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• • 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
  • 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)
  • A61K36/88—Liliopsida (monocotyledons)
  • A61K36/906—Zingiberaceae (Ginger family)
  • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
• • 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
• • 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
  • 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
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention describes a method for increasing the therapeutic efficacy of formulations comprising curcuminoids and their analogs when administered systemically.
• the method is characterized in that concomitantly with the administration of the formulation a quantifiable visible ultraviolet radiation is irradiated on the patient.
• the present invention also describes phototherapy equipment that emits visible light radiation over an area greater than 0.20 m2 and an irradiance greater than 2 mW / cm2 and its use in dermatological and / or proliferative diseases.
• Curcumin and its therapeutic or similar equivalents Turmeric rhizomes, extracts, curcuminoids (desmethoxycurcumin, bisdesmethoxycurcumin, tetrahydrocurcumin), prodrugs and metabolites have shown different pharmacological activities such as antioxidant, antiproliferative agent, apoptosis inducer, etc. Based on the results in Vitro Turmeric is a potential agent for the treatment of the diseases described in the state of the art, for example, psoriasis, cancer, inflammatory processes or vitiligo, etc.
• curcumin and its equivalents have an almost zero bioavailability.
• Br J Cancer. 2004 Mar 8; 90 (5): 1011-5 describes that after the administration of curcumin only traces of its metabolites were found in liver and not curcumin, therefore, Curcuminoids suffer from efficacy in vivo or is very reduced compared to the activity shown in vitro.
• J Am Acad Dermatol. 2008 Apr; 58 (4): 625-31 corroborates this fact (published after the priority date). He teaches that a phase II, uncontrolled trial in patients older than 18 years who were given 4.5 grams curcuminoids / day had to be abandoned because only 17% of patients responded to treatment with a reduction in 75% of the psoriatic plaque.
• Phototherapy is used to treat neonatal jaundice.
• the neonate with a body area of 0.20 m2, is irradiated with a visible light, preferably with a maximum emission at 550 nm, with an approximate irradiance of 40 W / m2 to destroy bilirubin.
• Actinic light maximal emission 420 nm
• the surface irradiated by these lamps is less than 400 cm2.
• Chemotherapy photo concomitant administration of psoralens and irradiation with ultraviolet light is the treatment of choice in the treatment of moderate-severe psoriasis, but the treatment has many side effects: hyperpigmentation, hepatotoxicity or hypersensitization reactions and the dose should be carefully adjusted irradiated
• curcumin In the particular case of curcumin, the state of the art shows that it is very bioavailable and, in addition, it is also known that curcuminoids show photo decomposition when they are irradiated with visible-ultraviolet light both in solution and in solid state.
• the major degradation product is a curcumin cyclization product formed by the loss of 2 hydrogen atoms.
• Psoriasis is a chronic disease of unknown etiology. Clinically it is characterized by the presence of erythematous papules or plaques of diverse size and dark red tone, bounded edges and usually covered with scales that are due to alterations in cell proliferation marked by genetic and immunological mechanisms. In this way, psoriasis is considered a proliferative disease.
• the severity of psoriasis is determined by PASI (Psoriasis Area and Severity Index or Severity Index Psoriasis Area), BSA (body surface area and PGA (overall clinical assessment) so that according to the PGA psoriasis can be classified as :
• -Moderate psoriasis It is still possible to control the disease with topical treatment; BSA> 10% PASI 10 or higher, -Moderate-severe psoriasis: Topical treatment cannot control the disease; BSA> 10% PASI 10-20; thick lesions in difficult to treat regions,
• the PASI objective index that measures the severity of Psoriasis, is used to evaluate the therapeutic efficacy of drugs.
• the criteria of the European Medicines Agency establish that a patient is respondent and the treatment is effective if the PASI is reduced by more than 75% over the baseline.
• Efalizumab recently authorized for the treatment of psoriasis is effective.
• the 12-week studies show percentages of 22-35% of patients who reach PASI-75 (75% improvement).
• EP1133992 describes the photosensitizing activity with UV-visible light of curcuminoids administered as an extract topically for the treatment of psoriasis.
• the cream described in EP1133992 should be applied before radiation, but the treatment is abandoned by patients, since Turmeric extracts are colored products and stain clothes.
• Moderate-severe psoriasis which affects more than 10% of the body surface, cannot be treated topically, because patients do not respond to topical treatments.
• the results obtained in topical phototherapy cannot be extrapolated to the systemic route as described for aminolevulinic acid.
• photodynamic therapy Another type of phototherapy used today is photodynamic therapy.
• a drug is administered and irradiated to the patient with a high pulsed light irradiance, approximately 300 mW / cm2, for a short time to radiate 100 J / cm2 on a small surface, but this therapy causes pain in the patients.
• the phototherapy equipment closest to the invention are: - cabins that radiate 2-30 mW / cm2 of ultra-violet light over the entire body surface of the patient, but without emitting visible light, visible light equipment that radiates a small surface, approximately 500 cm2, but in any case a smaller surface to 10% of the body surface of an adult,
• Discharge tubes that emit in the visible 400-550 nm and that are attachable in UV cabins, for example Phillips TLK 40 W / 03 or TLK 140 W / 03 tubes but these tubes are used for aquarium lighting and in Photo printing
• filters that can selectively absorb certain wavelengths and transmit radiation with wavelengths 400-430 nm.
• the problem solved by the invention is to increase the therapeutic efficacy of curcuminoids and their therapeutic equivalents when administered systemically.
• the solution found by the inventors is to combine the systemic administration of curcuminoids with a quantifiable visible-ultraviolet light radiation.
• the PASI is reduced by more than 75% after being irradiated with both visible light and UV light of 1-18 J / cm2 in more than 80% of psoriatic patients, with a 80% probability and the therapeutic efficacy specified by the EMEA is achieved.
• curcumin In the preferred modes for the treatment of psoriasis, the therapeutic equivalents of curcumin are Turmeric extracts (12% hydroalcoholic in curcuminoids or 90% alcoholic in curcuminoids).
• curcumin is administered parenterally (intraperitoneally) to inhibit tumor growth in mice combined with visible light while curcumin alone or light alone did not inhibit tumor growth.
• the combination of visible and / or UV light with curcuminoids produces a synergistic effect and can be used for the treatment of all pathologies in which curcumin has suggested a potential activity.
• visible light is already preferred.
• the use of curcuminoids or their equivalents systemically allows the drug to be administered with the main meals and not two hours before the radiation.
• curcumin, curcuminoids, their metabolites or their prodrugs orally for the treatment of psoriasis concomitantly with visible UV radiation avoids the usual problems associated with chemotherapy.
• the irradiated dose is increased per phototherapy session, reducing the number of phototherapy sessions and the bleaching time of psoriatic lesions is shortened,
• the problem solved by the invention is to find a phototherapy equipment for the treatment of proliferative diseases, especially moderate-severe and / or severe psoriasis.
• the solution found by the inventors is a phototherapy system characterized in that it radiates visible light with an irradiance greater than 2 mW / cm2 on an area greater than 0.2 m2.
• the maximum emission wavelength is 420 nm and the light source is the LEDs and optionally the equipment can have an ultraviolet light source to produce optimal pigmentation and a healthy tan.
• Curcuminoids in the form of curcumin, alcoholic extracts of Turmeric (90% curcuminoids) or hydroalcoholic extracts of Turmeric 12% curcuminiodes), increase their therapeutic efficacy in vivo when their systemically administered with a visible-UV light radiation (315-550 nm).
• curcuminoids described in the prior art, for example, those described in Anand et al Biochem Pharmacol. 2008 Aug 19. [Epub ahead of print], Turmeric rhizomes or curcumin cycled by the action of irradiation will increase their efficacy in vivo when administered concomitantly with visible UV radiation.
• the visible light / curcuminoid combination When curcuminodes are administered orally, the visible light / curcuminoid combination has the same effectiveness in moderate-severe psoriasis as the Ultraviolet light combination.
• the visible light irradiated on the mice combined with curcumin intraperitoneally produces a 70% inhibition of the proliferation of epidermal human carcinoma cells (A431).
• the combination of visible-ultraviolet light with systemic curcuminoids will be effective in the treatment of any type of tumors, for example, epidermal, esophagus, duodenum, colon, breast, liver, kidney or prostate.
• any irradiance and any type of light, incoherent, polarized, pulsed or laser may be used due to the absence of side effects.
• irradiations between 2 - 300 mW / cm2 and more preferably irradiations between 2-30 mW / cm2 can be used to irradiate between 1-18 J / cm2.
• the curcuminoid / visible-UV light combination is therapeutically effective at lower doses than those described in the prior art, for example 1 mg / kg day in oral psoriasis or 50 mg / kg day in the Tumor inhibition in a murine model in intraperitoneal administration.
• the UV / curcuminoid combination produces pigmentation in treated patients without producing sores, the combination of curcuminoids / visible light plus UV light will allow the homogeneous pigmentation of all patients who are treated with curcuminoids / visible light.
• formulations which comprise at least one curcuminoid or anagula together with excipients acceptable for systemic administration, and optionally other active ingredients.
• any phototherapy system that comprises means for irradiating a visible wavelength (400-550 nm) with an irradiance greater than 2 mW / cm2 on an area greater than 0.20 m2.
• light sources for example, discharge tubes, LEDs, polarized light, a laser beam or filtered solar radiation can be used.
• the Phillips TLK 40W / 03 or Phillips TLK 140W / 03 tubes can be mentioned.
• the dimensions of the tubes are 60 * 4 cm and 140 * 4 cm respectively.
• 10 Phillips TLK 40W / 03 tubes at a distance of 45 cm emit 5500 Ix which corresponds to an irradiance of 3 mW / cm2. Logically, if the distance between the source and the irradiated surface decreases the irradiance will increase.
• J Invest Dermatol. 2002 JuI; 119 (1): 77-83 uses LED panels to radiate a surface of 30 cm2 radiating from 9-11 mW / cm2, but without specifying the distance between the source and the psoriatic plate. If the distance between the emission source decreases the irradiated surface will decrease but the irradiance will increase. By irradiating at a distance of 5 cm, it is possible to obtain irradiations of 30 mW / cm2 with the currently marketed LEDs.
• UV radiation -Medication 24 mg of curcuminoids in the form of a hydroalcoholic extract of Turmeric longa at 12% in curcuminoids.
• the excipients used in the formulation were: cellulose, magnesium stearate, corn starch, sodium starch glycolate, potassium hydrogen phosphate and silicon dioxide.
• the pH of a dispersion in water of a 5% tablet (w / v) was 5.
• the extract of Turmeric was obtained according to the following process: Extraction of the rhizomes of Turmeric longa with ethanol, evaporation of the solvent and quantification of the content in curcuminoids expressed as curcumin; Extraction of the rhizomes in the previous phase with water and evaporation of the solvent; Mix the above extracts to obtain an extract with 10-15% in curcuminoids.
• -Administration regime 3 tablets a day before meals. (72 mg curcuminoids / day)
• - Radiation source PUVA COMBI LIGHT cabin equipped with 32 Philips UVA 100 W UVA lamps (315-400 nm maximum 365 nm).
• - Irradiated surface The entire naked body, except the genitals, approximately 2 m2
• -Dosis There were two phototherapy sessions per week. Initially, 2.5 J / cm2 were irradiated. The dose was increased by 0.5-1 J / cm2 until a slight erythema was achieved and subsequently by 2 J / cm2 per session until reaching 16 J / cm2. The exposure times to reach 16 J / cm2 were approximately 30 minutes.
• -Rescue medication -a emollient containing vitamin B3 for symptomatic relief of skin manifestations. -Desloratadine if itching occurs.
• the patients studied had skin phototype type I, II, III, IV.
• the average weight of the patients was 70 kg.
• the doses irradiated to patients 1, 2, 3 and 9 were: Patient 1 2 3 9 Patient 1 2 3 9
• Visit3 4.5 4.5 4.5 4 visit 12 16 16 16 16 visit 4 5.5 5.5 5.5 5 visit 13 16 16 16 16 visit 5 5.5 7.5 6.5 6 visit 14 16 16 16 16 visit 6 7.5 9.5 8.5 8 visit 15 16 16 16 16 visit 7 9.5 11.5 10.5 10 visit 16 16 16 16 16 visit 8 11.5 13.5 12.5 12
• Hepatic parameters were normal and hepatotoxicity was not estimated. An increase in the red series was observed.
• curcuminoids in the form of a 12% hydroalcoholic extract of Turmeric longa in curcuminoids.
• the excipients used in the formulation were: cellulose, magnesium stearate, corn starch, sodium starch glycolate, potassium hydrogen phosphate and silicon dioxide.
• the pH of a water dispersion of a 5% tablet (w / v) was 5.
• Turmeric extract was obtained in the same way as in the study cited above.
• -Administration regime 3 tablets a day before meals. (72 mg curcuminoids / day)
• Radiation source Philips TLK lamp 40W / 03 5500 visible-light 100 * 40 W) 400-550 nm, maximum emission 420 nm
• -Dosis There were two phototherapy sessions per week. The irradiated dose was 18 J / cm2, irradiation time 1 hour 40 minutes.
• -Rescue medication -an emollient containing vitamin B3 for the symptomatic relief of skin manifestations. -Desloratadine if itching occurs.
• the patients studied had skin phototype type II and III.
• the average weight of the patients was 70 kg.
• V16 85 90 89 88 87 The results obtained indicate that the same therapeutic efficacy is achieved using visible light than ultraviolet light. All patients reduced PASI to 80% before 8 weeks of treatment. The treatment was well tolerated and no anti histamines or corticosteroids were administered III Effect of an alcoholic extract of Turmeric longa administered orally in combination with visible light in severe moderate psoriasis A clinical study was conducted on 4 patients, mean age 48 years, average weight 68 Kg., diagnosed with moderate-severe psoriasis.
• the diagnostic criteria were PASI on a 30-35 cm2 plaque on the back or buttocks. Irradiation was carried out with a maximum emission LED lamp at 420 nm at a distance of 5 cm, an irradiance of 30 mW / cm2. The irradiated surface was 40 cm2.
• -Patient 1 Generalized vitiligo, great facial involvement. 8 phototherapy sessions. There is a rapid increase in tanning, without erythema or burns. -Patient 2. Vitiligo, involvement in hands, chin and legs. 8 phototherapy sessions on the hands of 12 J / cm2. Focal spots of pigments appear on the edges of some spots.
• V_ Effect of curcumin administered intraperitoneally in tumor growth inhibition in mice 5 * 10 6 A431 cells (human epidermal carcinoma) were injected subcutaneously in the right and left flanks of atimic mice (NMRI) of 5-6 weeks and 20-24 g Mice were fed in pathogen-free conditions. The animals were fed ad libitum with sterilized food. The animals were sterilized with ketamine / xylazine. For the treatment, 5 mg of curcumin was first dissolved in 50 ⁇ l of ethanol, diluted in 2 ml of a 1% solution of methylcellulose and sterilized. Mice were fed 2 times intraperitoneally 'up with 200 .mu.l of solution or methylcellulose alone.
• curcuminoids 50 mg curcuminoids / kg day.
• a group of mice (curcumin and methylcellulose) after injection were irradiated for 20 minutes with 5500 Ix.
• the irradiation system was formed by 10 Phillips TLK 40W / 03 lamps (60 cm length * 4 cm diameter), at a distance of 45 cm. The lamps had an emission range between 400-550 nm with a maximum at 420 nm.
• control groups methyl cellulose group and unirradiated curcumin group, were protected from light after one hour of injection.
• the tumor was measured initially and 10-12 days later, the tumor volume and weight was determined twice a week. At the end of the experiment 29 days, the animals were anesthetized and sacrificed.

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