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
  • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/18—Sulfonamides
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • 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
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
  • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
  • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• • 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
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
  • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
• • 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

Definitions

• a method for female controlled on-demand contraception comprising a pharmaceutical preparation containing levonorgestrel (LNG) and a COX inhibitor selected from the group of indomethacin, diclofenac, naproxen, ibuprofen, nimesulide, ketoprofen, meloxicam, piroxicam if necessary in a period of up to 24, preferably in a period of 0-12 hours before one
• LNG levonorgestrel
• COX inhibitor selected from the group of indomethacin, diclofenac, naproxen, ibuprofen, nimesulide, ketoprofen, meloxicam, piroxicam if necessary in a period of up to 24, preferably in a period of 0-12 hours before one
• the pharmaceutical preparation used in the process can also consist of 2 tablets, the first being taken before sexual intercourse and the second immediately after sexual intercourse.
• Another object of the invention relates to an application regime for "on-demand" contraception, in which an oral pharmaceutical composition containing a COX inhibitor and levonorgestrel in a dose of 50-500 micrograms in a period of 0-12 hours before sexual intercourse, followed by another oral pharmaceutical composition containing 500 to 1500 ⁇ g of LNG and optionally a COX inhibitor in a period of up to 48 hours after the
• Another object of the invention relates to a kit for "on demand"
• Suitable COX inhibitors are the abovementioned COX inhibitors.
• the hormonal contraception with daily administered orally low
• IUS intrauterine system
• Oral contraception requires a continuous, daily intake of hormone-based pills, regardless of the frequency of sexual intercourse and thus the need for contraceptive protection.
• contraception demand In the literature, the terms contraception demand, precoale contraception, and pericontal contraception are also used as synonyms for a contraception as required.
• pericontal contraception In a study conducted in Ghana in 2003, it is reported that women take norethisterone tablets for the treatment of various gynecological
• Levonorgestrel despite generally good tolerability, is very high. Thus, this amount corresponds to a dose such as would otherwise be given over a period of 2 months with regular intake of a hormone-containing pill (such as Microgynon®). If such an emergency contraceptive pill is used several times a month, the monthly hormone dose can easily lead to a 10-fold higher hormone load than would be achieved with regular oral contraceptive use.
• a hormone-containing pill such as Microgynon®
• WO 2010/1 19030 describes an "on-demand" preparation in which progestogen levonorgestrel or norgestrel in a dose range of 0.5 to 1, 5 mg are used, the preparation used 24 hours before sexual intercourse
• This product does not show the desired efficacy, as demonstrated by Family Health International's Contraception on Demand (CoD) study of 0.75 mg levonorgestrel, which showed a Pearl Index of only 18.3% (95%
• Condoms and other barrier methods in typical use see, for example: United Nations Development Program / United Nations Population Fund / World Health Organization / World Bank Special Program of Research, Development and
• Brache et al. have also studied the effect of a single vaginal administration of levonorgestrel gel on ovulation immediately before sexual intercourse (Brache et al, Contraception, 2007; 76: 1 1 1 -1 16).
• a vaginal application of levonorgestrel or norgestrel for on-demand contraception is also proposed in WO 2010/1 19030 (Ulmann et al.).
• the active ingredients are preferably administered via a vaginal ring, which is used 24 hours before sexual intercourse.
• Oral, transdermal, buccal, sublingual, parenteral or rectal administration is also suggested there.
• the dose range claimed by Ulmann is within the range of the emergency contraceptive dose (750 - 1500 ⁇ g LNG).
• WO2007 / 045513 (Schering AG) describes a gestagen (i.a.
• Levonorgestrel and ethinyl estradiol-containing patch for "on-demand” contraception in which the active substance is administered transdermally.
• On-demand hormonal contraception failed in practice because the methods described do not provide the contraceptive safety achieved by the regular intake of a hormone-containing "pill", which is explained, inter alia, by the effect of the drug on the inhibition of ovulation Only a certain time after taking the drug occurs, so that one can not speak of an "on-demand" drug in the true sense.
• a dose would be required at least 1 to 2 days before sexual intercourse, if a similar effectiveness as with a regular pill intake should be achieved.
• the duration of action of such a premature administration is too short, so that a pregnancy can occur even with timely ingestion, as sperm in the cervix are viable up to 5 days after sexual intercourse 4 .
• the methods described do not provide the contraceptive safety achieved by the regular intake of a hormone-containing "pill”, which is explained, inter alia, by the effect of the drug on the inhibition of ovulation Only a certain time after taking the drug occurs, so that one can not speak of an "on-demand" drug in the true
• the hormone burden in the user can lead to at least one cycle disorder.
• the object of the present invention was therefore to provide a method for "on-demand" contraception, which in comparison to hormonal
• Postcoital methods ensure a higher contraceptive safety, is under the control of the woman and is taken immediately before the planned sexual intercourse (up to a maximum of 24 hours previously). Furthermore, a higher
• Compatibility can be achieved as with hormonal agents for emergency contraception by using only a reduced hormone dose.
• this object is achieved by the use of a preparation containing levonorgestrel and a COX inhibitor selected from the group of indomethacin, diclofenac, naproxen, ibuprofen, nimesulide, ketoprofen, piroxicam, meloxicam.
• a COX inhibitor selected from the group of indomethacin, diclofenac, naproxen, ibuprofen, nimesulide, ketoprofen, piroxicam, meloxicam.
• the invention thus relates to a method for female controlled "on demand" Contrazeption, in which a pharmaceutical preparation containing levonorgestrel and a COX inhibitor selected from the group of indomethacin, diclofenac, naproxen, ibuprofen, nimesulides, ketoprofen, meloxicam , Piroxicam, if necessary in a period of 0-24 hours before an expected
• Another object of the invention relates to the use of
• COX inhibitors indomethacin, diclofenac, naproxen, ibuprofen, nimesulide, ketoprofen or piroxicam are preferred, indomethacin, diclofenac, naproxen, ibuprofen or piroxicam are particularly preferred.
• Another object of the invention relates to an application regime for "on-demand" contraception, in which an oral pharmaceutical composition containing a COX inhibitor and levonorgestrel in a dose of 50-500 micrograms, preferably 100-200 micrograms of LNG in one Period of 0-24 hours, preferably 6-12 hours before intercourse, followed by another oral pharmaceutical composition containing a COX inhibitor and levonorgestrel in a dose of 50-500 micrograms, preferably 100-200 micrograms of LNG in one Period of 0-24 hours, preferably 6-12 hours before intercourse, followed by another oral
• composition containing 500 to 1500 .mu.g LNG and optionally a COX inhibitor in a period of up to 48 hours after sexual intercourse, is taken.
• sperm as previously stated, in the female genital tract a
• the hormonal burden can be further reduced in cases where it has not come to the expected sexual intercourse, adding to the intake of the second tablet containing the higher
• Hormone dose contains, is omitted.
• Another object of the invention thus also relates to a kit for on-demand contraception containing 2 orally administered pharmaceutical
• Piroxicam are preferred.
• the single-dose preparation for on-demand hormonal contraception is preferably applied in the period of 0-24, preferably 6-12 hours before the planned intercourse. Further preferred is the intake of the single-dose preparation in a period of 0 - 1 h.
• the single-dose preparation can also be taken up to a maximum of 2 hours after sexual intercourse.
• Hormone-containing dosage forms for contraception such as vaginal rings (e.g., Nuvaring®) or hormone coils (e.g., Mirena®) are available.
• vaginal rings e.g., Nuvaring®
• hormone coils e.g., Mirena®
• the preparation is administered as one or two tablets. It is also the gift in the form of other oral dosage forms such as hard capsules, orodispersible tablets, effervescent tablets or granules possible. Other forms of administration are also an option for on-demand applications, such as intravaginal rings, which are already widely used in contraception as an alternative to the "normal pill”.
• Nuvaring® which is described in the European patent
• EP 00876815 B1 is described.
• the Nuvaring® is worn over a period of 3 weeks and offers the user a cycle-consistent contraceptive protection.
• this ring is not suitable for "on-demand” application because the release kinetics of this ring is set for long-term delivery, and fast, short-term drug release, as required for an on-demand situation, is not possible with such a ring to reach.
• a ring for an "on-demand" application which guarantees a safe contraception shortly after insertion, contains according to the invention in addition to the hormone (levonorgestrel) as further active ingredient nor the COX inhibitor by a corresponding ring structure, for example by introducing the different active ingredients in different compartments of the ring, a different release kinetics can be achieved (2-phase ring).
• the ring is 0-24 hours before the scheduled by the user
• Sexual intercourse is used and then remains up to 148 hours, preferably 72 hours after sexual intercourse in the vagina.
• the administration of the active ingredients via a vaginal ring has the advantage over a preparation as a tablet that the ring can be removed by the user, if it does not come to the planned sexual intercourse.
• the hormone load of the user would thus further reduced, especially in a 2-phase ring, as it releases in the first 24 hours after insertion for the most part only the COX inhibitor.
• Another advantage is that with a vaginal ring more constant drug levels over a longer period while avoiding very high peak plasma concentrations, such as occur shortly after oral administration, can be achieved. Compared to administration via a tablet, this leads overall to a reduced systemic load on active substances and thus to fewer undesired effects ("side effects").
• Oral pharmaceutical preparations such as those used in the method for female controlled on-demand contraception, contain levonorgestrel in an amount of 50-1500, preferably 250-1500 ⁇ g, in the case of a single-dose preparation is an amount of levonorgestrel of 250 - 500 ⁇ g.
• COX inhibitors are indomethacin, diclofenac, naproxen, ibuprofen, nimesulides, ketoprofen, piroxicam, meloxicam in question, with piroxicam, naproxen, ibuprofen, diclofenac and indomethacin are preferred.
• the amount of COX inhibitor contained in the pharmaceutical preparation varies depending on the inhibitor selected. According to the invention, the following dose ranges are suitable for an "on demand" application:
• Diclofenac 50-400 mg / day
• Naproxen 500 - 3000 mg / day
• Ibuprofen 500 - 5000 mg / day
• Nimesulide 100-500 mg / day
• Ketoprofen 100-500 mg / day
• Piroxicam 10 - 80 mg / day
• the oral pharmaceutical preparation as used in the method for female controlled “on demand” contraception, consists of 2 tablets, contains the first tablet in addition to one of the aforementioned COX inhibitors in said dose ranges also low metered LNG in a dose of 50-500 ⁇ g, preferably 100-200 ⁇ g LNG and the second tablet "high-dose” LNG in a dose of 500-1500 ⁇ g, preferably 500-1000 ⁇ g LNG, the second tablet optionally also in addition a COX inhibitor may contain.
• Corresponding preparations containing LNG and a COX inhibitor can, as disclosed in EP 2445491 A1, be prepared by the active ingredients are mixed with the usual pharmaceutical excipients and then compressed into a tablet. Other manufacturing possibilities are disclosed in Examples 3-5 of the present application.
• Doses of 20, 40 and 80 mg administered as a single oral dose In total, 72 women were treated, 18 of whom received 20 mg, 17 women 40 mg, 20 women 80 mg piroxicam, and 17 women a placebo supplement.
• Ovulation inhibition or delay came.
• 2 women showed an ovulation delay of at least plus 24 hours compared to the untreated pre-cycle.
• 20 mg group was 8 women, in the 40 mg
• Table 1.1 Number of women showing at least a 24-hour ovulation delay compared to the median duration between LH surge and ovulation in the untreated pre-cycle; final evaluation set
• the rat is a particularly suitable animal model, since the cycle can be easily observed by vaginal smears and a mating reliably generates a high number of offspring.
• the animals were housed in macroion cages in controlled exposed rooms (12 hours darkness: 12 hours brightness), fed on a standard diet and soaked in water ad libitum.
• Levonorgestrel was dissolved in benzyl benzoate / castor oil (1 + 4 v / v) and the daily dose in a volume of 1 ml / kg body weight s.c. applied.
• the animals were treated in the pro-oestrus, the day in the cycle at the evening of the LH peak, with the test substances either alone or in combination once. On the evening of the Pro- ⁇ strus a male rat took the
• Table 2.2 Influence of a single application of levonorgestrel (LNG) or indomethacin alone or in combination on the fertility of the female rat.
• LNG levonorgestrel
• Table 2.4 Influence of a single application of levonorgestrel (LNG) or ibuprofen alone or in combination on the fertility of the female rat.
• LNG levonorgestrel
• Single dose has the same effect as piroxicam, indomethacin, diclofenac and ibuprofen on ovulation.
• the method of female controlled on-demand contraception is characterized in that a pharmaceutical preparation containing levonorgestrel and naproxen is required and once in a period of 0-24 Is administered hours before expected sexual intercourse, the subject of the invention.
• the cervical mucus plays an important role in the contraception, because it promotes cycle-dependent sperm migration from the vagina into the uterus.
• the otherwise viscous cervical mucus under the influence of estrogen formed at this time is thin, clear and stringy.
• the characteristic formation of fern-like NaCI crystals occurs in the dried cervical mucus (Ferning). This structure allows the sperm to ascend into the uterus.
• the cervical mucus under the influence of progesterone loses this property and is viscous to sticky, of poppy consistency and closes as a natural barrier the cervix.
• the cervical mucus on the infertile days prevents the migration of sperm into the uterus.
• contraception of progestogen-containing contraceptives is due to the effect of progestogens on cervical mucus.
• the effect of the progestogens on the cervical mucus is important for on-demand contraception compared to emergency contraception, as it contributes significantly to the efficacy of gestagens in on-demand contraception.
• Granulating fluid which consists of 60 g of hydroxypropylmethylcellulose 5cP, 15 g of sodium lauryl sulfate and 1440 g of water. After drying the granules in the fluidized bed granulator and subsequent sieving, the granules with 15 g
• Finish film powder powder consists of 50.56% of hypromellose 5cP, 10.12% macrogol3350, 10.12% talc, 23.20% titanium dioxide and 6.00% iron oxide yellow.
• the tablets must be taken by the woman 6 - 12 hours before the scheduled sexual intercourse.
• Example 4 Kit containing 100 mg diclofenac and 1 mg levonorgestrel
• a carton is made containing Diclofenac Retard capsules 100 mg and Levonorgestrel tablets 1 mg.
• the carton also contains a package leaflet which states that the diclofenac prolonged-release capsules are to be taken orally by the woman 6 to 12 hours before intercourse and the levonorgestrel tablets within 24 hours thereafter. It is also stated in the package leaflet that the intake of levonorgestrel tablets may be omitted if sexual intercourse does not occur.
• the diclofenac sustained-release capsules 100 mg are prepared as described in EP 0519870B1.
• levonorgestrel tablets 1 mg in a fluid bed granulator 17.6 g levonorgestrel, 907 g lactose, 459 g microcrystalline cellulose and 45 g croscarmellose sodium submitted.
• the powder mixture is mixed with a
• Example 2 The Diclofenac Retardkapseln and the levonorgestrel tablets are sealed in two blister pens of a blister strip, the blister strips have also printed a note that the capsule before and the tablet may be taken after sexual intercourse.
• Example 5 Orodispersible tablets containing 75 mg indomethacin and 0.25 mg levonorgestrel
• a premix of 31, 3 g of levonorgestrel and 0.282 kg of the above excipient mixture is prepared.
• the premix is mixed with 9.38 kg indomethacin, 31, 1 kg of the above excipient mixture and 638 g peppermint flavor. It is added to 1, 06 kg of magnesium stearate and mixed again.
• This press-ready mixture is compressed on a rotary tablet press to orally disintegrating tablets of 340 mg mass and a diameter of 10 mm.
• Each 2 orodispersible tablets are sealed in an aluminum / aluminum blister and packed in a folding box together with a leaflet.
• the package leaflet contains a note that at least 6 hours before the scheduled sexual intercourse, an orodispersible tablet and within 24 hours after intercourse, another orodispersible tablet is to be taken. If no sexual intercourse occurs, the intake of the 2nd orodispersible tablet can be omitted. Furthermore, the leaflet describes that the tablets are to be taken without water by placing in the mouth. The tablet disintegrates on the tongue and the resulting dispersion is swallowed. Description of the pictures:
• Adapted Kaplan-Meier curve showing the ovulation delay after administration of piroxicam compared to administration of a placebo preparation.
• the representation is based on the values shown in Table 1 .2.
• the time after the LH surge is plotted in days.
• the Y-axis shows the number of examined women who have not yet ovulated [%].
• the individual curves represent the individual treatment groups: placebo group (continuous line); Piroxicam 20 mg (dashed line consisting of short dashes), 40 mg piroxicam (dashed line consisting of long dashes) and 80 mg piroxicam (dashed line consisting of alternate long and short dashes).

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• 2013
  • 2013-11-19 KR KR1020157013076A patent/KR20150085512A/ko not_active Application Discontinuation
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