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
  • A61K31/12—Ketones
  • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• • 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
  • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
• • 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
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
  • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• • 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
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• the present invention relates to the field of novel formulations for oral administration.
• the present invention relates to novel oral photosensitizer formulations for anticancer, antimetastatic, antibacterial, antifungal, antiprotozoic, antiviral, antiprionic and PDT treatments.
• photosensitizers may produce different damaging effects. Some photosensitizers induce cell self-destruction due to their ability to generate active proteases, such as caspase while other photosensitizers are likely to induce apoptosis because they localize or are produced in mitochondria. Hydrophobic photosensitizers present an increased affinity to neoplasic tissues. Aggregates as well as hydrophilic photosensitizers are likely to be taken up by pinocytosis and/or endocytosis and are localized in lysosomes and endosomes. When activated, vesicles become permeable and photosensitizers and hydrolytic enzymes are released into the cytosol.
• Sensitizing dyes in the cytosol can damage tubulin leading to accumulation of cells in mitosis followed by cell death.
• many applications depending on the photosensitizers' sub-cellular targets may be developed.
• most photosensitizers are usually formulated to be delivered by invasive routes such as intravenous or subcutaneous injections, the development of effective photosensitizer formulations for oral administration would be highly advantageous. This can be achieved by increasing the oral absorption of the photosensitizer through the use of formulations that protect the macromolecule and/or enhance its uptake through the gastrointestinal tract.
• Enteric route has all the advantages of a non-invasive procedure.
• it may present some uptake difficulties associated with the size, solubility and stability of the active substance to be delivered such as poor absorption of macromolecules, gastrointestinal destruction of labile molecules and impediment to go through gastrointestinal biological barriers.
• the absorption of bioactive agents in an unaltered form and avoidance of massive spleen or liver accumulation should be guaranteed. This can be done by incorporation of the active substance into oral drug delivery systems or novel designed drug formulations.
• Present invention fulfills the needs of prior art formulations providing enhanced bioavailability and stable photosensitizer formulations for oral administration easy to manufacture and handle. Moreover, the present invention provides photosensitizer formulations for oral administration to improve effectiveness of anticancer, antimetastatic, antibacterial, antifungal, antiprotozoic, antiviral, antiprionic and PDT treatments for a wide variety of applications.
• the present invention provides novel drug formulations for oral administration to treat diverse medical applications including anticancer, antimetastatic, antibacterial, antifungal, antiprotozoic, antiviral, antiprionic and PDT treatments for diagnostic and therapeutic purposes.
• the oral drug formulation comprises a photosensitizer and suitable excipients and may be administered in multiple doses over an extended period of time with exposure to activating radiation occurring generally between individual doses or in a light-independent manner.
• PDT methods for treating hyperplasia and neoplasia for localizing hyperplasic and neoplasic tissues and pathogen bacteria by fluorescence, for treating infections caused by pathogen bacteria in complex body fluids and for fat reduction, skin disorders and vascular diseases are provided.
• Fig. 1 illustrates examples of some preferred photosensitizer structure families, including tetrapyrroles derivatives and phenazine dyes.
• novel photosensitizer formulations for oral administration are provided.
• Present invention provides stable compounds with improved bioavailability of the photosensitizers and enhanced bio -distribution in target tissues.
• present invention offers optimized treatment regimes to minimize light sensitivity and to maximize the potential of the drug while at the same time limiting necroses and causing sequential killing of the target tissue such as cancer dysplasia or other unwanted tissue, even fat, while maximizing beneficial body support reactions such as immune system support.
• photosensitizer formulations may be administered orally or involving any part of the gastrointestinal tract such as mouth, pharynx, esophagus, stomach, small intestine (duodenum, jejunum, ileum), large intestine (cecum, colon, rectum) and anus.
• Active substances may be administered with assimilable edible carriers, inert diluents or incorporated directly with food.
• Pharmaceutical dosage form includes but it is not limited to hard or soft shell gelatin capsule, tablet, pill, powder, solution, suspension, elixir, syrup, wafer, gel, buccal or sublingual tablet, thin film, suppository and enema.
• compositions for pharmaceutical dosage forms may be employed depending on the particular medical application.
• Pharmaceutical excipients may be used to modulate the solubility and bioavailability of the photosensitizer, increase its stability, help to maintain preferred polymorphic forms and conformations, maintain pH and/or osmolality of liquid formulations, modulate immunogenic responses of the host and act as emulsifying agent, antioxidant, aerosol propellants, tablet binders, tablet disintegration agents.
• Preferred pharmaceutical excipient includes, but it is not limited to binders/fillers, coating agents, disintegration agents, lubricants and sweeteners compatible with the photosensitizer used.
• the oral photosensitizer formulation further comprises means for blocking the active efflux mechanism without harming the patient.
• the active efflux mechanism is performed by multiple-drug efflux pumps (MDR) present on the surface of epithelial cells of the duodenum and the small intestine which operate as active transporters by an active efflux mechanism expelling substances considered toxic outside the cell.
• MDR multiple-drug efflux pumps
• the most abundant and most active of these MDR pumps are p-glycoprotein (MDRl, ABCBl), BCRP (Breast
• the oral photosensitizer formulation of present invention also comprises MDR-pump-b locking agents including but not limited to Vitamin-E-TPGS, Cremophor EL/RH40, Solutol HS, Tween 20, Tween 80, Labrasol, Peceol, PEGs, Polysorbate 80, Brij 30 and Pluronic P85.
• MDR-pump-b locking agents including but not limited to Vitamin-E-TPGS, Cremophor EL/RH40, Solutol HS, Tween 20, Tween 80, Labrasol, Peceol, PEGs, Polysorbate 80, Brij 30 and Pluronic P85.
• novel photosensitizer formulations for oral administration of present invention may be produced without any formulation additives or with other drug delivery systems known in the art such as combinations with liposome forming components, vectored and non-vectored proteins, organic and inorganic nanoparticles, nano- and micro- emulsions, nanocrystals, individual solvents or appropriate solvent mixtures, components like lactose,
• photosensitizer formulations for oral administration may be used in a light-independent manner or may be activated by an electromagnetic radiation source including coherent and incoherent radiation sources such as laser radiation source, light emitting diodes source, lamp radiation source (incandescent, xenon arc and metal halide lamps) and/or sunlight or other radiation sources from the environment.
• electromagnetic radiation may be delivered transdermally, inside a body cavity or lumen or interstitially by optical fibers with or without diffuser tips.
• a photosensitizer formulation for oral administration for treating hyperplasia and neoplasia is provided.
• Photosensitizers are preferably tetrapyrroles and their derivates and phenazine dyes and their derivatives, selected from the group consisting of, but not limited to porphyrins, chlorins, bacteriochlorins, pheophorbide, bacteriopheophorbide, corroles and phthalocyanines.
• An embodiment of a PDT method for the treatment of hyperplasia and neoplasia comprises the steps of: 1) selecting appropriate amount of photosensitizer in the oral dosage form, preferably tetrapyrrole and their derivatives; 2) administering orally a single or multiple pharmaceutical dosage forms; 3) allowing a period of time for drug absorption at proper sites of the GI tract and preferential accumulation of the photosensitizer at the hyperproliferative tissue; 4) delivering light radiation of one or more wavelengths single or multiple times to activate the photosensitizer accumulated at the treatment area; 5) if needed repeating the treatment more times.
• PDT induces a tumor-specific immune reaction that could be mediated by immune cells such as macrophages and/or dendritic cells which serve as antigen presenting cells.
• immune cells such as macrophages and/or dendritic cells which serve as antigen presenting cells.
• PDT can induce immunity even against less immunogenic tumors providing a systemic immune response effect.
• multiple photosensitizer dosage forms are orally administered for long-term tumor control, preventing the recurrence of PDT-treated tumors.
• Administration of multiple dosage forms of present invention can stimulate immune cells to be sensitized by the tumor and then they would be able to eliminate small foci of viable cancer cells that have escaped other PDT mediated antitumor effect.
• An embodiment of PDT method for long-term control of neoplasia comprises the steps of: 1) selecting therapeutically effective amount of photosensitizer in the oral dosage form, preferably tetrapyrrole and their derivatives; 2) administering orally a pharmaceutical dosage form; 3) after administration allowing a period of time for drug absorption at proper sites of the GI tract and preferential accumulation of the photosensitizer at the hyperproliferative tissue; 4) delivering light radiation of one or more wavelengths to activate the photosensitizer for stimulating tumor-immune response; 5) allowing a period of time for photosensitizer replenishment at the treating hyperproliferative tissue by other body tissues; 6) delivering light radiation of one or more wavelengths to activate replenished photosensitizer for stimulation of host tumor-immune response; 7) after a suitable period of time repeating steps 1-6 multiple times for long-term anti-
• Main advantages of PDT long-term anti-neoplastic control via oral route of administration comprise the administration of lower effective doses of photosensitizer compared to prior art formulations, thus limiting unintended necrosis and reducing extended skin photo-sensitivity. Additionally, this approach increases immune system support by stimulating host tumor-immune response and increases effectiveness by using for each photosensitizer administration multiple irradiation steps, after allowing photosensitizer replenishment at treated sites.
• a photosensitizer formulation for oral administration for treating infections caused by pathogen bacteria in complex body fluids such as whole blood, blood products, saliva and others is provided.
• Photosensitizers are preferably phenazine dyes and/or their derivatives, selected from the group consisting of, but not limited to methylene blue, safranin, etc.
• An embodiment of a PDT method of treatment of pathogen bacteria in complex body fluids comprises the steps of: 1) selecting appropriate amount of photosensitizer in the oral dosage form, preferably safranin O; 2) administering orally a single or multiple pharmaceutical dosage forms; 3) allowing a period of time for drug absorption at proper sites of the GI tract and preferential accumulation of the photosensitizer at the infected tissue; 4) delivering light radiation of one or more wavelengths to activate the photosensitizer accumulated at the treatment area, preferably in an intermittent manner; 5) allowing a period of time for photosensitizer replenishment at the treating infected tissue by other body tissues; 6) delivering light radiation of one or more wavelengths to activate replenished photosensitizer; 7) after a suitable period of time repeating steps 1-6 multiple times for long-term antibacterial control.
• the present method provides long-term antibacterial control by sequentially killing or inactivating infective agents such as bacteria.
• a photosensitizer formulation to be administered by the oral route for antiprionic treatments is provided.
• Prions are infectious pathogens that cause neurodegenerative diseases involving the modification of the prion protein (PrP).
• PrP prion protein
• Bovine spongiform encephalopathy, scrapie of sheep, and Creutzfeldt-Jakob disease of humans are among the most notable transmissible spongiform encephalopathies or prion diseases.
• Certain porphyrins and phthalocyanines may act as inhibitors of the abnormal protease-resistant PrP accumulation and may also inhibit the conversion to abnormal protease-resistant PrP without apparent cytotoxic effect.
• a photosensitizer formulation for oral administration for localizing hyperplasic or neoplasic tissues and bacteria by fluorescence is provided.
• a PDT method for localizing hyperplasic or neoplasic tissues and bacteria by fluorescence via the oral administration of appropriate amount of photosensitizer in a proper oral dosage form allows visualization of the target material with the aid of a fluorescence microscope or any other appropriate means.
• an advantageous combined method includes diagnosis and treatment of hyperplasic or neoplasic tissue in the same treatment.
• the area is first illuminated with a light radiation absorbed by the photosensitizer but with shallow penetration depth, allowing accurate visualization of the area to be treated. Then, the selected areas to be treated should be illuminated with a light radiation absorbed by the photosensitizer but with deeper penetration depth to activate the photosensitizer and destroy the hyperproliferative tissue.
• Body Mass Index is a number calculated from a person's weight and height. It provides a reliable indicator of body fat accumulation for most people. For adults, standard weight status categories are associated with BMI. A BMI less than 18.5kg/m indicates underweight, a BMI between 25-29.9 kg/m indicates overweight and a BMI of 30 kg/m or higher indicates obesity. Excess body fat may affect a subject physically, physiologically and psychologically and is associated with aesthetical disorders and various diseases such as cardiovascular diseases, diabetes mellitus type II, obstructive sleep apnea and others.
• photosensitizer formulations for oral administration are used in PDT treatments for fat reduction by destroying undesired fat cells in the body.
• the photosensitizer is progressively accumulated in adipose cells in the subcutaneous layer.
• light radiation of one or more wavelengths is delivered to activate the photosensitizer accumulated at treatment areas to reduce or eliminate adipose tissue.
• Light radiation delivery may be performed multiple times allowing replenishment of photosensitizer from other body tissues to the treating adipose areas between light irradiations.
• the photodynamic treatment can be performed multiple times until desired fat elimination or reduction is achieved.
• Light radiation may be laser or LED radiation delivered with the aid of a lamp or an optical fiber.
• Irradiation may be delivered transdermally with the aid of an appropriate handpiece or interstitially with the aid an optical fiber with a diffuser tip.
• PDT has been also used for neoplastic and non-neoplastic dermatological disorders such as basal cell carcinoma, actinic keratoses, viral warts, acne and others.
• photosensitizer formulations for oral administration are used in PDT treatments for skin disorders in which the photosensitizer accumulated and activated by light radiation at the treatment area produces cytotoxic effects on neoplastic and non-neoplastic unhealthy skin cells.
• photosensitizer formulations for oral administration of the present invention are used for hair PDT treatments.
• PDT may be utilized for removal of unwanted hair in human subjects or animals.
• the extension of area to be treated and properties of hair to be removed would determine whether multiple or single drug and/or light administration are needed and the precise photosensitizer amount therapeutically effective.
• Present method allows undesired hair elimination by inactivating or destroying the hair follicles or destroying the tissue feeding the hair follicles.
• PDT treatment can stimulate hair growth by inducing, reviving, renewing, replacing or activating hair growth.
• PDT stimulates hair growth of hairs produced by follicles with sebaceous glands which are found on the scalp, beard, arm and pubic areas.
• hair loss such as androgenetic alopecia, chemotherapy and drug-induced alopecia and alopecia areata can be treated with appropriate PDT settings.
• photosensitizer formulations for oral administration are used in PDT treatments for vascular disorders.
• PDT may be utilized for treating varicose and spider veins by administering appropriate amount of photosensitizer in oral dosage form.
• the photosensitizer is preferentially accumulated or adhered to unhealthy vein wall vessels and/or achieves appropriate blood concentration
• pulsed or continuous light radiation of one or more wavelengths is delivered endoluminally or transdermally to activate the photosensitizer.
• the vein wall or endothelium is damaged and/or irritated leading to immediate or progressive vein closure by irreversible evolution into fibrotic tissue.
• photosensitizers are tetrapyrroles and their derivatives, irradiated with a laser source of wavelengths in the range of 400 to 800nm.
• joint disorders affects many people in all age groups, some of which are of chronic nature.
• the main symptom of such disorders is acute pain. Due to decreased movement because of pain, regional muscles may gradually atrophy and ligaments may become more lax, leading over time to deformity and disability.
• One of the most common joint disorders is rheumatoid arthritis, a disease affecting million of people in United States. To reduce pain, conservative cares such as weight control, rest, regular exercise or mechanical support devices may be helpful. But if pain increases medical treatments are required, including non steroidal anti-inflammatory drugs, local injections of glucocorticoid or hyaluronan and in severe cases, joint replacement surgery.
• the present invention provides an alternative non-invasive prophylactic and treatment method to enhance cartilage regeneration and provide people suffering from this disease an improved quality of life.
• the present invention is further illustrated by the following examples, but is not limited thereby.
• tablet formulations may include but are not limited to the following: Capsule 1) Hypromellose, Ethylcellulose, Lactose monohydrate, Magnesium stearate; Capsule shell: Titanium dioxide (E 171), Yellow iron oxide (E 172), Red iron oxide (E 172), Gelatin.
• Printing ink (Opacode S-l-15083): Shellac, Lecithin (soya), Simethicone, Red iron oxide (E
• Polysorbate 20 Capsule shell: Gelatin, Titanium dioxide ( E171), Iron oxide, red (E172).
• the active substance is the photosensitizer. The amount of active substance would be determined depending on the desired therapeutic application in order to achieve the optimal therapeutic effect.
• Tablet 1 Tablet core: Maize starch, Pregelatinised starch, Sodium starch glycollate, Povidone, Glycerol dibehenate, Magnesium stearate; Film coat: Hypromellose, Glycerol triacetate, Talc, Titanium dioxide (El 71), Iron oxide yellow (E 172), Iron oxide red (E 172), Ethylcellulose; Tablet 2) Lactose monohydrate, Powdered cellulose, Pregelatinised maize starch, Maize starch, Colloidal anhydrous silica, Magnesium stearate; Tablet 3) Maize starch, Microcrystalline cellulose, Hydroxypropyl cellulose, Magnesium stearate, Indigo carmine aluminium lake; Tablet 4) Tablet core: Lactose monohydrate, Microcrystalline Cellulose, Crospovidone, Silica, colloidal anhydrous / Colloidal silicon dioxide,

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