WO2009022894A1 - Composition pharmaceutique comprenant la combinaison d'un agent anti-androgénique, d'un agent oestrogénique stéroïdien synthétique et d'agents vitaminiques, utile pour la lutte contre et le traitement de l'acné tardif chez la femme - Google Patents

Composition pharmaceutique comprenant la combinaison d'un agent anti-androgénique, d'un agent oestrogénique stéroïdien synthétique et d'agents vitaminiques, utile pour la lutte contre et le traitement de l'acné tardif chez la femme Download PDF

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WO2009022894A1
WO2009022894A1 PCT/MX2008/000101 MX2008000101W WO2009022894A1 WO 2009022894 A1 WO2009022894 A1 WO 2009022894A1 MX 2008000101 W MX2008000101 W MX 2008000101W WO 2009022894 A1 WO2009022894 A1 WO 2009022894A1
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Prior art keywords
vitamin
agent
pharmaceutical composition
acne
formulation
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PCT/MX2008/000101
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English (en)
Spanish (es)
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María Elena GARCÍA ARMENTA
Josefina Santos Murillo
Víctor Guillermo ALVAREZ OCHOA
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ESPINOZA ABDALA, Leopoldo de Jesùs
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Priority to ARP080103244A priority Critical patent/AR067699A1/es
Publication of WO2009022894A1 publication Critical patent/WO2009022894A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/07—Retinol compounds, e.g. vitamin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/28—Antiandrogens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens

Definitions

  • the present invention has application in the pharmaceutical industry and describes a pharmaceutical composition comprising the synergistic combination of an antiandrogenic agent, such as the active ingredient: Acetate, Cyproterone, a synthetic steroidal estrogenic agent, as is the active ingredient: Ethinylestradiol and vitamin agents, as are the active ingredients: Vitamin A and E, in addition to pharmaceutically acceptable excipients; which are formulated in a single dosage unit to be administered orally, which is indicated for the control and treatment of late acne manifested in women.
  • an antiandrogenic agent such as the active ingredient: Acetate, Cyproterone, a synthetic steroidal estrogenic agent, as is the active ingredient: Ethinylestradiol and vitamin agents, as are the active ingredients: Vitamin A and E, in addition to pharmaceutically acceptable excipients; which are formulated in a single dosage unit to be administered orally, which is indicated for the control and treatment of late acne manifested in women.
  • Acne is an inflammatory skin disease caused by a bacterial infection that affects the pilo-sebaceous follicle. It is produced by obstruction of the pores of the skin, with the consequent formation of inflamed and infected pimples and abscesses.
  • acne vulgaris The most common form of acne is known as: acne vulgaris. This is a frequent and self-limited disorder that affects adolescents; however, it may continue or appear for the first time in later stages, as is the case with late acne that usually occurs at 20 years of age or later.
  • Late acne occurs most frequently in women, significantly affecting their quality of life, - appearing as a result of an elevation in androgen levels and, typically, responds well to hormonal therapy administered alone or in combination with Other agents
  • Acne manifests itself as a series of excessive secretions of sebaceous glands that, combined with dead skin cells, block the hair follicle.
  • a defect in the process of keratinization of the skin which leads to abnormal effusion of the skin lining found in the pores.
  • fat secretions are produced that provide a perfect environment for the propionibacterium acnes epidermal bacteria, which produces an infection in the pore that will excrete pus, causing acne to multiply uncontrollably.
  • the skin becomes inflamed causing a visible lesion.
  • Acne can become very annoying with pain in the pores of the skin and also becomes a trauma for aesthetic reasons.
  • Acne is a pathological process characterized by: abnormal keratinization of the pilo-sebaceous apparatus, increased production of sebaceous secretion, colonization by P. acnes and the presence of inflammation.
  • Sebaceous duct blockage due to abnormal keratinization causes microcomedon.
  • Bacterial colonization induces a response inflammatory that manifests itself in the form of papules, pustules and inflammatory cysts.
  • the sebaceous glands are distributed throughout the body but are more abundant in the face. They produce secretion in response to androgens; The higher the sebaceous secretion the greater the severity of acne.
  • the ovary contributes 50% of the circulating androgens. In certain pathologies, ovarian tumors and polycystic ovarian syndrome, there is an excess in the production of androgens.
  • the adrenal gland contributes to the rest of the androgenic production.
  • hormonal activity related to menstrual cycles at puberty
  • stress driven by discharges from the adrenal glands
  • the overactive sebaceous glands the accumulation of dead skin cells
  • the bacteria lodged in the pores, to which the body becomes allergic the use of anabolics
  • skin irritation or any form of exfoliation will activate inflammation
  • any medicine containing halogens, lithium, barbiturates or androgens exposure to high levels of chlorine compounds.
  • chlorine dioxides can cause lasting acne known as chloracne.
  • Acne vulgaris in older adults may be characteristic of an underlying condition such as pregnancy and disorders, such as: polycystic ovarian axis syndrome or Cushing's syndrome.
  • acne Although most patients report that acne began after age 20, some have a history of acne at puberty that never improved. Characteristically, acne essentially affects the lower part of the face, but there may also be signs of activity in the neck and back.
  • Menstrual irregularity is defined in the presence of amenorrhea of more than three months or irregularity of the menstrual cycle of more than 7 days in a standard cycle of 28 days, for three consecutive cycles.
  • Other signs of hyperandrogenism, such as hirsutism, that is present in about 29% of patients with late onset acne should be evaluated.
  • Obesity, hirsutism and irregular menstrual cycles are findings of polycystic ovarian syndrome but are not always present. It is considered that 50% of women with late or persistent acne have polycystic ovarian syndrome.
  • Late-onset acne may be indistinguishable from teenage acne.
  • the physical exam must Emphasize the distribution of lesions, the severity and presence of manifestations compatible with hyperandrogenism, such as hirsutism and alopecia.
  • Late-onset acne is usually located in the lower part of the face, including in the neck; Puberty acne usually affects the middle region or the T zone (forehead, nose and cheeks).
  • hormonal evaluation is indicated in patients with late acne that should include: determination of free testosterone, dehydroepiandrosterone sulfate, sex hormone binding globulin and relationship between hormone concentration luteinizing and stimulating follicle.
  • High testosterone levels suggest hyperandrogenism without clarifying the origin.
  • the increase in dehydroepiandrosterone concentration suggests adrenal pathology, congenital adrenal hyperplasia or tumor.
  • the increase in testosterone with an increase in the relationship between luteinizing hormone and stimulating follicle supports polycystic ovary syndrome.
  • the ovaries and adrenal glands are often responsible for overproduction. of androgens in women with late acne. Blood samples should be obtained in the early follicular phase (day 1 to 7) of the menstrual cycle. The intake of oral contraceptives should be discontinued one month before the tests.
  • Hormonal treatment is very effective in women with late onset acne with or without elevated androgen levels. Such treatment reduces sebaceous secretion and is more effective when used in combination with other anti-acne therapies, such as topical keratolytic agents. Hormonal treatment is indicated in patients with peripheral, adrenal or ovarian hyperandrogenism, - in polycystic ovarian syndrome; in moderate or severe forms that do not respond to conventional treatment; in cases of recurrence, after multiple courses of antibiotics or a course of isotritinoin and as an alternative to the administration of repeated cycles of the latter drug.
  • the estrogenic component of oral contraceptives suppresses ovarian synthesis of androgens and stimulates the production of sex hormone binding globulin, thereby lowering the level of free testosterone In this way, the sebaceous gland is exposed to less androgenic stimulation. All combined oral contraceptives are effective, but some preparations have androgenic progestins, norgestrel and levonorgestrel; So they may be less useful. Preparations with sparingly androgenic progestins, desogestrel, signodene and norgestimate are available as anti-acne therapy.
  • the ovary contributes 50% of the circulating androgens.
  • the adrenal gland contributes to the rest of the androgenic production. It is common for the ovaries and adrenal glands to be responsible for excessive androgen production in women with late acne.
  • Hormonal treatment is very effective in women with late onset acne with or without elevated androgen levels.
  • the estrogenic component of oral contraceptives suppresses ovarian synthesis of androgens and stimulates the production of sex hormone binding globulin, thereby lowering the level of free testosterone. In this way, the sebaceous gland is exposed to less androgenic stimulation.
  • the use of a hormonal therapy that produces an antiandrogenic activity, in the long term of treatment causes dryness in the face and increased skinning due to the low levels of vitamin A and E in patients with moderate to severe acne; For this reason, we have investigated the fact of adding two vitamin substances that will promote greater benefit to the skin, producing a synergistic activity between the compounds. In studies, it has been found that the concentrations of vitamin A and E in plasma of patients with acne are significantly lower than those who do not have acne, or who have less acne.
  • the pharmaceutical composition object of the present invention is composed of the combination synergistic of an agent with antiandrogenic activity, a synthetic steroidal estrogenic agent and vitamin agents; which produce a satisfactory therapeutic effect when administered together in a single oral dosage unit, unlike when they are administered independently, generating benefits such as: lower concentrations of the active ingredients contained in the formula, lower administered doses, faster action, greater efficacy of the therapeutic effect and lower risks of adverse effects at the skin level.
  • Antiandrogenic agents or androgenic antagonists are a group of drugs that exert an antagonistic action or hormonal suppression capable of preventing or inhibiting the biological effects of male androgen sex hormones and the normal responses of body tissues to these hormones.
  • Antiandrogens normally act by blocking androgenic receptors, competing with the binding sites on the surface of cells, literally obstructing the function of androgens.
  • Antiandrogens are indicated and used in multiple diseases and non-medical situations respectively: a) acne; b) androgenic alopecia; c) hirsutism, - d) as antineoplastic agents, either palliatively, adjuvant or neoadjuvant hormonal treatment in prostate cancer; e) benign prostatic hyperplasia; f) occasionally they are also used in men as a contraceptive method; g) to prevent or counteract masculinization in cases of men who become transsexuals; h) to prevent symptoms associated with a testosterone deficit, such as spfocos, after a castration; i) antiandrogens are often indicated to treat serious sexual disorders, such as hypersexuality or excessive sexual desire and sexual deviations, especially paraphilias. Signs of androgenic disorders manifest mainly in the skin and hair
  • ovarian syndrome acne, seborrhea, hirsutism, alopecia
  • PCOS polycystic ovarian syndrome
  • the hyperandrogenemia is linked to menstrual disorders, amenorrhea, obesity and metabolic disorders (insulin resistance, atherogenic lipid profile and increased risk of cardiovascular disease, breast cancer and endometrium). Androgens come from ovarian (25%) and adrenal (25%) synthesis, from peripheral conversion from precursors (50%) and androgen secreting tumors.
  • these drugs have antigonadotrophic and antiandrogenic activity.
  • ACP is fully absorbed after oral administration; Its bioavailability is close to 100%. As it does not bind to transport proteins, 93% circulates bound to albumin. Retention exerted by subcutaneous fatty cell tissue improves its clinical effectiveness.
  • ACM is rapidly absorbed after oral administration; its bioavailability is close to 100%; It also accumulates in fatty tissue and its removal is slow.
  • DG is a hybrid progestogen that combines the properties of 19-nortestosterone with those of progesterone derivatives. It is rapidly absorbed from the gastrointestinal tract and has a bioavailability of 90%. The DRSP has rapid absorption and bioavailability of 76%.
  • Antiandrogenic progestogens combined with ethinylestradiol (EE) are used to treat androgenization signs.
  • EE ethinylestradiol
  • This combination acts through the following mechanisms of action: 1) competition at the level of androgenic receptors with testosterone and 5 ⁇ -dihydrotestosterone, - 2) increased elimination of androgens in the liver and reduced peripheral activation of 5 ⁇ -reductase in the skin; 3) reduction of LH secretion, with decrease in ovarian androgen secretion; 4) increase in EE-mediated sex hormone transport proteins, with consequent decrease in free testosterone.
  • Cyproterone Acetate is an antiandrogenic progestin derived from progesterone that inhibits ovulation and blocks the binding of androgens to the peripheral receptors of the sebaceous gland, canceling the conversion or passage of testosterone to 5- ⁇ -dihydrotestosterone, decreasing in a way important sebum production.
  • the combination of Cyproterone Acetate and Ethinylestradiol is very effective for the treatment of acne in women with mild to moderate hyperandrogenism.
  • the therapeutic indications of this drug are:
  • Cyproterone Acetate is rapidly and completely absorbed over a wide dosage range.
  • the maximum serum concentrations present after administration of Cyproterone Acetate are 15 ng./mL. and are reached after 1.6 hours. Subsequently, serum levels of Cyproterone Acetate decrease biphasically, with half-lives of 8 hours for the first phase and approximately 2.3 days for the second phase.
  • Cyproterone Acetate The total serum clearance rate of Cyproterone Acetate is 3.6 mL./min./kg. Cyproterone Acetate is metabolized by the hepatic route, through the processes of hydroxylation and conjugation. In human serum, the main metabolite is the 15-hydroxy-cyproterone derivative.
  • Cyproterone Acetate is almost exclusively bound to plasma albumin, approximately only 3.5 to 4% of the total concentration of Cyproterone Acetate is not bound to proteins.
  • the binding of cyproterone acetate to plasma proteins is nonspecific, so variations in the concentrations of SVG (sex hormone binding globulin) do not affect the pharmacokinetics of cyproterone acetate.
  • Cyproterone Acetate Due to the prolonged half-life of the final plasma distribution phase and the daily dose, Cyproterone Acetate accumulates in the serum during a treatment cycle. Maximum serum concentrations increased from 15 ng./mL. (day 1) at 21 ng./mL. and 24 ng./mL. at the end of the first and third cycle of treatment, respectively. The profile of the area under the concentration-time curve increased 2.2 times (at the end of the first cycle) and 2.4 times (at the end of the third cycle). The equilibrium conditions were reached after approximately 10 days of treatment. During long-term administration, Cyproterone Acetate accumulates throughout the treatment cycles by a factor of 2.
  • Synthetic steroidal estrogenic agents derive from the nucleus of estrano, composed of 18 carbons, and also like all of them, it has an aromatic ring A (first ring). Modifications at the level of carbons 3 and 17 have a particular functional impact. In estrogen metabolism, it is necessary to differentiate the interconversion that they can experience with each other (with which the activity is maintained estrogenic) and liver metabolism by which they are degraded and eliminated.
  • estradiol can be converted to estrone (15%) or estrone sulfate (65%). This constitutes the main estrogenic plasma reserve, and when necessary, it becomes estrone (21%) or estradiol (5%). All these hydroxylated and methylated metabolites subsequently undergo conjugation with sulfate or glucuronide for elimination in the urine.
  • estrone is irreversibly metabolized in the liver and, to a lesser extent, in the kidney.
  • the hydroxylation of ring A causes the catecolandrogens (2,3-dihydroxiestrone and 3,4-dihydroxiestrone) that are subsequently methylated. Hydroxylation of the D-ring causes estriol and two other trihydroxylated isomers, 16-epiestriol and 17-epiestriol
  • Plasma estrogens are partially bound to plasma proteins (estradiol 37 to 40%; estrone 16% and estriol 1%), then being biologically inactive.
  • the conjugated estrogens are also inactive, but can easily be converted to their active forms
  • the ovary Under normal conditions, the ovary is the main organ that gives rise to estrogens. Estrogens mainly cause a proliferation of specific cells in the body and are the cause of the growth of most secondary sexual characteristics in women. The ovary also produces relaxin, inhibin, activins and other active local agents such as folistatin and prostaglandins.
  • Estrogens have an important function in the development of the endometrial lining. Continuous exposure to estrogens for prolonged periods causes abnormal endometrial hyperplasia that is usually associated with abnormal bleeding. Different synthetic sterols have estrogenic activity; one of them, ethinylestradiol, has been particularly useful therapeutically, because unlike natural estrogens it is equally active orally than intramuscularly.
  • Ethinylestradiol is a synthetic steroidal estrogen, derived from estradiol, for oral administration. Like estradiol, ethinyl estradiol causes an increase in the thickness and timing of the vagina and promotes proliferation of the endometrium.
  • Ethinylestradiol administered orally is absorbed rapidly and completely. After oral administration, the maximum serum concentrations of the drug are approximately 89 pg / mL. and are reached after 1.7 hours. From that moment, the plasma concentrations of ethinylestradiol are reduced biphasically with half-lives of 2 to 3 hours for the first phase and of approximately 20 hours for the second phase, which indicates that the drug experiences extensive enterohepatic circulation.
  • the apparent volume of distribution of ethinylestradiol was determined to be 5 L / kg. approximately and the plasma clearance rate is 5 mL. / min / kg Ethinylestradiol binds largely to serum albumin, although unspecifically (approximately 98.5%). 2% of the concentration of the drug is in free form. During absorption and the first passage through the liver, ethinylestradiol is metabolized, thereby reducing its absolute and variable oral bioavailability.
  • the plasma concentrations that reach the equilibrium phase are reached after 3 or 4 days and are between 30% and 40% higher than those obtained if a single dose is administered.
  • the relative bioavailability of the ethinylestradiol content is practically complete.
  • the systemic bioavailability of ethinylestradiol can vary both ways by the administration of other drugs. However, high doses of vitamin C do not affect it. After continued administration, ethinylestradiol induces the hepatic synthesis of SVG (sex hormone binding globulin) and CBG (corticoid fixing globulin).
  • the magnitude of the SVG induction depends on the chemical structure and the dose of the co-administered progestogen.
  • serum SVG concentrations increased from approximately 100 nmol / L to 300 nmol / L
  • serum CBG concentrations increased from 50 ⁇ g / mL to 95 ⁇ g / mL.
  • Ethinylestradiol undergoes presystemic conjugation in the mucosa of the small intestine and in the liver. It is first metabolized by aromatic hydroxylation, forming a variety of methylated and hydroxylated metabolites, which are presented as free metabolites and as conjugates with glucuronides and sulfates.
  • the drug is not excreted without first becoming its active and inactive metabolites.
  • Metabolites Ethinylestradiol is excreted by the urinary and biliary routes (feces) in a ratio of 4: 6, with a half-life of approximately 1 day.
  • Vitamin agents or vitamins are organic substances, of varied nature and composition, essential in the metabolic processes that take place in the nutrition of living things. They do not provide energy, since they are not used as fuel, but without them the body is not able to take advantage of the constructive and energetic elements supplied by the food. Vitamins are labile substances, since they are easily altered by changes in temperature, pH and also by prolonged storage. Normally, vitamins are used inside the cells as precursors of coenzymes, from which thousands of enzymes that regulate the chemical reactions that keep the body's cells alive are made. Its effect is to help convert food into energy.
  • Vitamin needs vary according to gender, age and activity performed by the individual, both physical and intellectual.
  • Vitamins must be provided through food, since the human body cannot synthesize them. An exception is vitamin D, which can be formed on the skin with sun exposure and vitamins K, B 1 , B ⁇ 2 and folic acid, which are formed in small amounts in the intestinal flora. Certain vitamins are ingested as provitamins (inactive) and subsequently the human metabolism transforms them into active ones (in the intestine, in the liver, in the skin, etc.), after some modification in their molecules.
  • Organic disorders in relation to vitamins may refer to:
  • Avitaminosis if there are total deficiencies of one or several vitamins. Hypovitaminosis: if there is partial lack of vitamins. Hypervitaminosis: if there is an excess due to accumulation of one or several vitamins, over all those that are poorly soluble in water and, therefore, difficult to eliminate in the urine.
  • Vitamins are designated using capital letters, according to the name of the disease that causes their lack or the name of their chemical constitution. Traditionally, 2 groups of vitamins are established according to their dissolution capacity: water-soluble and fat-soluble vitamins.
  • Fat-soluble vitamins are consumed along with foods that contain fat, dissolving in fatty substances and oils. They are stored in the liver and fatty tissues, and because they can be accommodated in body fat, it is not necessary to take them every day so it is possible, after sufficient consumption, to survive a considerable time without their contribution. If consumed in excess (more than 10 times the recommended amounts) can be toxic. This can happen especially to athletes, who although they maintain a balanced diet resort to high-dose vitamin supplements, with the idea that they can increase their physical performance, being this totally false.
  • Liposoluble Vitamins are: Vitamin A (Retinol); Vitamin D (Calciferol); Vitamin
  • Vitamin E Tocopherol
  • Vitamin K Antihemorrhagic
  • Water-soluble vitamins are those that dissolve in water. These are coenzymes or coenzyme precursors, necessary for many chemical reactions that occurred as part of human metabolism. They are characterized by having a wide capacity to dissolve in water, so they can be transported through washing water or cooking food. Many foods rich in this type of vitamins do not give us the same amount they initially contained at the end of their preparation. To recover part of these vitamins (some are destroyed by heat), you can take advantage of the cooking water of the vegetables for broths or soups. Unlike fat-soluble vitamins, water-soluble vitamins are not stored in the body, this means that they must be provided regularly and can only be dispensed with for a few days. The excess of water-soluble vitamins is excreted in the urine, so they have no toxic effect no matter how high their intake is, although abnormalities in the kidney could be manifested because they cannot evacuate all the fluid. Water-soluble Vitamins are: Vitamin C or Acid
  • Vitamin B2 or Riboflavin Vitamin B2 or Riboflavin
  • Vitamin B6 or Pyridoxine
  • Vitamin B8 or Biotin, -
  • Vitamin B9 or Folic Acid and Vitamin B12 or Cobalamin are Vitamin B9 or Folic Acid and Vitamin B12 or Cobalamin.
  • Retinol Palmitate or Vitamin A is a fat-soluble vitamin; It is present as such in food of animal origin and in vegetables is found as provitamin A, in the form of carotenes, which are transformed into vitamin A in the human body. It is stored in the liver in large quantities and also in the fatty tissue of the skin (palms of the hands and feet mainly), so it can last long periods without its consumption. It is an antioxidant substance, since it eliminates free radicals and protects DNA from its mutagenic action, thus contributing to slow down cell aging.
  • vitamin A The main function of vitamin A is to intervene in the formation and maintenance of soft and bone tissues, skin, mucous membranes, clients and bones. It acts as a regulator of normal skin development and is used to correct dryness and peeling conditions. It has an important regulatory function in the differentiation of epidermal cells and in the activity of epithelial tissues. It also participates in the elaboration of enzymes in the liver and sexual and adrenal hormones.
  • vitamin A insufficiency is night blindness (difficulty adapting to darkness); Other symptoms are excessive dry skin, lack of secretion of the mucous membrane and dry eyes due to the malfunction of the tear. In contrast, excess of this vitamin causes growth interference, bone disorders or alterations, absence of menstruation and can also damage the red blood cells.
  • Vitamin A The consumption of foods rich in Vitamin A is recommended in people prone to respiratory infections (flu, tonsillitis or inflammation), eye problems (photophobia, dryness or night blindness) or with dry and rough skin (acne included) . Cooking food for a short time can achieve a better use of the vitamins they contain, but leaving them for a long time reduces their vitamin properties, so it is more convenient to consume, if possible, fresh foods.
  • Vitamin A The main sources of Vitamin A are: Fish liver oil, Egg yolk, Soybean oil, Butter. Carrot, Spinach, Liver, Parsley, Milk, Cheese, Tomato and Lettuce, among others.
  • Vitamin E is absorbed from the gastrointestinal tract by a mechanism similar to that of other fat-soluble vitamins. Vitamin E can act as a cofactor in some enzyme systems. From 20 to 80% it is absorbed in the duodenum and requires dietary fat and the presence of bile salts for its absorption to be effective. It enters the bloodstream through lymph, appears first in chylomicrons and then mainly associated with plasma beta-lipoproteins.
  • Vitamin E is distributed throughout all tissues. 70 to 80% of an intravenous dose of radioactive Vitamin E is excreted by the liver for a week, the rest appears as a metabolite in the urine. Your metabolism is liver. Urinary metabolites are glucuronides of tocopherolic acid and its gammalactone. Other metabolites of a quinone-like structure are found in tissues, one of them is similar to the structure of ubiquinone and may be related to the active form of the vitamin. Its elimination is bile and renal. Its main function is to participate as an antioxidant, forming a protective shield of cell membranes that does not age or deteriorate by free radicals that contain oxygen and can be toxic and carcinogenic.
  • Vitamin E as an antioxidant is of the utmost importance in the prevention of diseases where there is a destruction of important cells.
  • Vitamin E protects the lung against contamination, provides oxygen to the body and retards cell aging, keeping the human body rejuvenated. It also accelerates the healing of burns, helps prevent miscarriages and leg cramps.
  • the Vitamin E participates in the formation of red blood cells, muscles and other tissues. It is needed for the formation of male sex cells and in anti-sterilization.
  • Vitamin E deficiency can be caused by two causes: by not eating food that contains it or by poor absorption of fats. Vitamin E because it is a fat-soluble vitamin, it needs fat to be present for its absorption in the intestine. Its deficiency produces muscular dystrophy, loss of fertility and anemia. There is no history that its excess produces massive toxic effects.
  • Vitamin E The main sources of Vitamin E are: Vegetable oils, Wheat germ, Chocolates, Legumes, Vegetables, Milk, Sunflower seeds, Fruits, Corn, Soy and Liver, among others.
  • the pharmaceutical composition protected by the present invention is formulated to be administered orally in a single dosage unit in the form of a capsule or tablet, in which the synergistic combination of the active ingredients is contained: Cyproterone Acetate, Ethinylestradiol, Retinol palmitate equivalent to Vitamin A and dl-alpha-tocopherol equivalent to Vitamin E; as well as pharmaceutically acceptable excipients.
  • Said pharmaceutical composition has been developed with the purpose of providing a useful pharmaceutical alternative for the control and treatment of diseases such as: late acne manifested in women and the decrease in vitamin A and E caused by said disease, as well as other related pathologies ; It offers significant advantages such as: lower concentrations of the active ingredients contained in the formulation, lower dosages administered, faster action, greater efficacy of the therapeutic effect, effective control of symptoms manifested by the presence of acne and lower risks of the occurrence of adverse effects that cause damage at the skin level.
  • the antiandrogenic agent used in the pharmaceutical composition object of the present invention is the active ingredient: Cyproterone Acetate, which is present in the formulation in a concentration range of 1.0 mg. to 50.0 mg., being preferably used a concentration of about 1.0 mg. at 2.0 mg , per dose unit.
  • the synthetic steroidal estrogenic agent used in the pharmaceutical composition object of the present invention is the active ingredient:
  • Ethinylestradiol which is present in the formulation in a concentration range of 1.0 ⁇ g. to
  • Vitamin A is present in the formulation in a concentration range of 1.0 mg. at 100.0 mg , preferably a concentration of approximately 1.0 mg being used. at 2.0 mg , per unit dose.
  • vitamin E dl-alpha-tocopherol also known as Vitamin E, which is present in the formulation in a concentration range of 1.0 mg at 100.0 rag. , preferably a concentration of approximately 1.0 mg being used. at 15.0 mg., per dose unit.
  • Group 1 received: Cyproterone Acetate / Ethinylestradiol.
  • Testosterone 64 ⁇ 33 mg./dL 62 ⁇ 35 mg./dL DHEA 276 ⁇ 93 mg./dL 266 ⁇ 70 mg./dL
  • Testosterone 21 ⁇ 11 mg./dL 14.7 ⁇ 6 mg./dL DHEA 173 ⁇ 65 mg./dL 140 ⁇ 63 mg./dL

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dermatology (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique constituée par la combinaison synergique d'un agent anti-androgénique, tel que le principe actif Acétate de ciprotérone, d'un agent oestrogénique stéroïdien synthétique, tel que le principe actif Etinilestradiol et d'agents vitaminiques, tels que les principes actifs Palmitate de rétinol aussi connu sous le nom de Vitamine A et dl-alfa-tocoférol aussi connu sous le nom de Vitamine E; lesquels sont préparés en dose unitaire destinée à être administrée par voie orale sous forme de capsule ou de comprimé. Ladite composition est indiquée pour la lutte contre et le traitement de maladies telles que: l'acné tardif se manifestant chez la femme et la diminution de la vitamine A et E provoquée par ladite maladie, ainsi que d'autres pathologies associées.
PCT/MX2008/000101 2007-07-27 2008-07-25 Composition pharmaceutique comprenant la combinaison d'un agent anti-androgénique, d'un agent oestrogénique stéroïdien synthétique et d'agents vitaminiques, utile pour la lutte contre et le traitement de l'acné tardif chez la femme WO2009022894A1 (fr)

Priority Applications (1)

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ARP080103244A AR067699A1 (es) 2007-07-27 2008-07-25 Composicion farmaceutica que comprende la combinacion de un agente antiandrogenico, un agente estrogenico esteroidico sintetico y agentes vitaminicos, util para el control y tratamiento del acne tardio en la mujer

Applications Claiming Priority (2)

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MXMX/A/2007/009120 2007-07-27
MX2007009120A MX2007009120A (es) 2007-07-27 2007-07-27 Composicion farmaceutica que comprende la combinacion de un agente antiandrogenico, un agente estrogenico esteroidico sintetico y agentes vitaminicos, util para el control y tratamiento del acne tardio en la mujer.

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WO2009022894A1 true WO2009022894A1 (fr) 2009-02-19

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AR (1) AR067699A1 (fr)
MX (1) MX2007009120A (fr)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022076733A1 (fr) * 2020-10-08 2022-04-14 Fortress Biotech, Inc. Compositions d'acétate de cyprotérone et leurs utilisations

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ALEGRE R.C.H.M.: "Tratamento da acne com oxitetraciclina associada as vitaminas A e E", FOHLA THE MEDICA, vol. 85, no. 4, 1982, pages 795 - 799 *
AYRES S. ET AL.: "Synergism of vitamins A and E in acne vulgaris", INTERNATIONAL JOURNAL OF DERMATOLOGY, vol. 20, no. 9, 1981, pages 616 *
COLLEGE DES EINSEIGNANTS. MISE AU POINT THEMATIQUE: "Acne. Diagnostic, physiopathologie et traitement", ANNALES OF DERMATOLOGIE ET OF VENEREOLOGIE, vol. 127, 2000, pages A186 - A191 *
STRUMIA R.: "Dermatologic signs in patients with eating disorders", AMERICAN JOURNAL OF CLINICAL DERMATOLOGY, vol. 6, no. 3, 2005, pages 165 - 173 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022076733A1 (fr) * 2020-10-08 2022-04-14 Fortress Biotech, Inc. Compositions d'acétate de cyprotérone et leurs utilisations

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UY31248A1 (es) 2009-01-30
AR067699A1 (es) 2009-10-21

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