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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
• • 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
  • A61K31/535—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/536—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 oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
• • 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
  • A61K31/57—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
  • 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
  • A61P5/34—Gestagens

Definitions

• progestin/estrogen combination oral contraceptives pills in 1960
• POPs progestin-only pills
• the dose of the progestin in the POPs was made lower than in the combined OCs to minimize the occurrence of amenorrhea resulting from complete ovarian suppression. Consequently, ovulation was inhibited in about half the users of POPs.
• the standard POPs primarily depend upon cervical mucus thickening to provide contraceptive protection for those who ovulate).
• POP users have a much higher rate of unscheduled breakthrough bleeding and spotting than combination OC users.
• POPs are used by only about 1-2% of contracepting women, compared to about 30% using combination OCs.
• the present invention provides a contraceptive regimen which involves delivery of an effective amount of a progestin for 21 to 27 consecutive days followed by 1 to 7 consecutive days without delivery of same.
• the progestin is 5-(4,4-Dimethyl-2-thioxo-l,4-dihydro-2H-benzo[d][l,3]oxazin-6-yl)-l- methyl- lH-pyrrole-2-carbonitrile, also termed tanaproget.
• the invention further provides a pharmaceutical kit for use in delivery of the regimen.
• the present invention provides a method of contraception in a female of child-bearing age.
• a progestin, or combination of progestins is delivered for a period of consecutive days as the sole active (i.e., anti- contraceptive) agent in order to prevent conception.
• the present invention provides for the use of a progestin, or combination of progestins, in preparing a medicament useful for contraception in a female of child-bearing age.
• the medicament comprises one phase in which, from 21 to 27 daily dosage units are consecutively administered, each containing an active agent comprising a progestin.
• the medicament also comprises from 1 to 7 daily dosage units of a pharmaceutically acceptable placebo for administration in a second phase.
• progestins are useful in preparing medicaments useful in any of the methods of contraception described herein. Without wishing to be bound by theory, it is believed that this invention will reduce the bleeding problems of conventional progestin-only contraceptives in two ways.
• progestin refers to any progestationally active compound, i.e., any compound that binds to and activates the progesterone receptor.
• Representative progestins include progesterone synthetic derivatives such as, for example, 17-hydroxy progesterone esters, 19-nor-17-hydroxy progesterone esters, 17 ⁇ -ethinyl testosterone and derivatives thereof, 17 ⁇ -ethinyl-19-nor-testosterone and derivatives thereof, norethindrone, norethindrone acetate, ethynodiol diacetate, dydrogesterone, medroxy-progesterone acetate, norethynodrel, allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone, dimethiderome, ethisterone, cyproterone acetate, levonorg
• the progestin is 5-(4,4-Dimethyl-2-thioxo-l,4- dihydro-2H-benzo[d][l ,3]oxazin-6-yl)-l-methyl-lH-pyrrole-2-carbonitrile, also termed tanaproget and NSP-989.
• This compound can have the formula:
• the progestin compounds useful in the present invention can be used in the form of salts derived from pharmaceutically or physiologically acceptable acids or bases.
• These salts include, but are not limited to, the following salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and, as the case may be, such organic acids as acetic acid, oxalic acid, succinic acid, and maleic acid.
• Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium in the form of esters, carbamates and other conventional "pro-drug" forms, which, when administered in such form, convert to the active moiety in vivo.
• the method of the invention is performed for a period of time corresponding to the length of a menstrual cycle, i.e., in the range of 23 to 35 days, with 28 days being the average.
• the method of the invention involves delivering a daily dosage unit containing an effective amount of an active agent consisting of a progestin to a female of child bearing age over a period of 18 to 28 consecutive days followed by 1 to 7 consecutive days in which no effective amount of an active agent is delivered to the subject.
• the term "effective amount" of a progestin(s) is a dosage that provides contraception. Without being bound by theory, this is achieved primarily by preventing ovulation.
• no effective amount of a progestin(s) is used to refer to the 1 to 7 days following delivery of an effective amount of the progestin(s). During this period, preferably, no amount of a progestin(s) is delivered to the animal. However, it is possible, that a sustained release formulation or other delivery method may be “leaky” and continue to deliver low amounts of a progestin which are not effective at contraception during this period. The phrase “no effective amount” encompasses delivery of no amount of progestin(s).
• a female is preferably a human.
• a female can include non-human mammals, e.g., cattle or livestock, horses, pigs, domestic animals, etc.
• the method of invention involves delivering a daily dosage unit containing an active agent consecutively for at least 21 of 28 consecutive days.
• the regimen consists of delivering a progestin to a female of child bearing age over a period of 21 to 27 consecutive days followed by 1 to 7 consecutive days in which no effective amount or no amount of active agent is delivered to the subject.
• the period of 1 to 7 days in which no effective amount of an active agent is delivered to the subject can involve delivery of a second phase of daily dosage units of 1 to 7 days of a pharmaceutically acceptable placebo.
• no placebo is administered.
• the method of the invention involves delivering a progestin as the sole active agent for 21 consecutive days followed by 7 days in which no effective amount of an active agent is delivered.
• a second phase of 7 daily dosage units of an orally and pharmaceutically acceptable placebo can be delivered.
• the method of the invention involves delivering a progestin as the sole active agent for 23 consecutive days followed by 5 days in which no effective amount of an active agent is delivered.
• a second phase of 5 daily dosage units of an orally and pharmaceutically acceptable placebo can be delivered.
• the method of the invention involves delivering a progestin as the sole active agent for 25 consecutive days followed by 3 days in which no effective amount of an active agent is delivered.
• a second phase of 3 daily dosage units of an orally and pharmaceutically acceptable placebo can be delivered.
• the method of the invention involves delivering a progestin as the sole active agent for 27 consecutive days followed by 1 day in which no effective amount of an active agent is delivered.
• a second phase of 1 daily dosage unit of an orally and pharmaceutically acceptable placebo can be delivered.
• This invention includes the use of pharmaceutical compositions containing one or more progestin compound(s) as the sole active ingredient in the formulation and regimen.
• the progestin compounds are formulated with a pharmaceutically acceptable carrier or excipient.
• the progestins used in the invention are formulated for delivery by any suitable route including, e.g., transdermal, mucosal (intranasal, buccal, vaginal), oral, parenteral, etc, by any suitable delivery device including, e.g., transdermal patches, topical creams or gels, a vaginal ring, among others.
• the progestins are delivered by any suitable route in a sustained release formulation. Such sustained release formulations are known to those of skill in the art.
• the compounds When the compounds are employed for the above utilities, they may be combined with one or more pharmaceutically acceptable carriers or excipients, for example, solvents, diluents and the like.
• the progestin compound When formulated for oral delivery, can be in the form of a tablet, capsule, caplet, gel tab, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing, for example, from about 20 to 50% ethanol, and the like.
• compositions When formulated for parenteral delivery, the compositions can be delivered in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium.
• Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight.
• the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration and the degree of ovarian suppression desired. However, in general, satisfactory results are obtained when the compounds of the invention are administered at a daily dosage of from about 0.03 to 0.6 mg, or about 0.1 to about 0.5 mg, preferably given daily or in a sustained release form.
• This dosage regimen may be adjusted to provide the optimal therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
• Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, non-ionic surfactants, ethanol (e.g., glycerol, propylene glycol and liquid polyethylene glycols), suitable mixtures thereof, and vegetable or edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired.
• Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA.
• the preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard- filled or liquid-filled capsules. Oral administration of the compounds is preferred.
• vaginal ring may also be administered via a vaginal ring.
• use of the vaginal ring is timed to the 28 day cycle.
• the ring is inserted into the vagina, and it remains in place for 3 weeks.
• the vaginal ring is removed and menses occurs.
• the following week a new ring is inserted to be worn another 3 weeks until it is time for the next period.
• the vaginal ring is inserted weekly, and is replaced for three consecutive weeks. Then, following one week without the ring, a new ring is inserted to begin a new regimen.
• the vaginal ring is inserted for longer, or shorter periods of time.
• a progestin compound is formulated in a manner similar to that described for contraceptive compounds previously described for delivery via a vaginal ring. See, e.g., US Patent Nos. 5,972,372; 6,126,958; and 6,125,850.
• a progestin composition can be formulated for parenteral delivery in a sustained release formulation and administered by injection, e.g., monthly or quarterly.
• a progestin compound is formulated for delivery via a cream or a gel, by a suitable route.
• carriers for such routes are known to those of skill in the art.
• the progestin compound(s) are delivered via a transdermal patch.
• use of the patch is timed to the 28 day cycle.
• the patch is applied via a suitable adhesive on the skin, where it remains in place for 1 week and is replaced weekly for a total period of three weeks. During the fourth week, no patch is applied and menses occurs. The following week a new patch is applied to be worn to begin a new regimen. In yet another embodiment, the patch remains in place for longer, or shorter periods of time.
• This invention also includes kits or packages of pharmaceutical formulations designed for use in the regimens described herein.
• the kits contain one or more progestin compounds as described herein.
• the progestin is selected from among 17-hydroxy progesterone esters, 19-nor-17-hydroxy progesterone esters, 17 ⁇ -ethinyltestosterone and derivatives thereof, 17 ⁇ -ethinyl-19- nor-testosterone and derivatives thereof, norethindrone, norethindrone acetate, ethynodiol diacetate, dydrogesterone, medroxy-progesterone acetate, norethynodrel, allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone, norgestrienone, dimethiderome, ethisterone, cyproterone acetate, levonorgestrel, dl-norgestrel, d-17 ⁇ - acetoxy-13/3-ethyl-17 ⁇ -a-ethinyl-gon-4-en-3-one oxime
• the progestin is NSP-989, also termed tanaproget, or a pharmaceutically acceptable salt or prodrug thereof.
• the progestin is formulated for the desired delivery vehicle and route.
• a progestin can be formulated for oral delivery, parenteral delivery, vaginal ring, transdermal delivery, or mucosal delivery.
• the kit of the invention is designed for daily oral administration over a 28-day cycle, preferably for one oral administration per day, and organized so as to indicate a single oral formulation or combination of oral formulations to be taken on each day of the 28-day cycle.
• each kit will include oral tablets to be taken on each the days specified; preferably one oral tablet will contain each of the combined daily dosages indicated.
• a kit of the invention can contain 21 to 27 daily dosage units of an effective amount of an active agent and, optionally, 1 to 7 daily dosage units of a placebo and other appropriate components including, e.g., instructions for use.
• the kit of the invention is preferably a pack (e.g. a blister pack) containing daily doses arranged in the order in which they are to be taken.
• the kit of the invention is designed for weekly or monthly administration via a vaginal ring over a 28-day cycle.
• a kit contains individual packaging for each of the vaginal rings, i.e. one to three, required for a monthly cycle and other appropriate components, including, e.g., instructions for use.
• the kit of the invention is designed for weekly or monthly administration via a transdermal patch over a 28-day cycle.
• a kit contains individual packaging for each of the patches, i.e. one to three, required for a monthly cycle and other appropriate components including, e.g., instructions for use.
• the kit of the invention is designed for parenteral delivery of the progestin.
• a kit is typically designed for delivery at home and may include needles, syringes, and other appropriate packaging and instructions for use.
• the kit of the invention contains a progestin compound in a gel or cream formulation.
• the kit can include appropriate packaging such as a tube or other container, an applicator, and/or instructions for use.
• the daily dosage of each pharmaceutically active component of the regimen remain fixed in each particular phase in which it is administered.
• the daily dose units described are to be administered in the order described, with the first phase followed in order by the optional second phase.
• the kits contain the placebo described for the final days of the cycle.
• each package or kit comprise a pharmaceutically acceptable package having indicators for each day of the 28-day cycle, such as a labeled blister package, dial dispenser, or other packages known in the art.
• dosage regimens may be adjusted to provide the optimal contraceptive effect.
• several divided doses of each component may be administered daily or the dose may be proportionally increased or reduced as indicated by the contraceptive effectiveness.
• reference to a daily dosage unit may also include divided units which are administered over the course of each day of the cycle contemplated. The following examples are illustrative only and are not intended to be a limitation on the present invention.
• Example 1 Ovulation Inhibition by the Progestin Compound NSP-989
• the activity of NSP-989 was evaluated orally in three 3 different rat models for progestin activity along with reference progestins medroxyprogesterone acetate (MPA) and trimegestone (TMG) in 2% Tween 80/0.5% methylcellulose vehicle. These models are described in Parts A, B and C of this example.
• NSP-989 was a compound's ability to inhibit ovulation in adult female rats. This activity is essential for contraceptive efficacy.
• Random cycling mature female Sprague-Dawley rats (-200 g) were obtained from Charles River Laboratory (Boston, MA). Rats were synchronized for estrus with 2 ⁇ g of LHRH (in phosphate buffered saline containing 0.1% bovine serum albumin) administered subcutaneously (sc) per rat at 0900 h and again at 1600 h. Animals were allowed to rest for 8 days before the administration of test compounds. Animals were then grouped, with 7 to 9 rats per treatment group. The morning of the ninth day following LHRH treatment, the rats were treated with test compounds once daily, by gavage. This continued for 4 consecutive days. The animals were euthanized the morning following the last treatment. Oviducts were removed, placed between 2 glass slides, and viewed through a dissecting microscope to count ova. The number of animals presenting ova in the oviduct from each treatment group and the number of ova in the oviduct of each animal were recorded.
• LHRH in phosphate buffered saline
• the second rat model to determine progestational activity is the uterine decidualization assay in adult ovariectomized rats. Only compounds that are progesterone receptor agonists will be active in this model, as a progestin is absolutely required to transform uterine stromal cells to differentiated decidual cells. Rat decidualization assay was run as described previously [Lundeen SG, et al., "Rat uterine complement C3 expression as a model for progesterone receptor modulators: characterization of the new progestin trimegestone", J Steroid Biol MoI Biol.
• NSP-989 induced endometrial decidualization with an ED 50 value of 0.01 mg/kg (n 23) and was approximately 40- and 100-fold more potent than MPA and TMG, respectively (Table 1).
• the third model for PR agonist activity was the adult ovariectomized rat uterine C3 model. This assay evaluates the ability of a progestin to block estrogen-induced C3 expression in the uterine epithelium.
• Ovariectomized female, 60 day-old Sprague-Dawley rats were obtained from Harlan (Indianapolis, IN). Ovariectomies were performed by the supplier a minimum of 8 days prior tobefore treatment. The rats were randomized and placed in groups of 6. The animals were treated once daily for (2) two days orally by gavage (p.o.) in a volume of 0.5 mL. On the second day of treatment, the animals were also treated with EE (0.08 mg/kg body weight (BW)) orally by gavage. Approximately 24 hours after the final treatment, the animals were euthanized by CO 2 asphyxiation. The uteri were then removed, stripped of remaining fat and mesentery, weighed, and snap-frozen on dry ice.
• EE body weight
• C3 messenger RNA (mRNA) levels were normalized to 18s 18S ribosomal RNA contained within each sample reaction using primers and probe supplied by PE Applied Biosystems.
• NSP-989 was 3010- to 10060- fold more potent than the reference progestins used in these studies.
• NSP-989 was also evaluated in the Clauberg model, a classic progestational assay in the rabbit endometrial transformation model [McPhail MK, "The assay of progestin.” J .PAy 1 SZo/. 1934; 83: 145-1567]. Briefly, immature female New Zealand White rabbits ( ⁇ 1 kg body weight) were injected subcutaneously with 5 ⁇ g 17 ⁇ -estradiol (E 2 )/rabbit/day for six consecutive days. Beginning 24 hours after the final E 2 injection, vehicle alone or test compounds were given orally for (5) five consecutive days. Progestational activity was determined by increases in uterine weight and endometrial glandular arborization (McPhail Index). In limited dose response studies, NSP-989 had an estimated ED 50
• DSG combination steroidal OC desogestrel
• the study will have 2 parts. Part 1 (days 1-84) of the study will evaluate the ability of NSP-989 to produce ovarian suppression, along with evaluating cycle control, side effects, and metabolic data. Part 2 (days 85-168) will continue to follow the subjects to collect cycle control, side effects, and metabolic data.
• the study will be monitored routinely by the blinded project medical monitor and study team for efficacy failures and safety Each subject will participate for up to 9 months, depending on the length of the subject's screening period. Eight (8) cycles will be observed. The first cycle will be a baseline observation of ovulation. Six (6) treatment cycles will be followed by 1 posttreatment observation cycle to assess return to ovulation.
• the subjects will be healthy women of > 18 years of age who are younger than 36 years at the time of randomization. Subjects must have had spontaneous regular (24- to 32-day) menstrual cycles for the 3-month period preceding entry into the pretreatment observation cycle, excluding postabortal and nonbreastfeeding postpartum subjects. Postabortal and nonbreastfeeding postpartum subjects must have completed at least 1 regular (24- to 32-day) spontaneous menstrual cycle before entry into the pretreatment observation cycle.
• the pretreatment observation cycle for all subjects will begin on day 1 of the subsequent spontaneous menses after completion of the prestudy screening (visit 1).
• the pretreatment observation cycle is a control cycle; no test article will be administered.
• Each subject will begin test article on the first day of her menstrual bleeding (first subject pack only). Each subject pack will contain NSP-989 or the steroid combination OC comparator. Subjects will take NSP-989 orally, once daily for 21 days (days 1 through 21), followed by 7 days of placebo pills (days 22 through 28) for 6 cycles. Subjects assigned to a steroid combination OC comparator, DSG 150 ⁇ g, will take test article orally, once daily for 21 days (days 1 through 21), followed by 2 days of placebo pills (days 22 through 23), followed by 5 days of 10 ⁇ g EE (days 24 through 28) for 6 cycles. There will also be a posttreatment cycle in which no test article will be administered and return to ovulation will be assessed. Each subject will be randomly assigned to receive one of the following:
• Each subject will begin test article on the first day of her menstrual bleeding (first subject pack only). Subjects will take test article orally, once daily for 28 days, at approximately the same time each day. All subsequent subject packs will begin following day 28 of the previous pill pack. Subjects will take test article daily without interruption during the treatment cycles.
• a blister pack with 28 blister containers is made with a cardboard, paperboard, foil or plastic backing and enclosed in a suitable cover.
• the blister containers are arranged to house a sequence of 21 pills each providing a daily dose of 100 ⁇ g of
• Each blister container may conveniently be numbered or otherwise marked, e.g., starting with the first of the 21 dosage units that contain the active ingredient followed by 7 empty blisters or by 7 dosage units that contain no active agent.

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