic stimulation of a photosensitizing agent, e.g., PpIX, can cause oxidation and decomposition of the unwanted material(s), thereby degrading and removing unwanted material from the pore. Additionally, this treatment can also cause the opening to the infundibulum to become modified, e.g., the pore opening is enlarged. Consequently, alteration of the pore opening, such as enlargement of the pore opening, a change in the pore shape, or enlargement of the pore opening prevents unwanted dirt, bacteria, viruses and/or oils from building up in the treated area, e.g., the infundibulum.

Preferably, the energy source produces an exposure area of between about 3 to about 100 millimeters to treat a section of skin afflicted with a sebaceous gland disorder, as described above. The fluence is limited such that the skin is not damaged while the sebaceous gland disorder is treated, e.g., eradicated, inhibited, or prevented. The fluence is controlled such that localized destruction to the undesired sebaceous gland disorder occurs with little or no non-specific necrosis of surrounding tissue.

Suitable energy sources include light-emitting diodes, incandescent lamps, xenon arc lamps, lasers or sunlight. Suitable examples of continuous wave apparati include, for example, diodes. Suitable flash lamps include, for example pulse dye lasers and Alexandrite lasers. Representative lasers having wavelengths strongly absorbed by PpIX, within the epidermis and infundibulum, or sebaceous gland, include the short-pulsed green dye laser (504 and 510 nm), yellow long-pulsed dye laser (585-600 nm)the copper vapor laser (511 nm) and the Q-switched neodymium (Nd):YAG laser having a frequency doubled wavelength using a potassium diphosphate crystal to produce visible green light having a wavelength of 532 nm. Further examples of lasers which are suitable for use as energy sources include those in the following table of lasers:

Types of Laser

Commercial Laser Types, Organized by Wavelength

The depth of penetration of the energy, e.g., light, emitted from the energy source, such as a laser, is dependent upon its wavelength. Wavelengths in the visible in to near IR have the best penetration and are therefore best for use to treat the sebaceous gland and infundibulum located within the dermis.

For example, ALA, adapted to accumulate selectively in the infundibulum and/or the sebaceous gland, is first applied to the region of afflicted skin to be treated. Following absorption of the ALA, the ALA undergoes conversion to PpIX via the porphyrin synthetic pathway, is exposed to an energy source, e.g., a laser, capable of producing a wavelength readily absorbed by the converted ALA, e.g., PpIX, thereby selectively photodynamically treating those regions of the dermis known to have trapped oils, bacteria, dirt, etc. i.e., the pilosebaceous unit, which includes the pore opening, infundibulum and sebaceous gland. Because the PpIX is selectively concentrated within or about these undesired deposits, the deposits are degraded by photodynamically reactive species generated from the activated material. There is minimal to no destruction of normal adjacent epidermal and dermal structures.

Preferably, the treatment of the invention modifies the pore opening to the infundibulum such that the geometry, e.g., the shape, of the opening is permanently altered. Adjustment of the concentration of the ALA and the amount of energy applied by the energy source effects the increased opening size of the pore, thereby preventing accumulation of dirt, oils, and/or bacteria, in that follicle. The operator will need to assess the parameters to illicit the desired effect and will be determined on a patient by patient basis. Generally, it is most desirable to alter the shape of the pore, leaving the pore enlarged and no longer prone to buildup of sebum and/or foreign materials which would cause pore pluggage.

As previously stated, the present invention involves the use of energy sources, e.g., lasers, to target sebaceous glands and cause their photodynamic alteration, e.g., diminishment in size. Sebaceous glands are mainly composed of amorphous lipid material and do not contain effective amounts of PpIX to cause photodynamic stimulation of the tissue/gland/pathogenic species. In order to achieve selective photodynamic treatment of sebaceous glands and confine the extent of any injury in the surrounding tissue, topically applied ALA with selective distribution to the pilosebaceous unit can be utilized. The introduction of ALA in sebaceous glands followed by exposure to energy (light) with a wavelength that corresponds to the absorption peak of the PpIX, will increase the local absorption of light in tissue and lead to selective photodynamic damage of sebaceous glands.

The infundibulum is a critical site in the pathogenesis of many of the disease states, especially acne. There is evidence that abnormal proliferation and desquamation of infundibular keratinocytes leads to the formation of microcomedones and, later on, to clinically visible follicular "plugs" or comedones. Clinically, it appears that some sebaceous follicles are more prone than others to develop acne lesions, possibly due to an inherent structural difference or functional abnormality of the infundibulum, that predisposes them to form plugs and occlude. The self-resolving nature of acne in most patients may reflect the elimination of such "acne-prone" follicles which are eventually replaced by normal skin or fibrosis after repeated bouts of inflammation. If the architecture of the infundibulum is important in the pathogenesis of acne, then selective destruction of this portion of the follicle through

ALA assisted energy, e.g., laser, targeting can help eliminate or correct the "pathologic" site by reshaping the infundibulum so as to extrude any occluded material.

Delivery of ALA to the follicle matrix can be achieved by topical application, injection, liposome encapsulation technology, massage, iontophoresis or ultrasonic technology, or other means for delivery of compounds into the dermal region of the skin, e.g., pharmaceutically acceptable carriers.

The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting ALA of the present invention within or to the subject such that it can performs its intended function. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. Preferred carriers include those which are capable of entering a pore by surface action and solvent transport such that the ALA is carried into or about the pore, e.g., into the sebaceous gland, to the plug, into the infundibulum and/or into the sebaceous gland and infundibulum.

Wening agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening and perfuming agents, preservatives and antioxidants can also be present in the compositions.

Liquid dosage forms for topical administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, creams, lotions, ointments, suspensions and syrups. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, peach, almond and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

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

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

The term "cream" is art recognized and is intended to include semi-solid emulsion systems which contain both an oil and water. Oil in water creams are water miscible and are well absorbed into the skin, Aqueous Cream BP. Water in oil (oily) creams are immiscible with water and, therefore, more difficult to remove from the skin. These creams are emollients, lubricate and moisturize, e.g., Oily Cream BP. Both systems require the addition of either a natural or a synthetic surfactant or emulsifier.

The term "ointment" is art recognized and is intended to include those systems which have oil or grease as their continuous phase. Ointments are semi-solid anhydrous substances and are occlusive, emollient and protective. Ointments restrict transepidermal water loss and are therefore hydrating and moisturizing. Ointments can be divided into two main groups-fatty, e.g., White soft paraffin (petrolatum, Vaseline), and water soluble, e.g., Macrogol (polyethylene glycol) Ointment BP.

The term "lotion" is art recognized and is intended to include those solutions typically used in dermatological applications.

The term "gel" is art recognized and is intended to include semi-solid permutations gelled with high molecular weight polymers, e.g., carboxypolymethylene (Carbomer BP) or methylcellulose, and can be regarded as semi-plastic aqueous lotions. They are typically non-greasy, water miscible, easy to apply and wash off, and are especially suitable for treating hairy parts of the body.

In a one embodiment, liposomes are used to deliver ALA to the follicle matrix. Liposomes provide site-specific transdermal delivery to the follicle matrix. In this embodiment, the ALA is microencapsulated within the liposome and topically applied to the epidermis of the skin.

As noted above, the carrier according to the present invention potentially involves encapsulating the effective amount of ALA within a specific liposome to provide for efficient transdermal delivery of ALA through the layers of the skin. These liposomal compositions are topically applied to the skin and deliver the encapsulated ALA to the follicle region including the sebaceous gland and infundibulum. Following delivery of ALA, irradiation results in highly specific targeting of the follicle matrix and destruction of oils, dirt, bacteria, mites, or viruses within the infected area.

Liposomes are microscopic spherical membrane-enclosed vesicles or sacks (0.5-500 mm in diameter) made artificially in the laboratory using a variety of methods. Within the scope of the present invention, the liposomes should be non-toxic to living cells and they should deliver the contents, in this case ALA, into the follicle and immediately surrounding tissue. The liposomes according to the present invention may be of various sizes and may comprise either one or several membrane layers separating the internal and external compartments.

The liposomes may be made from natural and synthetic phospholipids, and glycolipids and other lipids and lipid congeners; cholesterol, cholesterol derivatives and other cholesterol congeners; charged species which impart a net charge to the membrane; reactive species which can react after liposome formation to link additional molecules to the lysome membrane; and other lipid soluble compounds which have chemical or biological activities.

A general discussion of the liposomes and liposome technology can be found in an article entitled, "Liposomes" by Marc J. Ostro, published in SCIENTIFIC AMERICAN, January 1987, Vol. 256, pp. 102-111 and in a three volume work entitled, "Liposome Technology" edited by G. Gregorriadis, 1984, published by CRC press, Boca Raton, Fla. the pertinent portions of which are incorporated herein by reference.

Topically-applied ALA initially enters the infundibulum and later is distributed to the sebaceous glands. It is possible to actively drive the ALA into the follicles by massage, pressure, ultrasound, or iontophoresis, after topically applying the ALA to the skin surface. ALA can be rapidly driven into sebaceous follicles and eccrine sweat ducts by iontophoresis. Wiping the surface with or without a solvent after delivery into the follicles, can be used to remove residual material from the skin surface. Thus, after appropriate application and wiping, the ALA can be preferentially located in follicles, within the infundibula or the infundibula and sebaceous glands.

For photodynamic effects, lower average irradiance exposures given over longer exposure time would be appropriate for example approximately 10-100 mW/cm2 delivered for about 100-2000 seconds (total fluence, 1-200 J/cm2). For photodynamic effect, light sources such as light-emitting diodes, incandescent lamps, xenon arc lamps, lasers or sunlight can be used.

In order to form and retain a plug within the infundibulum, there must be a constriction along the outflow tract. As material including sebum, cells, or bacteria accumulate and are concentrated onto the plug, walls of the infundibulum are dilated until the middle or lower part of the infundibulum is larger in diameter than its outlet (the surface pore). If the outlet diameter can be increased, the plug is more likely to be expelled and pressure within the sebaceous follicle decreased before rupture can occur. The upper region of the infundibulum is also the source of follicular neck cells which shed into the infundibulum and add to the plug. For these reasons, the walls of the upper portion of the infundibulum and especially its pore at the skin surface are the primary target for ALA-assisted sebaceous gland disorder treatment, e.g. acne treatment. In a manner conceptually similar to laser skin "resurfacing", the shape and size of the infundibulum and its outlet pore can be affected by ALA-assisted photodynamic treatment. The dermis immediately surrounding sebaceous follicles, is largely responsible for maintaining shape of the infundibulum, and should be altered to produce a permanent affect.

Claim 1 of 13 Claims

1. A method for treating at least one of acne vulgaris, acne rosacea, and sebaceous gland hyperplasia comprising the steps of:

a) topically applying 5-aminolevulinic acid (ALA) at a low dose in a range between about 0.10 and 1.0 percent by weight to a section of skin afflicted with at least one of acne vulgaris, acne rosacea, and sebaceous gland hyperplasia, wherein the ALA is compounded for delivery, to sebaceous glands and is converted into a photosensitizing agent actuable by energy that penetrates outer layers of epidermis; and

b) exposing the infiltrated section of skin to energy to cause the photosensitizing agent to become photodynamically activated to kill bacteria and thereby treat at least one of acne vulgaris, acne rosacea, and sebaceous gland hyperplasia without modifying the sebaceous gland.

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