WO2012028758A1 - Use of crassula for treating proliferative diseases - Google Patents

Use of crassula for treating proliferative diseases Download PDF

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Publication number
WO2012028758A1
WO2012028758A1 PCT/ES2011/070608 ES2011070608W WO2012028758A1 WO 2012028758 A1 WO2012028758 A1 WO 2012028758A1 ES 2011070608 W ES2011070608 W ES 2011070608W WO 2012028758 A1 WO2012028758 A1 WO 2012028758A1
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Prior art keywords
skin
pharmaceutical composition
wart
plants
treatment
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PCT/ES2011/070608
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Spanish (es)
French (fr)
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José Manuel RUIZ CHINCHILLA
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Servicio Andaluz De Salud
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    • 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)
    • A61K36/41—Crassulaceae (Stonecrop family)
    • 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
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • 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
    • A61P31/20—Antivirals for DNA viruses
    • 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 is within the field of pharmacology, pharmacognosy and medicine, and refers to the use of plants of the genus Crassula, and more specifically of the Crassula argéntea plant, of the extracts of said plants or of a principle active obtained from said plant material or extracts, and from the pharmaceutical forms containing said plant, its extracts or the active ingredients or useful secondary metabolites, such as antimitotics and antiproliferatives, for the treatment of proliferative diseases, for the treatment of warts, and specifically, for the treatment of plantar wart.
  • a papilloma is a general term that refers to a benign tumor of epithelial cells that grows with external projection similar to very small fronds.
  • a papilla refers to the projection created by the tumor and not a tumor growing on a preexisting papilla, such as the nipple. They are usually born and grow from the skin, conjunctiva, mucous membranes or glandular ducts.
  • HPV Human papillomavirus
  • Papillomaviridae Human papillomavirus
  • HPVs Like all viruses in this family, HPVs only establish productive infections in the stratified epithelium of the skin and mucous membranes of humans, as well as a variety of animals (ICD-10 B 97.7, b 95; ICD-9 079.4 078.1; 079 ; DiseasesDB 6032; MeSH D030361). About 200 different types of HPV have been identified, most of which cause no symptoms in most people.
  • HPV HPV
  • Some types of HPV can cause warts or condylomas, while others can generate subclinical infections, which can (in a minority of cases) lead to cervical cancer, vulvar cancer, vagina and anus in women, or anal and penile cancer in men .
  • a wart is a skin lesion caused by human papillomavirus (HPV).
  • HPV human papillomavirus
  • Viral warts are benign, epidermal, viral and easily transmitted neo formations. Warts are among the 10 most frequent dermatoses, affect both sexes, with a prevalence of HPV infection of 79% in the general population (Lizárraga et al., 2009. Cent Dermatol Easter, 18 (1): 5-18). They have a variable shape, usually globular, that can affect different areas of the skin. Its removal is not easy since warts have their own blood supply system that causes heavy bleeding when they are removed by non-clinical means; They can also regenerate with greater virulence. Additionally it compromises several nerve terminals, so its extraction or manipulation causes great pain. The development of warts is favored when there are failures in the immune system.
  • the affected area is different: the hands, face, neck, feet, ano-genital area, armpits, or any other part of the body.
  • the three most common clinical forms are: vulgar (70%), plantar (26%) and flat (4%) warts (Woolf et al., 2005. Fitzpatrick's, atlas color & synopsis of clinical dermatology. 5th ed. Philadelphia; McGraw -hill, 776-81; Arenas, 2005. Dermatology Diagnosis and treatment 3rd ed Mexico; McGraw-Hill... 656-667)
  • Verruciform epidermodisplasia more than 15 types
  • Table 1 HPV-induced diseases.
  • the vulgar wart is associated with HPV genotypes 1, 2, 4 and 7 and is presented as circumscribed excrescences of the same skin color, with a corneal surface and a scratchy touch. They can appear on any skin surface, preferably on the back of the hands and fingers, followed in frequency: face, neck and scalp.
  • Anogenital warts have characteristics and variable oncogenic potential.
  • Plantar warts which appear on the soles of the feet, are also called fish eyes. Plantar warts (pedis wart; VP; Viral infections characterized by skin lesions and mucous membranes CIE-10: B07 // ICD-9-CM Diagnosis Code 078.19) are, therefore, warts caused by the human papillomavirus ( HPV) Affecting between 7% and 10% of the general population (Chicharro and Alonso, 2007), no significant differences were found in the prevalence of this disease by sex (Pique and cois., 1997; Lipke, 2006) and the largest The frequency of this lesion occurs in patients aged between 5 and 20 years (Palomo, 2000.
  • HPV human papillomavirus
  • patients who have had plantar and palm warts are 3 times more likely to develop new lesions than those not affected (Palomo, 2000. Podoscopio, 1 (1 1): 24-32; Lipke, 2006. Clinical Medicine & Research, 4 (4), 273-293).
  • Warts can be painful or not, depending on their size, evolution time, location and subtype of human papillomavirus. Sometimes they are grouped giving rise to thickened plates with granular surface that are called mosaic warts. VPs often differ from helomas by observing skin stretch marks. The feet, like the hands, are covered with these stretch marks commonly called fingerprints.
  • plantar warts When plantar warts occur, stretch marks surround the lesion; when it is not for wart you ask, the cellular DNA is not altered and the stretch marks continue above it.
  • plantar warts tend to cause pain by applying pressure to the sides of the lesion rather than directly; Helomas tend to do it the opposite way and they hurt when pressed directly and not by the banks.
  • the most common areas of the appearance of plantar warts or papillomas are below the metatarsal, lateral toes of the first finger and heel.
  • the palmar papillomas appear in the palm of the hands and palmar area of the fingers, the so-called vulgar warts being the ones on the back of the hands, fingers and periungers that must be distinguished from the previous ones.
  • the place where both types of papillomas appear implies, as a rule, a limitation in the activities of daily life (Lafuente et al., 1999. Revista Espa ⁇ ola de Podolog ⁇ a, X (2): 92-96 ).
  • HPVs are typically transmitted through sexual contact, infecting the anogenital region.
  • Some types of sexual transmission of HPV can cause genital warts.
  • other types of HPV that can infect the genitals do not cause any appreciable signs of infection.
  • a persistent infection with a subgroup of about 13 sexually transmitted HPVs including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 , 68 - which are different from those that cause warts - may favor the development of:
  • VIN intraepithelial vulvar neoplasia
  • PIN intraepithelial penile neoplasia
  • HPV squamous cell oropharyngeal carcinoma
  • head and neck cancer Several types of HPV, particularly type 16, have been found associated with squamous cell oropharyngeal carcinoma, a form of head and neck cancer.
  • HPV infection There is evidence that a large number of cancers have their origin in HPV infection (Zur Hausen 1996. Biochim Biophys Acta Oct 9; 1288 (2): F55-F78), which include: cervical cancer ( cervical) and cancer of various organs, such as: oral mucosa, tonsil, pharynx, larynx, esophagus, breast, prostate, ovary, urethra and skin. Recent works on melanocytic line tumors give this virus an important role, especially in the evolutionary aspects of the disease (Dreau et al., 2000. Annals of Surgery 231: 664-671). HPV-induced cancers often have viral sequences integrated into cellular DNA.
  • HPV genes such as E6 and E7
  • the p53 protein prevents cell growth in the presence of primarily damaged DNA through the X-protein domain associated with BCL-2 (BAX) (which blocks the effects of mitochondrial BCL-2 receptor antiapoptosis.
  • BAX BCL-2
  • p53 it also overregulates the p21 protein, blocking the formation of the cyclin D / Cdk4 complex, and thus preventing the phosphorylation of RB and, in turn, causing the cell cycle progression to prevent activation of E2F.
  • p53 is a tumor suppressor gene that arrests the cell cycle, when there is damaged DNA.
  • the E6 and E7 proteins work by inhibiting tumor suppressor genes, in such a process: E6 inhibits p53, while E7 inhibits p53, p21, and RB.
  • HPV high-risk types of HPV
  • women without a history of viruses do not develop this type of cancer.
  • most HPV infections are quickly resolved by the immune system and do not progress to cervical cancer.
  • cancer occurs in people who have been infected with HPV for a long time, usually a decade or more.
  • sexually transmitted HPVs can also cause the largest fraction of anal cancer and approximately 25% of mouth and throat cancer (oropharynx). The latter is commonly present in the area of the tonsils, and HPV is linked to the increase in oral cancer in non-smokers.
  • Types of HPV 6 and 1 1 can cause a rare condition known as recurrent laryngeal papillomatosis (a respiratory papillomatosis), where warts form in the larynx or other areas of the respiratory tract. These warts can recur frequently, and require repetitive surgeries, interfere with breathing, and in extremely rare cases progress towards cancer.
  • a respiratory papillomatosis a respiratory papillomatosis
  • cryotherapy In the second line of action is cryotherapy, with this local cold, up to 80% of plantar warts are mirmecia type and 50% in mosaic warts, followed by intralesional immunotherapy (Candida antigen) and pulsed laser.
  • the third line of action would include cytotoxic agents (intralesional bleomycin and podophyllinum), immunomodulars (iniquimod, cimetidine) and surgical excision. These treatments are usually used in recalcitrant warts when the first and second lines of action have failed (Micali et al., 2004. American Journal of Clinical Demartology, 5: 31 1-317). Recurrences are very common with the vast majority of treatments because they fail to eliminate the virus completely (Gibbs et al., 2003. Cochrane Datábase Syst Rev. (3): CD00178)
  • the authors of the present invention have identified the therapeutic effect of plants of the genus Crassula and specifically of the plant Crassula argéntea and of its extracts against proliferative diseases, both benign and malignant, and mainly against proliferative diseases of the skin, including warts caused by human papillomavirus infections, and especially against plantar warts.
  • This treatment has the advantages that it is painless, easy to apply by the patient (self-care), very low cost, and also reduces the functional incapacitation of the patient from the beginning of treatment. In addition, it improves the healing time, decreases the size of the papillomas and reduces the pain associated with the process with respect to treatment with salicylic acid.
  • a first aspect of the invention relates to the plant material of plants of the genus Crassula, the extracts of said plants, or an active ingredient obtained from said plant material or extracts, hereinafter plant material, extract or active principle of the invention, for the treatment of proliferative diseases or alternatively, to the use of plant material of plants of the genus Crassula, of the extracts of said plants, or of an active principle obtained from said plant material or of the extracts , for the treatment of proliferative diseases.
  • plant material means both the aerial or underground parts of plants or other plant materials such as juices, resins, fatty oils, essential oils and any other substances of this nature, such as combinations thereof, in condition raw or in the form of vegetable preparations.
  • Extracts are concentrated preparations of liquid, solid or intermediate consistency, normally obtained from fresh, or more preferably dried, plant material.
  • the material to be extracted may require prior treatment, such as enzyme inactivation, crushing or degreasing.
  • the extracts are prepared by maceration, percolation or by other suitable validated methods using ethanol or other solvent. After extraction, if necessary, unwanted substances are removed.
  • Extraction methods are known to those skilled in the art, and are described, for example, but not limited to, in the Royal Spanish Pharmacopoeia or the European Pharmacopoeia. Extraction technologies include extraction in supercritical fluids and other more conventional methods, such as steam entrainment, extraction by solution (solid - liquid or liquid - liquid) and centrifugal extraction.
  • the disease refers to any substance used for prevention, diagnosis, relief, treatment or cure of diseases in man and animals.
  • the disease is a proliferative disease, preferably it is a proliferative disease of the skin or mucous membranes, even more preferably it is an infection of the human papillomavirus, and even more preferably it is the plantar wart.
  • the medicine can be an herbal medicine.
  • Herbal medicines are defined herein as finished and labeled medicinal products whose active ingredients are formed by aerial or underground parts of plants or other plant materials or combinations thereof, in the raw state or in the form of plant preparations. Herbal medicines may also contain natural organic or inorganic active ingredients that are not of plant origin.
  • Vegetable preparations include crushed or powdered plant materials, extracts, tinctures, fatty or essential oils, juices obtained by expression and preparations whose production involves fractionation, purification or concentration.
  • the plant material is a plant preparation.
  • plant in this report, all organisms that can be classified within the Viridiplantae kingdom are understood, which includes green algae and terrestrial plants (Embryophyta).
  • Plants of the genus Crassula are herbaceous plants, in our annual latitudes; in other perennial latitudes, shrubs or succulent sub-shrubs. Leaves ⁇ fleshy, opposite, usually ordered, sometimes welded forming a sheath Basilar, usually simple, undivided and whole, flat, semi-cylindrical, cylindrical, ovoid, etc. Tetrámeras or pentámeras flowers, exceptionally trimeric, symmetrical, small and not very showy, solitary, in pairs, in peaks clustered in sessile or pedunculated fascicles, in thyroidal or corymbous, axillary or terminal inflorescences. Sepals free or ⁇ soldiers at the base, ⁇ succulent.
  • Persistent corolla usually white, sometimes pink, red or carmine, but only rarely yellow; erect, crashed petals, ⁇ patents, welded at the base forming a short ⁇ tube. Stamens free and with the filaments welded at the base of the corolla tube, alternate them; ovate, oblong or sub-spherical anthers. Free carpets or soldiers at the base, attenuated or contracted in a style, funky or papillose in the suture; sometimes very short or subnull style; 1 -4 or numerous seminal rudiments in each carpel. Polyfolicle fruit. Seeds 1-12 in each follicle. Nectariferous scales shorter than carpels, hyalines, red-bellied or pink, from spatula to obovate or cuneate.
  • the genus is composed of more than 300 species, most of them from South Africa, others from tropical Africa, North America, Madagascar, India, Europe and some, finally, of subcosmopolitan distribution.
  • the plant belongs to the species Crassula argéntea Thunb. (Nova Acta Phys.-Med. Acad. Caes. Leop.-Carol. Nat. Cur. 6: 329, 337. 1778).
  • the plant belongs to the species Crassula ovata (Mili.) Druce (Bot. Soc. Exch. Club. Brit. Isles: 617, 1917)
  • the organisms of the species Crassula argéntea and C .vata belong to
  • Proliferative diseases can be benign or malignant, and among them are, for example, but not limited to, tumors and proliferative diseases of the skin.
  • tumors include but are not limited to: lung cancer (eg, pulmonary adenocarcinoma), pancreatic cancers (such as, for example, pancreatic carcinoma, exocrine pancreatic carcinoma), colon cancers (for example, colon-rectum carcinomas, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma and epidermal carcinoma.
  • lung cancer eg, pulmonary adenocarcinoma
  • pancreatic cancers such as, for example, pancreatic carcinoma, exocrine pancreatic carcinoma
  • colon cancers for example, colon-rectum carcinomas, for example, colon adenocarcinoma and colon adenoma
  • proliferative skin diseases include, but are not limited to, actinic keratosis, basal cell carcinoma, pavement cell carcinoma, fibrous histiocytoma, dermatofibrosarcoma protuberans, hemangioma, flaming nevus, xanthoma, Kaposi's sarcoma, mastocytosis, fungoid mycosis, lentigo , nevocellular nevus, malignant lentigo, malignant melanoma, metastatic carcinoma, psoriasis or productive infections of human papillomavirus (HPV or HPV) in the stratified epithelium of the skin and mucous membranes of humans, as well as a variety of animals .
  • HPV or HPV human papillomavirus
  • the proliferative disease is selected from the list comprising: lung cancer, pancreatic cancers, colon cancers, myeloid leukemias, thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma and proliferative diseases of the skin.
  • the proliferative disease is a proliferative disease of the skin.
  • the proliferative skin disease is selected from the list comprising: actinic keratosis, basal cell carcinoma, pavement cell carcinoma, fibrous histiocytoma, dermatofibrosarcoma protuberans, hemangioma, flaming nevus, xanthoma, Kaposi's sarcoma, mastocytosis, fungoid mycosis, lentigo, nevocellular nevus, lentigo malignant, malignant melanoma, metastatic carcinoma, psoriasis or human papillomavirus infections.
  • the diseases caused by human papillomavirus infection are selected from the list comprising: squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, cervical cancer, oral mucosal cancer, tonsil, pharynx, larynx, esophagus, breast, prostate, ovary, vulva, urethra, penis and skin, tumors of melanocytic lineage, common wart, plantar wart, flat skin wart, genital warts, verruciform epidermodisplasia, epithelial focal hyperplasia (oral), or oral papillomas .
  • the human papillomavirus infection is the plantar wart.
  • the plantar wart is caused by infection of human papillomavirus type 1.
  • the plantar wart is produced by the infection of the human papillomavirus type 2.
  • the plantar wart is produced by the infection of the human papillomavirus type 4.
  • compositions hereinafter the first composition of the invention, comprising the plant material, the extract or an active ingredient of the invention.
  • composition may be a pharmaceutical composition. Therefore, another aspect of the invention relates to a pharmaceutical composition, hereinafter second composition of the invention, comprising the plant material, the extract or an active ingredient of the invention.
  • compositions of the present invention can be formulated for administration to an animal, and more preferably to a mammal, including man, in a variety of ways known in the state of the art.
  • they can be, without limitation, in sterile aqueous solution or in biological fluids, such as serum.
  • Aqueous solutions may be buffered or unbuffered and have additional active or inactive components. Additional components include salts to modulate ionic strength, preservatives including, but not limited to, antimicrobial agents, antioxidants, chelators, and the like, and nutrients including glucose, dextrose, vitamins and minerals.
  • the compositions can be prepared for administration in solid form.
  • compositions can be combined with several inert vehicles or excipients, including but not limited to; binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid or corn starch; lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint or methyl salicylate.
  • binders such as microcrystalline cellulose, gum tragacanth, or gelatin
  • excipients such as starch or lactose
  • dispersing agents such as alginic acid or corn starch
  • lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin
  • flavoring agents such as peppermint or methyl salicylate.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises excipients.
  • the pharmaceutical composition may further comprise another active ingredient.
  • active ingredient means any component that potentially provides a pharmacological activity or other different diagnostic effect, cure, mitigation, treatment, or prevention of a disease, or that affects the structure or function of the body of man or other animals.
  • the term includes those components that promote a chemical change in the preparation of the drug and are present therein in a modified form intended to provide the specific activity or effect.
  • the pharmaceutical form of the invention which comprises the second composition of the invention.
  • the pharmaceutical form of the invention is selected from the list comprising: plaster, ointment, paste, cream, solution, suspension, emulsion, lotion, liniment, gel, foam, powder, or any of their combinations.
  • the pharmaceutical form is a plaster.
  • pharmaceutical form means the mixture of one or more active ingredients with or without additives that have physical characteristics for proper dosage, preservation, administration and bioavailability.
  • a “plaster” or “patch” is a pharmaceutical form that consists of a solid or semi-solid form that contains the active ingredient or additives, spread on a cloth, plastic or adhesive tape, which serves as a support and protection, in addition to having an occlusive effect and macerating action that also allows direct contact with the skin and softens with body temperature.
  • an “ointment” or “ointment” is a pharmaceutical form consisting of a soft consistency preparation that contains the active ingredient or additives incorporated into an appropriate base that gives it mass and consistency. It adheres and is applied to the skin and mucous membranes.
  • This base can be lioluble or id rosoluble, it is generally anhydrous or with a maximum of 20 percent water. It is also called hydrophilic ointment when it contains a washable or removable base with water.
  • a “paste” is a pharmaceutical form consisting of a semi-solid form containing the active ingredient or additives, made from a high concentration of insoluble powders (20 to 50 percent), in fatty or aqueous, absorbent or weak abrasives combined with soaps.
  • a “cream” is a pharmaceutical form that consists of a liquid or semi-solid preparation containing the active ingredient or additives necessary to obtain an emulsion, generally oil in water, with a water content greater than 20 percent.
  • a “solution” is a pharmaceutical form that consists of a liquid, transparent and homogeneous preparation, obtained by dissolving it or the active ingredients and additives in water, and which is used for external or internal use. In the case of injectable, ophthalmic and otic solutions they must be sterile solutions.
  • a “suspension” is a pharmaceutical form consisting of a dispersed system, composed of two phases, which contain the active ingredient or additives.
  • One of the phases is generally a liquid or a semi-solid and the dispersed or internal phase, is constituted of insoluble solids (active principles), but dispersible in the external phase.
  • An "emulsion” is a pharmaceutical form consisting of a heterogeneous system, generally consisting of two liquids not miscible with each other; in which the dispersed phase is composed of small globules distributed in the vehicle in which they are immiscible.
  • the dispersed phase is also known as internal and the dispersion medium is known as the external or continuous phase.
  • the active ingredient or additives may be in the external or internal phase.
  • a “lotion” is a pharmaceutical form that can be presented as a solution, suspension or emulsion, which contains the active ingredient (s) and additives, and whose dispersing agent is predominantly water.
  • a “liniment” is a pharmaceutical form that consists of a liquid presentation, solution or emulsion that contains the active ingredient or additives whose vehicle is aqueous, alcoholic or oily.
  • a “jelly” is a pharmaceutical form that consists of a semi-solid colloid that contains the active ingredient or additives, whose water-soluble base is usually made up of gums such as tragacanth, other bases used are: glycerin, pectin, alginates , boroglycerinated compounds, synthetic derivatives or natural substances such as carboxymethyl cellulose.
  • a “gel” is a pharmaceutical form consisting of semi-solid preparation, which contains the active ingredient or additives, solid in a liquid that can be water, alcohol or oil, such that a network of particles trapped in the liquid phase.
  • a “foam” is a pharmaceutical form consisting of a semi-solid preparation, consisting of two phases: a liquid that carries the active ingredient (s) and additives, and another gas that carries propellant gas so that the product comes out in the form of a cloud.
  • Another aspect of the invention relates to the use of the second composition or the pharmaceutical form of the invention, for the preparation of a medicament for the treatment of proliferative diseases, or alternatively, to the second composition or to the pharmaceutical form of the invention for the treatment of proliferative diseases.
  • the proliferative disease is selected from the list comprising: lung cancer, pancreatic cancers, colon cancers, myeloid leukemias, thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma and proliferative diseases of the skin.
  • proliferative skin disease is selected from the list comprising: actinic keratosis, basal cell carcinoma, pavement cell carcinoma, fibrous histiocytoma, dermatofibrosarcoma protuberans, hemangioma, flaming nevus, xanthoma, Kaposi's sarcoma, mastocytosis, fungoid mycosis, lentigo, nevocellular nevus, malignant lentigo, malignant melanoma, metastatic carcinoma, psoriasis or diseases caused by human papillomavirus infections.
  • diseases caused by infection of human papillomavirus are selected from the list comprising: squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, cervical cancer, oral mucosal cancer, tonsil, pharynx, larynx , esophagus, breast, prostate, ovary, vulva, urethra, penis and skin, tumors of melanocytic lineage, common wart, plantar wart, flat skin wart, genital warts, verruciform epidermodisplasia, epithelial focal hyperplasia (oral), or oral papillomas.
  • Another even more preferred embodiment relates to the use of a pharmaceutical composition or a pharmaceutical form of the invention, in the preparation of a medicament for the treatment of warts, or alternatively, a pharmaceutical composition or a pharmaceutical form of the invention for its use in the treatment of warts.
  • Another even more preferred embodiment relates to the use of a pharmaceutical composition or a pharmaceutical form of the invention, in the preparation of a medicament for the treatment of plantar wart, or alternatively, to a pharmaceutical composition or a pharmaceutical form of the invention for use in the treatment of plantar wart.
  • Another even more preferred embodiment relates to the use of a pharmaceutical composition or of a pharmaceutical form of the invention, in the preparation of a medicament for the treatment of the palmar wart, or alternatively, to a pharmaceutical composition or a pharmaceutical form of the invention for use in the treatment of palmar wart.
  • the viral disease is an infection of a human papillomavirus.
  • human papillomavirus infection results in a wart.
  • the wart is a plantar wart.
  • the wart is a palmar wart.
  • compositions and / or their formulations can be administered to an animal, including a mammal and, therefore, to man, in a variety of ways, including, but not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intracecal, intraventricular, oral. , enteral, parenteral, intranasal or topical.
  • the administration of the compositions of the invention is topical.
  • the dosage to obtain a therapeutically effective amount depends on a variety of factors, such as the age, weight, sex, tolerance, ... of the mammal.
  • the term "therapeutically effective amount” refers to the amount of plant material from plants of the genus Crassula, extracts or an active ingredient obtained from the plant material or extracts, which produce the desired effect. and, in general, it will be determined, among other cases, by the characteristics of its own prodrugs, derivatives or analogs and the therapeutic effect to be achieved.
  • the "adjuvants” and “pharmaceutically acceptable carriers” that can be used in said compositions are the vehicles known to those skilled in the art.
  • Fig. 4 Location of lesions, md: right hand; My left hand; mid: left and right hand; pd: right foot; pi: left foot; pid: left and right foot; mp: hand and foot.
  • Fig. 5 Number of injuries per patient.
  • Two tablespoons of the plant in 200 g of petroleum jelly are boiled over low heat for approximately ten minutes, it is possible to use a single plant or a mixture of fresh or dried roots, leaves or flowers.
  • Preferably sheets are used.
  • a mixture of various oils can be used as a base instead of petroleum jelly. This mixture of oils acts as a vehicle for the active components and helps them to penetrate through the skin, in addition to helping to achieve the desired texture.
  • Compresses or promotions are a very effective method to apply medicinal substances to the skin.
  • a compress is prepared with a cloth (cotton, gauze) that is soaked in an infusion or hot decoction on the affected area. The heat increases the effect of the plants, the compress will have to be changed when it cools or a plastic is placed on it.
  • the mode of action of the plaster is very similar to that of a compress, but with the difference that is prepared with solid plant material instead of liquid.
  • the leaves or the material from the root should be applied directly to the skin or wrapped with thin gauze. If it is dry plants, a paste is prepared by adding hot water or apple cider vinegar, until it acquires the right consistency. To keep the poultice warm, place a bottle of hot water on the poultice.
  • An infusion of Crassula argéntea leaves is prepared by soaking approximately 4 cm 3 of said leaves in 1 liter of water, at a suitable temperature, and for a time not less than 10 minutes. If desired, pressure may be exerted on the residue before administration.
  • the infusion can be used 16 m 3 leaves per liter of water.
  • the infusion can also be prepared from water that has previously boiled, or by cooking the residue in the water.
  • a tincture can be prepared by soaking the plant material of Crassula argues in a solution of approximately 60% ethanol and 40% water. Pure ethanol, acetone, chloroform, vinegar or other similar agents can be used. The volume of the resulting solution must be 3 or 4 times the volume of the plant material used. The mixture should be stirred, at least occasionally, over a period of about two hours, with a maximum extraction obtained after 6 hours. If the tincture is left overnight, it produces excellent results. Drops can be prepared by reducing the tincture by heat, or by passive evaporation. The drops are concentrated by a factor of approximately 10 times.
  • a lotion, a cream, or a shampoo can be prepared by adding drops or tincture to a lotion, a cream, or a commercial shampoo to reach approximately 25% of the volume of said lotion, cream, or shampoo.
  • the most effective pharmaceutical form for the treatment of plantar warts are the plasters, even the direct application of the leaves of the plant and the affected area.
  • the application can be repeated several days, until the disappearance of the plantar wart.
  • the sheet should be approximately 3 to 5 cm long, 2 to 3 cm wide and about 2 or 3 millimeters thick.
  • the application should be daily, at night, at bedtime, and will consist of putting the part of the pulp in direct contact with the lesion and fasten it with a tape. In the morning remove the plant. The effectiveness of this treatment has been demonstrated in more than 160 patients.
  • Figures 1, 2 and 3 show images of the temporal evolution of two cases of plantar warts, and one of palmar warts,
  • composition of the invention has been administered topically to an initial total of 158 patients, 65 men and 93 women, with prior consent, for the treatment of plantar and palmar papilloma, warts, hardnesses and hielomas. All patients were instructed to apply the study composition
  • the mean age was 33.8 ⁇ 19.4 years, with approximately 70% of patients between 18 and 50 years.
  • the lesions were mostly located in the left foot, distributed mainly in an area, almost never combined. 5.3% were located simultaneously in the right and left hand, also 5.3% was located simultaneously in the right and left foot, 13.8% was located in the left hand, 19.1% was located on the right hand, 21, 1% was located on the right foot, and 34.2% was located on the left foot (Fig. 4).
  • the treatment period was 5 months, reviewing 80 cases in the first month, and 60 cases in the third month of treatment.
  • the pathology had disappeared in 43.8% of the cases, having been reduced in 25% of the cases, 1 1, 3% of the patients did not follow the treatment, and could not be located 7.5% of patients.
  • the pathology had disappeared in 48.5% of the cases, having been reduced in 9.1% of the cases, the follow-up could not be done to 18.2% of the patients .

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Abstract

The invention relates to the use of plants of the Crassula genus, the extracts thereof, or an active principle obtained from the plant material of the plants or the extracts of said plant material, for the treatment of both benign and malignant proliferative diseases, mainly proliferative skin diseases, including warts caused by the human papillomavirus, particularly plantar warts. The invention also relates to pharmaceutical compositions and formulations that include said plant material, extracts, or active principles.

Description

USO DE CRASSULA PARA EL TRATAMIENTO DE ENFERMEDADES  USE OF CRASSULA FOR THE TREATMENT OF DISEASES
PROLIFERATIVAS.  PROLIFERATIVES
La presente invención se encuentra dentro del campo de la de la farmacología, la farmacognosia y la medicina, y se refiere al uso de plantas del género Crassula, y más concretamente de la planta Crassula argéntea, de los extractos de dichas plantas o de un principio activo obtenido a partir de dicho material vegetal o de los extractos, y de las formas farmacéuticas que contengan dicha planta, sus extractos o los principios activos o metabolitos secundarios útiles, como antimitóticos y antiproliferativos, para el tratamiento de enfermedades proliferativas, para el tratamiento de verrugas, y específicamente, para el tratamiento de la verruga plantar. The present invention is within the field of pharmacology, pharmacognosy and medicine, and refers to the use of plants of the genus Crassula, and more specifically of the Crassula argéntea plant, of the extracts of said plants or of a principle active obtained from said plant material or extracts, and from the pharmaceutical forms containing said plant, its extracts or the active ingredients or useful secondary metabolites, such as antimitotics and antiproliferatives, for the treatment of proliferative diseases, for the treatment of warts, and specifically, for the treatment of plantar wart.
ESTADO DE LA TÉCNICA Según datos de la OMS, el 80% de la población mundial - principalmente en países del tercer mundo- se trata con remedios obtenidos de las plantas medicinales. De las cientos de miles de especies de platas que existen sobre la tierra, apenas una quinta parte ha sido probada médicamente. Además, cada especie puede tener varios principios activo, con igual o distinto efecto terapéutico. También según datos de la OMS, el 25% de las medicinas que se recetan en los países industrializados tienen ya un origen vegetal, mientras que otro 25% está constituido por derivados modificados químicamente de productos naturales. STATE OF THE TECHNIQUE According to WHO data, 80% of the world's population - mainly in third world countries - is treated with remedies obtained from medicinal plants. Of the hundreds of thousands of species of silver that exist on earth, only one fifth has been medically tested. In addition, each species can have several active ingredients, with the same or different therapeutic effect. Also according to WHO data, 25% of the medicines prescribed in industrialized countries already have a plant origin, while another 25% is made up of chemically modified derivatives of natural products.
En medicina, un papiloma es un término general que se refiere a un tumor benigno de células epiteliales que crece con proyección externa a semejanza de frondas muy pequeñas. En ese contexto, una papila se refiere a la proyección creada por el tumor y no a un tumor creciendo sobre una papila preexistente, como el pezón. Por lo general nacen y crecen desde la piel, conjuntiva, membranas mucosas o conductos glandulares. In medicine, a papilloma is a general term that refers to a benign tumor of epithelial cells that grows with external projection similar to very small fronds. In that context, a papilla refers to the projection created by the tumor and not a tumor growing on a preexisting papilla, such as the nipple. They are usually born and grow from the skin, conjunctiva, mucous membranes or glandular ducts.
Los virus del papiloma humano (VPH o HPV del inglés human papilomavirus) son un grupo diverso de virus ADN perteneciente a la familia de los Papillomaviridae. Como todos los virus de esta familia, los VPH sólo establecen infecciones productivas en el epitelio estratificado de la piel y mucosas de humanos, así como de una variedad de animales (CIE-10 B 97.7, b 95; CIE-9 079.4 078.1 ; 079; DiseasesDB 6032; MeSH D030361 ). Se han identificado alrededor de 200 tipos diferentes de VPH, la mayoría de los cuales no causan ningún síntoma en la mayor parte de la gente. Algunos tipos de VPH pueden causar verrugas o condilomas, mientras otros pueden generar infecciones subclínicas, que pueden (en una minoría de casos) dar lugar a cáncer cervical, cáncer de vulva, vagina y ano en mujeres, o cáncer de ano y pene en hombres. Human papillomavirus (HPV or HPV) is a diverse group of DNA viruses belonging to the Papillomaviridae family. Like all viruses in this family, HPVs only establish productive infections in the stratified epithelium of the skin and mucous membranes of humans, as well as a variety of animals (ICD-10 B 97.7, b 95; ICD-9 079.4 078.1; 079 ; DiseasesDB 6032; MeSH D030361). About 200 different types of HPV have been identified, most of which cause no symptoms in most people. Some types of HPV can cause warts or condylomas, while others can generate subclinical infections, which can (in a minority of cases) lead to cervical cancer, vulvar cancer, vagina and anus in women, or anal and penile cancer in men .
Una verruga es una lesión cutánea causada por el virus del papiloma humano (VPH). Las verrugas virales son neo formaciones benignas, epidérmicas, de origen viral y de fácil transmisión Las verrugas se encuentran entre las 10 dermatosis más frecuentes, afectan a ambos sexos, con una prevalencia de infección por VPH del 79% en la población general (Lizárraga et al., 2009. Cent Dermatol Pascua, 18 (1 ): 5-18). Presentan una forma variable, generalmente de forma globular, que pueden afectar a distintas zonas de la piel. Su extirpación no es fácil ya que las verrugas tienen su propio sistema de irrigación sanguínea que causan sangrados abundantes cuando su extracción es por medios no clínicos; además pueden regenerarse con mayor virulencia. Adicionalmente compromete varios terminales nerviosos, por lo que su extracción o manipulación causa gran dolor. El desarrollo de verrugas se favorece cuando hay fallos en el sistema inmunitario. A wart is a skin lesion caused by human papillomavirus (HPV). Viral warts are benign, epidermal, viral and easily transmitted neo formations. Warts are among the 10 most frequent dermatoses, affect both sexes, with a prevalence of HPV infection of 79% in the general population (Lizárraga et al., 2009. Cent Dermatol Easter, 18 (1): 5-18). They have a variable shape, usually globular, that can affect different areas of the skin. Its removal is not easy since warts have their own blood supply system that causes heavy bleeding when they are removed by non-clinical means; They can also regenerate with greater virulence. Additionally it compromises several nerve terminals, so its extraction or manipulation causes great pain. The development of warts is favored when there are failures in the immune system.
Dependiendo del serotipo del virus, la zona afectada es distinta: las manos, la cara, la nuca, los pies, la zona ano-genital, las axilas, o cualquier otra parte del cuerpo. Las tres formas clínicas más frecuentes son: verrugas vulgares (70%), plantares (26%) y planas (4%) (Woolf et al., 2005. Fitzpatrick's, color atlas & synopsis of clinical dermatology. 5a ed . Philadelphia; McGraw-Hill, 776-81 ; Arenas, 2005. Dermatología. Diagnóstico y tratamiento. 3a ed. México; McGraw-Hill: 656-667) Depending on the virus serotype, the affected area is different: the hands, face, neck, feet, ano-genital area, armpits, or any other part of the body. The three most common clinical forms are: vulgar (70%), plantar (26%) and flat (4%) warts (Woolf et al., 2005. Fitzpatrick's, atlas color & synopsis of clinical dermatology. 5th ed. Philadelphia; McGraw -hill, 776-81; Arenas, 2005. Dermatology Diagnosis and treatment 3rd ed Mexico; McGraw-Hill... 656-667)
Enfermedad Tipo VPH HPV Type Disease
Verruga común 2, 7 Common wart 2, 7
Verruga plantar 1 , 2, 4Plantar wart 1, 2, 4
Verruga cutánea chata 3, 10 Flat wart 3, 10
Verruga genital anal 6, 1 1 , 42, 43, 44, 55 y otras Genital wart anal 6, 1 1, 42, 43, 44, 55 and others
Malignidades genitales 16, 18, 31 , 33, 35, 39, 45, 51Genital malignancies 16, 18, 31, 33, 35, 39, 45, 51
Epidermodisplasia verruciforme más de 15 tipos Verruciform epidermodisplasia more than 15 types
Hiperplasia focal epitelial (oral) 13, 32  Focal epithelial hyperplasia (oral) 13, 32
Papilomas orales 6, 7, 1 1 , 16, 32  Oral papillomas 6, 7, 1 1, 16, 32
Tabla 1 . Enfermedades inducidas por el VPH.  Table 1 . HPV-induced diseases.
La verruga vulgar se asocia a los genotipos de VPH 1 , 2, 4 y 7 y se presenta como excrecencias circunscritas del mismo color de la piel, con superficie córnea y tacto rasposo. Pueden aparecer en cualquier superficie cutánea, preferentemente en el dorso de las manos y dedos, le siguen en frecuencia: cara, cuello y cuero cabelludo. The vulgar wart is associated with HPV genotypes 1, 2, 4 and 7 and is presented as circumscribed excrescences of the same skin color, with a corneal surface and a scratchy touch. They can appear on any skin surface, preferably on the back of the hands and fingers, followed in frequency: face, neck and scalp.
Las verrugas planas se asocian al tipo 3 de VPH, y se presentan como lesiones ligeramente elevadas, de 2-4 mm de diámetro, coloración amarillenta y difícilmente distinguibles de la piel normal. Su consistencia es blanda y la superficie suave al tacto. Flat warts are associated with type 3 HPV, and present as slightly elevated lesions, 2-4 mm in diameter, yellowing and hardly distinguishable from normal skin. Its consistency is soft and the surface soft to the touch.
Las verrugas anogenitales tienen características y variable potencial oncogénico. Anogenital warts have characteristics and variable oncogenic potential.
Las verrugas plantares, que aparecen en las plantas de los pies, también son llamadas ojos de pescado. Las verrugas plantares (verruca pedís; VP; Infecciones virales caracterizadas por lesiones de la piel y membranas mucosas CIE-10: B07 // ICD-9-CM Diagnosis Code 078.19) son, por tanto, verrugas causadas por el virus del papiloma humano (VPH). Afectan a entre el 7% y 10% de la población general (Chicharro y Alonso, 2007), no se han encontrado diferencias significativas en la prevalencia de esta enfermedad por sexos (Pique y cois., 1997; Lipke, 2006) y la mayor frecuencia de esta lesión se da en pacientes con edades comprendidas entre 5 y 20 años (Palomo, 2000. Podoscopio, 1 (1 1 ):24-32), calculándose que el 10% de los adolescentes la padecen. Las personas adultas afectadas con este virus presentan con mucha frecuencia un sistema inmunológico deprimido (Llórente, 2003. Podoscopia, 22: 4-12). La incidencia depende de la edad del paciente, la hiperhidrosis y el sistema inmunológico. Además los pacientes que han tenido verrugas plantares y palmares tienen 3 veces más posibilidades de desarrollar nuevas lesiones que los no afectados (Palomo, 2000. Podoscopio, 1 (1 1 ):24-32; Lipke, 2006. Clinical Medicine & Research, 4(4), 273-293). Son lesiones pequeñas que aparecen en las plantas de los pies, tienen la apariencia de una coliflor y se caracteriza por tener un halo blanquecino y presentar unos puntos de color marrón negruzco que son las papilas del papiloma. Debido a la presión que ejerce el cuerpo sobre las plantas de los pies, puede formarse un endurecimiento de la piel encima de la verruga. Las verrugas pueden ser dolorosas o no serlo, según su tamaño, tiempo de evolución, localización y subtipo de virus del papiloma humano. En ocasiones se agrupan dando lugar a placas engrosadas con superficie granulosa que se denominan verrugas en mosaico. Las VP se diferencian a menudo de los helomas al observar las estrías cutáneas. Los pies, al igual que las manos, están cubiertos de estas estrías comúnmente llamadas huellas dactilares. Cuando se presentan verrugas plantares, las estrías rodean a la lesión; cuando ésta no es por verruca pedís, el ADN celular no se altera y las estrías continúan por encima de ella. Además, las verrugas plantares tienden a causar dolor al aplicar presión a los lados de la lesión más que directamente; los helomas tienden a hacerlo de manera opuesta y duelen al presionarlos directamente y no por las orillas. Las zonas más comunes de la aparición de las verrugas plantares o papilomas son debajo de las cabezas metatarsales, lateral de primer dedo y talón. Plantar warts, which appear on the soles of the feet, are also called fish eyes. Plantar warts (pedis wart; VP; Viral infections characterized by skin lesions and mucous membranes CIE-10: B07 // ICD-9-CM Diagnosis Code 078.19) are, therefore, warts caused by the human papillomavirus ( HPV) Affecting between 7% and 10% of the general population (Chicharro and Alonso, 2007), no significant differences were found in the prevalence of this disease by sex (Pique and cois., 1997; Lipke, 2006) and the largest The frequency of this lesion occurs in patients aged between 5 and 20 years (Palomo, 2000. Podoscopio, 1 (1 1): 24-32), with 10% of adolescents suffering from it. Adults affected with this virus often have a depressed immune system (Llorente, 2003. Podoscopia, 22: 4-12). The incidence depends on the patient's age, hyperhidrosis and the immune system. In addition, patients who have had plantar and palm warts are 3 times more likely to develop new lesions than those not affected (Palomo, 2000. Podoscopio, 1 (1 1): 24-32; Lipke, 2006. Clinical Medicine & Research, 4 (4), 273-293). They are small lesions that appear on the soles of the feet, have the appearance of a cauliflower and is characterized by having a whitish halo and presenting blackish brown spots that are the papilloma papillae. Due to the pressure exerted by the body on the soles of the feet, a hardening of the skin can form on top of the wart. Warts can be painful or not, depending on their size, evolution time, location and subtype of human papillomavirus. Sometimes they are grouped giving rise to thickened plates with granular surface that are called mosaic warts. VPs often differ from helomas by observing skin stretch marks. The feet, like the hands, are covered with these stretch marks commonly called fingerprints. When plantar warts occur, stretch marks surround the lesion; when it is not for wart you ask, the cellular DNA is not altered and the stretch marks continue above it. In addition, plantar warts tend to cause pain by applying pressure to the sides of the lesion rather than directly; Helomas tend to do it the opposite way and they hurt when pressed directly and not by the banks. The most common areas of the appearance of plantar warts or papillomas are below the metatarsal, lateral toes of the first finger and heel.
Se transmiten comúnmente en baños y piscinas públicas, al compartir zapatos, etcétera. They are commonly transmitted in public bathrooms and swimming pools, when sharing shoes, and so on.
Los papilomas palmares aparecen en la palma de las manos y zona palmar de los dedos, siendo las del dorso de manos, dedos y periungeales las denominadas verrugas vulgares que hay que diferenciar de las anteriores. El lugar en el que aparecen ambos tipos de papilomas (palmares y plantares) implica, por regla general una limitación en las actividades de la vida cotidiana (Lafuente et al., 1999. Revista Española de Podología, X (2): 92-96). The palmar papillomas appear in the palm of the hands and palmar area of the fingers, the so-called vulgar warts being the ones on the back of the hands, fingers and periungers that must be distinguished from the previous ones. The place where both types of papillomas appear (palmar and plantar) implies, as a rule, a limitation in the activities of daily life (Lafuente et al., 1999. Revista Española de Podología, X (2): 92-96 ).
Entre 30 y 40 de los VPH se transmiten típicamente por contacto sexual, infectando la región anogenital. Algunos tipos de transmisión sexual de VPH (tipos 6 y 1 1 ), pueden causar verrugas genitales. Sin embargo, otros tipos de VPH que pueden infectar los genitales no causan ningunos signos apreciables de infección. Between 30 and 40 of HPVs are typically transmitted through sexual contact, infecting the anogenital region. Some types of sexual transmission of HPV (types 6 and 1 1), can cause genital warts. However, other types of HPV that can infect the genitals do not cause any appreciable signs of infection.
Además, una persistente infección con un subgrupo de cerca de 13 VPH sexualmente transmitidos, llamados «de alto riesgo», incluyendo a los tipos 16, 18, 31 , 33, 35, 39, 45, 51 , 52, 56, 58, 59, 68 — que son diferentes de los que causan verrugas— pueden favorecer el desarrollo de: In addition, a persistent infection with a subgroup of about 13 sexually transmitted HPVs, called "high-risk", including types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 , 68 - which are different from those that cause warts - may favor the development of:
• CIN (neoplasia cervical intraepitelial),  • CIN (intraepithelial cervical neoplasia),
• VIN (neoplasia vulvar intraepitelial),  • VIN (intraepithelial vulvar neoplasia),
· PIN (neoplasia peneana intraepitelial), o  PIN (intraepithelial penile neoplasia), or
• AIN (neoplasia anal intraepitelial).  • AIN (intraepithelial anal neoplasia).
Esas son lesiones precancerosas y pueden progresar a cáncer invasivo. Una infección de VPH es un factor necesario en el desarrollo de casi todos los casos de cáncer cervical. Those are precancerous lesions and can progress to invasive cancer. An HPV infection is a necessary factor in the development of almost all cases of cervical cancer.
Varios tipos de VPH, particularmente el tipo 16, han sido hallados asociados con carcinoma orofaríngeo de células escamosas, una forma de cáncer de cabeza y cuello. Several types of HPV, particularly type 16, have been found associated with squamous cell oropharyngeal carcinoma, a form of head and neck cancer.
Existen evidencias de que un gran número de cánceres tienen su origen en la infección por VPH (Zur Hausen 1996. Biochim Biophys Acta Oct 9;1288(2):F55-F78), entre los cuales se incluyen: cáncer del cuello del útero (cervicouterino) y cáncer de varios órganos, tales como: mucosa oral, amígdala, faringe, laringe, esófago, mama, próstata, ovario, uretra y de piel. Trabajos recientes sobre tumores de estirpe melanocítica dan a este virus un relevante rol, sobre todo en los aspectos evolutivos de la enfermedad (Dreau et al., 2000. Annals of Surgery 231 :664-671 ). Los cánceres inducidos por VPH con frecuencia tienen secuencias virales integradas en el ADN celular. Algunos de los genes "tempranos" de VPH, como E6 y E7, se conocen de actuar como oncógenos promoviendo el crecimiento tumoral y la transformación a maligno. La proteína p53 previene el crecimiento celular en presencia de ADN dañado primariamente a través del dominio de la proteína X asociada con BCL-2 (BAX) (que bloquea los efectos de la antiapoptosis del receptor BCL-2, mitocondrial. En adición, el p53 también sobrerregula la proteína p21 , bloqueando la formación del complejo ciclina D/Cdk4, y así previniendo la fosforilación de RB y, a su vez, haciendo titubear la progresión del ciclo celular por prevenir la activación de E2F. Abreviando, p53 es un gen supresor tumoral que arresta el ciclo celular, cuando hay ADN dañado. Las proteínas E6 y E7 trabajan inhibiendo los genes supresores de tumores, en tal proceso: E6 inhibe p53, mientras E7 inhibe a p53, p21 , y a RB. There is evidence that a large number of cancers have their origin in HPV infection (Zur Hausen 1996. Biochim Biophys Acta Oct 9; 1288 (2): F55-F78), which include: cervical cancer ( cervical) and cancer of various organs, such as: oral mucosa, tonsil, pharynx, larynx, esophagus, breast, prostate, ovary, urethra and skin. Recent works on melanocytic line tumors give this virus an important role, especially in the evolutionary aspects of the disease (Dreau et al., 2000. Annals of Surgery 231: 664-671). HPV-induced cancers often have viral sequences integrated into cellular DNA. Some of the "early" HPV genes, such as E6 and E7, are known to act as oncogens promoting tumor growth and malignant transformation. The p53 protein prevents cell growth in the presence of primarily damaged DNA through the X-protein domain associated with BCL-2 (BAX) (which blocks the effects of mitochondrial BCL-2 receptor antiapoptosis. In addition, p53 it also overregulates the p21 protein, blocking the formation of the cyclin D / Cdk4 complex, and thus preventing the phosphorylation of RB and, in turn, causing the cell cycle progression to prevent activation of E2F. In short, p53 is a tumor suppressor gene that arrests the cell cycle, when there is damaged DNA. The E6 and E7 proteins work by inhibiting tumor suppressor genes, in such a process: E6 inhibits p53, while E7 inhibits p53, p21, and RB.
Una historia de infección con uno o más tipos de VPH de alto riesgo, se cree ser un prerrequisito para el desarrollo de cáncer; de acuerdo a la "Sociedad Estadounidense de Cáncer, ACS", las mujeres sin historia de virus no desarrollan ese tipo de cáncer. Y, la mayoría de las infecciones de VPH son resueltas rápidamente por el sistema inmune y no progresan a cáncer cervical. Debido a que el proceso de transformar células cervicales normales en cancerosas es lento, el cáncer ocurre en gente que han sido infectadas con HPV por un largo tiempo, usualmente una década o más. Los VPH sexualmente transmitidos también pueden causar la mayor fracción de cáncer anales y aproximadamente el 25% de cáncer de boca y garganta (orofaringe). Este último comúnmente presente en el área de las amígdalas, y el VPH se enlaza con el incremento de cáncer oral en no fumadores. Los tipos de VPH 6 y 1 1 pueden causar una rara condición conocida como papilomatosis laríngea recurrente (una papilomatosis respiratoria), en donde las verrugas se forman en la laringe o en otras áreas del tracto respiratorio. Esas verrugas pueden recurrir frecuentemente, y requerir cirugías repetitivas, interferir con la respiración, y en casos extremadamente raros progresar hacia cáncer. A history of infection with one or more high-risk types of HPV is believed to be a prerequisite for the development of cancer; According to the "American Cancer Society, ACS," women without a history of viruses do not develop this type of cancer. And, most HPV infections are quickly resolved by the immune system and do not progress to cervical cancer. Because the process of transforming normal cervical cells into cancerous cells is slow, cancer occurs in people who have been infected with HPV for a long time, usually a decade or more. Sexually transmitted HPVs can also cause the largest fraction of anal cancer and approximately 25% of mouth and throat cancer (oropharynx). The latter is commonly present in the area of the tonsils, and HPV is linked to the increase in oral cancer in non-smokers. Types of HPV 6 and 1 1 can cause a rare condition known as recurrent laryngeal papillomatosis (a respiratory papillomatosis), where warts form in the larynx or other areas of the respiratory tract. These warts can recur frequently, and require repetitive surgeries, interfere with breathing, and in extremely rare cases progress towards cancer.
Respecto a los tratamientos, no existe antivíricos específicos para el VPH (Gilaberte y Puig, 2000. Farmacia Profesional, 14 (12): 76-81 ), no hay ningún tratamiento que cure el 100% de los papilomas, y los distintos tratamientos de que se disponen van a prender destruir todas las células infectadas por el virus o lograr que el propio sistema inmunitario del individuo lo realice. Regarding treatments, there are no specific antivirals for HPV (Gilaberte and Puig, 2000. Professional Pharmacy, 14 (12): 76-81), there is no treatment that cures 100% of papillomas, and the different treatments of that are arranged will try to destroy all the cells infected by the virus or get the individual's own immune system to do it.
Existen tratamientos basados en fórmulas de mediana acidez o con agentes queratolíticos, para eliminar las células infectadas por el virus, el tejido de la verruga, con varias aplicaciones. Por ejemplo, soluciones de ácido salicílico al 20-40%, fórmulas magistrales de gluteraldehido en forma de gel al 10% o de solución acuosa al 5-10%, retinoides tópicos como la tretinoína al 0.025 - 0.05% para el tratamiento de verrugas planas, nitrato de plata, soluciones de cantaridina al 0.7%. Para tratar verrugas resistentes existen otras opciones, q ue incluyen el tratam iento por congelación (criocirugía), quemarlas por corriente eléctrica (electrocirugía), quemarlas con ácidos más fuertes, cirugía láser y reserción quirúrgica. Chicharro y Alonso (2007. Revista Española de Podología, 18: 218-22) aconsejan comenzar por las modalidades más sencillas, menos dolorosas y menos costosos, así la primera línea de actuación serían los queratolíticos, destacando el ácido salicílico (20 - 40%), por su alta eficacia y su fácil aplicación con una tasa de curación entre el 60% y 80% (Gibbs y Harvey, 2003. Cochrane Datábase Syst Rev. (3):CD00178; Llórente et al., 2003. Podoscopia, 22: 4-12; Llarden et al., 2006. Formación Médica Continuada en Atención Primaria 13, 1 : 45-54). En la segunda línea de actuación está la crioterapia, con este frío local se elimina hasta el 80% de verrugas plantares tipo mirmecia y un 50% en verrugas tipo mosaico, seguido de la inmunoterapia intralesional (antígeno Cándida) y el láser pulsado. En la tercera línea de actuación se incluirían los citotóxicos (bleomicina intralesional y podofilino), los inmunomodulares (iniquimod, cimetidina) y la escisión quirúrgica. Estos tratamientos se suelen utilizar en verrugas recalcitrantes cuando han fallado la primera y segunda línea de actuación (Micali et al., 2004. American Journal of Clinical Demartology, 5: 31 1 -317). Las recurrencias son muy comunes con la gran mayoría de los tratamiento ya que no logran eliminar el virus completamente (Gibbs et al., 2003. Cochrane Datábase Syst Rev. (3):CD00178 ) There are treatments based on formulas of medium acidity or with keratolytic agents, to eliminate the cells infected by the virus, the wart tissue, with several applications. For example, 20-40% salicylic acid solutions, master formulas of 10% gel gluteraldehyde or aqueous solution at 5-10%, topical retinoids such as 0.025 - 0.05% tretinoin for the treatment of flat warts, silver nitrate, 0.7% cantaridine solutions. To treat resistant warts there are other options, which include freeze treatment (cryosurgery), burn them by electric current (electrosurgery), burn them with stronger acids, laser surgery and surgical reservoir. Chicharro and Alonso (2007. Revista Española de Podología, 18: 218-22) advise starting with the simplest, least painful and less expensive modalities, so the first line of action would be keratolytics, highlighting salicylic acid (20 - 40% ), due to its high efficiency and its easy application with a cure rate between 60% and 80% (Gibbs and Harvey, 2003. Cochrane Datábase Syst Rev. (3): CD00178; Llorente et al., 2003. Podoscopia, 22 : 4-12; Llarden et al., 2006. Continuing Medical Training in Primary Care 13, 1: 45-54). In the second line of action is cryotherapy, with this local cold, up to 80% of plantar warts are mirmecia type and 50% in mosaic warts, followed by intralesional immunotherapy (Candida antigen) and pulsed laser. The third line of action would include cytotoxic agents (intralesional bleomycin and podophyllinum), immunomodulars (iniquimod, cimetidine) and surgical excision. These treatments are usually used in recalcitrant warts when the first and second lines of action have failed (Micali et al., 2004. American Journal of Clinical Demartology, 5: 31 1-317). Recurrences are very common with the vast majority of treatments because they fail to eliminate the virus completely (Gibbs et al., 2003. Cochrane Datábase Syst Rev. (3): CD00178)
Por lo tanto, dada la gran incidencia de las infecciones por VPH , de las verrugas y, especialmente, de as verrugas o papilomas plantares y palmares, la variabilidad de tratamientos sin efectividad asegurada, el dolor ocasionado -tanto al tener la lesión como tras la aplicación de algunos tratamientos-, el deterioro de la calidad de vida por incapacidades funcionales y laborales, así como los costes de los tratamientos y bajas, es necesario encontrar un tratamiento para las infecciones por virus de VPH, y capaz de eliminar las lesiones cutáneas con una afectación mínima de los tejidos normales. Therefore, given the high incidence of HPV infections, warts and, especially, plantar and palmar warts or papillomas, the variability of treatments without assured effectiveness, the pain caused - both when having the lesion and after application of some treatments-, the deterioration of the quality of life due to functional and occupational disabilities, as well as the costs of treatments and casualties, it is necessary to find a treatment for HPV virus infections, and able to eliminate skin lesions with minimal involvement of normal tissues.
DESCRIPCIÓN DE LA INVENCIÓN DESCRIPTION OF THE INVENTION
Los autores de la presente invención han identificado el efecto terapéutico de plantas del género Crassula y específicamente de la planta Crassula argéntea y de sus extractos frente a enfermedades proliferativas, tanto benignas como malignas, y principalmente frente a enfermedades proliferativas de la piel, incluyendo las verrugas producidas por infecciones de virus del papiloma humano, y especialmente frente a las verrugas plantares. Este tratamiento presenta las ventajas de que es indoloro, sencillo de aplicar por el propio paciente (autocuidados), de bajísimo coste, y además reduce la incapacitación funcional del enfermo prácticamente desde el inicio del tratamiento. Además, mejora el tiempo de la curación, disminuye el tamaño de los papilomas y reduce el dolor asociado al proceso con respecto al tratamiento con ácido salicílico. Por tanto, un primer aspecto de la invención se refiere al material vegetal de plantas del género Crassula, los extractos de dichas plantas, o un principio activo obtenido a partir de dicho material vegetal o de los extractos, de ahora en adelante material vegetal, extracto o principio activo de la invención, para el tratamiento de enfermedades proliferativas o alternativamente, al uso de material vegetal de plantas del género Crassula, de los extractos de dichas plantas, o de un principio activo obtenido a partir de dicho material vegetal o de los extractos, para el tratamiento de enfermedades proliferativas. The authors of the present invention have identified the therapeutic effect of plants of the genus Crassula and specifically of the plant Crassula argéntea and of its extracts against proliferative diseases, both benign and malignant, and mainly against proliferative diseases of the skin, including warts caused by human papillomavirus infections, and especially against plantar warts. This treatment has the advantages that it is painless, easy to apply by the patient (self-care), very low cost, and also reduces the functional incapacitation of the patient from the beginning of treatment. In addition, it improves the healing time, decreases the size of the papillomas and reduces the pain associated with the process with respect to treatment with salicylic acid. Therefore, a first aspect of the invention relates to the plant material of plants of the genus Crassula, the extracts of said plants, or an active ingredient obtained from said plant material or extracts, hereinafter plant material, extract or active principle of the invention, for the treatment of proliferative diseases or alternatively, to the use of plant material of plants of the genus Crassula, of the extracts of said plants, or of an active principle obtained from said plant material or of the extracts , for the treatment of proliferative diseases.
En esta memoria, por "material vegetal" se entiende tanto las partes aéreas o subterráneas de plantas u otros materiales vegetales tales como jugos, resinas, aceites grasos, aceites esenciales y cualesquiera otras sustancias de esta naturaleza, como combinaciones de los mismos, en estado bruto o en forma de preparaciones vegetales. Los "extractos" son preparaciones concentradas de consistencia líquida, sólida o intermedia, obtenidas normalmente a partir de material vegetal, fresco o más preferiblemente desecado. Para algunas preparaciones, el material a extraer puede requerir un tratamiento previo, como por ejemplo, inactivación de enzimas, trituración o desengrasado. Los extractos se preparan por maceracion, percolación o por otros métodos validados adecuados que utilizan etanol u otro disolvente. Después de la extracción, si es necesario, se eliminan las sustancias no deseadas. Métodos de extracción son conocidos por el experto en la materia, y son descritos, por ejemplo pero sin limitarse, en la Real Farmacopea Española o en la Farmacopea Europea. Entre las tecnologías de extracción se encuentra la extracción en fluidos supercríticos y otros métodos más convencionales, como los de arrastre de vapor, los de extracción por solución (sólido - líquido o líquido - líquido) y los de extracción por centrifugación. In this report, "plant material" means both the aerial or underground parts of plants or other plant materials such as juices, resins, fatty oils, essential oils and any other substances of this nature, such as combinations thereof, in condition raw or in the form of vegetable preparations. "Extracts" are concentrated preparations of liquid, solid or intermediate consistency, normally obtained from fresh, or more preferably dried, plant material. For some preparations, the material to be extracted may require prior treatment, such as enzyme inactivation, crushing or degreasing. The extracts are prepared by maceration, percolation or by other suitable validated methods using ethanol or other solvent. After extraction, if necessary, unwanted substances are removed. Extraction methods are known to those skilled in the art, and are described, for example, but not limited to, in the Royal Spanish Pharmacopoeia or the European Pharmacopoeia. Extraction technologies include extraction in supercritical fluids and other more conventional methods, such as steam entrainment, extraction by solution (solid - liquid or liquid - liquid) and centrifugal extraction.
El término "medicamento", tal y como se usa en esta memoria, hace referencia a cualquier sustancia usada para prevención, diagnóstico, alivio, tratamiento o curación de enfermedades en el hombre y los animales. En el contexto de la presente invención, la enfermedad es una enfermedad proliferativa, preferiblemente es una enfermedad proliferativa de la piel o mucosas, aún más preferiblemente es una infección de virus del papiloma humano, y aún mucho más preferiblemente es la verruga plantar. El medicamento puede ser un medicamento herbario. The term "medication", as used herein, refers to any substance used for prevention, diagnosis, relief, treatment or cure of diseases in man and animals. In the context of the present invention, the disease is a proliferative disease, preferably it is a proliferative disease of the skin or mucous membranes, even more preferably it is an infection of the human papillomavirus, and even more preferably it is the plantar wart. The medicine can be an herbal medicine.
Los medicamentos herbarios se definen en esta memoria como productos medicinales acabados y etiquetados cuyos ingredientes activos están formados por partes aéreas o subterráneas de plantas u otros materiales vegetales o combinaciones de los mismos, en estado bruto o en forma de preparaciones vegetales. Los medicamentos herbarios pueden también contener ingredientes activos naturales orgánicos o inorgánicos que no son de origen vegetal. Herbal medicines are defined herein as finished and labeled medicinal products whose active ingredients are formed by aerial or underground parts of plants or other plant materials or combinations thereof, in the raw state or in the form of plant preparations. Herbal medicines may also contain natural organic or inorganic active ingredients that are not of plant origin.
Las preparaciones vegetales incluyen materiales vegetales tritu rados o pulverizados, extractos, tinturas, aceites grasos o esenciales, jugos obtenidos por expresión y preparaciones en cuya producción intervienen el fraccionamiento, la purificación o la concentración. Vegetable preparations include crushed or powdered plant materials, extracts, tinctures, fatty or essential oils, juices obtained by expression and preparations whose production involves fractionation, purification or concentration.
En una realización preferida de este aspecto de la invención, el material vegetal es un preparado vegetal. In a preferred embodiment of this aspect of the invention, the plant material is a plant preparation.
Por "planta" en esta memoria, se entienden todos los organismos que pueden ser clasificados dentro del reino Viridiplantae, que incluye las algas verdes y a las plantas terrestres (Embryophyta). Los organismos del género Crassula pertenecen al Superreino Eukaryota,By "plant" in this report, all organisms that can be classified within the Viridiplantae kingdom are understood, which includes green algae and terrestrial plants (Embryophyta). The organisms of the genus Crassula belong to Superuk Eukaryota,
Reino Viridiplantae, Phylum Streptophyta, Orden Saxifragales, Familia Crassulaceae. Kingdom Viridiplantae, Phylum Streptophyta, Order Saxifragales, Family Crassulaceae.
Las plantas del género Crassula son plantas herbáceas, en nuestras laitudes anuales; en otras latitudes perennes, arbustos o subarbustos suculentos. Hojas ± carnosas, opuestas, decusadas de ordinario, a veces soldadas formando una vaina basilar, generalmente simples, indivisas y enteras, planas, semicilíndricas, cilindricas, ovoides, etc. Flores tetrámeras o pentámeras, excepcionalmente trímeras, simétricas, pequeñas y poco vistosas, solitarias, en parejas, en cimas agrupadas en fascículos sésiles o pedunculados, en inflorescencias tirsoideas o corimbosas, axilares o terminales. Sépalos libres o ± soldados en la base, ± suculentos. Corola persistente, generalmente blanca, a veces rosada, roja o de color carmín, pero solo en muy raras ocasiones amarilla; pétalos erectos, estrellados, ± patentes, soldados en la base formando un tubo ± corto. Estambres libres y con los filamentos soldados en la base del tubo de la corola, alternipétalos; anteras ovadas, oblongas o subesféricas. Carpelos libres o soldados en la base, atenuados o contraídos en un estilo, graboso o papiloso en la sutura; estilo a veces muy corto o subnulo; rudimentos seminales 1 -4 o numerosos en cada carpelo. Fruto polifolículo. Semillas 1 -12 en cada folículo. Escamas nectarífera más cortas que los carpelos, hialinas, rojo-acastañadas o rosadas, de espatuladas a obovadas o cuneadas. Plants of the genus Crassula are herbaceous plants, in our annual latitudes; in other perennial latitudes, shrubs or succulent sub-shrubs. Leaves ± fleshy, opposite, usually ordered, sometimes welded forming a sheath Basilar, usually simple, undivided and whole, flat, semi-cylindrical, cylindrical, ovoid, etc. Tetrámeras or pentámeras flowers, exceptionally trimeric, symmetrical, small and not very showy, solitary, in pairs, in peaks clustered in sessile or pedunculated fascicles, in thyroidal or corymbous, axillary or terminal inflorescences. Sepals free or ± soldiers at the base, ± succulent. Persistent corolla, usually white, sometimes pink, red or carmine, but only rarely yellow; erect, crashed petals, ± patents, welded at the base forming a short ± tube. Stamens free and with the filaments welded at the base of the corolla tube, alternate them; ovate, oblong or sub-spherical anthers. Free carpets or soldiers at the base, attenuated or contracted in a style, funky or papillose in the suture; sometimes very short or subnull style; 1 -4 or numerous seminal rudiments in each carpel. Polyfolicle fruit. Seeds 1-12 in each follicle. Nectariferous scales shorter than carpels, hyalines, red-bellied or pink, from spatula to obovate or cuneate.
El género está integrado por más de 300 especies, la mayor parte de ellas propias de África del Sur, otras de África tropical, América del Norte, Madagascar, la India, Europa y algunas, por último, de distribución subcosmopolita. The genus is composed of more than 300 species, most of them from South Africa, others from tropical Africa, North America, Madagascar, India, Europe and some, finally, of subcosmopolitan distribution.
Algunos autores segregan las especies herbáceas, diminutas (con todas sus partes reducidas), adaptadas a vivir dependiendo del medio húmedo (semiacuáticas), con una diferente apertura de los folículos y con menor número de rudimentos seminales, en un género autónomo, que se denominaría Tillada L. (tipo: T. muscosa L). Todas las especies que espontáneamente se crían e la Península y en las Islas Baleares pertenecerían a este género.  Some authors segregate the herbaceous species, tiny (with all its small parts), adapted to live depending on the humid environment (semi-aquatic), with a different opening of the follicles and with less number of seminal rudiments, in an autonomous genus, which would be called Tillada L. (type: T. muscosa L). All species that spontaneously breed on the Peninsula and in the Balearic Islands would belong to this genus.
Por el contrario, el género Crassula, s.str (tipo: C. perfoliata L.) pertenecen plantas que esporádicamente se pueden hallar como asilvestradas en España., como C. lycopodioides Lam, Encycl. 2: 173 (1783), Crassula argéntea Thunb. (Nova Acta Phys.-Med. Acad. Caes. Leop.-Carol. Nat. Cur. 6: 329, 337. 1778, C. rupestres L. fil., Suppl. Pl.: 189 (1782) y C. arborescens Willd., Sp. Pl. 1 : 1554(1798). On the contrary, the genus Crassula, s.str (type: C. perfoliata L.) belong to plants that sporadically can be found as feral in Spain, such as C. lycopodioides Lam, Encycl. 2: 173 (1783), Crassula argues Thunb. (Nova Acta Phys.-Med. Acad. Caes. Leop.-Carol. Nat. Cur. 6: 329, 337. 1778, C. rupestres L. fil., Suppl. Pl .: 189 (1782) and C. arborescens Willd., Sp. Pl. 1: 1554 (1798).
En otra realización preferida de este aspecto de la invención, la planta pertenece a la especie Crassula argéntea Thunb. (Nova Acta Phys.-Med. Acad. Caes. Leop.-Carol. Nat. Cur. 6: 329, 337. 1778). En otra realización preferida de este aspecto de la invención, la planta pertenece a la especie Crassula ovata (Mili.) Druce (Bot. Soc. Exch. Club. Brit. Isles: 617, 1917) Los organismos de la especie Crassula argéntea y C. ovata pertenecen alIn another preferred embodiment of this aspect of the invention, the plant belongs to the species Crassula argéntea Thunb. (Nova Acta Phys.-Med. Acad. Caes. Leop.-Carol. Nat. Cur. 6: 329, 337. 1778). In another preferred embodiment of this aspect of the invention, the plant belongs to the species Crassula ovata (Mili.) Druce (Bot. Soc. Exch. Club. Brit. Isles: 617, 1917) The organisms of the species Crassula argéntea and C .vata belong to
Superreino Eukaryota, Reino Viridiplantae, Phylum Streptophyta, Orden Saxifragales, Familia Crassulaceae y Género Crassula. Superuk Eukaryota, Kingdom Viridiplantae, Phylum Streptophyta, Order Saxifragales, Family Crassulaceae and Genus Crassula.
Las enfermedades proliferativas pueden ser benignas o malignas, y entre ellas se encuentran , por ejemplo pero sin limitarse, los tumores y las enfermedades proliferativas de la piel. Ejemplos de tumores incluyen pero sin limitación: cáncer pulmonar (por ejemplo, adenocarcinoma pulmonar), cánceres pancreáticos (tal como por ejemplo, carcinoma pancreático, carcinoma pancreático exócrino), cánceres de colon (por ejemplo, carcinomas colonorrectales, por ejemplo, adenocarcinoma de colon y adenoma de colon), leucemias mieloides (por ejemplo, leucemia mielógena aguda (AML)), cáncer folicular de tiroide, síndrome mielodisplástico (MDS), carcinoma de vejiga y carcinoma epidérmico. Ejemplos de enfermedades proliferativas de la piel se encuentran, pero sin limitarse, queratosis actínica, carcinoma de células básales, carcinoma de células pavimentosas, histiocitoma fibroso, dermatofibrosarcoma protuberans, hemangioma, nevo flamígero, xantoma, sarcoma de Kaposi, mastocitosis, micosis fungoides, léntigo, nevo nevocelular, léntigo maligno, melanoma maligno, carcinoma metastático, psoriasis o infecciones productivas de virus del papiloma humano (VPH o HPV del inglés human papilomavirus) en el epitelio estratificado de la piel y mucosas de humanos, así como de una variedad de animales. Proliferative diseases can be benign or malignant, and among them are, for example, but not limited to, tumors and proliferative diseases of the skin. Examples of tumors include but are not limited to: lung cancer (eg, pulmonary adenocarcinoma), pancreatic cancers (such as, for example, pancreatic carcinoma, exocrine pancreatic carcinoma), colon cancers (for example, colon-rectum carcinomas, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma and epidermal carcinoma. Examples of proliferative skin diseases include, but are not limited to, actinic keratosis, basal cell carcinoma, pavement cell carcinoma, fibrous histiocytoma, dermatofibrosarcoma protuberans, hemangioma, flaming nevus, xanthoma, Kaposi's sarcoma, mastocytosis, fungoid mycosis, lentigo , nevocellular nevus, malignant lentigo, malignant melanoma, metastatic carcinoma, psoriasis or productive infections of human papillomavirus (HPV or HPV) in the stratified epithelium of the skin and mucous membranes of humans, as well as a variety of animals .
En otra realización preferida, la enfermedad proliferativa se selecciona de la lista que comprende: cáncer pulmonar, cánceres pancreáticos, cánceres de colon, leucemias mieloides, cáncer folicular de tiroide, síndrome mielodisplástico (MDS), carcinoma de vejiga, carcinoma epidérmico y enfermedades proliferativas de la piel. En otra realización preferida, la enfermedad proliferativa es una enfermedad proliferativa de la piel. En otra realización aún más preferida la enfermedad proliferativa de la piel se selecciona de la lista que comprende: queratosis actínica, carcinoma de células básales, carcinoma de células pavimentosas, histiocitoma fibroso, dermatofibrosarcoma protuberans, hemangioma, nevo flamígero, xantoma, sarcoma de Kaposi, mastocitosis, micosis fungoides, léntigo, nevo nevocelular, léntigo maligno, melanoma maligno, carcinoma metastático, psoriasis o infecciones de los virus del papiloma humano. In another preferred embodiment, the proliferative disease is selected from the list comprising: lung cancer, pancreatic cancers, colon cancers, myeloid leukemias, thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma and proliferative diseases of the skin. In another preferred embodiment, the proliferative disease is a proliferative disease of the skin. In another even more preferred embodiment the proliferative skin disease is selected from the list comprising: actinic keratosis, basal cell carcinoma, pavement cell carcinoma, fibrous histiocytoma, dermatofibrosarcoma protuberans, hemangioma, flaming nevus, xanthoma, Kaposi's sarcoma, mastocytosis, fungoid mycosis, lentigo, nevocellular nevus, lentigo malignant, malignant melanoma, metastatic carcinoma, psoriasis or human papillomavirus infections.
En otra realización aún más preferida, las enfermedades provocadas por la infección del virus del papiloma humano se selecciona de la lista que comprende: carcinoma de células escamosas de piel, neoplasia intraepitelial cervical, cáncer cervicouterino, cáncer de la mucosa oral, amígdala, faringe, laringe, esófago, mama, próstata, ovario, vulva, uretra, pene y de piel, tumores de estirpe melanocítica, verruga común, verruga plantar, verruga cutánea chata, verrugas genitales, epidermodisplasia verruciforme, hiperplasia focal epitelial (oral), o papilomas orales. En otra realización aún más preferida, la infección del virus del papiloma humano es la verruga plantar. En una realización particular la verruga plantar es producida por la infección del virus del papiloma humano tipo 1 . En otra realización particular la verruga plantar es producida por la infección del virus del papiloma humano tipo 2. En otra realización particular la verruga plantar es producida por la infección del virus del papiloma humano tipo 4. In another even more preferred embodiment, the diseases caused by human papillomavirus infection are selected from the list comprising: squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, cervical cancer, oral mucosal cancer, tonsil, pharynx, larynx, esophagus, breast, prostate, ovary, vulva, urethra, penis and skin, tumors of melanocytic lineage, common wart, plantar wart, flat skin wart, genital warts, verruciform epidermodisplasia, epithelial focal hyperplasia (oral), or oral papillomas . In another even more preferred embodiment, the human papillomavirus infection is the plantar wart. In a particular embodiment, the plantar wart is caused by infection of human papillomavirus type 1. In another particular embodiment the plantar wart is produced by the infection of the human papillomavirus type 2. In another particular embodiment the plantar wart is produced by the infection of the human papillomavirus type 4.
Otro aspecto de la invención se refiere a una composición, de ahora en adelante primera composición de la invención, que comprende el material vegetal, el extracto o un principio activo de la invención. Another aspect of the invention relates to a composition, hereinafter the first composition of the invention, comprising the plant material, the extract or an active ingredient of the invention.
Dicha composición puede ser una composición farmacéutica. Por tanto, otro aspecto de la invención se refiere a una composición farmacéutica, de ahora en adelante segunda composición de la invención, que comprende el material vegetal, el extracto o un principio activo de la invención. Said composition may be a pharmaceutical composition. Therefore, another aspect of the invention relates to a pharmaceutical composition, hereinafter second composition of the invention, comprising the plant material, the extract or an active ingredient of the invention.
Las composiciones de la presente invención pueden formularse para su administración a un animal, y más preferiblemente a un mamífero, incluyendo al hombre, en una variedad de formas conocidas en el estado de la técnica. Así, pueden estar, sin limitarse, en disolución acuosa estéril o en fluidos biológicos, tal como suero. Las disoluciones acuosas pueden estar tamponadas o no tamponadas y tienen componentes activos o inactivos adicionales. Los componentes adicionales incluyen sales para modular la fuerza iónica, conservantes incluyendo, pero sin limitarse a, agentes antimicrobianos, antioxidantes, quelantes, y similares, y nutrientes incluyendo glucosa, dextrosa, vitaminas y minerales. Alternativamente, las composiciones pueden prepararse para su administración en forma sólida. Las composiciones pueden combinarse con varios vehículos o excipientes inertes, incluyendo pero sin limitarse a; aglutinantes tales como celulosa microcristalina, goma tragacanto, o gelatina; excipientes tales como almidón o lactosa; agentes dispersantes tales como ácido algínico o almidón de maíz; lubricantes tales como estearato de magnesio, deslizantes tales como dióxido de silicio coloidal; agentes edulcorantes tales como sacarosa o sacarina; o agentes aromatizantes tales como menta o salicilato de metilo. The compositions of the present invention can be formulated for administration to an animal, and more preferably to a mammal, including man, in a variety of ways known in the state of the art. Thus, they can be, without limitation, in sterile aqueous solution or in biological fluids, such as serum. Aqueous solutions may be buffered or unbuffered and have additional active or inactive components. Additional components include salts to modulate ionic strength, preservatives including, but not limited to, antimicrobial agents, antioxidants, chelators, and the like, and nutrients including glucose, dextrose, vitamins and minerals. Alternatively, the compositions can be prepared for administration in solid form. The compositions can be combined with several inert vehicles or excipients, including but not limited to; binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid or corn starch; lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint or methyl salicylate.
Por tanto, en una realización preferida de este aspecto de la invención, la composición farmacéutica puede comprender, además un vehículo farmacéuticamente aceptable. En otra realización preferida la composición farmacéutica comprende, además, excipientes. En otra realización preferida la composición farmacéutica puede comprender, además, otro principio activo. Therefore, in a preferred embodiment of this aspect of the invention, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier. In another preferred embodiment the pharmaceutical composition further comprises excipients. In another preferred embodiment the pharmaceutical composition may further comprise another active ingredient.
Como se emplea aquí, el término "principio activo", "sustancia activa", "sustancia farmacéuticamente activa", "ingrediente activo" ó "ingrediente farmacéuticamente activo" significa cualquier componente que potencialmente proporcione una actividad farmacológica u otro efecto diferente en el diagnóstico, cura, mitigación, tratamiento, o prevención de una enfermedad, o que afecta a la estructura o función del cuerpo del hombre u otros animales. El término incluye aquellos componentes que promueven un cambio químico en la elaboración del fármaco y están presentes en el mismo de una forma modificada prevista que proporciona la actividad específica o el efecto. As used herein, the term "active ingredient", "active substance", "pharmaceutically active substance", "active ingredient" or "pharmaceutically active ingredient" means any component that potentially provides a pharmacological activity or other different diagnostic effect, cure, mitigation, treatment, or prevention of a disease, or that affects the structure or function of the body of man or other animals. The term includes those components that promote a chemical change in the preparation of the drug and are present therein in a modified form intended to provide the specific activity or effect.
Otro aspecto de la invención se refiere a una forma farmacéutica, de ahora e adelante forma farmacéutica de la invención, que comprende la segunda composición de la invención. En una realización preferida de este aspecto de la invención la forma farmacéutica de la invención se selecciona de la lista que comprende: emplasto, pomada, pasta, crema, solución, suspensión, emulsión, loción, linimento, gel, espuma, polvo, o cualquiera de sus combinaciones. En una realización aún mucho más preferida, la forma farmacéutica es un emplasto. Another aspect of the invention relates to a pharmaceutical form, hereafter referred to as the pharmaceutical form of the invention, which comprises the second composition of the invention. In a preferred embodiment of this aspect of the invention the pharmaceutical form of the invention is selected from the list comprising: plaster, ointment, paste, cream, solution, suspension, emulsion, lotion, liniment, gel, foam, powder, or any of their combinations. In an even more preferred embodiment, the pharmaceutical form is a plaster.
En esta memoria se entiende por "forma farmacéutica" la mezcla de uno o más principios activos con o sin aditivos que presentan características físicas para su adecuada dosificación, conservación, administración y biodisponibilidad. Un "emplasto" o "parche" es una forma farmacéutica que consiste en una forma sólida o semisólida que contiene el o los principios activos y aditivos, extendidos sobre una tela, plástico o cinta adhesiva, que sirve como soporte y protección, además de tener un efecto oclusivo y acción macerante que permite además el contacto directo con la piel y se reblandece con la temperatura corporal. In this specification, "pharmaceutical form" means the mixture of one or more active ingredients with or without additives that have physical characteristics for proper dosage, preservation, administration and bioavailability. A "plaster" or "patch" is a pharmaceutical form that consists of a solid or semi-solid form that contains the active ingredient or additives, spread on a cloth, plastic or adhesive tape, which serves as a support and protection, in addition to having an occlusive effect and macerating action that also allows direct contact with the skin and softens with body temperature.
Un "ungüento" o "pomada" es una forma farmacéutica que consiste en una preparación de consistencia blanda que contiene el o los principios activos y aditivos incorporados a una base apropiada que le da masa y consistencia. Se adhiere y se apl ica en la piel y m ucosas . Esta base puede ser li posol u ble o h id rosoluble, generalmente es anhidra o con un máximo de 20 por ciento de agua. También se denomina ungüento hidrofílico cuando contiene una base lavable o removible con agua. Una "pasta" es una forma farmacéutica que consiste en una forma semisólida que contiene el o los principios activos y aditivos, hecha a base de una alta concentración de polvos insolubles (20 a 50 por ciento), en bases grasas o acuosas, absorbentes o abrasivos débiles combinados con jabones. Una "crema" es una forma farmacéutica que consiste en una preparación líquida o semisólida que contiene el o los principios activos y aditivos necesarios para obtener una emulsión, generalmente aceite en agua, con un contenido de agua superior al 20 por ciento. Una "solución" es una forma farmacéutica que consiste en un preparado líquido, transparente y homogéneo, obtenido por disolución de él o los principios activos y aditivos en agua, y que se utiliza para el uso externo o interno. En el caso de soluciones inyectables, oftálmicas y óticas deben ser soluciones estériles. Una "suspensión" es una forma farmacéutica que consiste en un sistema disperso, compuesto de dos fases, las cuales contienen el o los principios activos y aditivos. Una de las fases, la continua o la externa es generalmente un líquido o un semisólido y la fase dispersa o interna, esta constituida de sólidos (principios activos) insolubles, pero dispersables en la fase externa. En el caso de inyectables deben ser estériles. Una "emulsión" es una forma farmacéutica que consiste en un sistema heterogéneo, generalmente constituido por dos líquidos no miscibles entre sí; en el que la fase dispersa está compuesta de pequeños glóbulos distribuidos en el vehículo en cual son inmiscibles. La fase dispersa se conoce también como interna y el medio de dispersión se conoce como fase externa o continua. Existen emulsiones de tipo agua / aceite o aceite / agua y pueden presentarse como semisólidos o líquidos. El o los principios activos y aditivos pueden estar en la fase externa o interna. An "ointment" or "ointment" is a pharmaceutical form consisting of a soft consistency preparation that contains the active ingredient or additives incorporated into an appropriate base that gives it mass and consistency. It adheres and is applied to the skin and mucous membranes. This base can be lioluble or id rosoluble, it is generally anhydrous or with a maximum of 20 percent water. It is also called hydrophilic ointment when it contains a washable or removable base with water. A "paste" is a pharmaceutical form consisting of a semi-solid form containing the active ingredient or additives, made from a high concentration of insoluble powders (20 to 50 percent), in fatty or aqueous, absorbent or weak abrasives combined with soaps. A "cream" is a pharmaceutical form that consists of a liquid or semi-solid preparation containing the active ingredient or additives necessary to obtain an emulsion, generally oil in water, with a water content greater than 20 percent. A "solution" is a pharmaceutical form that consists of a liquid, transparent and homogeneous preparation, obtained by dissolving it or the active ingredients and additives in water, and which is used for external or internal use. In the case of injectable, ophthalmic and otic solutions they must be sterile solutions. A "suspension" is a pharmaceutical form consisting of a dispersed system, composed of two phases, which contain the active ingredient or additives. One of the phases, the continuous or the external one is generally a liquid or a semi-solid and the dispersed or internal phase, is constituted of insoluble solids (active principles), but dispersible in the external phase. In the case of injectables they must be sterile. An "emulsion" is a pharmaceutical form consisting of a heterogeneous system, generally consisting of two liquids not miscible with each other; in which the dispersed phase is composed of small globules distributed in the vehicle in which they are immiscible. The dispersed phase is also known as internal and the dispersion medium is known as the external or continuous phase. There are emulsions of the water / oil or oil / water type and can be presented as semi-solids or liquids. The active ingredient or additives may be in the external or internal phase.
Una "loción" es una forma farmacéutica que se puede presentar como solución, suspensión o emulsión, que contiene el o los principios activos y aditivos, y cuyo agente dispersante es predominantemente agua. A "lotion" is a pharmaceutical form that can be presented as a solution, suspension or emulsion, which contains the active ingredient (s) and additives, and whose dispersing agent is predominantly water.
Un "linimento" es una forma farmacéutica que consiste en una presentación líquida, solución o emulsión que contiene el o los principios activos y aditivos cuyo vehículo es acuoso, alcohólico u oleoso. A "liniment" is a pharmaceutical form that consists of a liquid presentation, solution or emulsion that contains the active ingredient or additives whose vehicle is aqueous, alcoholic or oily.
Una "jalea" es una forma farmacéutica que consiste en un coloide semisólido que contiene el o los principios activos y aditivos, cuya base hidrosoluble por lo general esta constituida por gomas como la de tragacanto, otras bases usadas son: la glicerina, pectina, alginatos, compuestos boroglicerinados, derivados sintéticos o sustancias naturales como la carboximetilcelulosa. A "jelly" is a pharmaceutical form that consists of a semi-solid colloid that contains the active ingredient or additives, whose water-soluble base is usually made up of gums such as tragacanth, other bases used are: glycerin, pectin, alginates , boroglycerinated compounds, synthetic derivatives or natural substances such as carboxymethyl cellulose.
Un "gel" es una forma farmacéutica que consiste en preparación semisólida, que contiene el o los principios activos y aditivos, sólidos en un liquido que puede ser agua, alcohol o aceite, de tal manera que se forma una red de partículas atrapadas en la fase liquida. A "gel" is a pharmaceutical form consisting of semi-solid preparation, which contains the active ingredient or additives, solid in a liquid that can be water, alcohol or oil, such that a network of particles trapped in the liquid phase.
Una "espuma" es una forma farmacéutica que consiste en una preparación semisólida, constituida por dos fases: una líquida que lleva el o los principios activos y aditivos, y otra gaseosa que lleva gas propulsor para que el producto salga en forma de nube. A "foam" is a pharmaceutical form consisting of a semi-solid preparation, consisting of two phases: a liquid that carries the active ingredient (s) and additives, and another gas that carries propellant gas so that the product comes out in the form of a cloud.
El "polvo" es una forma farmacéutica que consiste en una forma sólida que contiene el o los principios activos y aditivos finamente molidos y mezclados para asegurar su homogeneidad. Otro aspecto de la invención se refiere al uso de la segunda composición o de la forma farmacéutica de la invención, para la elaboración de un medicamento, o alternativamente, a la segunda composición o a la forma farmacéutica de la invención para su uso como medicamento. The "powder" is a pharmaceutical form that consists of a solid form that contains the active ingredient (s) and finely ground and mixed additives to ensure its homogeneity. Another aspect of the invention relates to the use of the second composition or of the pharmaceutical form of the invention, for the preparation of a medicament, or alternatively, to the second composition or to the pharmaceutical form of the invention for use as a medicament.
Otro aspecto de la invención se refiere al uso de la segunda composición o de la forma farmacéutica de la invención, para la elaboración de un medicamento para el tratamiento de enfermedades proliferativas, o alternativamente, a la segunda composición o a la forma farmacéutica de la invención para el tratamiento de enfermedades proliferativas. En una realización preferida de este aspecto de la invención donde la enfermedad proliferativa se selecciona de la lista que comprende: cáncer pulmonar, cánceres pancreáticos, cánceres de colon, leucemias mieloides, cáncer folicular de tiroide, síndrome mielodisplástico (MDS), carcinoma de vejiga, carcinoma epidérmico y enfermedades proliferativas de la piel. Another aspect of the invention relates to the use of the second composition or the pharmaceutical form of the invention, for the preparation of a medicament for the treatment of proliferative diseases, or alternatively, to the second composition or to the pharmaceutical form of the invention for the treatment of proliferative diseases. In a preferred embodiment of this aspect of the invention where the proliferative disease is selected from the list comprising: lung cancer, pancreatic cancers, colon cancers, myeloid leukemias, thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma and proliferative diseases of the skin.
En otra realización preferida de este aspecto de la invención la enfermedad proliferativa de la piel se selecciona de la lista que comprende: queratosis actínica, carcinoma de células básales, carcinoma de células pavimentosas, histiocitoma fibroso, dermatofibrosarcoma protuberans, hemangioma, nevo flamígero, xantoma, sarcoma de Kaposi, mastocitosis, micosis fungoides, léntigo, nevo nevocelular, léntigo maligno, melanoma maligno, carcinoma metastático, psoriasis o enfermedades provocadas por infecciones de los virus del papiloma humano. En otra realización más preferida las enfermedades provocadas por la infección de los virus del papiloma humano se seleccionan de la lista que comprende: carcinoma de células escamosas de piel, neoplasia intraepitelial cervical, cáncer cervicouterino, cáncer de la mucosa oral, amígdala, faringe, laringe, esófago, mama, próstata, ovario, vulva, uretra, pene y de piel, tumores de estirpe melanocítica, verruga común, verruga plantar, verruga cutánea chata, verrugas genitales, epidermodisplasia verruciforme, hiperplasia focal epitelial (oral), o papilomas orales. Otra realización aún más preferida se refiere al uso de una composición farmacéutica o de una forma farmaceútica de la invención, en la elaboración de un medicamento para el tratamiento de verrugas, o alternativamente, a una composición farmacéutica o de una forma farmaceútica de la invención para su uso en el tratamiento de verrugas. Otra realización aún más preferida se refiere al uso de una composición farmacéutica o de una forma farmaceútica de la invención, en la elaboración de un medicamento para el tratamiento de la verruga plantar, o alternativamente, a una composición farmacéutica o de una forma farmaceútica de la invención para su uso en el tratamiento de la verruga plantar. Otra realización aún más preferida se refiere al uso de una composición farmacéutica o de una forma farmaceútica de la invención, en la elaboración de un medicamento para el tratamiento de la verruga palmar, o alternativamente, a una composición farmacéutica o de una forma farmaceútica de la invención para su uso en el tratamiento de la verruga palmar. In another preferred embodiment of this aspect of the invention, proliferative skin disease is selected from the list comprising: actinic keratosis, basal cell carcinoma, pavement cell carcinoma, fibrous histiocytoma, dermatofibrosarcoma protuberans, hemangioma, flaming nevus, xanthoma, Kaposi's sarcoma, mastocytosis, fungoid mycosis, lentigo, nevocellular nevus, malignant lentigo, malignant melanoma, metastatic carcinoma, psoriasis or diseases caused by human papillomavirus infections. In another more preferred embodiment, diseases caused by infection of human papillomavirus are selected from the list comprising: squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, cervical cancer, oral mucosal cancer, tonsil, pharynx, larynx , esophagus, breast, prostate, ovary, vulva, urethra, penis and skin, tumors of melanocytic lineage, common wart, plantar wart, flat skin wart, genital warts, verruciform epidermodisplasia, epithelial focal hyperplasia (oral), or oral papillomas. Another even more preferred embodiment relates to the use of a pharmaceutical composition or a pharmaceutical form of the invention, in the preparation of a medicament for the treatment of warts, or alternatively, a pharmaceutical composition or a pharmaceutical form of the invention for its use in the treatment of warts. Another even more preferred embodiment relates to the use of a pharmaceutical composition or a pharmaceutical form of the invention, in the preparation of a medicament for the treatment of plantar wart, or alternatively, to a pharmaceutical composition or a pharmaceutical form of the invention for use in the treatment of plantar wart. Another even more preferred embodiment relates to the use of a pharmaceutical composition or of a pharmaceutical form of the invention, in the preparation of a medicament for the treatment of the palmar wart, or alternatively, to a pharmaceutical composition or a pharmaceutical form of the invention for use in the treatment of palmar wart.
Otro aspecto de la invención se refiere al uso de la segunda composición o de la forma farmacéutica de la invención, para la elaboración de un medicamento para el tratamiento de enfermedades virales, o alternativamente, a la segunda composición o a la forma farmacéutica de la invención, para el tratamiento de enfermedades virales. En una realización preferida de este aspecto de la invención, la enfermedad viral es una infección de un virus del papiloma humano. En otra realización más preferida, la infección del virus del papiloma humano da lugar a una verruga. En una realización aún más preferida, la verruga es una verruga plantar. En otra realización más preferida, la verruga es una verruga palmar. Another aspect of the invention relates to the use of the second composition or the pharmaceutical form of the invention, for the preparation of a medicament for the treatment of viral diseases, or alternatively, to the second composition or to the pharmaceutical form of the invention, for the treatment of viral diseases. In a preferred embodiment of this aspect of the invention, the viral disease is an infection of a human papillomavirus. In another more preferred embodiment, human papillomavirus infection results in a wart. In an even more preferred embodiment, the wart is a plantar wart. In another more preferred embodiment, the wart is a palmar wart.
Las composiciones y/o sus formulaciones pueden administrarse a un animal, incluyendo un mamífero y, por tanto, al hombre, en una variedad de formas, incluyendo, pero sin limitarse a, intraperitoneal, intravenoso, intramuscular, subcutáneo, intracecal, intraventricular, oral, enteral, parenteral, intranasal o tópica. Preferiblemente, la administración de las composiciones de la invención es tópica. The compositions and / or their formulations can be administered to an animal, including a mammal and, therefore, to man, in a variety of ways, including, but not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intracecal, intraventricular, oral. , enteral, parenteral, intranasal or topical. Preferably, the administration of the compositions of the invention is topical.
La dosificación para obtener una cantidad terapéuticamente efectiva depende de una variedad de factores, como por ejemplo, la edad, peso, sexo, tolerancia,... del mamífero. En el sentido utilizado en esta descripción, la expresión "cantidad terapéuticamente efectiva" se refiere a la cantidad de materia vegetal de plantas del género Crassula, extractos o un principio activos obtenido a partir del material vegetal o de los extractos, que produzcan el efecto deseado y, en general, vendrá determinada, entre otras ca u sas , por l as ca racterísticas propi as d e d i ch os profármacos, derivados o análogos y el efecto terapéutico a conseguir. Los "adyuvantes" y "vehículos farmacéuticamente aceptables" que pueden ser utilizados en dichas composiciones son los vehículos conocidos por los técnicos en la materia. A lo largo de la descripción y las reivindicaciones la palabra "comprende" y sus variantes no pretenden excluir otras características técnicas, aditivos, componentes o pasos. Para los expertos en la materia, otros objetos, ventajas y características de la invención se desprenderán en parte de la descripción y en parte de la práctica de la invención. Los siguientes ejemplos y dibujos se proporcionan a modo de ilustración, y no se pretende que sean limitativos de la presente invención. The dosage to obtain a therapeutically effective amount depends on a variety of factors, such as the age, weight, sex, tolerance, ... of the mammal. In the sense used in this description, the term "therapeutically effective amount" refers to the amount of plant material from plants of the genus Crassula, extracts or an active ingredient obtained from the plant material or extracts, which produce the desired effect. and, in general, it will be determined, among other cases, by the characteristics of its own prodrugs, derivatives or analogs and the therapeutic effect to be achieved. The "adjuvants" and "pharmaceutically acceptable carriers" that can be used in said compositions are the vehicles known to those skilled in the art. Throughout the description and the claims the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. For those skilled in the art, other objects, advantages and features of the invention will be derived partly from the description and partly from the practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention.
DESCRIPCIÓN DE LAS FIGURAS Fig. 1. Caso 1 de verruga plantar. A) Imagen de la región afectada elDESCRIPTION OF THE FIGURES Fig. 1. Case 1 of plantar wart. A) Image of the affected region on
27.01.07. B) Imagen de la región afectada el 24.06.07. C) Imagen de la región afectada el 24.05.08. D) Imagen de la región afectada el 01 .07.08 tras el tratamiento. E) Imagen de la región afectada el 21 .10.10 tras el tratamiento. Fig. 2. Caso 2 de verruga plantar. A) Imagen de la región afectada el27.01.07. B) Image of the affected region on 24.06.07. C) Image of the affected region on 24.05.08. D) Image of the affected region on 01.07.08 after treatment. E) Image of the affected region on 21.10.10 after treatment. Fig. 2. Case 2 of plantar wart. A) Image of the affected region on
30.09.09. B) Imagen de la región afectada el 28.10.09. C) Imagen de la región afectada el 25.1 1 .09. D) Imagen de la región afectada el 02.12.09 tras el tratamiento. E) Imagen de la región afectada el 03.02.10 tras el tratamiento. Fig. 3. Caso de verruga palmar. A) Imagen de la región afectada el 23.12.09.30.09.09. B) Image of the affected region on 10.28.09. C) Image of the affected region on 25.1 1 .09. D) Image of the affected region on 02.12.09 after treatment. E) Image of the affected region on 03.02.10 after treatment. Fig. 3. Case of palmar wart. A) Image of the affected region on 23.12.09.
B) Imagen de la región afectada el 17.02.10 tras el tratamiento. B) Image of the affected region on 02.17.10 after treatment.
Fig. 4. Localización de las lesiones, md: mano derecha; mi: mano izquierda; mid: mano izquierda y derecha; pd: pie derecho; pi: pie izquierdo; pid: pie izquierdo y derecho; mp: mano y pie. Fig. 4. Location of lesions, md: right hand; My left hand; mid: left and right hand; pd: right foot; pi: left foot; pid: left and right foot; mp: hand and foot.
Fig. 5. Número de lesiones por paciente. Fig. 5. Number of injuries per patient.
Fig. 6. Resultados al finalizar el tratamiento. Fig. 6. Results at the end of the treatment.
EJEMPLOS EXAMPLES
A continuación se ilustrará la invención mediante unos ensayos realizados por los inventores. Elaboración de una pomada a partir de material vegetal de Crassula argéntea. The invention will now be illustrated by tests carried out by the inventors. Preparation of an ointment from plant material of Crassula argéntea.
Se hierven a fuego lento dos cucharadas soperas de la planta en 200 g de vaselina durante aproximadamente diez minutos, es posible usar una sola planta o una mezcla de raíces frescas o secas, hojas o flores. Preferiblemente se emplean hojas. Alternativamente se puede utilizar como base una mezcla de diversos aceites en lugar de vaselina. Esta mezcla de aceites actúa como vehículo para los componentes activos y contribuye a que penetren a través de la piel, además de ayudar a conseguir la textura deseada. Two tablespoons of the plant in 200 g of petroleum jelly are boiled over low heat for approximately ten minutes, it is possible to use a single plant or a mixture of fresh or dried roots, leaves or flowers. Preferably sheets are used. Alternatively, a mixture of various oils can be used as a base instead of petroleum jelly. This mixture of oils acts as a vehicle for the active components and helps them to penetrate through the skin, in addition to helping to achieve the desired texture.
Elaboración de compresas o emplastos a partir de material vegetal de Crassula argéntea. Las compresas o fomentos, así como las cataplasmas o emplastos, son un método muy eficaz para aplicar sustancias medicinales a la piel. Preparation of compresses or plasters from plant material from Crassula argéntea. Compresses or promotions, as well as poultices or plasters, are a very effective method to apply medicinal substances to the skin.
Una compresa se prepara con una tela (algodón, gasa) que se empapa en una infusión o decocción caliente sobre la zona afectada. El calor aumenta el efecto de las plantas, habrá que cambiar la compresa cuando se enfríe o colocar sobre ella un plástico. A compress is prepared with a cloth (cotton, gauze) that is soaked in an infusion or hot decoction on the affected area. The heat increases the effect of the plants, the compress will have to be changed when it cools or a plastic is placed on it.
El modo de actuar del emplasto es muy semejante al de una compresa, pero con la diferencia que se prepara con material vegetal sólido en lugar de líquido. The mode of action of the plaster is very similar to that of a compress, but with the difference that is prepared with solid plant material instead of liquid.
Para preparar emplasto se puede emplear la planta fresca o seca. En el primer caso, se deben aplicar las hojas o el material procedente de la raíz directamente sobre la piel o envuelto con una gasa fina. Si se trata de plantas secas, se prepara una pasta mediante la adición de agua caliente o vinagre de manzana, hasta que adquiera la consistencia adecuada. Para mantener la cataplasma caliente colocar una botella con agua caliente sobre la cataplasma. To prepare plaster you can use the fresh or dried plant. In the first case, the leaves or the material from the root should be applied directly to the skin or wrapped with thin gauze. If it is dry plants, a paste is prepared by adding hot water or apple cider vinegar, until it acquires the right consistency. To keep the poultice warm, place a bottle of hot water on the poultice.
También se puede aplicar la planta directamente sobre la piel. Cuando se aplica la planta directamente sobre la piel, conviene recubrir esta con un poco de aceite, con el fin de protegerla y facilitar la retirada posterior del emplasto. Otras formas de preparación You can also apply the plant directly to the skin. When the plant is applied directly to the skin, it should be coated with a little oil, in order to protect it and facilitate subsequent removal of the plaster. Other forms of preparation
Una infusión de hojas de Crassula argéntea se prepara poniendo en remojo aproximadamente 4 cm3 de dichas hojas en 1 litro de agua, a una temperatura adecuada, y durante un tiempo no inferior a 10 minutos. Si se desea, se puede ejercer presión sobre el residuo antes de la administración. An infusion of Crassula argéntea leaves is prepared by soaking approximately 4 cm 3 of said leaves in 1 liter of water, at a suitable temperature, and for a time not less than 10 minutes. If desired, pressure may be exerted on the residue before administration.
SI se desea una infusión más potente, se pueden emplear 16 m3 de hojas por cada litro de agua. La infusión se puede preparar, también, a partir de agua que ha hervido previamente, o cociendo el residuo en el agua. IF a stronger infusion is desired, they can be used 16 m 3 leaves per liter of water. The infusion can also be prepared from water that has previously boiled, or by cooking the residue in the water.
Una tintura se puede preparar poniendo en remojo el material vegetal de Crassula argéntea en una solución de aproximadamente un 60% de etanol y un 40% de agua. Se puede emplear etanol puro, acetona, cloroformo, vinagre u otros agentes similares. El volumen de la solución resultante debe ser de 3 o 4 veces el volumen del material vegetal empleado. La mezcla debe agitarse, al menos ocasionalmente, en un periodo de alrededor de dos horas, con un máximo de extracción obtenido después de 6 horas. SI se deja la tintura toda la noche, produce excelentes resultados. Se pueden prepara gotas reduciendo la tintura mediante calor, o mediante evaporación pasiva. Las gotas se concentran en un factor de aproximadamente 10 veces. A tincture can be prepared by soaking the plant material of Crassula argues in a solution of approximately 60% ethanol and 40% water. Pure ethanol, acetone, chloroform, vinegar or other similar agents can be used. The volume of the resulting solution must be 3 or 4 times the volume of the plant material used. The mixture should be stirred, at least occasionally, over a period of about two hours, with a maximum extraction obtained after 6 hours. If the tincture is left overnight, it produces excellent results. Drops can be prepared by reducing the tincture by heat, or by passive evaporation. The drops are concentrated by a factor of approximately 10 times.
Se puede preparar una loción, una crema, o un champú, añadiendo a una loción, una crema, o un champú comercial gotas o tintura hasta alcanzar aproximadamente el 25% del volumen de dicha loción, crema, o champú. A lotion, a cream, or a shampoo can be prepared by adding drops or tincture to a lotion, a cream, or a commercial shampoo to reach approximately 25% of the volume of said lotion, cream, or shampoo.
Administración a pacientes con verrugas. Se debe considerar el área de infección y la sensibilidad del paciente. Cuando la sensibilidad es elevada, se deben emplear infusiones. Las infusiones funcionan bien en el cuero cabelludo, o como baños para pies, área genital, o como ducha. Las gotas, de mayor concentración, pueden emplearse en áreas menos sensibles, y se recomienda el empleo de tinturas o emplastos en estas áreas. Para el tratamiento de verrugas orales o de cuello, puede emplearse un aerosol o una loción. Administración a pacientes con verrugas plantares ( verruga pedis). Administration to patients with warts. The area of infection and the sensitivity of the patient should be considered. When the sensitivity is high, infusions should be used. Infusions work well on the scalp, or as foot baths, genital area, or as a shower. The drops, of greater concentration, can be used in less sensitive areas, and the use of tinctures or plasters in these areas is recommended. For the treatment of oral or neck warts, an aerosol or lotion may be used. Administration to patients with plantar warts (wart pedis).
La forma farmacéutica más efectiva para el tratamiento de las verrugas plantares son los emplastos, incluso la aplicación directa de las hojas de la planta e el área afectada. La aplicación puede repetirse varios días, hasta la desaparición de la verruga plantar. The most effective pharmaceutical form for the treatment of plantar warts are the plasters, even the direct application of the leaves of the plant and the affected area. The application can be repeated several days, until the disappearance of the plantar wart.
También se puede aplicar directamente la pulpa de la hoja de planta Crassula argéntea que obtendremos al abrir la hoja longitudinalmente, como si fuésemos a hacer un bocadillo. La hoja debe tener un tamaño aproximado de 3 a 5 cm de largo, de 2 a 3 cm de ancho y unos 2 ó 3 milímetros de grosor. La aplicación deberá de ser diaria, por la noche, al acostarse, y consistirá en poner la parte de la pulpa en contacto directo con la lesión y sujetar la misma con un esparadrapo. Por la mañana retirar la planta. La efectividad de este tratamiento se ha demostrado en más de 160 pacientes.You can also directly apply the pulp of the Crassula plant leaf argue that we will obtain by opening the leaf longitudinally, as if we were going to make a sandwich. The sheet should be approximately 3 to 5 cm long, 2 to 3 cm wide and about 2 or 3 millimeters thick. The application should be daily, at night, at bedtime, and will consist of putting the part of the pulp in direct contact with the lesion and fasten it with a tape. In the morning remove the plant. The effectiveness of this treatment has been demonstrated in more than 160 patients.
En las Fig. 1 , 2 y 3 se muestran imágenes de la evolución temporal de dos casos de verrugas plantares, y uno de verruga palmar, Figures 1, 2 and 3 show images of the temporal evolution of two cases of plantar warts, and one of palmar warts,
Ensayo en pacientes Trial in patients
La composición de la invención se ha administrado tópicamente a un total inicial de 158 pacientes, 65 hombres y 93 mujeres, previo consentimiento, para el tratamiento del papiloma plantar y palmar, verrugas, durezas y hielomas. Todos los pacientes fueron instruidos para aplicar la composición del estudio The composition of the invention has been administered topically to an initial total of 158 patients, 65 men and 93 women, with prior consent, for the treatment of plantar and palmar papilloma, warts, hardnesses and hielomas. All patients were instructed to apply the study composition
La edad media fue de 33.8 ± 19.4 años, encontrándose aproximadamente el 70% de los pacientes entre los 18 y los 50 años. Las lesiones se localizaron mayoritariamente en el pie izquierdo, distribuyéndose principalmente en una zona, casi nunca combinados. El 5,3 % se localizaron simultáneamente en la mano derecha e izquierda, también el 5,3 % se localizó simultáneamente en el pie derecho e izquierdo, un 13,8% se localizó en la mano izquierda, un 19,1 % se localizó en la mano derecha, un 21 ,1 % se localizó en el pié derecho, y un 34,2% se localizó en el pie izquierdo (Fig. 4). The mean age was 33.8 ± 19.4 years, with approximately 70% of patients between 18 and 50 years. The lesions were mostly located in the left foot, distributed mainly in an area, almost never combined. 5.3% were located simultaneously in the right and left hand, also 5.3% was located simultaneously in the right and left foot, 13.8% was located in the left hand, 19.1% was located on the right hand, 21, 1% was located on the right foot, and 34.2% was located on the left foot (Fig. 4).
De la totalidad de los pacientes, el 82,9% sufrían de papilomas, el 6,3% presentaban verrugas, el 5,1 % presentaba hielomas, el 3,8% presentaba úlceras, y el 1 ,9% presentaba durezas (Fig. 5). Of all the patients, 82.9% suffered from papillomas, 6.3% had warts, 5.1% had hielomas, 3.8% had ulcers, and 1.9% had hardnesses (Fig . 5).
Se realizaron tres consultas programadas para evaluar la eficacia del tratamiento: al final del primer mes, tres meses después del inicio del tratamiento, y en el momento en el que fue dado de alta al paciente con las recomendaciones correspondientes. Three scheduled consultations were carried out to evaluate the efficacy of the treatment: at the end of the first month, three months after the start of the treatment, and at the time the patient was discharged with the corresponding recommendations.
El período de tratamiento fue de 5 meses, haciendo una revisión de 80 casos al primer mes, y de 60 casos en el tercer mes de tratamiento. De los 80 casos revisados al primer mes, la patología había desaparecido en el 43,8% de los casos, habiéndose reducido en el 25% de los casos, Un 1 1 ,3% de los pacientes no siguió el tratamiento, no pudiendo localizarse al 7,5% de los pacientes. De los 60 casos revisados al tercer mes de tratamiento la patología había desaparecido en el 48,5 % de los casos, habiéndose reducido en el 9,1 % de los casos, No se pudo hacer el seguimiento al 18,2 % de los pacientes. The treatment period was 5 months, reviewing 80 cases in the first month, and 60 cases in the third month of treatment. Of the 80 cases reviewed at the first month, the pathology had disappeared in 43.8% of the cases, having been reduced in 25% of the cases, 1 1, 3% of the patients did not follow the treatment, and could not be located 7.5% of patients. Of the 60 cases reviewed at the third month of treatment the pathology had disappeared in 48.5% of the cases, having been reduced in 9.1% of the cases, the follow-up could not be done to 18.2% of the patients .
Al finalizar el estudio, se comprobó el estado de 155 pacientes, de los cuales el 70,3 % presentaron una curación total, el 16,1 % no era papiloma, el 8,4 % no siguieron el tratamiento, un 3,9% no se pudo contactar, y únicamente un 1 ,3% no se curaron. Hubo en general un alto grado de satisfacción con la facilidad de aplicación, el coste del tratamiento y los resultados. No fueron reportaron efectos secundarios adversos. At the end of the study, the status of 155 patients was verified, of which 70.3% had a total cure, 16.1% was not papilloma, 8.4% did not follow the treatment, 3.9% could not be contacted, and only 1.3% were not cured. In general, there was a high degree of satisfaction with the ease of application, the cost of the treatment and the results. No adverse side effects were reported.

Claims

REIVINDICACIONES
1. Uso de: 1. Use of:
a. material vegetal de plantas del género Crassula, b. los extractos de las plantas de (a), o  to. plant material of plants of the genus Crassula, b. plant extracts from (a), or
c. de un principio activo de (a) ó (b),  C. of an active substance of (a) or (b),
para la elaboración de un medicamento para el tratamiento de enfermedades proliferativas.  for the development of a medicine for the treatment of proliferative diseases.
2. Uso de: 2. Use of:
a. material vegetal de plantas del género Crassula, b. los extractos de las plantas de (a), o  to. plant material of plants of the genus Crassula, b. plant extracts from (a), or
c. de un principio activo de (a) ó (b),  C. of an active substance of (a) or (b),
según la reivindicación anterior, donde la planta pertenece a la especie according to the preceding claim, wherein the plant belongs to the species
Crassula argéntea. Crassula argues.
3. Uso de: 3. Use of:
a. material vegetal de plantas del género Crassula, b. los extractos de las plantas de (a), o  to. plant material of plants of the genus Crassula, b. plant extracts from (a), or
c. de un principio activo de (a) ó (b),  C. of an active substance of (a) or (b),
según cualquiera de las reivindicaciones 1-2, donde la enfermedad proliferativa se selecciona de la lista que comprende: cáncer pulmonar, cánceres pancreáticos, cánceres de colon, leucemias mieloides, cáncer folicular de tiroide, síndrome mielodisplástico (MDS), carcinoma de vejiga, carcinoma epidérmico y enfermedades proliferativas de la piel  according to any of claims 1-2, wherein the proliferative disease is selected from the list comprising: lung cancer, pancreatic cancers, colon cancers, myeloid leukemias, thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, carcinoma epidermal and proliferative skin diseases
4. Uso de: 4. Use of:
a. material vegetal de plantas del género Crassula, b. los extractos de las plantas de (a), o  to. plant material of plants of the genus Crassula, b. plant extracts from (a), or
c. de un principio activo de (a) ó (b),  C. of an active substance of (a) or (b),
según la reivindicación 3, donde la enfermedad proliferativa de la piel se selecciona de la lista que comprende: queratosis actínica, carcinoma de células básales, carcinoma de células pavimentosas, histiocitoma fibroso, dermatofibrosarcoma protuberans, hemangioma, nevo flamígero, xantoma, sarcoma de Kaposi, mastocitosis, micosis fungoides, léntigo, nevo nevocelular, léntigo maligno, melanoma maligno, carcinoma metastático, psoriasis o enfermedades provocadas por la infección de los virus del papiloma humano. according to claim 3, wherein the proliferative skin disease is selected from the list comprising: actinic keratosis, basal cell carcinoma, pavement cell carcinoma, fibrous histiocytoma, dermatofibrosarcoma protuberans, hemangioma, flaming nevus, xanthoma, Kaposi's sarcoma, mastocytosis, fungoid mycosis, lentigo, nevocellular nevus, malignant lentigo, malignant melanoma, metastatic carcinoma, psoriasis or diseases caused by infection of human papillomavirus.
5. Uso de: 5. Use of:
a. material vegetal de plantas del género Crassula, b. los extractos de las plantas de (a), o  to. plant material of plants of the genus Crassula, b. plant extracts from (a), or
c. de un principio activo de (a) ó (b),  C. of an active substance of (a) or (b),
según la reivindicación 4, donde las enfermedades provocadas por la infección de los virus del papiloma humano se seleccionan de la lista que comprende: carcinoma de células escamosas de piel, neoplasia intraepitelial cervical, cáncer cervicouterino, cáncer de la mucosa oral, amígdala, faringe, laringe, esófago, mama, próstata, ovario, vulva, uretra, pene y de piel, tumores de estirpe melanocítica, verruga común, verruga plantar, verruga cutánea chata, verrugas genitales, epidermodisplasia verruciforme, hiperplasia focal epitelial (oral), o papilomas orales.  according to claim 4, wherein the diseases caused by the infection of the human papillomavirus are selected from the list comprising: squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, cervical cancer, oral mucosal cancer, tonsil, pharynx, larynx, esophagus, breast, prostate, ovary, vulva, urethra, penis and skin, tumors of melanocytic lineage, common wart, plantar wart, flat skin wart, genital warts, verruciform epidermodisplasia, epithelial focal hyperplasia (oral), or oral papillomas .
6. Uso de: 6. Use of:
a. material vegetal de plantas del género Crassula, b. los extractos de las plantas de (a), o  to. plant material of plants of the genus Crassula, b. plant extracts from (a), or
c. de un principio activo de (a) ó (b),  C. of an active substance of (a) or (b),
según la reivindicación 5, para el tratamiento de la verruga plantar.  according to claim 5, for the treatment of the plantar wart.
7. Composición farmacéutica que comprende materia vegetal de plantas del género Crassula, los extractos de dichas plantas o los principios activos según se describe en cualquiera de las reivindicaciones 1 -6. 7. Pharmaceutical composition comprising plant material of plants of the genus Crassula, extracts of said plants or active ingredients as described in any of claims 1-6.
8. Composición farmacéutica según la reivindicación anterior, que además que comprende un vehículo farmacéuticamente aceptable. 8. Pharmaceutical composition according to the preceding claim, further comprising a pharmaceutically acceptable carrier.
9. Composición farmacéutica según cualquiera de las reivindicaciones 7-8, que además comprende otro principio activo. 9. Pharmaceutical composition according to any of claims 7-8, which further comprises another active ingredient.
10. Forma farmacéutica que comprende la composición farmacéutica según cualquiera de las reivindicaciones 7-9. 10. Pharmaceutical form comprising the pharmaceutical composition according to any of claims 7-9.
1 1 . Forma farmacéutica según la reivindicación anterior que se selecciona de la lista que comprende: emplasto, pomada, pasta, crema, solución, suspensión, emulsión, loción, linimento, jalea, gel, espuma, polvo, o cualquiera de sus combinaciones. eleven . Pharmaceutical form according to the preceding claim which is selected from the list comprising: plaster, ointment, paste, cream, solution, suspension, emulsion, lotion, liniment, jelly, gel, foam, powder, or any combination thereof.
12. Uso de una composición farmacéutica según cualquiera de las reivindicaciones 7-9 o de una forma farmaceútica según cualquiera de las reivindicaciones 10-1 1 , para la elaboración de un medicamento. 12. Use of a pharmaceutical composition according to any of claims 7-9 or in a pharmaceutical form according to any of claims 10-1 1, for the preparation of a medicament.
13. Uso de una composición farmacéutica según cualquiera de las reivindicaciones 7-9 o de una forma farmaceútica según cualquiera de las reivindicaciones 10-1 1 , para la elaboración de un medicamento para el tratamiento de enfermedades proliferativas. 13. Use of a pharmaceutical composition according to any of claims 7-9 or in a pharmaceutical form according to any of claims 10-1 1, for the preparation of a medicament for the treatment of proliferative diseases.
14. Uso de una composición farmacéutica o de una forma farmaceútica según la reivindicación anterior, donde la enfermedad proliferativa se selecciona de la lista que comprende: cáncer pulmonar, cánceres pancreáticos, cánceres de colon, leucemias mieloides, cáncer folicular de tiroide, síndrome mielodisplástico (MDS), carcinoma de vejiga, carcinoma epidérmico y enfermedades proliferativas de la piel. 14. Use of a pharmaceutical composition or of a pharmaceutical form according to the preceding claim, wherein the proliferative disease is selected from the list comprising: lung cancer, pancreatic cancers, colon cancers, myeloid leukemias, thyroid follicular cancer, myelodysplastic syndrome ( MDS), bladder carcinoma, epidermal carcinoma and proliferative skin diseases.
15. Uso de una composición farmacéutica o de una forma farmaceútica según la reivindicación 14, donde la enfermedad proliferativa de la piel se selecciona de la lista que comprende: queratosis actínica, carcinoma de células básales, carcinoma de células pavimentosas, histiocitoma fibroso, dermatofibrosarcoma protuberans, hemangioma, nevo flamígero, xantoma, sarcoma de Kaposi, mastocitosis, micosis fungoides, léntigo, nevo nevocelular, léntigo maligno, melanoma maligno, carcinoma metastático, psoriasis o enfermedades provocadas por infección de los virus del papiloma humano. 15. Use of a pharmaceutical composition or a pharmaceutical form according to claim 14, wherein the proliferative skin disease is selected from the list comprising: actinic keratosis, basal cell carcinoma, pavement cell carcinoma, fibrous histiocytoma, dermatofibrosarcoma protuberans , hemangioma, flaming nevus, xanthoma, Kaposi's sarcoma, mastocytosis, mycosis fungoides, lentigo, nevocellular nevus, malignant lentigo, malignant melanoma, metastatic carcinoma, psoriasis or diseases caused by infection of human papillomavirus.
16. Uso de una composición farmacéutica o de una forma farmaceútica según la reivindicación 15, donde las enfermedades provocadas por la infección de los virus del papiloma humano se seleccionan de la lista que comprende: carcinoma de células escamosas de piel, neoplasia intraepitelial cervical, cáncer cervicouterino, cáncer de la mucosa oral, amígdala, faringe, laringe, esófago, mama, próstata, ovario, vulva, uretra, pene y de piel, tumores de estirpe melanocítica, verruga común, verruga plantar, verruga cutánea chata, verrugas genitales, epidermodisplasia verruciforme, hiperplasia focal epitelial (oral), o papilomas orales. 16. Use of a pharmaceutical composition or a pharmaceutical form according to claim 15, wherein the diseases caused by the infection of the human papillomavirus are selected from the list comprising: squamous cell carcinoma of the skin, cervical intraepithelial neoplasia, cancer cervical, oral mucosal cancer, tonsil, pharynx, larynx, esophagus, breast, prostate, ovary, vulva, urethra, penis and skin, tumors of melanocytic lineage, common wart, plantar wart, flat skin wart, genital warts, verruciform epidermodisplasia, focal epithelial hyperplasia (oral), or oral papillomas.
17. Uso de una composición farmacéutica o de una forma farmaceútica según la reivindicación 16, para el tratamiento de las verrugas. 17. Use of a pharmaceutical composition or a pharmaceutical form according to claim 16, for the treatment of warts.
18. Uso de una composición farmacéutica o de una forma farmaceútica según la reivindicación 17, para el tratamiento de la verruga plantar. 18. Use of a pharmaceutical composition or a pharmaceutical form according to claim 17, for the treatment of plantar wart.
19. Uso de una composición farmacéutica o de una forma farmaceútica según la reivindicación 17, para el tratamiento de la verruga palmar. 19. Use of a pharmaceutical composition or of a pharmaceutical form according to claim 17, for the treatment of the palmar wart.
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