Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
  • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
• • 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
  • 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
  • A61K41/0061—5-aminolevulinic acid-based PDT: 5-ALA-PDT involving porphyrins or precursors of protoporphyrins generated in vivo from 5-ALA
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
  • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • 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
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • 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
  • A61P17/10—Anti-acne agents
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/06—Free radical scavengers or antioxidants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/08—Anti-ageing preparations
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
  • C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
  • C07C53/16—Halogenated acetic acids

Definitions

• the present disclosure relates to salts of 5-aminolevulinic acid (5-ALA) and salts of 5-ALA esters, their preparation, formulation and use as photosensitizing agents in photodynamic therapy, diagnosis or cosmetic treatment.
• 5-ALA 5-aminolevulinic acid
• 5-ALA esters their preparation, formulation and use as photosensitizing agents in photodynamic therapy, diagnosis or cosmetic treatment.
• Photodynamic therapy is a therapeutic technique that uses a photosensitizing agent and a particular light source to activate the photosensitize! " .
• the photosensitizer Upon exposure to visible light, the photosensitizer is activated to high energy states and further reacts with oxygen or transfer its energy to oxygen molecules to create reactive oxygen species (ROS), such as singlet oxygen or free oxygen radicals.
• ROS reactive oxygen species
• the activated photosensitizer can also return to a lower energy level partly by emitting red fluorescence, which can be used for diagnostic purposes.
• PDT has a wide range of clinical applications in fields such as dermatology, diagnosis and cosmetic treatment.
• PDT using 5-ALA and its esters has proven to be a safe and effective therapeutic strategy with excellent cosmetic outcomes (Fonda-Pascual et al, Methods, 2016, 109, 190-202) in the treatment of certain cancers, pre-cancerous disorders, noncancerous lesion and in cancer diagnoses (Jichlinski et al, J Urol, 2003, 170: 226-9). Since these agents are unstable and prone to polymerization, they are provided as hydrochloride salts in clinical applications.
• Levulan® (20% 5-aminolevulinic acid hydrochloride, DUSA Pharmaceuticals, Wilmington, MA, USA) is approved for the treatment of actinic keratosis in US and ALA (20% 5-ALA hydrochloride, Fudan- Zhangjiang Bio-Pharma, Shanghai, China) for the treatment of external condyloma acuminatum in China.
• Metvix® (16% 5-MAL hydrochloride, PhotoCure ASA, Norway) is used for the treatment of actinic keratosis, superficial basal cell carcinoma and Bowen's disease.
• Hexvix® (5-HAL hydrochloride, PhotoCure ASA, Oslo, Norway) is a highly potent photosensitizer for the diagnoses of bladder cancer.
• 5-ALA and 5-MAL are also currently in multiple clinical trials and in off-label use for the treatment of moderate to severe acne vulgaris (Mavilia et al, Br J Dematol, 2007, 157:779-846).
• 5- ALA and its esters are effective to treat bacterial (Fotinos et al, Antimicrob Agents Chemother, 2008, 52:1366-1373) and fungal infections (Calzavara-Pinton et al,
• Photochem Photobiol, 2012, 88:512-522 inflammatory disorders (e.g. morphea, actinic cheiliti, acne) and infections associated with virus and cancers (e.g. viral warts).
• inflammatory disorders e.g. morphea, actinic cheiliti, acne
• infections associated with virus and cancers e.g. viral warts.
• US 8,692,014 describes that sulfonate salts of 5-ALA analogs exhibit reduced hydroscopicity and enhanced fluorescence production in cells in comparison with hydrochloride salts.
• US 8,173,839 describes that 5-ALA phosphate salt is less stimulating/irritating to tongue surface of the body than 5-ALA hydrochloride.
• Trichloroacetic acid is a small organic acid with a molecular weight greater than acetic acid and hydrochloric acid. It is a potent chemical cauterant and widely used as topical medication and in cosmetic treatment. The acid has proven ability to penetrate deeper layers of skin, coagulate epidermal protein, to destruct and remove damaged skin cells. TCA also exhibits anti-bacterial and anti-inflammatory activities, and further it can stimulate cell division in the basal skin layer to form new cells and uniformly distribute natural skin pigment melanin. Therapeutic outcomes of TCA are often dependent to the depth of its penetration, which is directly proportional to its concentrations applied.
• TCA low concentrations of TCA (10-20%) are used as superficial peels or epidermal peels, which penetrate and affect the depth of the epidermis and the interface of the dermis-epidermis. This concentration range is used to treat mild photoaging, melisma, comedonal acne and postinflammatory erythema.
• Medium-depth peels or dermal peels of TCA (20-50%), extending the penetration through the epidermis to the papillary dermis, are used for the treatment of moderate photoaging, actinic keratosis and mild acne scarring (Di et al, Photodermatol Photoimmunol
• TCA peeling and 5-ALA or 5-MAL PDT are widely used in dermatology and cosmetic care but often show different therapeutic profiles.
• comedonal acne/noninflammatory lesions respond well to TCA peels
• papulopustular acne/inflammatroty lesions show moderate improvement (Meguid et al, Dermatol Surg, 2015, 41 :1398-1404).
• 5-ALA PDT produces significant improvements in papulopustular acne/inflammatory lesions, but poor responses in comedonal/noninflammatory lesions. The different outcomes may be explained by their mechanism of actions.
• 5-ALA PDT selectively destructs the sebaceous unit (Wan et al, Clin Cosmed Investig Dermatol, 2014, 7:145-163).
• the mechanism of TCA in the treatment of acne vulgaris is believed to be due to its ability to diminish corneocyte cohesion and keratinocyte plugging. Therefore, a salt of TCA with 5-ALA or its esters may provide synergistic effects or dual activities in treating acne vulgaris and other diseases or disorders described herein.
• the present inventors have found that the salts of TCA with 5-ALA or its esters are less irritating/stimulating to the sensitive surface of the body when compared with the hydrochloride salts.
• the present inventors have also found that TCA salts of 5-MAL and 5-HAL are resistant to moisture and much less hygroscopic than corresponding hydrochloride salts.
• a salt has formula (I):
• R and X are defined as below.
• a method of preparing a salt of 5-ALA or derivatives thereof comprises: providing a solution of N-protecting group-5-aminolevulinic acid or derivative thereof; and adding a hydrogenation agent, H 2 , and X-COOH to provide the salt of 5-ALA or derivatives thereof.
• X is defined as below.
• a method of preparing a salt of 5-aminolevulinic acid or derivatives thereof comprises: passing 5-aminolevulinic acid or derivatives thereof through a resin; collecting the eluent; and mixing the eluent with X-COOH to provide the salt of 5-aminolevulinic acid or derivatives thereof.
• X is defined as below.
• the present disclosure relates to salts of 5-aminolevulinic acid (5-ALA) and its esters, in particular, to trichloroacetic acid salts.
• the acid selected to form new salts with 5-ALA and its esters as described in the present disclosure may provide a synergistic therapeutic effects or duel actions in PDT.
• the new salts in the present disclosure possess improved physicochemical properties such as reduced hydroscopicity, important features in manufacture and in quality control during storage, and lower skin irritation than their corresponding hydrochloride salts.
• halogen or halo means a chlorine, bromine, iodine, or fluorine atom.
• alkyl means a hydrocarbon group that may be linear, cyclic, or branched or a combination thereof having the number of carbon atoms designated (i.e., C 2 - 12 means two to twelve carbon atoms).
• alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl, cyclopropylmethyl, bicyclo[2.2.1 ]heptane, bicyclo[2.2.2]octane, etc.
• Alkyl groups can be substituted or unsubstituted, unless otherwise indicated. Examples of substituted alkyl groups include haloalkyl, thioalkyl, aminoalkyl, and the like.
• alkenyl means a hydrocarbon group that contains at least one carbon-to-carbon double bond.
• Alkenyl groups can include, e.g., allyl, 1 -butenyl, 2- hexenyl and 3-octenyl groups. Alkenyl groups can be substituted or unsubstituted, unless otherwise indicated.
• alkynyl means a hydrocarbon group that contains at least one carbon-to-carbon triple bond. Alkynyl groups can include, e.g., ethynyl, propargyl, and 3-hexynyl. Alkynyl groups can be substituted or unsubstituted, unless otherwise indicated.
• aryl means a polyunsaturated, aromatic hydrocarbon group having 5-10 atoms and forming a single ring (monocyclic, preferably with 6 atoms such as phenyl) or multiple rings (bicyclic (preferably with 10 atoms such as naphthyl) or polycyclic), which can be fused together or linked covalently.
• aryl groups include phenyl and naphthalene-1 -yl, naphthalene-2-yl, biphenyl and the like.
• Aryl groups can be substituted or unsubstituted, unless otherwise indicated.
• heteroaryl means an aromatic group containing 5-10 atoms and at least one heteroatom (such as S, N, O, Si), where the heteroaryl group may be monocyclic (with preferably 5 or 6 atoms) or bicyclic (with preferably 9 or 10 atoms).
• heteroaryl group may be monocyclic (with preferably 5 or 6 atoms) or bicyclic (with preferably 9 or 10 atoms). Examples include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl, purinyl,
• benzimidazolyl benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiazolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl or thienyl.
• cycloalkyl refers to saturated monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon groups. Any atom can be substituted, e.g., by one or more substituents. A ring carbon serves as the point of attachment of a cycloalkyl group to another moiety. Cycloalkyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Cycloalkyl moieties can include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl
• heterocyclyl or “heterocyclic”, which are synonymous as used herein, means a saturated or unsaturated non-aromatic ring containing at least 5-10 atoms (preferably 5 or 6) and at least one heteroatom (typically 1 to 5 heteroatoms) selected from nitrogen, oxygen or sulfur.
• the heterocyclyl ring may be monocyclic (with preferably 5 or 6 atoms) or bicyclic (with preferably 9 or 10 atoms).
• the ring system has 1 -4 heteroatoms if monocyclic, 1 -8 heteroatoms if bicyclic, or 1 -10 heteroatoms if tricyclic, the heteroatoms selected from O, N, or S (and mono and dioxides thereof, e.g., N ⁇ O " , S(O), SO2).
• the heterocyclyl groups can contain fused rings. Fused rings are rings that share a common carbon atom.
• heterocycle groups include pyrrolidine, piperidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1 ,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-dioxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine and the like.
• ring means a compound whose atoms are arranged in formulas in a cyclic form.
• the ring compound can be either carbocyclic or heterocyclic.
• substituted refers to a group “substituted” on, e.g., an alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, heteroaryl, arylcycloalkyl, heteroarylcycloalkyl, arylcycloalkenyl, heteroarylcycloalkenyl, arylheterocyclyl, heteroarylheterocyclyl, arylheterocycloalkenyl, or heteroarylheterocycloalkenyl group at any atom of that group.
• the substituent(s) on a group are independently any one single, or any combination of two or more of the permissible atoms or groups of atoms delineated for that substituent.
• a substituent may itself be substituted with any one of the above substituents.
• substituent (radical) prefix names are derived from the parent hydride by either (i) replacing the "ane” in the parent hydride with the suffixes "yl,” “diyl,” “triyl,” “tetrayl,” etc.; or (ii) replacing the "e” in the parent hydride with the suffixes "yl,” “diyl,” “triyl,” “tetrayl,” etc. (here the atom(s) with the free valence, when specified, is (are) given numbers as low as is consistent with any established numbering of the parent hydride).
• Accepted contracted names e.g., adamantyl, naphthyl, anthryl, phenanthryl, furyl, pyridyl, isoquinolyl, quinolyl, and piperidyl, and trivial names, e.g., vinyl, allyl, phenyl, and thienyl are also used herein throughout.
• Conventional numbering/lettering systems are also adhered to for substituent numbering and the nomenclature of fused, bicyclic, tricyclic, polycyclic rings.
• embodiments include both substituted and unsubstituted forms of the indicated groups. These groups may be substituted multiple times, as chemically allowed.
• composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
• pharmaceutically-acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• compositions for the administration of the salts of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
• the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
• the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
• compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self emulsifications, hard or soft capsules, or syrups or elixirs.
• Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of
• compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
• Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
• excipients may be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
• the tablets may be uncoated or they may be coated enterically or otherwise by known techniques to delay disintegration and absorption in the
• a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
• Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
• an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
• water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
• emulsions can be prepared with a non-water miscible ingredient such as oils and stabilized with surfactants such as mono-diglycerides, PEG esters and the like.
• Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
• excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose,
• dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate.
• phosphatide for example lecithin
• condensation products of an alkylene oxide with fatty acids for example polyoxyethylene stearate
• condensation products of ethylene oxide with long chain aliphatic alcohols for example heptadecaethyleneoxycetanol
• condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol
• the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
• preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
• coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
• coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
• flavoring agents for example ethyl, or n-propyl, p-hydroxybenzoate
• sweetening agents such as sucrose or saccharin.
• Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
• a dispersing or wetting agent exemplified by those already mentioned above.
• Additional excipients for example sweetening, flavoring and coloring agents, may also be present.
• the pharmaceutical compositions of the disclosure may also be in the form of oil in water emulsions.
• the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
• Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
• the emulsions may also contain sweetening and flavoring agents.
• the salts of the present disclosure may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable nonirritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. Additionally, the salts can be administered via ocular delivery by means of solutions or ointments. Still further, transdermal delivery of the subject salts can be accomplished by means of iontophoretic patches and the like. [0037] For topical use, creams, ointments, jellies, solutions or suspensions containing the disclosed salts are employed. As used herein, topical application is also meant to include the use of mouth washes and gargles.
• compositions and methods of the present disclosure may further comprise other therapeutically active compounds as noted herein, such as those applied in the treatment of the above mentioned pathological conditions.
• “Pharmaceutically acceptable” carrier, diluent, or excipient is a carrier, diluent, or excipient compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• “Therapeutically effective amount” refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
• Treating or “treatment” as used herein refers to the treating or treatment of a disease or medical condition (such as a cancer) in a patient, such as a mammal
• ameliorating the disease or medical condition i.e., eliminating or causing regression of the disease or medical condition in a patient
• suppressing the disease or medical condition i.e., slowing or arresting the development of the disease or medical condition in a patient;
• Certain salts of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, both solvated forms and
• Certain salts of the present disclosure may exist in multiple crystalline or amorphous forms (i.e., as polymorphs). In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present invention.
• the salts of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such salts.
• the salts may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 l) or carbon-14( 14 C). All isotopic variations of the salts of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
• a salt of formula (I) can be administered alone or in combination with one or more other therapeutic agents, possible combination therapy taking the form of fixed combinations or administration of a compound of the invention and one or more other therapeutic agents being staggered or given independently of one another.
• R is selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted Ce-12 aryl, unsubstituted or substituted 3-12 membered heterocyclic, and unsubstituted or substituted 5-12 membered heteroaryl.
• X is selected from hydrogen, -CY 1 R 1 R 2 , -CY 1 Y 2 R 1 , and -CY 1 Y 2 Y 3 .
• Y 1 , Y 2 , and Y 3 are independently selected from F, CI, Br, and I.
• R 1 and R 2 are independently selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted Ce-12 aryl, unsubstituted or substituted 3-12 membered heterocyclic, and unsubstituted or substituted 5-12 membered heteroaryl.
• R 1 and R 2 may combine with an atom or atoms to which it is attached to form unsubstituted or substituted C 3 -i 2 cycloalkyl, unsubstituted or substituted 3- to 12- membered heterocyclic, unsubstituted or substituted Ce-12 aryl, or unsubstituted or substituted 5- to 12- membered heteroaryl.
• R is hydrogen
• R is substituted or unsubstituted Ci- 2 oalkyl. In some embodiments, R is unsubstituted d-salkyl. In some embodiments, R is selected from the group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, sec-propyl, sec-butyl, tert-butyl, sec-pentyl, and sec-hexyl. In some embodiments, R is methyl. In some embodiments, R is hexyl. In some embodiments, R is benzyl. In some embodiments, R is methylbenzyl.
• R is alkyl substituted with at least one selected from the group consisting of hydroxyl, thiol, carboxyl, carbamoyl, ester, amino, alky-amino, amide, halogen, nitro and cyano group.
• R is unsubstituted or substituted carbocyclic. In some embodiments, R is unsubstituted or substituted C 3 - 6 carbocyclic. In some embodiments, R is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
• R is unsubstituted or substituted C 6 -12 aryl. In some embodiments, R is unsubstituted or substituted benzyl. In some embodiments, R is selected from the group consisting of benzyl, 2- methyl benzyl, 4- methyl benzyl, 4- chloro-benzyl, 4- chloro-benzyl, 2- nitro-benzyl, 4- nitro-benzyl, 2- isopropyl benzyl, 4- isopropyl benzyl, 4- fluoro-benzyl, and 4- fluoro-benzyl.
• R is selected from the group consist of hydrogen, methyl, ethyl, propyl, butyl, pentyl, hexyl, sec-propyl, sec-butyl, tert-butyl, sec-pentyl, sec-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, 2- methyl benzyl, 4- methyl benzyl, 4- chloro-benzyl, 4- chloro-benzyl, 2- nitro-benzyl, 4- nitro-benzyl, 2- isopropyl benzyl, 4- isopropyl benzyl, 4- isopropyl benzyl, 4- fluoro-benzyl, and 4- fluoro-benzyl.
• X is -CY 1 H 2 .
• Y 1 is CI or F.
• Y 1 is CI.
• X is -CY 1 Y 2 H.
• Y 1 and Y 2 are independently selected from CI and F.
• Y 1 and Y 2 are CI.
• X is - CY 1 Y 2 Y 3 .
• Y 1 , Y 2 and Y 3 are independently selected from CI and F.
• Y 1 , Y 2 and Y 3 are CI.
• X is selected from the group consisting of -CH 2 CI, - CHCI 2 and -CCI3. In some embodiments, X is -CCI3. In some embodiments, X is - CH 2 CI.
• X-COOH is selected from the group consisting of 2- chloroacetic acid and 2,2,2-trichloroacetic acid.
• the salt is selected from the group consisting of 5- aminolevulinic acid 2,2,2-trichloroacetate, methyl 5-aminolevulinate 2,2,2- trichloroacetate, hexyl 5-aminolevulinate 2,2,2-trichloroacetate, benzyl 5- aminolevulinate 2,2,2-trichloroacetate, 2- or 4-methylbenzyl 5-aminolevulinate 2,2,2- trichloroacetate.
• Preferred salts include 5-aminolevulinic acid 2-monochloroacetate, 5- aminolevulinic acid 2.2-dichloroacetate, 5-aminolevulinic acid 2,2,2-trichloroacetate, methyl 5-aminolevulinate 2-monochloroacetate, methyl 5-aminolevulinate 2,2- dichloroacetate, methyl 5-aminolevulinate 2,2,2-trichloroacetate, ethyl 5-aminolevulinate 2-monochloroacetate, ethyl 5-aminolevulinate 2,2-dichloroacetate, ethyl 5- aminolevulinate 2,2,2-trichloroacetate, propyl 5-aminolevulinate 2-monochloroacetate, propyl 5-aminolevulinate 2,2-dichloroacetate, propyl 5-aminolevulinate 2,2,2- trichloroacetate, butyl 5-aminolevulinate 2-monochloroacetate, butyl 5-amin
• ester analogs of 5-ALA described in US patent publication 2015/0191419 can also react with organic acids described in the current disclosure (in particular trichloroacetic acid) to form the salts in the present disclosure.
• organic acids described in the current disclosure in particular trichloroacetic acid
• New salts from the present disclosure can be taken up by cells and converted to endogenous porphyrins with photosensitizing activities, indicating that they are useful therapeutic agents for PDT. These salts can be used either as raw materials or preferably, as pharmaceutical compositions.
• the present disclosure provides a pharmaceutical composition comprising a compound from the disclosure and at least one pharmaceutically or cosmetically acceptable excipient or carrier and optionally one or more therapeutic ingredients.
• a composition comprises the salt of formula (I) and at least one of a pharmaceutically acceptable carrier and a cosmetically acceptable carrier.
• the composition further comprises hydroxylethyl cellulose gel.
• the composition comprises the salt of formula (I) and the salt is from about 0.01 % to about 95% by weight.
• the salt is from about 0.1 % to about 50% by weight.
• the salt is about 0.1 % to about 20% by weight.
• a composition comprises the salt of formula (I) and hydroxylethyl cellulose gel.
• the hydroxylethyl cellulose gel has a molecular weight from about 250k to about 725k. In some embodiments, the
• composition comprises the salt of formula (I) and the salt is from about 0.01 % to about 95% by weight. In some embodiments, the salt is from about 0.1 % to about 50% by weight. In some embodiments, the salt is about 0.1 % to about 20% by weight.
• a composition comprises the salt of formula (I) and a cream, such as Unguentum Merck cream (Almirall Hermal) or Cetaphil @ (Galderma).
• the composition comprises the salt of formula (I) and the salt is from about 0.01 % to about 99% by weight.
• the salt is from about 0.1 % to about 50% by weight.
• the salt is about 0.1 % to about 20% by weight.
• the composition comprises the salt of formula (I) as a first photosensitizing agent, and a second photosensitizing agent.
• the second photosensitizing agent can be any suitable agent.
• the second photosensitizing agent can be any suitable agent.
• the second photosensitizing agent can be any suitable agent.
• photosensitizing agent is selected from the group consisting of indium-bound
• pyropheophorbides pyrrole-derived macrocyclic compounds, porphyrins, chlorins, phthalocyanines, indium chloride methyl pyropheophorbide, naphthalocyanines, porphycenes, porphycyanines, pentaphyrins, sapphyrins, benzochlorins, chlorophylls, azaporphyrins, purpurins, anthracenediones, anthrapyrazoles, aminoanthraquinone, phenoxazine dyes, photofirn, hypocrellins, and derivatives thereof.
• excipients or carriers in the composition herein described include an aqueous or oil base, thickening or gelling agents, hydrogels, emulsifying, nanoemulsifying, dispersing, solubilizing, stabilizing, suspending, and dispersing agents, coloring agents or propellant.
• the technique to produce formulations described herein is known in the art and a person skilled in the art will be able to select proper excipients for pharmaceutical or cosmetic compositions of present disclosure.
• compositions may be formulated as tablets, capsules, suspensions and solutions containing an active component from present disclosure and one or more carriers and/or diluents, including water, ethanol, glycerol, sorbitol, corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, propyleneglycol, stearylalcohol, propyleneglycol, stearylalcohol, polyethyleneglycol, carboxymethylcellulose or fatty substances, saline and buffer solutions.
• carriers and/or diluents including water, ethanol, glycerol, sorbitol, corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, propyleneglycol, stearylalcohol, propyleneglycol, stearylalcohol,
• the topical formulations can assume any of a variety of dosage forms, including solutions, suspensions, ointments, and solid inserts, hydrogel suppositories. Examples are creams, lotions, gels, ointments, suppositories, sprays, foams, liniments, aerosols, buccal and sublingual tablets, various passive and active topical devices for absorption through the skin and mucous membranes, including transdermal
• Typical pharmaceutically acceptable carriers for topical formulations are, for example, water, mixtures of water and water-miscible solvents such as lower alkanols or vegetable oils, and water-soluble pharmaceutically acceptable non-toxic polymers, for example, alginate, cellulose derivatives such as methylcellulose.
• a typical cream or ointment-type carrier for topical application that can be used according to the methods and compositions described herein include a mixture of water, glycerin, propylene glycol, and methylparaben.
• Topical carriers may also include other conventional emulsifiers and emollients including alginates, glyceryl stearate, PEG-100 stearate, cetyl alcohol, propylparaben, butylparaben, sorbitols, polyethoxylated anhydrosorbitol monostearate (TWEEN), white petrolatum (VASELINE), triethanolamine, Emu oil, aloe vera extract, lanolin, cocoa butter, and the like. Suitable topical carriers are well known to the skilled artisan.
• Unguentum Merck (Almirall Hermal) or Cetaphil @ (Galderma) is admixed in the compositions described herein.
• the Unguentum Merck base or Cetaphil @ will make up more than about 70% of the total composition and more preferably about 80% of the composition is the cream.
• Alternative ointment bases are known to persons skilled in the art such as Lipoderm® (PCCA).
• a formulation comprises the salt of formula (I) and a cream, such as Unguentum Merck cream (Almirall Hermal) or Cetaphil @ (Galderma).
• the formulation comprises the salt of formula (I) and the salt is from about 0.01 % to about 99% by weight.
• the salt is from about 0.1 % to about 50% by weight.
• the salt is about 0.1 % to about 20% by weight.
• a typical transdermal formulation comprises a conventional aqueous or nonaqueous vehicle, for example, a cream, ointment lotion or paste or in the form of a medicated plaster, patch or membrane.
• transdermal delivery also includes numerous different systems for the transdermal delivery of active agents known in the art.
• Transdermal delivery systems include but are not limited to passive devices such as drug-in-adhesive transdermal patches and "active" transdermal technologies such as iontophoresis, electroporation, sonophoresis, magnetophoresis, microneedle devices, needle free injection and those devices that use thermal energy to make the skin more permeable.
• the salts and compositions according to present disclosure may be formulated or administered with other photosensitizing agents (e.g. Photofrin, hypocrellins or the like) to enhance treatment efficacies.
• photosensitizing agents e.g. Photofrin, hypocrellins or the like
• Other agents may also be used to increase the accumulation and absorption of PplX, including any chelating agents published in the literature (such as EDTA, CDTA and the like) to chelate ferrous ions blocking the conversion of PplX to heme; and any surface-penetration assisting agents described in the literatures (such as DMSO, surfactants or non-surfactants, fatty acids, and bile salts) may be applicable to enhance absorption of salts from the present disclosure.
• the surface penetration agent may be used in a concentration range of about 0.2 to about 50% (weight/volume), e.g. about 5%.
• the chelating agent may be provided at a concentration of about 0.05 to about 20% (weight/volume), e.g. about 0.1 to about 5%.
• compositions described herein can further comprise non-physiologically active ingredients or components usually admixed in such topical preparations.
• the compositions may also include additional ingredients such as other carriers, moisturizers, oils, fats, waxes, surfactants, thickening agents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, perfumes, dyestuffs, lower alkanols, humectants, emollients, dispersants, antibacterials, antifungals, disinfectants, vitamins, antibiotics, or other anti-acne agents, as well as other suitable materials that do not have a significant adverse effect on the activity of the topical composition.
• Additional inactive ingredients for inclusion in the carrier may be sodium acid phosphate moisturizer, witch hazel extract carrier, glycerin humectant, apricot kernel oil emollient, corn oil dispersant, and the like which are further detailed below.
• additional inactive ingredients which can be admixed in the compositions described herein.
• a kit for photodynamic therapy or diagnosis comprises a first container comprising a pharmaceutically or cosmetically effective amount of salt of formula (I) or composition thereof, and a second container comprising a dissolution medium.
• the second container can further comprise at least one of a carrier, a chelating agent including EDTA, CDTA and a surface penetration agent such as DMSO, surfactants or non-surfactants, fatty acids or bile salts.
• Surface penetration agents can be included in some embodiments to optimize transfer of the salt of formula (I) through the stratum corneum and into the
• penetration enhancers in topical formulations see generally, Percutaneous Penetration Enhancers (Eric W. Smith & Howard I. Maibach eds. 1995); Ghosh, T. K. et al. 17 Pharm. Tech. 72 (1993); Ghosh, T. K. et al. 17 Pharm. Tech. 62 (1993); Ghosh, T. K. et al. 17 Pharm. Tech. 68 (1993), all of which citations are hereby incorporated herein by reference.
• the penetration agents should be pharmacologically inert, non-toxic, and non-allergenic, have rapid and reversible onset of action, and be compatible with the compositions of the invention.
• penetration agents include, but are not limited to ethyl alcohol, isopropyl alcohol, lauryl alcohol, salicylic acid, octolyphenylpolyethylene glycol, polyethylene glycol 400, propylene glycol, N-decylmethylsulfoxide, DMSO and the azacyclo compounds, as disclosed in US 4,755,535; US 4,801 ,586; US 4,808,414; and 4,920,101 , all of which patents are hereby expressly incorporated herein by reference.
• the dissolution medium is an aqueous or non-aqueous medium.
• the dissolution medium is sodium chloride solution.
• the aqueous solution is about 0.9% sodium chloride solution.
• the aqueous solution is a buffer solution.
• the aqueous solution is phosphate-buffered saline.
• the salt of formula (I) is a first photosensitizing agent
• the second container comprises a second photosensitizing agent.
• the second photosensitizing agent can be any suitable agent.
• the second photosensitizing agent is selected from the group consisting of indium-bound
• pyropheophorbides pyrrole-derived macrocyclic compounds, porphyrins, chlorins, phthalocyanines, indium chloride methyl pyropheophorbide, naphthalocyanines, porphycenes, porphycyanines, pentaphyrins, sapphyrins, benzochlorins, chlorophylls, azaporphyrins, purpurins, anthracenediones, anthrapyrazoles, aminoanthraquinone, phenoxazine dyes, photofirn, hypocrellins, and derivatives thereof.
• the present disclosure provides a method of administering the new salts of formula (I) or compositions of formular (I) extracellularly, intracellular photosensitizer porphyrins (in particular PplX) at the treated site are produced via the porphyrin biosynthesis pathway. Subsequent light activation of porphyrins at the treated site can induce cytotoxicity.
• the salts and their pharmaceutical compositions from the present disclosure can be used in PDT treating diseases or disorders of internal and external surfaces of the body.
• the internal and external surface of the body described herein include skin, all epithelial and mucosa surfaces, such as skin and conjunctiva, lining of the nasal passages, nasal sinuses, trachea, bronchi, lining of the mouth, pharynx, oesophagus, stomach, intestines, rectum, and anal canal; lining of the ureters, urinary bladder, and urethra; and lining of the vagina, uterine cervix, and uterus.
• the new salts from the present disclosure possess a number of advantages over their corresponding hydrochloride salts that are currently used in the clinic.
• the salts from the present disclosure are less hygroscopic than hydrochloride salts of 5-ALA or its esters, an important parameter to reduce
• the salts from the present disclosure are less irritating to the skin. When administrations to sensitive surfaces such as urethra, rectal, vagina and uterine cervix, reduced skin irritating is desirable especially when multiple treatments are needed.
• the activity of salts of the present disclosure is similar to that of corresponding hydrochloride salts.
• acids in the new salts from the present disclosure such as TCA may provide duel activity and/or enhance skin penetration of 5-ALA or its esters in PDT.
• a method of photodynamic therapy to treat a target area in a subject comprises: administering an effective amount of the salt of formula (I) or the composition comprising salt of formula (I) to the target area; waiting for a time period for adequate absorption and conversion of the salt of formula (I) or the composition comprising salt of formula (I) to PplX; exposing the target area to a light with an amount and a wavelength effective to induce cytotoxicity; thereby administering photodynamic therapy to the target tissue in the subject.
• the wavelength is from about 400 to about 1000 nm. In some embodiments, the wavelength is from about 380 to about 440 nm. In some embodiments, the wavelength from about 620 to about 750 nm.
• the target tissue is skin
• the method is used to treat a dermatological disorder.
• the target tissue is skin
• the method is used for cosmetic treatment of skin conditions.
• the skin conditions comprise diffuse or mottled pigmentation, rosacea, sebaceous hyperplasia, photoaging, rough sun damaged skin, wrinkles, enlarged pores and skin texture, acne, acne scar, tactile roughness, sallowness and dull skin.
• the method is used for skin rejuvenation.
• the method is used to treat cancers, basal cell carcinoma, cervical intraepithelial neoplasia, actinic keratosis, Bowen's disease, vulvar Paget's disease, acne, acne vulgaris, psoriasis, nevus flammeus, lupus erythematosus , condyloma acuminata, refractory palmoplantar wart, cutaneous T cell lymphoma, bacterial infections, fungal infections, inflammation disorders and virus infections.
• the method is used to promote hair growth, tissue repair and wound healing.
• the cancers comprise bladder cancer, colorectal cancer, lung cancer, brain cancer, stomach cancer, uterine cancer, skin cancer, and oral cancers, rectal cancers and cholangiocarcinoma.
• formula (I) or composition thereof is by an oral route, organ Instillation, parenteral injection, needle free injection or by a topical route.
• the light sources may be lamps (e. g. fluorescent lamps), lasers, light emitting diodes (LED) or filtered intense pulse lights.
• Optical fibers may be used to reach inaccessible regions.
• the light wavelength may be in the range of about 300 to about 1200 nm, and preferably, about 380 to about 800 nm.
• the dose level of irritation would be about 5 to about 200 J/cm 2 , and preferably, about 10 to about 120 J/cm 2 .
• Daylight may also be applied as an alternative light source (Rubel et al, Br J Dermatol, 2014, 171 , 1 164-1 171 ).
• the time interval (incubation time) between drug application and exposure to light may be about 0.1 to about 24 hours, and preferably, from about 0.3 to about 4 hours.
• a red light e.g. 600-750 nm
• a blue light e.g. 380-440 nm
• the concentration of the salt in the composition may be about 0.01 to about 95% (w/w or w/v), and preferably, about 0.1 to about 50% (w/w), about 0.1 to about 30%, or about 0.1 to about 20%.
• the effective dose may be determined according to factors such as age, weight, lesion area, and conditions of diseases, or different purposes (e.g. cosmetic, treatment or diagnosis). In general, the effective dosage would be in the range of about 0.001 to about 3 g/day, and preferably, in the range of about 0.01 to about 2g/ day.
• the exemplary salts for treatment are 5-aminolevulinic acid 2- monochloroacetate, 5-aminolevulinic acid 2.2-dichloroacetate, 5-aminolevulinic acid 2,2,2-trichloroacetate, methyl 5-aminolevulinate 2-monochloroacetate, methyl 5- aminolevulinate 2,2-dichloroacetate, methyl 5-aminolevulinate 2,2,2-trichloroacetate, ethyl 5-aminolevulinate 2-monochloroacetate, ethyl 5-aminolevulinate 2,2- dichloroacetate, ethyl 5-aminolevulinate 2,2,2-trichloroacetate, propyl 5-aminolevulinate 2-monochloroacetate, propyl 5-aminolevulinate 2,2-dichloroacetate, propyl 5- aminolevulinate 2,2,2-trichloroacetate, butyl 5-aminolevulinate 2-monochloroacetate, butyl 5-
• the salt or its composition from present disclosure can be used for an in vivo cancer tissue detection assisting surgeons to resect tumor tissue more effectively, or for an in vitro diagnoses of diseases or disorders by examining body fluid or tissue.
• a method of in vivo diagnosis comprises: administering the salt of formula (I) or composition thereof to a subject; waiting for a time period (e. g. 1 -4 hours) allowing adequate absorption and conversion of said agents to
• the photosensitizers exposing the target area to a light having a wavelength of about 380 to about 440 nm; and detecting areas with enhanced fluorescence levels.
• the fluorescence levels are fluorescence spectra.
• the fluorescence levels are fluorescence images.
• a method of in vitro diagnosis of diseases in a subject comprises: providing a sample from a subject, incubating the salt of formula (I) or the composition thereof with the sample to provide a mixture; exposing the mixture to a light having a wavelength of about 380 to about 440 nm; and comparing the fluorescence level with control references.
• the sample is body fluid or a tissue.
• the sample is selected from the group consisting of blood, urine, semen, stool, tears, sputum, spinal fluid, bone marrow, and biopsy tissues.
• the present disclosure provides a process for preparing the salts of present disclosure comprising reacting 5-ALA or its esters with an acid (e.g. trichloroacetic acid).
• an acid e.g. trichloroacetic acid
• a base can be used to neutralize before adding the acid described in present disclosure.
• a hydrochloride salt of 5-ALA or its esters is treated with a base, followed by reacting with an acid from present disclosure to yield the desired salt as described in Example 1 .
• Another process to yield the desired salts from present disclosure was to remove N-protecting group of 5-ALA or its ester derivatives in the presence of an acid from present disclosure (e.g. trichloroacetic acid).
• the starting material may have an N- Boc (N-tert-butyloxycarbonyl) or an N-Cbz (N-carboxybenzyl) protecting group.
• reaction can be carried out in one-pot to remove protecting group, followed by formation of the desired salt as described in Example 3 and Example 4.
• the starting materials in this aspect were 5-N-Boc-aminolevulinic acid, N-Bn or 5-N-Cbz-aminolevulinic acid, or their corresponding ester derivatives (e.g.
• a method of preparing a salt of 5-aminolevulinic acid or derivatives thereof comprises: providing a solution of N-protecting group-5- aminolevulinic acid or derivative thereof; and adding a hydrogenation agent, H 2 , and X- COOH to provide the salt of 5-aminolevulinic acid or derivatives thereof.
• X is selected from hydrogen, -CY 1 R 1 R 2 , -CY 1 Y 2 R 1 , and -CY 1 Y 2 Y 3 .
• Y 1 , Y 2 , and Y 3 are independently selected from F, CI, Br, and I.
• R 1 and R 2 are independently selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted carbocyclic, unsubstituted or substituted C 6 -12 aryl, unsubstituted or substituted 3-12 membered heterocyclic, and unsubstituted or substituted 5-12 membered heteroaryl.
• R 1 and R 2 may combine with an atom or atoms to which it is attached to form unsubstituted or substituted C 3 -i 2 cycloalkyl, unsubstituted or substituted 3- to 12- membered heterocyclic, unsubstituted or substituted C 6 -12 aryl, or unsubstituted or substituted 5- to 12- membered heteroaryl.
• the protecting group is carboxybenzyl.
• the hydrogenation agent is palladium on carbon.
• Additional process provided by present disclosure is ion exchange technique, a standard method to form salts well known in the art.
• Either acidic ion exchange resins or basic ion exchange resins may be used, and preferably, basic ion exchange resins such as Amberlyst A26(OH).
• basic ion exchange resins such as Amberlyst A26(OH).
• starting materials are in salt forms such as a hydrochloride salt (e.g. 5-ALA methyl ester hydrochloride)
• the CI " can be exchanged for a basic ion such as OH " and the resulting eluent can be mixed with an acid from present disclosure to produce the target salt.
• the ion exchange process involves eluting the 5-ALA salt solution through a column packed with a strong basic ion exchange resin Amberlyst A26(OH) to remove CI " and sequentially mixing the eluent with an acid from the present disclosure.
• a strong basic ion exchange resin Amberlyst A26(OH) Amberlyst A26(OH)
• this can also be achieved by stirring a solution of 5-ALA ester hydrochloride in the presence of a basic ion exchange resin, [e.g. Amberlyst A26(OH)]. After removal of the resin, an acid from present disclosure is added to the filtrate.
• Amberlyst A26(OH) Amberlyst A26(OH)
• Reactions from present disclosure can be carried out in one solvent or a mixture of solvents such as acetone, methanol, ethanol, propanol, isopropanol, butanol,
• the new salts from present disclosure can be purified by crystallization or triturating using a solvent or a mixture of solvents mentioned above.
• the reaction temperature may be from about -15 to about 100°C and optimal conditions are chosen according to solvents used and reactions.
• a method of preparing a salt of 5-aminolevulinic acid or derivatives thereof comprises: passing 5-aminolevulinic acid or derivatives thereof through a resin; collecting the eluent; and mixing the eluent with X-COOH to provide the salt of 5-aminolevulinic acid or derivatives thereof.
• X is selected from hydrogen, - CY 1 R 1 R 2 , -CY 1 Y 2 R 1 , and -CY 1 Y 2 Y 3 .
• Y 1 , Y 2 , and Y 3 are independently selected from F, CI, Br, and I.
• R 1 and R 2 are independently selected from the group consisting of hydrogen, unsubstituted or substituted alkyl, unsubstituted or substituted alkenyl, unsubstituted or substituted alkynyl, unsubstituted or substituted carbocyclic,
• R 1 and R 2 may combine with an atom or atoms to which it is attached to form unsubstituted or substituted C3-12 cycloalkyl, unsubstituted or substituted 3- to 12- membered heterocyclic, unsubstituted or substituted C6-12 aryl, or unsubstituted or substituted 5- to 12- membered heteroaryl.
• the resin is a basic ion exchange resin.
• Example 1 Methyl 5-aminolevulinate 2,2,2-trichloroacetate (5-MAL TCA).
• Hexyl 5-aminolevulinate hydrochloride (2.5 g, 10 mmol) was dissolved in 50% aqueous ethanol (10 mL) and this solution was passed through a column packaged with Amberlyst 26(OH) (5 g) into a solution of trichloroacetic acid (1 .6 g, 10 mmol) in ethanol (5 mL). The column was washed with 50% aqueous ethanol (20 mL) and combined eluents were evaporated to dryness to give 5-HAL TCA as a white solid (2.1 g, 56%).
• the following salts of the present disclosure can be prepared by using the general methods described in Example 1 to Example 4: 5-aminolevulinic acid 2- monochloroacetate, 5-aminolevulinic acid 2,2-dichloroacetate 5-aminolevulinic acid 2,2,2-trichloroacetate, methyl 5-aminolevulinate 2-monochloroacetate, methyl 5- aminolevulinate 2,2-dichloroacetate, methyl 5-aminolevulinate 2,2,2-trichloroacetate, ethyl 5-aminolevulinate 2-monochloroacetate, ethyl 5-aminolevulinate 2,2- dichloroacetate, ethyl 5-aminolevulinate 2,2,2-trichloroacetate, propyl 5-aminolevulinate 2-monochloroacetate, propyl 5-aminolevulinate 2,2-dichloroacetate, propyl 5- aminolevulinate 2,2,2-trichloroacetate, butyl 5-aminolev
• Table 1 Measurement of irritation/stimulation on tongue surface.
• A no irritation
• B irritation
• C strong irritation
• D very strong irritation
• Test samples were dissolved with sterile saline to a concentration of 100 imM as stock solution.
• the stock solution was diluted to desired concentrations with culture medium or phosphate buffered solution (PBS).
• PBS phosphate buffered solution
• A549 cells (ATCC), derived from human lung carcinoma, were grown in F12 medium (Gibco) containing 4.5 g/L glucose, 10% FCS, and penicillin/streptomycin, at 37°C and 6% CO 2 in a humid environment. For measurement purposes, the cells were sub-cultured in 48-well or 96-well dishes to give 5 X 10 4 cells/well 24 hours prior to incubation with test salts. The cells were washed twice with PBS and test solutions were added to the culture.
• F12 medium Gibco
• Example 8 Solution Formulation 1 .
• 5-HAL TCA 250 mg was dissolved in 0.9% of sodium chloride aqueous solution (5 mL) to form a solution of 5% 5-HAL TCA.
• Similar solution formulations may be prepared using buffers (such as PBS) for different treatment purposes.
• 5-HAL TCA 250 mg was dissolved in 0.9% of sodium chloride aqueous solution (5 mL) containing tricloroacetic acid (100 mg) to form a solution of 5% 5-ALA hexyl ester TCA containing 2% trichloroacetic acid.
• Example 1 1 . Gel Formulation 2.
• Example 12 Cream Formulation 1 .
• Example 13 Cream Formulation 2.
• 5-MAL TCA (1 .5 g) was mixed thoroughly with Cetaphir (8.2 g) and TCA (0.3 g) to yield a pale to light yellow cream of 150 mg/g 5-MAL TCA, containing 3% TCA.
• Example 14 Cream Formulation 3.
• 5-MAL TCA (1 g) was mixed thoroughly with Cetaphil @ (9 g), which contains 1 % DMAO, to yield a pale to light yellow cream of 0.1 g/g 5-MAL TCA containing 1 % DMSO.
• 5-ALA 5-aminoalevulinic acid
• EDTA ethylenediaminetetraacetic acid
• CDTA trans-1 ,2-Cyclohexanediaminetetraacetic acid
• 5-HAL hexyl 5-aminolevulinate or 5-hexaminolevulinate
• 5-MAL methyl 5-aminolevulinate or 5-methylaminolevulinate
• PBS phosphate buffered saline

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Organic Chemistry (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Dermatology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Biochemistry (AREA)
• Molecular Biology (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Birds (AREA)
• Gerontology & Geriatric Medicine (AREA)
• Toxicology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
• Nitrogen Condensed Heterocyclic Rings (AREA)
• Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
• Medicinal Preparation (AREA)
• Cosmetics (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Investigating Or Analysing Biological Materials (AREA)
• Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Priority Applications (3)

Applications Claiming Priority (4)

Publications (2)

Family

ID=57493289

Family Applications (1)

Country Status (6)

Cited By (1)

Families Citing this family (8)

Family Cites Families (28)

• 2016
  • 2016-07-20 CN CN202010877014.7A patent/CN112010772A/zh active Pending
  • 2016-07-20 CN CN201610568868.0A patent/CN106187793A/zh active Pending
• 2017
  • 2017-01-24 JP JP2018538746A patent/JP6832358B2/ja active Active
  • 2017-01-24 WO PCT/US2017/014791 patent/WO2017132178A2/en not_active Ceased
  • 2017-01-24 US US16/071,485 patent/US10653653B2/en active Active
  • 2017-01-24 EP EP17744788.5A patent/EP3408254B1/en active Active
  • 2017-01-25 TW TW106102897A patent/TWI736577B/zh active

Also Published As

Similar Documents

Legal Events