[go: up one dir, main page]

WO2005092346A1 - Utilisation d'une combinaison d'oestrogene et de progestine a dose ultra-faible pour une contraception orale de longue duree - Google Patents

Utilisation d'une combinaison d'oestrogene et de progestine a dose ultra-faible pour une contraception orale de longue duree Download PDF

Info

Publication number
WO2005092346A1
WO2005092346A1 PCT/CN2004/000348 CN2004000348W WO2005092346A1 WO 2005092346 A1 WO2005092346 A1 WO 2005092346A1 CN 2004000348 W CN2004000348 W CN 2004000348W WO 2005092346 A1 WO2005092346 A1 WO 2005092346A1
Authority
WO
WIPO (PCT)
Prior art keywords
progestin
estrogen
days
combination
ethinyl estradiol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2004/000348
Other languages
English (en)
Inventor
Kewen Dong
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
DONG KEJUAN
Original Assignee
DONG KEJUAN
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by DONG KEJUAN filed Critical DONG KEJUAN
Publication of WO2005092346A1 publication Critical patent/WO2005092346A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • 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
    • 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
    • A61P5/34—Gestagens

Definitions

  • the menstrual cycle In the majority of woman, the menstrual cycle lasts about 25 to 30 days.
  • the menstrual cycle can be divided into two phases: (1) the follicular phase, at which time new follicles are recruited and their growth and development eventually lead to a single mature follicle; (2) the luteal phase, at which time the matured oocyte has been released and a new structure, the corpus luteum, is formed.
  • the follicular phase and the luteal phase In a typical cycle of 28 days, the follicular phase and the luteal phase are of equal length.
  • the endometrial tissue responds to the changes of hormones such as, estrogen and progestin.
  • Menstruation signifies the beginning of a new menstrual cycle and the first day of menses is, by definition, counted as DAY ONE.
  • the superficial layers of the endometrium are sloughed because the demise of the corpus luteum is associated with a loss of progesterone secretion in the non- fertile menstrual cycle.
  • Ovarian follicular maturation occurs resulting in a rise in the circulating levels of estrogen, which in turn leads to new endometrial proliferation.
  • the dominant ovarian follicle undergoes ovulation, which is induced by the gonadotropin surge, generally between menstrual cycle days 12 to 16 and is converted from a predominantly estrogen source to a predominantly progesterone source (the corpus luteum).
  • the increasing level of progesterone in the uterus converts the endometrium from a proliferative phase to a secretory phase in which tissue proliferation has promptly abated, leading to the formation of endometrial glands or organs.
  • the secretory endometrium and the conceptus interact to bring about implantation, beginning about 6 to 8 days after fertilization.
  • a process call "implantation" may occur, resulting in the establishment of an ongoing pregnancy.
  • the embryo will attach and burrow into the secretory endometrium and begin to produce human chorionic gonadotropin.
  • the human chorionic gonadotropin in turn stimulates corpus luteum function and maintains an elevated progesterone level.
  • menses does not occur in the fertile menstrual cycle.
  • Pregnancy is then established.
  • the waning level of progesterone in the blood causes the endometrial tissue to slough. This starts a subsequent menstrual cycle.
  • estradiol is known to decrease gonadotropin release, such as follicle-stimulation hormone, by feedback inhibition. By the negative feedback loop, estradiol can also inhibit luteinizing hormone secretion.
  • estrogen may also can cause a positive effect for the releasing of the gonadotropins.
  • Estradiol just before the ovulation cause the luteinizing hormone surge which is responsible for the final maturation and ovulation of the oocyte. Giving a woman high-doses estrogen immediately post-coitally also can prevent conception probably by interference with implantation.
  • progestin makes the cervical mucus thick, tenacious and cellular. These changes in female reproductive system are believed to impede spermatozoal transport. Administration of progestin also inhibits luteinizing hormone secretion and blocks ovulation in humans. Therefore, progestins can also provide contraception.
  • the most used medication for oral contraception is a pill that has both an estrogen and a progestin component, a so-called combined oral contraceptive preparation.
  • An alternative hormonal method of oral contraception is a pill that contains progestin only.
  • progestin-only preparations have a more varied spectrum of side effects than the combined preparations, an example being breakthrough bleeding. It is also less efficacious than the combined oral contraceptives.
  • the combined preparations are the preferred oral contraceptives in use today (Sheth et al., Contraception 25:243, 1982).
  • Pat. No. 4,390,531 shows a tri-phasic medication in which each phase uses about 20-40 meg ethinyl estradiol.
  • the phases 1 and 3 use 0.3-0.8 norethindrone and phase 2 doubles the amount of the norethindrone. In a 28 day cycle, these three phases account for the first 21 days.
  • Pat. No. 490,531 shows a tri-phasic medication in which each phase uses about 20-40 meg ethinyl estradiol.
  • the phases 1 and 3 use 0.3-0.8 norethindrone and phase 2 doubles the amount of the norethindrone. In a 28 day cycle, these three phases account for the first 21 days.
  • Pat. No. 5,098,714 (U.S.) describes an osmotic, oral dosage form. One pill is taken each day but the administration is, in effect, polyphasic.
  • the dosage form is constructed such that it provides an initial pulse delivery of estrogen and progestin followed by prolonged delivery of estrogen.
  • the Pat. No. 0 253 607 shows a monophasic contraceptive preparation containing units having 0.008-0.03 g of ethinyl estradiol and 0.025-0.1 mg of desogestrel and a medication where the preparation is administered over a 23-25 day period, preferably 24 days, followed by a 2-5 day of pill-free period.
  • the object of this medication is to provide contraceptive protection and for hormonal replacement therapy the pre-menopausal woman in need thereof by supplying a low dose of an estrogen combined with a low dose of a progestogen.
  • Pat. No. 5,552,394 shows a female contraception method.
  • the method is characterized by a reduced incidence of breakthrough bleeding after the first cycle which involves administering a combination of estrogen and progestin for 23-25 consecutive days of a 28 day cycle in a monophasic fashion.
  • the daily amounts of estrogen and progestin are equivalent to about 5-35 ⁇ g of ethinyl estradiol and about 0.025 to 10 mg of norethindrone acetate, respectively.
  • the weight ratio of estrogen to progestin is at least 1 :45, calculated as ethinyl estradiol to norethindrone acetate.
  • the medication enhances compliance by involving fewer stop/start transitions per year and also results in less blood loss in patients with anemia. Having fewer menstrual intervals can enhance lifestyles and convenience.
  • the fewer "pill-free intervals" also should contribute to increased efficacy since they eliminate the intervals around which errors of compliance can occur and allow follicular development and occasional development of "dominant follicles" that cannot be corrected subsequently by the subsequent intake of estrogen / progestin tablets.
  • This invention describes a method of female contraception which is characterized by a reduced number of withdrawal menses per year.
  • This is a new method of female contraception which involves administering, preferably in a monophasic fashion, a combination of estrogen and progestin for 180-364 consecutive days followed by 3-5 days of no administration, in which the daily amounts of the estrogen and progestin are equivalent to about 5-35 meg of ethinyl estradiol and about 0.050-0.150 mg of levonorgestrel, respectively,
  • a women in need of contraception is administered a combined dosage form of estrogen and progestin, preferably in a monophasic fashion, for 180-364 consecutive days, followed by an administration- free interval of 3 to 5 days, preferably about 3 days.
  • the daily amounts of estrogen and progestin are equivalent to about 5-35 ⁇ g of ethinyl estradiol and about 0.050-0.150 mg of levonorgestrel, respectively.
  • the preferred estrogen is ethinyl estradiol and progestins is levonorgestrel.
  • the weight ratio of these two active ingredients is at least 1 :5.
  • the preferable amount of ethinyl estradiol is about 10-20 ⁇ g and the preferable amount of levonorgestrel is about 0.050-0.150 mg.
  • Other estrogens vary in potency from ethinyl estradiol. For example, 30 ⁇ g of ethinyl estradiol is approximately equivalent to 60 ⁇ g of mestranol or 2,000 ⁇ g of 17-beta- estradiol.
  • other progestins vary in potency from norethindrone acetate.
  • 1 mg of levonorgestrel is roughly equivalent to 3.5 mg of norethindrone acetate or 1mg of desogestrel and 3-ketodesogestrel, 0.7 mg of gestodene, 10 mg of TMG (Wyeth) or 2 mg of chlormadinone.
  • the values given above are for the ethinyl estradiol and the norethindrone acetate and if a different estrogen or progestin is employed, an adjustment in the amount based on the relative potency should be made.
  • the relative potency of the various estrogens and progestins are known.
  • estrogens cannot be used. These estrogens include the esters of estradiol, estrone and ethinyl estradiol such as the acetate, sulfate, valerate or benzoate, conjugated equine estrogens, agnostic anti-estrogens, and selective estrogen receptor modulators.
  • the estrogen is administered in the conventional manner by any route where it is absorbed, such as orally or transdermally. Most of the estrogens are orally active and that route of administration is therefore preferred.
  • the forms of administration of estrogen and progestin can be tablets, dragees, capsules or pills which contain the estrogen or progestin and a pharmaceutically appropriate carrier.
  • the pharmaceutical formulations which contain progestin and a suitable carrier, can be solid oral dosage forms which includes tablets, capsules, cachets, pellets, pills, powders or granules; topical dosage forms which includes solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, creams, gels or jellies, foams and controlled release depot entities; and parenteral dosage forms which includes solutions, suspensions, emulsions or dry powder comprising an effective amount of progestin in this invention.
  • the progestin which is the active drug, can be contained in such formulations in addition to pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • pharmaceutically acceptable diluents fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like.
  • the methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance. For example, “Modern Pharmaceutics", Banker & Rhodes, Marcel Dekker, Inc. 1979; “Goodman & Gilman's The Pharmaceutical Basis of Therapeutics", 6th Edition, MacMillan Publishing Co.
  • the pharmaceutical formulations may be provided in kit form containing 28 active tablets to be taken once daily on successive days. The completion of one kit is immediately followed by the start of the next kit and the patient will take the tablets continuously for 180 to 364 days.
  • the studies begin with spontaneous menstruation in a pretreatment control cycle. At the onset of the next spontaneous menses, alternatively, they are assigned to receive on cycle day one an ultra low dose oral contraceptive for either 60 consecutive days, followed by 3 non-treatment days or 84 consecutive days, followed by a 7 non-treatment days. These regimens are continued through three treatment cycles. The study concludes with each group of primates being followed during a post-treatment spontaneous ovarian menstrual cycle.
  • Femoral blood is collected daily and the serum frozen for subsequent RIA of estradiol, progesterone, FSH and LH in the pretreatment and post-treatment cycles and every 3rd day during all three treatment cycles, except daily through the "pill free" interval.
  • Bleeding profiles are kept by daily vaginal swabs, indicating spontaneous menstruation, withdrawal bleeding, breakthrough bleeding, or withdrawal amenorrhea. Breakthrough bleeding is defined as detectable blood in the vagina outside of the first 8 days after the last dose of oral contraceptive or the onset of spontaneous menses in non-treatment cycles.
  • the medication is adjusted to fit the smaller (than human) body weight of these laboratory primates.
  • the dose of ethinyl estradiol is 1.2 ⁇ g/day, while the dose of norethindrone acetate is 0.06 mg/day.
  • This "in-house" reformulation is achieved by grinding to powder a commercially available monophasic pill (Loestrin 1/20, Parke Davis, Morris Plains, N.J.), which originally contained 1 mg of norethindrone acetate and 20 ⁇ g of ethinyl estradiol per tablet, contained in a conventional 21 -day pack along with 7 iron- containing placebos.
  • the daily dose received by the monkeys is about 12 ⁇ g of ethinyl estradiol and 0.6 mg of norethindrone acetate.
  • this ultra low dose oral contraceptive formulation presented a 40% reduction in daily estrogen- progestin exposure as compared to one of the lowest estrogen dose combination oral contraceptives commercially available today in America or Europe.

Landscapes

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

Abstract

Une méthode de contraception féminine orale consiste à administrer une combinaison d'oestrogène et de progestine sur une période de 180 à 364 jours consécutifs suite à une période maximale de 3 à 5 jours sans prise de ladite combinaison. Une dose ultra-faible de l'oestrogène et de la progestine sera utilisée. Les quantités quotidiennes d'oestrogène et de progestine sont équivalentes à environ 5 à 35 mcg d'éthinylestradiol et à environ 0,050 à 0,150 mg de lévonorgestrel, respectivement. Les avantages de cette méthode sont une plus faible anémie, un flux menstruel réduit, une exposition globale au médicament moins importante, une plus grande commodité et des taux d'observation supérieurs pour les patientes.
PCT/CN2004/000348 2004-03-26 2004-04-14 Utilisation d'une combinaison d'oestrogene et de progestine a dose ultra-faible pour une contraception orale de longue duree Ceased WO2005092346A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200410029600.7 2004-03-26
CNA2004100296007A CN1672685A (zh) 2004-03-26 2004-03-26 一种新的避孕药物

Publications (1)

Publication Number Publication Date
WO2005092346A1 true WO2005092346A1 (fr) 2005-10-06

Family

ID=35045627

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2004/000348 Ceased WO2005092346A1 (fr) 2004-03-26 2004-04-14 Utilisation d'une combinaison d'oestrogene et de progestine a dose ultra-faible pour une contraception orale de longue duree

Country Status (2)

Country Link
CN (1) CN1672685A (fr)
WO (1) WO2005092346A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2234491A4 (fr) * 2007-12-20 2010-12-22 Teva Womens Health Inc Schémas posologiques, compositions pharmaceutiques et emballages pour une contraception d'urgence
EP2079461A4 (fr) * 2006-10-30 2011-07-20 Teva Womens Health Inc Procédés de traitement hormonal utilisant des schémas posologiques cycliques prolongés à doses croissantes
WO2016187269A1 (fr) * 2015-05-18 2016-11-24 Agile Therapeutics, Inc. Compositions contraceptives et procédés d'amélioration de l'efficacité et de modulation d'effets secondaires

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AT12800U1 (de) * 2007-11-05 2012-11-15 Bayer Schering Pharma Ag Pharmazeutisches Präparat zur Verwendung bei der oralen Kontrazeption von Frauen mit Laktoseintoleranz
CN101455644B (zh) * 2008-02-05 2013-05-01 北京紫竹药业有限公司 一种长效复方避孕微球及其制备
CN102302779A (zh) * 2011-07-29 2012-01-04 岳中瑾 治疗包茎的乳膏制剂及其应用
WO2022246634A1 (fr) * 2021-05-25 2022-12-01 Zhejiang Jiachi Development Pharmaceuticals Ltd. Compositions pour le traitement de l'insomnie et leurs utilisations
CN114259498B (zh) * 2021-12-02 2023-04-28 南通联亚药业股份有限公司 一种包含去氧孕烯和炔雌醇的药物组合物及其制备方法和应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ANSBACHER R. ET AL, CONTRACEPTION., vol. 62, no. 6, December 2000 (2000-12-01), pages 285 - 288 *
BALOGH A. ET AL, CONTRACEPTION., vol. 62, no. 5, November 2000 (2000-11-01), pages 259 - 265 *
JAIN J.K. ET AL, CONTRACEPTION., vol. 61, no. 3, March 2000 (2000-03-01), pages 195 - 198 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2079461A4 (fr) * 2006-10-30 2011-07-20 Teva Womens Health Inc Procédés de traitement hormonal utilisant des schémas posologiques cycliques prolongés à doses croissantes
EP2234491A4 (fr) * 2007-12-20 2010-12-22 Teva Womens Health Inc Schémas posologiques, compositions pharmaceutiques et emballages pour une contraception d'urgence
WO2016187269A1 (fr) * 2015-05-18 2016-11-24 Agile Therapeutics, Inc. Compositions contraceptives et procédés d'amélioration de l'efficacité et de modulation d'effets secondaires
AU2016264137B2 (en) * 2015-05-18 2021-08-19 Agile Therapeutics, Inc. Contraceptive compositions and methods for improved efficacy and modulation of side effects

Also Published As

Publication number Publication date
CN1672685A (zh) 2005-09-28

Similar Documents

Publication Publication Date Title
USRE39861E1 (en) Methods of extended use oral contraception
US5552394A (en) Low dose oral contraceptives with less breakthrough bleeding and sustained efficacy
CA2188907C (fr) Compose pour contraception basee sur les oestrogenes naturels
US5382573A (en) Hormone preparation and method
US7855190B2 (en) Methods of hormonal treatment utilizing contraceptive regimens with continuous estrogen administration
EP1446128B1 (fr) Utilisation de composes oestrogenes combines a des composes progestogenes en therapie de substitution hormonale
US7772219B2 (en) Methods of hormonal treatment utilizing extended cycle contraceptive regimens
SK83196A3 (en) Contaceptive agent
EP0559240A2 (fr) Composition hormonale contenant de l'estrogen et du progestin
ZA200404249B (en) Oral contraceptives to prevent pregnancy and diminish premenstrual symptomatology
US20030018018A1 (en) Ultra low dose oral contraceptives with sustained efficacy and induced amenorrhea
JP2000515888A (ja) 経口避妊薬
EP2392333A1 (fr) Procédé de traitement hormonal utilisant des régimes de cycle étendu à dose croissante
WO2005092346A1 (fr) Utilisation d'une combinaison d'oestrogene et de progestine a dose ultra-faible pour une contraception orale de longue duree
EP1159965B1 (fr) Utilisation d'antagonistes du recepteur de la progesterone pour la prévention ou l'inhibition de la fertilisation
CA2596416A1 (fr) Methodes de contraception orale a utilisation prolongee
JP2007197459A (ja) 月経の出血を少なくし維持された効力を持つ超低投与量避妊薬
IE84449B1 (en) Contraceptive packages containing oestrogen and progestin
WO1996029078A1 (fr) AGENT INHIBITEUR D'OVULATION POUR CONTRACEPTION HORMONALE CONTENANT 50 A 70 νg DE LEVONORGESTREL ET PLUS DE 30 A 40 νg D'ETHINYLESTRADIOL

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

122 Ep: pct application non-entry in european phase