WO2023059180A1 - Treating skin diseases using a photodynamic therapy (pdt) and a topical agent photosensitizer formulation - Google Patents

Treating skin diseases using a photodynamic therapy (pdt) and a topical agent photosensitizer formulation Download PDF

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Publication number
WO2023059180A1
WO2023059180A1 PCT/MY2022/050081 MY2022050081W WO2023059180A1 WO 2023059180 A1 WO2023059180 A1 WO 2023059180A1 MY 2022050081 W MY2022050081 W MY 2022050081W WO 2023059180 A1 WO2023059180 A1 WO 2023059180A1
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skin
topical agent
formulation
pdt
photosensitizer
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PCT/MY2022/050081
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French (fr)
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Loke CHUI FUNG
Poh TZE VEN
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Tunku Abdul Rahman University Of Management And Technology (Tar Umt)
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Publication of WO2023059180A1 publication Critical patent/WO2023059180A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/19—Acanthaceae (Acanthus family)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/19—Acanthaceae (Acanthus family)
    • A61K36/195—Strobilanthes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/0616—Skin treatment other than tanning
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/065—Light sources therefor
    • A61N2005/0651—Diodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0662—Visible light
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/067—Radiation therapy using light using laser light

Definitions

  • the invention relates to a method for preparing the formulated topical agent containing standardized associated photosensitizer using photodynamic therapy (PDT) as means to enhance the efficacy of photosensitizer over a prolonged period for the treatment of skin diseases.
  • PDT photodynamic therapy
  • This also describes the administration of an effective dose of a photosensitizer on the lesion area; positioning the LED device, in proximity to the patient's body; and irradiating the patient's body.
  • Photosensitizers including 5-aminolevulinic acid, protoporphyrin IX would require a higher dosage for treatment and may lead to toxicity within the patients.
  • 5-Aminolevulinic acid is naturally synthesized in mitochondria from glycine and succinyl-CoA by ALA synthetase (ALAS).
  • 5-ALA is a small molecule involved in the early phase of porphyrin biosynthesis, which is responsible for heme production in mammals. It serves as the major substrate for protoporphyrin IX (PpIX) synthesis, a naturally fluorescent molecule that is overexpressed in cancerous tissue, especially malignant gliomas and meningiomas.
  • PpIX protoporphyrin IX
  • 5- ALA is the first universal tetrapyrrole precursor, (for heme production in mammals; for photosynthetic pigments in photosynthetic bacteria; chlorophyll synthesis in plants).
  • 5-ALA can be formed by two different pathways.
  • Members of the a-proteobacterial group which includes photosynthetic bacteria of the Rhodobacter and Rhodopseudomonas, and Rhodospirillum genera as well as the nonphotosynthetic genera Agrobacterium, Rhizobium, and Bradyrhizobium), and all eukaryotic organisms that do not contain chloroplasts (animals, yeasts, fungi), form ALA by condensation of succinyl-coenzyme A with glycine in a reaction catalyzed by the pyridoxal-P-containing enzyme ALA synthase.
  • ALA by a different route that begins with the five-carbon precursor, the amino acid Glu.
  • the three-step process begins with activation of Glu by ligation to tRNAGIu, followed by reduction of the a-carboxyl group of the activated Glu to form Glu 1 -semialdehyde (GSA), and then transamination of GSA to form ALA.
  • a photosensitizer comprises a therapeutically effective amount of aminolevulinic acid to the subject and two light radiations with first radiation at a wavelength of 320 nm to 450 nm and second radiation at a wavelength of 470 nm to 700 nm performed in coordination with administering an effective dose of the photosensitizer.
  • Exemplary embodiments of the present invention provide methods and devices for preventing or reducing the extent or likelihood of unwanted damage to epithelial tissue, or other non-targeted tissues, during PDT.
  • the present invention provides a topical agent formulation for the treatment of or for use in the treatment of superficial and subcutaneous skin with cancer lesions, or pre-cancerous lesions such as actinic keratosis and psoriasis provided as examples, which may be combined with the use of a device which is positioned in proximity of a patient body in a location selected from the group consisting of a breast, an arm, a neck, a leg, an abdomen, and/or any combination thereof.
  • the present invention provides formulated topical agents comprising a compound pheophorbide a in photosensitizer for use in photodynamic therapy (PDT), particularly for use in skin disorders, skin lesions, or skin cancer relates to medical inventions.
  • said formulated topical agents may also be for use in the treatment or for use in a method for treating said skin disorders, skin lesions, or related skin cancers.
  • the present invention further provides atopical agent photosensitizer formulation comprising acorn pound pheophorbide or pheophorbide a is extracted from Clinacanthus nutans and Strobilanthes crispusfor use in the PDT treatment of skin cancer or skin disorders.
  • said topical agent photosensitizer formulation comprises extracts from Clinacanthus nutans and Strobilanthes crispus, wherein said extract may be crude extract, or a solvent extract or an extract derived from said plant using a solvent.
  • said solvent may be selected from the group consisting of water, ethyl acetate, ethanol, methanol, or acetone.
  • LED light-emitting diode
  • the drug concentration of the pheophorbide a is applied to two different cell lines in the range of 0.2 pg/ml in skin cancer cells and 0.5 pg/mlin liver cancer cells is provided in an example.
  • the provided examples forirradiating the lesion area for treating cancer were at a power density in multiple sets of working ranges or range alternatives such as 1 to 1000 mW/cm 2 , 1 to 500 mW/cm 2 , 1 to 100 mW/cm 2 , 1 to 50 mW/cm 2 , 15 to 45 mW/cm 2 , 25 to 35 mW/cm 2 , or preferably 28.40 mW/cm 2 , wavelength selected at a range of 400-410 nm or 657-667, 402- 408 nm or 659-663, or most preferably 405.5 nm or 662.5 nm, duration of light exposure is preferably 600 sec and a dose of the photosensitizing agent is from 0.5 pg per cm 2 to 1 pg per cm 2 lesion area.
  • thesolution of the present invention presentsadvantage over pre-existing methods and parameters, including non- invasiveness, lowerconcentrations used at the site of action, reduced side effects, reduced exposure to irradiation, andbetter therapeutic effect.
  • the present invention provides a solution for better removal of epithelial cells of a lesion area is by using PDT at a specific spectrum, with defined irradiation power and fluence rate at an appropriate duration of irradiation.
  • Figure 1 discloses a process of chlorophyll breakdown to provide a pheophorbide a as an intermediate formed during the breakdown.
  • Figure 2 discloses a graph showing determined dosages or therapeutic effective amount of pheophorbide a in two different cell lines.
  • Figure 3 discloses an indication of energy absorption when the pheophorbide a is dissolved in methanol.
  • Figure 4A discloses a narrow bandwidth of laser for light irradiation at a specific wavelength.
  • Figure 4B discloses a wider spread of bandwidth of Light Emitting Diode (LED) for light irradiation. While the present invention will now be described in detail with reference to the figures, it is done so in connection with the illustrative embodiments.
  • LED Light Emitting Diode
  • the methods and device according to embodiments of the present invention utilize electromagnetic radiation to control and/or inhibit the formation of a photosensitizer administered to certain tissues for photodynamic therapy(PDT)procedures.
  • the present invention provides a topical agent formulation for treating superficial and subcutaneous skin with cancer lesions or pre-cancerous lesions such as actinic keratosis and psoriasis, which may be combined with a device which may be usedaspositioned in proximity of a patient body in a location selected from the group consisting of a breast, an arm, a neck, a leg, an abdomen and any combination thereof.
  • PDT requires three essential elements to complete the therapy via apoptosis or necrosis, which are
  • ROS reactive oxygen species
  • HO* hydroxyl radical
  • H 2 O 2 hydrogen peroxide
  • 1 O 2 singlet oxygen
  • *O 2 _ superanion oxide
  • ROO* peroxyl radical
  • the activated photosensitizer reacts with the oxygen-containing molecules inside the cell by transferring its proton or electron to form a radical cation or radical anion species (*O 2 _ , HO*) respectively.
  • the hydroxyl radical is the most reactive species of ROS, which can cause lipid damage by taking an electron away from polyunsaturated fatty acids and initiate lipid peroxidation.
  • the electron from the activated photosensitizer goes back to the ground state from the excited triplet state with a wave of energy transferred to molecular oxygen and leads to the formation of singlet oxygen ( 1 O 2 ).
  • Singlet oxygen can easily react with the four bases of DNA molecules, while guanine is the most susceptible base to single oxygen due to its low redox potential.
  • singlet oxygen is an unstable ephemeral biomolecule with a short shelf-life (about 6 ms in water and slightly longer in the cellular environment), it is unable to diffuse more than a single cell length in cell environments. Short shelf-life singlet oxygen, however, is able to suppress cellular proliferation.
  • the accumulation of ROS within the lesions will cause oxidative damage such as lipid peroxidation, oxidation of protein and DNA, eventually, lead to cell death.
  • formulated topical agents comprising a compound pheophorbide a in photosensitizer for use in photodynamic therapy (PDT) particularly in skin disorders, skin lesions, or skin cancer.
  • said formulated topical agents may also be for use in the treatment or for use in a method for treating said skin disorders, skin lesions, or related skin cancer exemplified herein.
  • Precancerous skin consists of various premalignant changes in the skin cells that increase the likelihood of developing skin cancer. These changes often appear as growths or lesions. Precancerous lesions can be found on the skin epidermis of the head, neck, hands, and forearms of older adults. Precancerous lesions include actinic keratosis, actinic cheilitis, Bowen disease, and leukoplakia. These precancerous skin lesions may naturally progress into squamous or basal cell carcinoma.
  • basal cell carcinoma BCC
  • Basal cell carcinoma BCC
  • its clinical variants are as follows: o Nodular basal cell carcinoma o Cystic basal cell carcinoma o Sclerodermiform (Morpheiform) basal cell carcinoma o Infiltrated basal cell carcinoma o Micronodular basal cell carcinoma o Superficial basal cell carcinoma o Pigment basal cell carcinoma o Fibroepithelioma of Pinkus
  • SCC squamous cell carcinoma
  • a topical agent photosensitizer formulation of the present embodiment comprising the compound pheophorbide or pheophorbide a is extracted from Clinacanthus nutans and Strobilanthes crispus for use in the PDT treatment of skin cancer or skin disorders is provided.
  • said topical agent photosensitizer formulation comprises extracts from Clinacanthus nutans and Strobilanthes crispus, wherein said extract may be crude extract, or a solvent extract or an extract derived from said plant using a solvent.
  • said solvent may be selected from the group consisting of water, ethyl acetate, ethanol, methanol, or acetone.
  • Clinacanthus nutans and Strobilanthes crispus were selected due totheir high chlorophyll a content which act as a precursor for pheophobide a, and further because of their high phenolic contents as well as they can exhibit high antioxidant activities. These two plants exhibited higher amounts of other bioactive compounds including apigenin, cycloclinacoside, clinacoside, clinamide, 2-cis-entadamide A, entadamide, gallic acid, kaempferol, quercetin, stigmasterol, and vitexin.
  • the photosensitizer formulation is subjected to a temperature between 15-30 c C and comprising 9% (v/v) mineral oil, about 3% (w/v) emulsifying agent such as Aery lates/C 10-30 Alkyl Acrylate Crosspolymer (0.42%), Hydroxyethyl Acrylate/Sodium Acryloyldimethyltaurate Copolymer (1.11 %), Polysorbate-80 (1.25%), about 10% (w/v) permeation enhancer, about 1% (w/v) preservative, about 76.9% (v/v) aqueous phase, and about 0.00005% to 0.0002% (wZv)pharmaceutical active ingredient
  • the method of producing a photosensitizer formulation includes:
  • Step 1 mixing an oil phase with an emulsifying agent and/or a thickener, or a stabilizing agent, and/or permeation enhancer, and/or preservative to form a mixture, agitating the mixture until homogenous.
  • Step 2 adding the aqueous phase to the mixture in step 1 , and continuing to agitate to form a formulation.
  • Step 3 adding a solid form of active ingredient to the formulation, and mix until homogenous to form a final topical formulation.
  • the photosensitizer formulation or topical agent photosensitizer formulation comprises an active ingredient, or a pharmaceutical active ingredient, wherein said active ingredient is pheophorbide a.
  • Said formulation may further comprise an emulsifying agent, a thickener, a stabilizing agent, a permeation enhancer, a preservative, or a combination thereof.
  • the photosensitizer formulation may be provided in crystallized form orpowder form after the freeze-drying from the initial methanolic extraction.
  • the final photosensitizer formulation is added as an oil-in-water formulation.
  • the photosensitizer formulation may be provided in a form of an ointment, gel, or emulsion form dueto the nature of the final product (pheophorbide a) is oil-soluble and alcohol-soluble.
  • the preferred drug concentration of the pheophorbide a is applied to two different cell lines in the range of 0.2 pg/ml to 1.0 pg/ml in skin cancer cells and 0.5 pg/ml to 1 .0 pg/ml in liver cancer cells.
  • a lightemitting diode (LED) or laser at wavelengths of 400-410 nm or 657-667, 402-408 nm or 659-663, or most preferably, and preferably 405.5nm and 662.5nm.
  • sources of irradiation for the irradiating device may include aLED, a Direct diode laser or diode-pumped solid-state (DPSS) laser, or a gas laser including ion laser.
  • suitable solid gain mediums are used to produce the laser with the desired wavelengths.
  • suitable gases are used to produce the laser with the desired wavelengths which may include He-Ne laser, which can produce 632.8nm.
  • He-Ne laser which can produce 632.8nm.
  • Another example of an ion laser is the krypton laser, which can produce 647.1 nm and 676.4nm and also other useful ultraviolet wavelengths like 413.1 nm, 415.4nm, 468. Onm, and 476.2nm. All these wavelengths can be absorbed by pheophorbide a.
  • the advantage of the laser is that it can produce a very narrow bandwidth of a specific wavelength like Fig 4A, which is one of the wavelengths produced by He-Ne gas laser. The actual bandwidth is even narrower.
  • Another advantage of lasers is that the beam can be made very focused.
  • Figure 1 discloses the process of chlorophyll breakdown (100).
  • the compound pheophorbide a (104) is one of the chlorophyll derivatives that is derived from plant primary pigment chlorophyll during senescence process.
  • the pheophorbide a (104) is one of the degraded forms of chlorophyll a (102) found in the leaves.
  • the pheophorbide a (104) is one of the intermediates formed during the chlorophyll breakdown (100).
  • the Pheophorbide a (104) is further degraded into red chlorophyll catabolites (RCC) (106).
  • RRCC red chlorophyll catabolites
  • Figure 2 discloses a graph showing dosages of pheophorbide a on two different cell lines such as HepG2 - liver cancer cellsin Fig. 2(i) and A431 - skin cancer cellsin Fig. 2(ii). It may be observed in the presented Fig. 2(i) and 2(ii) that not all dosages of C. nutans and S. crispus may be effective for PDT, or for specific wavelengths used for PDT, wherein Fig 2(i) showseffective dosages were only in the range of about 0.5 to 1.2 pg/mL concentration for skin cancer cells while Fig (2 ii) shows effective dosages were only in the range of about 0.2 to 1 .2 pg/mL applied in liver cancer cells. Such difference provided may also further establish that effective therapeutic dosages or effective therapeutic amounts or concentrations of used pheophorbide a applies uniquely to a specific type of cancer, andalso requires a separate confirmation to determine said effective amount specifically among skin related treatment applications.
  • Figure 3 discloses a graph (300) indicating an energy absorption is only at two peaks 405.5nm (302)and 662.5nm (304) when the pheophorbide a is dissolved in methanol.
  • combining the topical agent photosensitizer formulation and an irradiating device for the treatment of skin disorders wherein the light irradiation is provided by positioning a light-emitting diode (LED) were determined to be optimally absorbed or optimally therapeutic at about thewavelengths 405.5nm (302) and 662.5 nm (304). It may be directly observed that deviation from the use of said two unique wavelengths used 405.5 nm and 662.5 nm may result in decreased optimal energy absorption which may further contribute to the use of pheophorbide a in low non-toxic amounts which prevents compromise in the health of the subject in treatment.
  • the inventive determination of said optimized wavelengths for the formulation of the present invention also provides waste of materials in inaccurate or inefficient treatment methods and parameters.
  • Figure 4A discloses an advantage of a laser producing a very narrow bandwidth (400) of a specific wavelength at 632.8 nm (402), which is one of the wavelengths produced by He-Ne gas laser. The actual bandwidth is even narrower.
  • Another advantage of lasers is that the beam provides precise and/or focus treatment on the target contact surface or treatment surface.
  • Figure4B disclosesa wider spread of bandwidth of LED (410)wherein said narrow bandwidth might not provide further advantage because chlorophylls and their derivatives absorb quite a wide range of spectrum of light.
  • our solution presentsadvantages, including non- invasiveness, lowerconcentrations used at the site of action, reduced side effects, reduced exposure to irradiation, andbetter therapeutic effect.
  • the formulation of the present invention also providespreventionof development skin cancers.
  • the present invention's focus is also more on amelioration for precancerous skin lesion conditions from bad to better management of precancerous skin conditions.
  • the present invention provides a solution for better removal of epithelial cells of a lesion area is by using PDT at a specific spectrum, with defined irradiation power and fluence rate at an appropriate duration of irradiation.

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Abstract

The present invention discloses formulated topical agents comprising a compound pheophorbide a in photosensitizer for use in photodynamic therapy (PDT) particularly in skin disorders, skin lesions, or skin cancer.A topical agent compound pheophorbide a of the present embodiment is extracted from Clinacanthus nutans and Strobilanthes crispus. In this present invention, combining the photosensitizer with light irradiation in the PDT for treatingskin disorders, skin lesions, or skin cancer.

Description

TREATING SKIN DISEASES USING A PHOTODYNAMIC THERAPY (PDT) AND A TOPICAL AGENT PHOTOSENSITIZER FORMULATION
Field of Invention
The invention relates to a method for preparing the formulated topical agent containing standardized associated photosensitizer using photodynamic therapy (PDT) as means to enhance the efficacy of photosensitizer over a prolonged period for the treatment of skin diseases. This also describes the administration of an effective dose of a photosensitizer on the lesion area; positioning the LED device, in proximity to the patient's body; and irradiating the patient's body.
Background of Invention
Photosensitizers including 5-aminolevulinic acid, protoporphyrin IX, would require a higher dosage for treatment and may lead to toxicity within the patients.
5-Aminolevulinic acid (5-ALA) is naturally synthesized in mitochondria from glycine and succinyl-CoA by ALA synthetase (ALAS). 5-ALA is a small molecule involved in the early phase of porphyrin biosynthesis, which is responsible for heme production in mammals. It serves as the major substrate for protoporphyrin IX (PpIX) synthesis, a naturally fluorescent molecule that is overexpressed in cancerous tissue, especially malignant gliomas and meningiomas. Thus, 5-ALA has been used clinically for tumor detection especially for fluorescence imaging during surgery.
Generally, 5- ALA, is the first universal tetrapyrrole precursor, (for heme production in mammals; for photosynthetic pigments in photosynthetic bacteria; chlorophyll synthesis in plants). 5-ALA can be formed by two different pathways. Members of the a-proteobacterial group (which includes photosynthetic bacteria of the Rhodobacter and Rhodopseudomonas, and Rhodospirillum genera as well as the nonphotosynthetic genera Agrobacterium, Rhizobium, and Bradyrhizobium), and all eukaryotic organisms that do not contain chloroplasts (animals, yeasts, fungi), form ALA by condensation of succinyl-coenzyme A with glycine in a reaction catalyzed by the pyridoxal-P-containing enzyme ALA synthase. In contrast, all plants and algae, and all bacteria that are not in the a- proteobacterial group, including cyanobacteria, many photosynthetic bacteria, and archaea, form ALA by a different route that begins with the five-carbon precursor, the amino acid Glu. The three-step process begins with activation of Glu by ligation to tRNAGIu, followed by reduction of the a-carboxyl group of the activated Glu to form Glu 1 -semialdehyde (GSA), and then transamination of GSA to form ALA.
The prior art ‘US9345904B2’, titled “Photodynamic therapy using a photosensitizing agent or 5-aminolevulinic acid” clearly discloses a photodynamic therapy using a photosensitizing agent or 5-aminolevulinic acids, and administering a photosensitizing agent or 5-aminolevulinic acids followed by irradiation with excitation light at a wavelength of 480 to 580 nm.
The prior art ‘US10195459B2’, titled “Device for photodynamical therapy of cancer” clearly discloses a photodynamic therapy administering an effective dose of a photosensitizer 5-aminolaevulinic acid (5-ALA) and a wavelength of about 585 to about 740 nm performed in coordination with administering an effective dose of the photosensitizer.
The prior art ‘US9108045B2’, titled “Method and apparatus for optical inhibition of photodynamic therapy” clearly discloses a photosensitizer comprises a therapeutically effective amount of aminolevulinic acid to the subject and two light radiations with first radiation at a wavelength of 320 nm to 450 nm and second radiation at a wavelength of 470 nm to 700 nm performed in coordination with administering an effective dose of the photosensitizer.
Thus, we need a solution for better removal of epithelial cells of a lesion area is by using PDT at a specific spectrum, with defined irradiation power and fluence rate at an appropriate duration of irradiation.
Summary of Invention
Exemplary embodiments of the present invention provide methods and devices for preventing or reducing the extent or likelihood of unwanted damage to epithelial tissue, or other non-targeted tissues, during PDT.
The present invention providesa topical agent formulation for the treatment of or for use in the treatment of superficial and subcutaneous skin with cancer lesions, or pre-cancerous lesions such as actinic keratosis and psoriasis provided as examples, which may be combined with the use of a device which is positioned in proximity of a patient body in a location selected from the group consisting of a breast, an arm, a neck, a leg, an abdomen, and/or any combination thereof.
In another embodiment, the present invention providesformulated topical agents comprising a compound pheophorbide a in photosensitizer for use in photodynamic therapy (PDT), particularly for use in skin disorders, skin lesions, or skin cancer relates to medical inventions. In another embodiment, said formulated topical agents may also be for use in the treatment or for use in a method for treating said skin disorders, skin lesions, or related skin cancers.
The present invention further provides atopical agent photosensitizer formulation comprising acorn pound pheophorbide or pheophorbide a is extracted from Clinacanthus nutans and Strobilanthes crispusfor use in the PDT treatment of skin cancer or skin disorders. In another embodiment, said topical agent photosensitizer formulation comprises extracts from Clinacanthus nutans and Strobilanthes crispus, wherein said extract may be crude extract, or a solvent extract or an extract derived from said plant using a solvent. In a more specific embodiment, said solvent may be selected from the group consisting of water, ethyl acetate, ethanol, methanol, or acetone.
According to the present invention, combining the topical agent photosensitizer formulation and an irradiating device for the treatment of skin disorders wherein the light irradiation is provided by positioning a light-emitting diode (LED) at wavelengths 405.5 nm and 662.5 nm.
In this present invention, the drug concentration of the pheophorbide a is applied to two different cell lines in the range of 0.2 pg/ml in skin cancer cells and 0.5 pg/mlin liver cancer cells is provided in an example.
According to this present embodiment, the provided examples forirradiating the lesion area for treating cancer were at a power density in multiple sets of working ranges or range alternatives such as 1 to 1000 mW/cm2, 1 to 500 mW/cm2, 1 to 100 mW/cm2, 1 to 50 mW/cm2, 15 to 45 mW/cm2, 25 to 35 mW/cm2, or preferably 28.40 mW/cm2, wavelength selected at a range of 400-410 nm or 657-667, 402- 408 nm or 659-663, or most preferably 405.5 nm or 662.5 nm, duration of light exposure is preferably 600 sec and a dose of the photosensitizing agent is from 0.5 pg per cm2 to 1 pg per cm2 lesion area.
Compared to otherinventions, thesolution of the present invention presentsadvantage over pre-existing methods and parameters, including non- invasiveness, lowerconcentrations used at the site of action, reduced side effects, reduced exposure to irradiation, andbetter therapeutic effect.
Thus, the present invention provides a solution for better removal of epithelial cells of a lesion area is by using PDT at a specific spectrum, with defined irradiation power and fluence rate at an appropriate duration of irradiation.
These and other objects, features, and advantages of the present invention will become apparent upon reading the following detailed description of embodiments of the invention when taken in conjunction with the appended claims.
Brief Description of Drawings
Further objects, features, and advantages of the invention will become apparent from the following detailed description taken in conjunction with the accompanying figures showing illustrative embodiments of the invention, in which:
Figure 1 discloses a process of chlorophyll breakdown to provide a pheophorbide a as an intermediate formed during the breakdown.
Figure 2 discloses a graph showing determined dosages or therapeutic effective amount of pheophorbide a in two different cell lines.
Figure 3 discloses an indication of energy absorption when the pheophorbide a is dissolved in methanol.
Figure 4A discloses a narrow bandwidth of laser for light irradiation at a specific wavelength.
Figure 4B discloses a wider spread of bandwidth of Light Emitting Diode (LED) for light irradiation. While the present invention will now be described in detail with reference to the figures, it is done so in connection with the illustrative embodiments.
Detailed Description of Invention
The methods and device according to embodiments of the present invention utilize electromagnetic radiation to control and/or inhibit the formation of a photosensitizer administered to certain tissues for photodynamic therapy(PDT)procedures.
The present invention providesa topical agent formulation for treating superficial and subcutaneous skin with cancer lesions or pre-cancerous lesions such as actinic keratosis and psoriasis, which may be combined with a device which may be usedaspositioned in proximity of a patient body in a location selected from the group consisting of a breast, an arm, a neck, a leg, an abdomen and any combination thereof.
PDT requires three essential elements to complete the therapy via apoptosis or necrosis, which are
(i) photosensitizer,
(ii) light radiation, which corresponds to the maximum absorption wavelength of photosensitizer (in this case is at 405.5 nm or 662.5 nm), and
(iii) oxygen (presence within the blood veins of the skin lesions)
(The activated photosensitizer, upon light exposure, leads to the formation of reactive oxygen species (ROS) such as hydroxyl radical (HO*), hydrogen peroxide (H2O2), singlet oxygen (1O2), superanion oxide (*O2 _), and peroxyl radical (ROO*) through two different types of a pathway.
• In the Type I reaction of PDT, the activated photosensitizer reacts with the oxygen-containing molecules inside the cell by transferring its proton or electron to form a radical cation or radical anion species (*O2 _, HO*) respectively. The hydroxyl radical is the most reactive species of ROS, which can cause lipid damage by taking an electron away from polyunsaturated fatty acids and initiate lipid peroxidation. • In the Type II reaction of PDT, the electron from the activated photosensitizer goes back to the ground state from the excited triplet state with a wave of energy transferred to molecular oxygen and leads to the formation of singlet oxygen (1O2). Singlet oxygen can easily react with the four bases of DNA molecules, while guanine is the most susceptible base to single oxygen due to its low redox potential. However, singlet oxygen is an unstable ephemeral biomolecule with a short shelf-life (about 6 ms in water and slightly longer in the cellular environment), it is unable to diffuse more than a single cell length in cell environments. Short shelf-life singlet oxygen, however, is able to suppress cellular proliferation. In addition, the accumulation of ROS within the lesions will cause oxidative damage such as lipid peroxidation, oxidation of protein and DNA, eventually, lead to cell death.)
According to one embodiment, using formulated topical agents comprising a compound pheophorbide a in photosensitizer for use in photodynamic therapy (PDT) particularly in skin disorders, skin lesions, or skin cancer. In another embodiment, said formulated topical agents may also be for use in the treatment or for use in a method for treating said skin disorders, skin lesions, or related skin cancer exemplified herein.
Many superficial or subcutaneous non-melanoma skin cancers may arise from precancerous skin conditions. Precancerous skin consists of various premalignant changes in the skin cells that increase the likelihood of developing skin cancer. These changes often appear as growths or lesions. Precancerous lesions can be found on the skin epidermis of the head, neck, hands, and forearms of older adults. Precancerous lesions include actinic keratosis, actinic cheilitis, Bowen disease, and leukoplakia. These precancerous skin lesions may naturally progress into squamous or basal cell carcinoma.
In an example provided herein, there are three major types of common skin cancers:
• basal cell carcinoma (BCC), its clinical variants are as follows: o Nodular basal cell carcinoma o Cystic basal cell carcinoma o Sclerodermiform (Morpheiform) basal cell carcinoma o Infiltrated basal cell carcinoma o Micronodular basal cell carcinoma o Superficial basal cell carcinoma o Pigment basal cell carcinoma o Fibroepithelioma of Pinkus
• squamous cell carcinoma (SCC), and
• melanoma
In an embodiment, a topical agent photosensitizer formulation of the present embodiment comprising the compound pheophorbide or pheophorbide a is extracted from Clinacanthus nutans and Strobilanthes crispus for use in the PDT treatment of skin cancer or skin disorders is provided. In another embodiment, said topical agent photosensitizer formulation comprises extracts from Clinacanthus nutans and Strobilanthes crispus, wherein said extract may be crude extract, or a solvent extract or an extract derived from said plant using a solvent. In a more specific embodiment, said solvent may be selected from the group consisting of water, ethyl acetate, ethanol, methanol, or acetone.
Clinacanthus nutans and Strobilanthes crispuswere selected due totheir high chlorophyll a content which act as a precursor for pheophobide a, and further because of their high phenolic contents as well as they can exhibit high antioxidant activities. These two plants exhibited higher amounts of other bioactive compounds including apigenin, cycloclinacoside, clinacoside, clinamide, 2-cis-entadamide A, entadamide, gallic acid, kaempferol, quercetin, stigmasterol, and vitexin.
According to the present invention, the photosensitizer formulation is subjected to a temperature between 15-30cC and comprising 9% (v/v) mineral oil, about 3% (w/v) emulsifying agent such as Aery lates/C 10-30 Alkyl Acrylate Crosspolymer (0.42%), Hydroxyethyl Acrylate/Sodium Acryloyldimethyltaurate Copolymer (1.11 %), Polysorbate-80 (1.25%), about 10% (w/v) permeation enhancer, about 1% (w/v) preservative, about 76.9% (v/v) aqueous phase, and about 0.00005% to 0.0002% (wZv)pharmaceutical active ingredient In an example provided, the method of producing a photosensitizer formulation includes:
Step 1 : mixing an oil phase with an emulsifying agent and/or a thickener, or a stabilizing agent, and/or permeation enhancer, and/or preservative to form a mixture, agitating the mixture until homogenous.
Step 2: adding the aqueous phase to the mixture in step 1 , and continuing to agitate to form a formulation.
Step 3: adding a solid form of active ingredient to the formulation, and mix until homogenous to form a final topical formulation.
The photosensitizer formulation or topical agent photosensitizer formulation comprises an active ingredient, or a pharmaceutical active ingredient, wherein said active ingredient is pheophorbide a. Said formulation may further comprise an emulsifying agent, a thickener, a stabilizing agent, a permeation enhancer, a preservative, or a combination thereof.
The photosensitizer formulation may be provided in crystallized form orpowder form after the freeze-drying from the initial methanolic extraction. The final photosensitizer formulation is added as an oil-in-water formulation. The photosensitizer formulation may be provided in a form of an ointment, gel, or emulsion form dueto the nature of the final product (pheophorbide a) is oil-soluble and alcohol-soluble.
In this present invention, the preferred drug concentration of the pheophorbide a is applied to two different cell lines in the range of 0.2 pg/ml to 1.0 pg/ml in skin cancer cells and 0.5 pg/ml to 1 .0 pg/ml in liver cancer cells.
According to the present invention, combining the use of topical agent photosensitizer formulation and the use of an irradiating device for the treatment of skin disorders wherein the light irradiation is provided by positioning a lightemitting diode (LED) or laser at wavelengths of 400-410 nm or 657-667, 402-408 nm or 659-663, or most preferably, and preferably 405.5nm and 662.5nm. In one embodiment sources of irradiation for the irradiating device may includeaLED, a Direct diode laser or diode-pumped solid-state (DPSS) laser, or a gas laser including ion laser.
For DPSS, suitable solid gain mediums are used to produce the laser with the desired wavelengths. For gas lasers, suitable gases are used to produce the laser with the desired wavelengths which may include He-Ne laser, which can produce 632.8nm. Another example of an ion laser is the krypton laser, which can produce 647.1 nm and 676.4nm and also other useful ultraviolet wavelengths like 413.1 nm, 415.4nm, 468. Onm, and 476.2nm. All these wavelengths can be absorbed by pheophorbide a.
The advantage of the laser is that it can produce a very narrow bandwidth of a specific wavelength like Fig 4A, which is one of the wavelengths produced by He-Ne gas laser. The actual bandwidth is even narrower. Another advantage of lasers is that the beam can be made very focused.
Figure 1 discloses the process of chlorophyll breakdown (100). the compound pheophorbide a (104) is one of the chlorophyll derivatives that is derived from plant primary pigment chlorophyll during senescence process. The pheophorbide a (104) is one of the degraded forms of chlorophyll a (102) found in the leaves. The pheophorbide a (104) is one of the intermediates formed during the chlorophyll breakdown (100). The Pheophorbide a (104) is further degraded into red chlorophyll catabolites (RCC) (106). The pheophorbide a (104) isextracted from Clinacanthus nutans and Strobilanthes crispus using chromatography method.
Figure 2 discloses a graph showing dosages of pheophorbide a on two different cell lines such as HepG2 - liver cancer cellsin Fig. 2(i) and A431 - skin cancer cellsin Fig. 2(ii). It may be observed in the presented Fig. 2(i) and 2(ii) that not all dosages of C. nutans and S. crispus may be effective for PDT, or for specific wavelengths used for PDT, wherein Fig 2(i) showseffective dosages were only in the range of about 0.5 to 1.2 pg/mL concentration for skin cancer cells while Fig (2 ii) shows effective dosages were only in the range of about 0.2 to 1 .2 pg/mL applied in liver cancer cells. Such difference provided may also further establish that effective therapeutic dosages or effective therapeutic amounts or concentrations of used pheophorbide a applies uniquely to a specific type of cancer, andalso requires a separate confirmation to determine said effective amount specifically among skin related treatment applications.
Figure 3 discloses a graph (300) indicating an energy absorption is only at two peaks 405.5nm (302)and 662.5nm (304) when the pheophorbide a is dissolved in methanol.
Referring to Figure 3, combining the topical agent photosensitizer formulation and an irradiating device for the treatment of skin disorders wherein the light irradiation is provided by positioning a light-emitting diode (LED) were determined to be optimally absorbed or optimally therapeutic at about thewavelengths 405.5nm (302) and 662.5 nm (304). It may be directly observed that deviation from the use of said two unique wavelengths used 405.5 nm and 662.5 nm may result in decreased optimal energy absorption which may further contribute to the use of pheophorbide a in low non-toxic amounts which prevents compromise in the health of the subject in treatment. The inventive determination of said optimized wavelengths for the formulation of the present invention also provides waste of materials in inaccurate or inefficient treatment methods and parameters.
Figure 4A discloses an advantage of a laser producing a very narrow bandwidth (400) of a specific wavelength at 632.8 nm (402), which is one of the wavelengths produced by He-Ne gas laser. The actual bandwidth is even narrower. Another advantage of lasers is that the beam provides precise and/or focus treatment on the target contact surface or treatment surface.
Figure4B disclosesa wider spread of bandwidth of LED (410)wherein said narrow bandwidth might not provide further advantage because chlorophylls and their derivatives absorb quite a wide range of spectrum of light.
According to this present embodiment, irradiating the lesion area for treating cancer at a power density of 28.40 mW/cm2 with total light doses of 8.52 J/cm2, wavelength selected at a range of 405.4 nm or 662.5 nm, duration of light exposure is preferably 600 sec and a dose of the photosensitizing agent is from 0.5 pg per cm2 to 1 pg per cm2 lesion area. Compared to otherinventions, our solution presentsadvantages, including non- invasiveness, lowerconcentrations used at the site of action, reduced side effects, reduced exposure to irradiation, andbetter therapeutic effect.
For patients with precancerous skin lesions, the formulation of the present inventionalso providespreventionof development skin cancers. The present invention's focus is also more on amelioration for precancerous skin lesion conditions from bad to better management of precancerous skin conditions.
Thus, the present invention provides a solution for better removal of epithelial cells of a lesion area is by using PDT at a specific spectrum, with defined irradiation power and fluence rate at an appropriate duration of irradiation.
The foregoing merely illustrates the principles of the invention. Various modifications and alterations to the described embodiments will be apparent to those skilled in the art in view of the teachings herein. It will thus be appreciated that those skilled in the art will be able to devise numerous devices and methods which, although not explicitly shown or described herein, embody the principles of the invention and are thus within the spirit and scope of the present invention. In addition, all publications, patents, and patent applications referenced herein are incorporated herein by reference in their entireties.

Claims

1. Combined use of photodynamic therapy (PDT) and a topical agent photosensitizer formulation inamethod of treating skin disorders, skin lesions, or skin cancer wherein said photosensitizer ina topical agent formulation comprises extracts from Clinacanthus nutans and Strobilanthes crispus', and wherein said PDT comprises the use of light irradiation in treating said skin diseases.
2. The combined use of claim 1 , wherein saidlight irradiation is provided by positioning a light-emitting diode (LED) or lasersat wavelengths 405.5 nm and 662.5 nm.
3. The combined use of claim 1 , wherein said lightirradiation isprovidedat a power density of 28.40 mW/cm2with total light doses of 8.52 J/cm2
4. The combined use of claim 1 , wherein said light irradiation is provided at a wavelength of 405.5 nm or 662.5 nm.
5. The combined use of claim 1 , wherein said light irradiation is applied at a duration of a light exposure of 600 seconds.
6. The combined use of claim 1 , wherein said topical agent photosensitizerformulation is provided at a dose from 0.5 pg/cm2 to 1 pg/cm2 lesion area.
7. An irradiatingdevice forphotodynamic therapy (PDT) foruse in treating skin disorders, skin lesions, or skin cancer, said device comprising an irradiating source selected from the group consisting of light-emitting diode(LED), a direct diode laser or diode-pumped solid-state (DPSS) laser, a gas laser, and anion laserlight-emitting diode.
8. A topical agent photosensitizer formulation for use in photodynamic therapy (PDT) treatment ofskin disorders, skin lesions, or skin cancer comprising extracts from Clinacanthus nutans and Strobilanthes crispus.
9. The topical agent photosensitizer formulation for use of claim 8, wherein said extracts are crude extracts or solvent extracts.
10. The topical agent photosensitizer formulation for use of claim 8 or 9, wherein said extracts are solvent extracts selected from the group consisting of ethanol extract, methanol extract, ethyl acetate extract, or acetone extract. The topical agent photosensitizer formulation for use of claim 8, further comprising, 9% (v/v) mineral oil;
3% (w/v) emulsifying agent selected from the group consisting ofacrylates or Cio-Caoalkyl acrylate crosspolymer (0.42%), hydroxyethyl acrylate or sodium acryloyldimethyltaurate copolymer (1.11 %), andPolysorbate-80;
10% (w/v) permeation enhancer: 1 % (w/v) preservative; about 76.9% (v/v) aqueous phase; andO.00005% to 0.0002% (w/v) pharmaceutical active ingredient. The topical agent photosensitizer formulation for use of claim 8, wherein said formulation may be provided in a form of an ointment, gel, or emulsion. The topical agent photosensitizer formulation for use of claim 8, wherein said extracts from Clinacanthus nutans and Strobilanthes crispus contains pheophorbide a.
PCT/MY2022/050081 2021-10-06 2022-09-08 Treating skin diseases using a photodynamic therapy (pdt) and a topical agent photosensitizer formulation WO2023059180A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080096857A1 (en) * 2004-02-06 2008-04-24 Qlt Inc. Photodynamic Therapy For The Treatment Of Hyperactive Sebaceous Gland Disorders Using Topically Applied Hydrophobic Green Porphyrins
US20110250143A1 (en) * 2008-10-24 2011-10-13 Luis Guilherme Da Silva Arnaut Moreira Process for preparing chlorins and their pharmaceutical uses
US20160101029A1 (en) * 2009-04-02 2016-04-14 Sesvalia Usa, Llc Systems and Methods for Skin Rejuvenation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080096857A1 (en) * 2004-02-06 2008-04-24 Qlt Inc. Photodynamic Therapy For The Treatment Of Hyperactive Sebaceous Gland Disorders Using Topically Applied Hydrophobic Green Porphyrins
US20110250143A1 (en) * 2008-10-24 2011-10-13 Luis Guilherme Da Silva Arnaut Moreira Process for preparing chlorins and their pharmaceutical uses
US20160101029A1 (en) * 2009-04-02 2016-04-14 Sesvalia Usa, Llc Systems and Methods for Skin Rejuvenation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SIEW YIN-YIN; ZAREISEDEHIZADEH SOGAND; SEETOH WEI-GUANG; NEO SOEK-YING; TAN CHAY-HOON; KOH HWEE-LING: "Ethnobotanical survey of usage of fresh medicinal plants in Singapore", JOURNAL OF ETHNOPHARMACOLOGY, vol. 155, no. 3, 22 July 2014 (2014-07-22), IE , pages 1450 - 1466, XP029057368, ISSN: 0378-8741, DOI: 10.1016/j.jep.2014.07.024 *
TAN SHERI-ANN, LIM SHIYUN, LAW CHIEUSHIE, YUE CHENSON, POH TZEVEN, SAAD WANZUHAINIS, ISMAIL SAILA, YUSOFF KHATIJAHMOHAMAD, LOKE CH: "Antioxidative and Photocytotoxic Effects of Standardized Clinacanthus nutans and Strobilanthes crispus Extracts toward HepG2 Liver Cells", PHARMACOGNOSY MAGAZINE, vol. 15, no. 65, 1 January 2019 (2019-01-01), IN , pages 613 - 620, XP093057423, ISSN: 0973-1296, DOI: 10.4103/pm.pm_84_19 *

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