WO2016116587A1 - Triptolide et ses dérivés dans le traitement de tumeurs et de pathologies précancéreuses de la peau - Google Patents

Triptolide et ses dérivés dans le traitement de tumeurs et de pathologies précancéreuses de la peau Download PDF

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WO2016116587A1
WO2016116587A1 PCT/EP2016/051306 EP2016051306W WO2016116587A1 WO 2016116587 A1 WO2016116587 A1 WO 2016116587A1 EP 2016051306 W EP2016051306 W EP 2016051306W WO 2016116587 A1 WO2016116587 A1 WO 2016116587A1
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triptolide
skin
compound
use according
precancerous
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PCT/EP2016/051306
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English (en)
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Thien Nguyen
Bruno GOMES
Arnaud Pillon
Adrien COUSY
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Pierre Fabre Medicament
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/37—Celastraceae (Staff-tree or Bittersweet family), e.g. tripterygium or spindletree
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention concerns triptolide, derivatives thereof and pharmaceutically acceptable salts of same for use in the topical treatment and prevention of tumors and precancerous pathologies of the skin.
  • Tumors and precancerous pathologies of the skin constitute a serious public health problem. Some are caused by frequent exposure to UV rays and can develop into deadly cancerous forms. There are essentially two types of skin tumors:
  • Carcinomas develop from cells of the epidermis, either of the basal layer (basal cell carcinoma), or of the upper layers (squamous cell carcinoma). They are the most common, accounting for 90% of skin cancers, 75% of which are basal cell and 20% squamous cell. Basal cell carcinomas never metastasize; squamous cell carcinomas do so rather seldom, chiefly in the lymph nodes near the tumor. Cancers generally develop in several stages. For squamous cell carcinomas, the tumor often begins as a lesion located in the epidermis. A crust (actinic keratosis) or a kind of eczema (Bowen's disease) forms on the surface. It is the invasion of the dermis, deeper, that characterizes the stage of invasive carcinoma.
  • Melanomas develop from melanocytes, which are cells that produce melanin, responsible for the brown or red pigmentation of the skin. Indeed, there are two principal types of pigments: brown, which produce a tan and provide some UV protection, and red (freckled skin) which do not protect. Individuals who produce primarily red pigments do not tan and, as a result, are at greater risk of skin cancers.
  • Melanocytes are normally present in the epidermis, associated with epidermal cells of the deep part of the epidermis.
  • a "beauty spot,” or nevus is a benign lesion corresponding to an accumulation of melanocytes in the dermis, which explains its brown or red color. Melanomas are much rarer, but can develop in the young. They must be quickly detected and treated because they can diffuse throughout the body and produce metastases that are very hard to treat.
  • Actinic keratosis also called solar keratosis, is a dermatological pathology. It is a hypertrophy of the horny layers of the epidermis. AK is the first stage leading to the development of squamous cell carcinoma and is thus considered a "precancerous" lesion. Although the large majority of AK are benign, some studies report that about 10% can transform into squamous cell carcinoma. 40 to 60% of squamous cell carcinomas result from untreated AK. About 2 to 10% of squamous cell carcinomas spread to internal organs and threaten the prognosis in terms of mortality.
  • AK occurs on areas of the body often exposed to the sun (in particular to UVB rays).
  • AK adenosine kinase
  • cryotherapy surgery, topical photodynamic therapy (PDT), laser, curettage and electrocoagulation, topical applications containing imiquimod, 5-fluorouracil, ingenol mebutate or diclofenac.
  • PDT topical photodynamic therapy
  • electrocoagulation topical applications containing imiquimod, 5-fluorouracil, ingenol mebutate or diclofenac.
  • the treatment is suited to the location and features of the AK.
  • Triptolide (TRP) of formula (I) below and derivatives thereof, in particular of the diterpene type, are molecules extractable from Chinese medicinal plants of the family Celastraceae, in particular from the plant Tripterygium wilfordii.
  • triptolide The inventors have in a surprising manner demonstrated the efficacy of triptolide in the prevention and treatment of tumors or precancerous pathologies of the skin, in particular actinic keratosis. The inventors further showed that triptolide was effective topically with a low level of transcutaneous passage.
  • the present invention thus concerns a compound selected from triptolide, derivatives thereof, pharmaceutically acceptable salts of triptolide and derivatives thereof, and mixtures of same for use in the topical treatment and/or prevention of a tumor or precancerous pathology of the skin.
  • the present invention further relates to a topical composition
  • a topical composition comprising at least one compound according to the invention and at least one pharmaceutically acceptable excipient for use in the treatment and/or prevention of a tumor or precancerous pathology of the skin.
  • the present invention further relates to a method for treating and/or preventing a tumor or precancerous pathology of the skin by means of topical administration, to a patient in need thereof, of an effective amount of a compound or composition according to the invention.
  • the present invention further relates to the use of a compound or composition according to the invention for the manufacture of a topical medication for treating and/or preventing tumors or precancerous pathologies of the skin.
  • pharmaceutically acceptable is intended to mean that which is useful in the preparation of a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable and that is acceptable for both veterinary and human pharmaceutical use.
  • “Pharmaceutically acceptable salt” of a compound is intended to mean a salt that is pharmaceutically acceptable, as defined herein, and that has the desired pharmacological activity of the parent compound.
  • compositions include in particular:
  • pharmaceutically acceptable acid addition salts formed with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with pharmaceutically acceptable organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid, tri
  • triptolide derivative is meant, according to the invention, all triptolide derivatives having an efficacy equivalent to or greater than triptolide.
  • the efficacy of triptolide and derivatives thereof can be measured in particular by evaluating their effect on the variation in the number of actinic keratosis lesions during an efficacy test such as, in particular, that presented in the examples below.
  • efficacy equivalent to is meant that the triptolide derivative will have an efficacy between 50 and 100%, preferably between 80 and 100%, of that of triptolide. Consequently, by “efficacy equivalent to or greater than” is meant that the triptolide derivative will have an efficacy greater than or equal to 50%, preferably 80%, of that of triptolide.
  • Triptolide derivatives according to the present invention are described in particular in the article by Ma et al. (2007) Phytochemistry 68:1 172-1 178.
  • the triptolide derivatives are selected from the group comprising or consisting of triptonide, tripdiolide, triptolidenol, 16-hydroxytriptolide, triptriolide, 12-epitriptriolide, 14-epitriptolide, tripchlorolide and derivative PG-490-88 notably described in the form of its sodium salt in Liu, Q et al. (2004) Biochem. Biophys. Res. Com -986, of the formula below:
  • the triptolide derivative according to the invention can be active terpenoid metabolites such as, in particular, those cited in Brinker et al. (2007) Phytochemistry 68:732-766, including wilforine, euonine and cangorinine.
  • the triptolide derivatives according to the invention will be selected from triptolide derivatives of the diterpene type, namely from the group comprising or consisting of triptonide, tripdiolide, triptolidenol, 16-hydroxytriptolide, triptriolide, 12- epitriptriolide, 14-epitriptolide and derivative PG-490-88.
  • the triptolide derivatives according to the invention will be selected from triptonide, tripdiolide, and derivative PG-490-88.
  • the compound according to the invention is triptolide, triptonide, tripdiolide, derivative PG-490-88 or a pharmaceutically acceptable salt thereof.
  • the compound according to the invention is triptolide, derivative PG-490-88 or a pharmaceutically acceptable salt thereof, in particular triptolide or derivative PG-490-88 sodium salt.
  • the compound according to the invention is triptolide, triptonide, tripdiolide or a pharmaceutically acceptable salt thereof, notably triptolide, triptonide or tripdiolide.
  • Triptolide, triptonide and tripdiolide are structurally very similar and have comparable activities.
  • the compound according to the invention is triptolide or a pharmaceutically acceptable salt thereof, in particular triptolide.
  • Triptolide, derivatives thereof and pharmaceutically acceptable salts of same according to the invention can be obtained by all methods known to the person skilled in the art.
  • compositions according to the invention can contain triptolide and/or one or more triptolide derivatives and/or pharmaceutically acceptable salts thereof in purified form or in extract form, which may be crude or enriched, for example.
  • purified form is meant, in the context of the present invention, a compound comprising at least 90% by weight, in particular at least 95% by weight, in particular at least 99% by weight of triptolide, a triptolide derivative or a pharmaceutically acceptable salt thereof.
  • triptolide, derivatives thereof and pharmaceutically acceptable salts of same in purified form can be obtained by chemical synthesis (Miller NA, et al. Chem Commun (Camb). 2008 Mar 14;(10):1226-8).
  • triptolide, derivatives thereof and pharmaceutically acceptable salts of same in purified form can be obtained by extraction and purification from plants of the family Celastraceae, in particular from plants of the genus Tripterygium such as Tripterygium wilfordii or Tripterygium regelii.
  • the purification can be carried out by liquid chromatography.
  • a method for obtaining triptolide purified to more than 95% is described in particular in Ma et al. (2007) P ytoc emistry 68:1 172-1 178.
  • triptolide, derivatives thereof and pharmaceutically acceptable salts of same according to the invention can be in extract form after extraction from plants of the family Celastraceae, in particular from plants of the genus Tripterygium such as Tripterygium wilfordii or Tripterygium regelii.
  • This extract can be crude or enriched in triptolide, in a triptolide derivative and/or in a pharmaceutically acceptable salt thereof.
  • the extract can then optionally comprise components (including active components) from the plant other than triptolide, derivatives thereof and pharmaceutically acceptable salts of same.
  • the "crude extract” is the extract obtained directly from the plants.
  • enriched extract in particular an extract wherein the amount of triptolide, a derivative thereof and/or pharmaceutically acceptable salts of same is greater than 30% by weight, in particular greater than 50% by weight in relation to a crude extract.
  • triptolide-enriched extract according to the invention can be obtained by the method described in the international application WO201 1/054929.
  • Purified, crude or enriched extracts according to the invention can be obtained from any part of plants of the family Celastraceae, in particular the roots. Alternately, they can be obtained from plant cell cultures of these plants. In the case of plant cell cultures, this extract can in particular be obtained from the supernatant of said cell cultures (such as notably described in WO201 1/054929).
  • the compound according to the invention i.e., triptolide, a triptolide derivative or a pharmaceutically acceptable salt thereof, is in purified form.
  • tumor or precancerous pathology of the skin is meant in particular tumors or precancerous pathologies of the skin selected from the group comprising or consisting of UV-induced tumors or precancerous pathologies, metastases and cutaneous T-cell lymphomas.
  • the UV-induced tumor or precancerous pathology of the skin is in particular selected from the group comprising or consisting of actinic keratosis, basal cell carcinoma, melanoma and squamous cell carcinoma.
  • the UV-induced precancerous skin pathology according to the invention is actinic keratosis. All these tumors and precancerous pathologies of the skin are well-known to the person skilled in the art, who will easily know how to recognize and differentiate one from the other.
  • actinic keratosis can be characterized by the appearance of actinic keratosis lesions.
  • actinic keratosis lesion is meant hypertrophy of the upper layers of the epidermis resulting in thickening of the stratum corneum.
  • the first stage is characterized by the appearance of erythematous spots with imprecise borders, of variable size (on the order of one centimeter) and rough surface.
  • the thickening of the stratum corneum becomes more pronounced (yellow or brownish hyperkeratosis, which bleeds if one tries to remove it).
  • a histological examination skin biopsy
  • skin biopsy provides a definitive diagnosis (by the presence of ortho- and parakeratotic hyperkeratosis, of atrophic or hyperacanthotic epidermis made of dysplastic keratinocytes with numerous nuclear atypia).
  • the squamous cell carcinoma according to the invention will be preferably derived from a pre-existing actinic keratosis lesion.
  • metastases is meant, according to the invention, metastasis of the cutaneous localization of any type of tumor, for example metastases of breast or lung tumors, or of melanoma.
  • treatment is meant, according to the present invention, the inhibition of the development of, more particularly the regression of, preferably the disappearance of, the tumor or precancerous pathology of the skin according to the invention.
  • prevention is meant, according to the present invention, to prevent or delay the appearance of the tumor or precancerous pathology of the skin according to the invention.
  • the treatment or prevention according to the invention applies to humans or animals.
  • treatment of actinic keratosis is meant in particular the inhibition of the appearance of new actinic keratosis lesions, the inhibition of the development of existing actinic keratosis lesions (notably from microscopic to macroscopic), the inhibition of the growth of existing macroscopic actinic keratosis lesions, the regression of existing actinic keratosis lesions, and/or the disappearance of existing actinic keratosis lesions.
  • topical is meant, according to the invention, that the compound or composition according to the invention will be administered by application on the skin surface or the mucous membranes.
  • the topical composition according to the invention may in particular be in any form allowing topical application: cream, gel, ointment, patch, etc.
  • the composition according to the invention will be in cream form.
  • the topical composition according to the invention comprises triptolide and/or one or more derivatives thereof in a concentration between 0.0002% and 2% by weight relative to the weight of the final composition, for example between 0.001 % and 2% or between 0.001 % and 1 % or between 0.01 % and 1 % or between 0.01 % and 0.1 % or between 0.005 and 0.1 %.
  • the triptolide and/or one or more derivatives thereof can be in the form of a pharmaceutically acceptable salt.
  • the topical composition according to the invention comprises triptolide in a concentration between 0.0002% and 2% by weight relative to the weight of the final composition, for example between 0.001 % and 2% or between 0.001 % and 1 % or between 0.01 % and 1 % or between 0.01 % and 0.1 % or between 0.005% and 0.1 %.
  • the triptolide can be in the form of a pharmaceutically acceptable salt.
  • triptolide and/or one or more derivatives thereof are administered in a dose between 1 ⁇ g and 1 .5 mg/cm 2 or between 5 ⁇ g and 1 .5 mg/cm 2 of skin, for example between 1 ⁇ g and 1 mg/cm 2 or between 10 ⁇ g and 1 mg/cm 2 .
  • the triptolide and/or one or more derivatives thereof can be in the form of a pharmaceutically acceptable salt.
  • the compound or composition according to the invention will be administered one or more times per day, the duration of the treatment being variable according to the severity of the tumor or precancerous pathology of the skin to be treated and easily adjustable by the person skilled in the art or practitioner.
  • the composition will not be administered more than 1 , 2, 3, 4 or 5 times, for example more than 3 times.
  • pharmaceutically acceptable excipient is meant, according to the invention, an excipient that is compatible with the other ingredients of the composition and that produces no adverse effect, allergic reaction or other undesirable reaction when it is administered to an animal or a human.
  • excipient in particular one or more surfactants, for example macrogols, hydroxy stearates, ethoxylated fatty acid esters, ethoxylated fatty alcohols; one or more solvents, such as for example octyldodecanol, propylene glycol dicaprylocaprate; one or more hydrosoluble polymers, for example PVP, hyaluronic acid or sodium hyaluronate; one or more thickeners such as for example natural or semisynthetic gums; one or more gelling agents, for example carbomers; one or more inorganic fillers, for example zinc oxide, talc, clays; one or more emulsifiers such as cetearyl alcohol; one or more preservatives, for example phenoxyethanol; one or more antibacterials; one or more antiseptics; one or more antioxidants, for example tocopherol acetate; one or more chelating agents, for example EDTA;
  • surfactants for example macrogol
  • the composition is such that the compound(s) according to the invention do not penetrate through the skin.
  • Penetration through the skin can be measured by means of a test using a Franz static diffusion cell, in particular as described in OECD Guidelines for the Testing of Chemicals (new Guideline 428, Skin Absorption: In Vitro Method (13 April 2004)).
  • the compounds according to the invention are considered not to have penetrated the skin when more than 60%, for example more than 80% or 90%, of the compound(s) according to the invention administered is not absorbed.
  • Figure 1 Average number of actinic keratosis lesions before or after treatment with triptolide at various doses ⁇ g (carrier), 50 ⁇ g or 150 ⁇ g per mouse) and within or outside the treated area.
  • Figure 2 Photographs of the skin of mice treated with various doses ⁇ g
  • carrier 50 ⁇ g or 150 ⁇ g per mouse
  • Figure 3 Average number of actinic keratosis lesions before or after treatment with triptolide (" ⁇ g or 50 ⁇ g per mouse), triptolide PCC (" ⁇ g or 50 ⁇ g per mouse) or carrier (control) within the treated area.
  • FIG. 4 Photographs of the skin of mice treated with triptolide (" ⁇ g or 50 ⁇ g per mouse), triptolide PCC (" ⁇ g or 50 ⁇ g per mouse) or carrier (control) during time.
  • Example 1 Mouse study 1. Materials and methods
  • mice Female non inbred hairless SKH1 mice, between 6 and 8 weeks of age (Charles River Laboratories), are exposed to UVB rays daily for 14 weeks.
  • the UVB intensity confirmed by a luminometer, is 50 mJ/cm 2 /day for 10 days, then 55 mJ/cm 2 /day for 10 days, and finally 60 mJ/cm 2 /day for the remainder of the period.
  • a dose of 50 mJ/cm 2 /day was determined beforehand as being the minimal erythema dose for this strain of mice.
  • mice gradually develop microscopic and then macroscopic actinic keratosis lesions. These lesions were characterized at the histological and anatomopathological levels as being actinic keratosis lesions, comparable to the actinic keratosis lesions observed in humans.
  • the triptolide (Sequoia Research Products, U.K.) is formulated in a carrier consisting of 5% DMSO, 70% glycerol and 25% water.
  • the triptolide PCC plant cell culture extract
  • the triptolide PCC was purified from a meristematic cell culture from the Tripterygium wilfordii plant as described in the application WO 201 1/054929 (examples 1 to 7).
  • triptolide is administered to the animals in doses of 0.005% (or 10 ⁇ g per animal) or 0.025% (or 50 ⁇ g per animal) or 0.075% (or 150 ⁇ g per animal) by means of these compositions containing triptolide (triptolide or triptolide PCC).
  • 0.005% or 10 ⁇ g per animal
  • 0.025% or 50 ⁇ g per animal
  • 0.075% or 150 ⁇ g per animal
  • compositions to be evaluated are administered topically to the mice in order to evaluate the curative effect thereof on actinic keratosis lesions already present at the start of the treatment and the prophylactic effect thereof on the appearance of macroscopic lesions.
  • mice having visible actinic keratosis lesions are selected and randomized between the treatment and control groups according to the number of macroscopic lesions.
  • the groups comprise between 3 and 5 mice. UVB exposure is interrupted at the start of the treatments.
  • the products are administered in an occlusive manner in chambers of 19 mm in diameter (or 2.83 cm 2 ) placed and attached on a given area of each mouse using adhesive tape.
  • the composition containing triptolide is applied to the skin as a single occlusive application lasting 30 hours.
  • the occlusive dressing is removed after 30 hours and the animals are followed clinically for 4 weeks (weeks 17 to 20 after the start of UVB irradiation).
  • triptolide-free carrier is applied in the same manner. 1. 4. Evaluation of treatment efficacy
  • the animals are weighed three times per week between weeks 17 and 21.
  • the dorsal and lateral left and right surfaces of each animal are photographed once per week in order to follow changes in the actinic keratosis lesions.
  • the actinic keratosis lesions are counted within the treated area and outside this area in order to follow the progression of the lesions and the efficacy of the treatments.
  • Treated and untreated areas of skin from each animal are biopsied at the end of the study (week 21 ) for a histological and immunohistochemical analysis. The presence of actinic keratosis lesions is thus confirmed histologically and compared between the groups. The level of epidermal cell proliferation is evaluated by means of Ki67 labeling. 2. Results
  • 15C ⁇ g per animal are presented in Table 1 (Number of lesions per mouse and on average before and after the treatment) and Table 2 (Variation in % of the number of lesions per mouse and on average before and after the treatment).
  • Table 1 Number of lesions per mouse and averages before and after the treatment Variation in the number of lesions during the
  • Figure 1 in the form of a bar chart.
  • Figure 2 shows the macroscopic follow-up by means of photographs during time of the skin of treated mice representative of each group.
  • the number of actinic keratosis lesions increases systematically between week 17 and week 21 in the untreated areas for all the groups. This reflects the appearance of new lesions during this period as well as the development of microscopic lesions again in week 17 into macroscopic lesions ( Figure 1 ).
  • triptolide enables both the disappearance of existing lesions (shown by the systematic decrease in the number of lesions after the treatment) and the absence of the appearance of new lesions or of the development of microscopic lesions into macroscopic lesions, unlike within the untreated areas and in the controls.
  • the effect of triptolide is characterized by the induction, in the days following the treatment, of an erosion of the epidermis at the treated area, followed by reepithelialization of this area.
  • This effect is comparable to that observed with the reference products, namely ingenol mebutate and 5-fluorouracil. It should be noted that the effect obtained with both of these reference products seems to reach also the dermis and the hypodermis, leading to an increased skin toxicity (deep erosion, inflammation), which disturbs reepithelialization of the treated area, compared to the triptolide treatment.
  • a second study using this actinic keratosis model allows assessing triptolide (in a purified form obtained from plant) and triptolide PCC effect at doses of 1 C ⁇ g or 5C ⁇ g of triptolide per animal, triptolide being administered in compositions as defined previously containing purified triptolide or triptolide PCC.
  • a first group of mice has received 10 ⁇ g of triptolide in one application, a second group of mice has received 50 ⁇ g of triptolide in one application and a third group of mice (control group) has received only the carrier.
  • the results obtained are presented in Table 3 below.
  • Figure 3 in the form of a bar chart.
  • Figure 4 shows the macroscopic follow-up by means of photographs during time of the skin of treated mice representative of each group (carrier, triptolide 50 ⁇ g and triptolide PCC 50 ⁇ g).
  • the number of macroscopic actinic keratosis lesions is greatly reduced within the treated area between day 1 16 and day 136 with a reduction of 89% and 85% for a treatment with triptolide 50 ⁇ g and triptolide PCC 50 ⁇ g respectively and a reduction of 26% and 27% for a treatment with triptolide ⁇ ⁇ and triptolide PCC ⁇ ⁇ respectively.
  • the lesions present on the control mice increase of 30%.
  • triptolide The clinical efficacy of triptolide is further confirmed histologically after the animals are sacrificed and the skin biopsies are perfomed. Indeed, no actinic keratosis lesions are observed at the end of the study in the biopsies taken from within the treated areas. Normal epidermis is observed with dermal scar tissue.
  • a small fraction of epidermal cells has Ki67-positive labeling in normal epidermis, by immunohistochemical labeling with an anti— Ki67 antibody.
  • the increase in the number of proliferating (and thus Ki67-positive) epidermal cells is a histological feature of AK (acanthosis).
  • AK acanthosis
  • the amount of product in the plasma is below the method's lower limit of detection (i.e., below 10 ng/ml) in plasma, whereas about 2100 ng/g is detected in the treated skin.
  • Triptolide thus accumulates in the skin and exhibits very low or no transcutaneous passage, which is a very important and favorable point for use locally.
  • the kinetics and degree of penetration of triptolide through human skin were determined by the protocol known commonly as the Franz static diffusion cell (OECD Guideline for the Testing of Chemicals: New Guideline 428, Skin Absorption: In Vitro Method (13 April 2004)).
  • Franz cells are used to determine, ex vivo, the cutaneous penetration of exogenous substances. In fact, this technique measures the speed of passage through the various layers of the cutaneous barrier of molecules constituting the active ingredient deposited on the skin surface.
  • a composition containing the molecule to be studied is deposited in the so-called "donor” chamber of the device. The molecule then diffuses through a membrane (skin, in this case) and is collected in the so-called “receptor” chamber.
  • the skin fragment is deposited on a diffusion cell, called a Franz cell.
  • the deep side of the dermis is in contact with receptor solution, which is supposed to replace the interstitial fluid of the skin.
  • a formulation containing the molecule under study is deposited on the top of the skin.
  • the receptor solution is sampled at regular time intervals - in order to assay molecules having crossed the defatted skin - and replaced with fresh solution.
  • the assay of substances present in the sampled receptor phase makes it possible to determine the amount of molecules having crossed the skin.
  • the skin used in the present experiment is that of human donors.
  • the analysis involves liquid/liquid extraction, with hydrocortisone as the internal standard, followed by analysis by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).
  • compositions used are described in Table 4 below.
  • the placebo formulation serves as the control.
  • Composition A with triptolide
  • Receptor fluid Water:ethanol (80:20; v/v)
  • Table 4 Compositions and protocol on human skin
  • the results show low absorption of triptolide after 24 hours of application (about 1 .1 % of the amount applied is considered bioavailable). This amount corresponds to the amount found in the skin (epidermis + dermis) and the receptor fluid (RF).
  • Triptolide is known to be very reactive and also toxic in large amounts. This result of a low level of systemic passage is surprising and unexpected and makes it possible to envisage a topical application of triptolide with no danger to humans.

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Abstract

La présente invention concerne un composé choisi parmi le triptolide, ses dérivés et des sels pharmaceutiquement acceptables de triptolide et de ses dérivés, ou une composition comprenant un tel composé, destinés à être utilisés dans le traitement topique et/ou la prévention d'une tumeur ou d'une pathologie précancéreuse de la peau.
PCT/EP2016/051306 2015-01-22 2016-01-22 Triptolide et ses dérivés dans le traitement de tumeurs et de pathologies précancéreuses de la peau WO2016116587A1 (fr)

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CN111494319A (zh) * 2020-06-15 2020-08-07 沈阳药科大学 雷公藤甲素复方组合物及其制备方法与应用

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US20020068098A1 (en) * 2000-08-01 2002-06-06 Ashni Naturaceuticals, Inc. Combinations of diterpene triepoxide lactones and ditepene lactones or triterpenes for synergistic inhibition of cyclooxygenase-2
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111440185A (zh) * 2020-03-31 2020-07-24 中国农业科学院蜜蜂研究所 一种半抗原及其在检测雷公藤乙素和雷公藤甲素方面的应用

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