WO2006026844A1 - Composition hormonale a liberation differee a base de polyorganosiloxanes ou d'ethylene-acetate de vinyle, son procede de fabrication - Google Patents
Composition hormonale a liberation differee a base de polyorganosiloxanes ou d'ethylene-acetate de vinyle, son procede de fabrication Download PDFInfo
- Publication number
- WO2006026844A1 WO2006026844A1 PCT/BR2005/000183 BR2005000183W WO2006026844A1 WO 2006026844 A1 WO2006026844 A1 WO 2006026844A1 BR 2005000183 W BR2005000183 W BR 2005000183W WO 2006026844 A1 WO2006026844 A1 WO 2006026844A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hormone
- composition
- human body
- delayed release
- manufacture
- Prior art date
Links
- 229940088597 hormone Drugs 0.000 title claims abstract description 41
- 239000005556 hormone Substances 0.000 title claims abstract description 41
- 239000000203 mixture Substances 0.000 title claims abstract description 35
- 230000003111 delayed effect Effects 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims abstract description 22
- 230000008569 process Effects 0.000 title claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- 239000005038 ethylene vinyl acetate Substances 0.000 title claims abstract description 4
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 title claims abstract description 4
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000011159 matrix material Substances 0.000 claims abstract description 26
- 230000005865 ionizing radiation Effects 0.000 claims abstract description 14
- 229920000642 polymer Polymers 0.000 claims abstract description 10
- 230000004064 dysfunction Effects 0.000 claims abstract description 8
- 239000000463 material Substances 0.000 claims description 15
- 239000007943 implant Substances 0.000 claims description 10
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 claims description 9
- 229920000249 biocompatible polymer Polymers 0.000 claims description 7
- 229960005309 estradiol Drugs 0.000 claims description 5
- 238000000465 moulding Methods 0.000 claims description 5
- -1 polydimethylsiloxanes Polymers 0.000 claims description 5
- 230000005855 radiation Effects 0.000 claims description 5
- 238000009792 diffusion process Methods 0.000 claims description 4
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims description 4
- 229940011871 estrogen Drugs 0.000 claims description 4
- 239000000262 estrogen Substances 0.000 claims description 4
- 239000003550 marker Substances 0.000 claims description 4
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 4
- 238000007920 subcutaneous administration Methods 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 238000012856 packing Methods 0.000 claims description 2
- 229920006294 polydialkylsiloxane Polymers 0.000 claims description 2
- 229940079593 drug Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 6
- 238000004132 cross linking Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 4
- 238000013270 controlled release Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000003433 contraceptive agent Substances 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000004205 dimethyl polysiloxane Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000006116 polymerization reaction Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 206010046914 Vaginal infection Diseases 0.000 description 1
- 201000008100 Vaginitis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229920005601 base polymer Polymers 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 238000013021 overheating Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000012667 polymer degradation Methods 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229920002379 silicone rubber Polymers 0.000 description 1
- 125000005373 siloxane group Chemical group [SiH2](O*)* 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
Definitions
- Hormone delayed release composition on the basis of polyorganosiloxanes or ethylene vinyl acetate resp. process for its manufacture. »
- the present invention refers to an improvement in hormone delayed release compositions within the human body, more particularly to a non ⁇ biodegradable biocompatible composition comprising a polymeric matrix crosslinked by ionizing radiation wherein a hormone is dispersed.
- the present invention refers to the use of said composition to obtain a hormone delayed release device, to the process for the manufacture of said device, and to a method for the treatment of conditions or dysfunctions of the human body.
- Another common mean to obtain delayed release is to encapsulate the active principle with biodegradable coatings, such as cellulose derivatives, starches and polysaccharides, a technical widely used for the analgesics controlled release.
- biodegradable coatings such as cellulose derivatives, starches and polysaccharides
- said encapsulated drug presents problems for its use, such as difficulty to be located within the body and removed - for example, in case of allergic reactions - besides the difficulty of obtaining an appropriate distribution of the coating thickness (in order to provide the desired release) and the latency period of the coated agent in the gastrointestinal treat is relatively short, causing low efficacy of its use for delayed release. This is not the case of the present invention.
- US 3,279,996 refers to a slow drug release device, typically a silicon rubber matrix, i.e., a high or room temperature vulcanized organopolysiloxane (called RTV, “Room Temperature Vulcanizing”), wherein the drug is dispersed.
- RTV room temperature vulcanized organopolysiloxane
- US 3,948,254 refers to a vehicle containing a drug and an outside layer for said vehicle, both permeable to the passage of the drug to be released.
- the rate of passage of the drug through the outside layer is lower than the rate of passage of the drug through the solid vehicle, by diffusion.
- the vehicle is typically a polyorganosiloxane, obtained by traditional processes.
- US 4,957,119 refers to an implant of polymeric material for slow releasing of a contraceptive agent.
- the polymeric material is made of a core and an outside layer, both made of ethylene/vinyl acetate copolymer, separated by a membrane.
- the device is obtained by coextrusion, and therefore, under high temperature.
- US 6,117,442 refers to a controlled rate release device for a therapeutically active agent, comprising a core of fluorinated siloxane (3,3,3- trifluoropropyl groups linked to the silicon atoms of the siloxane group) and an elastomeric covering membrane.
- the device is obtained by traditional processes.
- catalytic systems crosslinkable polymers in the presence of solvents or under high temperatures, suffer loss of their mechanic and chemical properties, additionally generating oligomers which damage their use for subcutaneous application.
- the present invention provides a polymeric matrix and a device which are less susceptible to the problems of the prior art, in a simple way and with an advantageous cost-benefit ratio.
- This is due to the use of ionizing radiation to crosslink the polymer acting as a matrix for the hormone controlled release to be released, not depending on high temperatures, or the presence of catalysts or solvents.
- the cold cure or crosslinking of polymeric materials by means of the use of ionizing radiation is advantageous since it does not depend on the presence of catalysts or additives and may be made under any temperature.
- the lack of catalysts and chemical initiators assures to obtain much purer products not requiring expensive purification stages, besides avoiding the risk of local overheating causing strong polymer degradation, which could generate toxic byproducts (A.
- the dosage regimen for the hormones contained in the devices of the present invention varies according to known factors, such as the pharmacodynamic characteristics of the particular agent; the species, age, sex, health, medical conditions, and weight of the patient; the nature and extent of the symptoms; the sort of concurrent treatment; and the desired effect.
- a physician knows how to determine and prescribe the quantity and efficient rate of releasing of the hormone to be administered to the patient.
- Ionizing radiation as used in the invention typically gamma radiation or beam of electrons, fully penetrates in the body of the polymeric matrix, just reacting with electrons, not providing the formation of isotopes. It can be verified that the use of other types of radiation, like UV, provide substantially surface polymerization and are not an object of the present invention.
- the base polymer of the polymeric matrix is purer, not requiring expensive purification stages.
- the present invention therefore refers to a hormone delayed release composition, characterized in that it comprises a non-biodegradable biocompatible polymer matrix, crosslinked by ionizing radiation, wherein said matrix comprises one or more hormones dispersed therein.
- the invention refers to the use of said composition characterized in that it is for the manufacture of a device for hormones controlled release within the human body.
- the present invention also refers to a method for the treatment of conditions or dysfunctions, characterized in that it is by inserting and maintaining said composition inside the human body for enough time for said hormone to be delayed released within the body.
- a first object of the present invention is a hormone delayed release composition characterized in that it comprises (1 ) a non-biodegradable biocompatible polymeric matrix, crosslinked by means of ionizing radiation, and (2) a hormone dispersed in said polymeric matrix.
- This composition makes use of the diffusion phenomenon, according to which an active principle migrates through the polymeric matrix under delayed and/or controlled rate.
- the polymeric matrix of the present invention may comprise any substantially non-biodegradable biocompatible polymer of natural or synthetic origin. As known by a person skilled in the art, polymers with high molecular mass are generally biocompatible due to their chemical inertia. Said matrix provides important chemical and mechanical properties and allows optimized diffusion of the active principle contained therein to the site of absorption inside the user body.
- polyorganosiloxanes in general particularly polydialkylsiloxanes, such as polydimethylsiloxanes and EVA (ethylene and vinyl acetate copolymer) can be recited, with no exclusion of any other, provided it is crosslinkable by ionizing radiation.
- polydialkylsiloxanes such as polydimethylsiloxanes and EVA (ethylene and vinyl acetate copolymer)
- EVA ethylene and vinyl acetate copolymer
- the hormones which may be used by the invention are pharmaceutically acceptable ones, which may be delayed released, being dispersed within the polymeric matrix. They may be available under liquid or solid form, and the latter one is preferred. A particular example, are estrogens, efficient for the treatment of existing conditions in the animal body, particularly humans, or in the body fluids.
- the hormone releasing rate will depend on the affinity of each matrix-active principle set, wherein the release rate of each set should be verified, as the known by a person skilled in the art.
- the hormone may be loaded to the matrix until a limit concentration allowing its crosslinking and until the obtainment of appropriated mechanical properties. These limits, therefore, depend on each matrix and each active principle, as determined by a person skilled in the art.
- the hormone is an estrogen used, for example, for hormone reposition, vaginitis treatment, prostate cancer therapy and some cases of breast cancer, or as a contraceptive, ⁇ -estradiol is particularly used.
- composition of the present invention may also comprise other ingredients, such as inert fillers present in the polymeric matrix, under values of up to about 80% by weight.
- the composition of the present invention may also optionally comprise a radio-opaque marker, i.e. visible to X-ray, in order to facilitate its location, e.g. when used in implant, in case its location is required after accidental migration from the site of placement.
- the marker may be any compound known in the art, e.g. barium sulfate.
- the amount of barium sulfate is particularly of more than 0.1 % by weight in relation to the rest of the composition, which is enough to make the device visible to X-ray, preferably between 0.1% and 2% by weight.
- a second object of the present invention is the use of said composition for the manufacture of a hormone delayed release device within the human body, e.g. by subcutaneous implantation, or an insert to the human body acting as an artificial gland.
- Another object of the present invention is hormone delayed release devices within the human body, which comprise the composition containing the polymeric matrix as disclosed.
- the release device of the present invention may also optionally comprise an outside layer to improve the control of the active principle release rate.
- an outside layer may be made of the same material as the polymeric matrix, or a different material. A person skilled in the art knows how to establish the measurements of said outside layer, based on available data in the prior art.
- the release device of the present invention may present various geometries, such as bands with various crosswise sections, sticks, cylinders and spherical tubes, preferably spherical tubes. It has particularly the shape of a
- 1-12 cm long stick preferably 2 to 4 cm and about 0.3 to 10 mm diameter, preferably 2 to 4 mm.
- Another object of the present invention is a process for the manufacture of a device for hormone delayed release within the human body. Said process comprises the steps of: (i) Mixing one or more substantially non-biodegradable biocompatible polymers with one or more hormones and additives, if any;
- step (ii) to expose the molded mixture of step (ii) above to ionizing radiation, for previous crosslinking and to already start sterilization;
- step (iii) coat the material with an outside layer, particularly of biocompatible polymeric material, optionally with the same polymeric material of item (i).
- the polymer of item (i) and the optional outside layer are made of polyorganosiloxane, more particularly polydimethylsiloxane.
- a further object of the present invention is a method for the treatment of conditions or dysfunctions of the human body, characterized in that it uses the device as obtained according to the process described above, particularly as a subcutaneous implant.
- the device of the invention may also be used for the treatment of conditions or dysfunctions as an anal, vaginal, oral, nasal or any other insert. Below an example of use of the device of the present invention is presented, but its mention does not bring any limitation than the ones presented in the claims as further disclosed below.
- Cylindrically-shaped implants with 2 mm diameter and 20 mm long constituted by polydimethylsiloxane, 50 mg of 17 ⁇ -estradiol and barium sulfate as the radio marker were prepared.
- Crestar ® dischargeable heparinized syringes were used, and the blood should be obtained by means of venous puncture with a 25 x 8 needle.
- An implant was subcutaneously injected in a mammal into its upper dorsal region, between pallets to facilitate application. That region was depilated.
- Samples of blood from the mamma! were collected a few days before inserting the implant and for a period of about 17 days after its placement. After this period, ten other samples were collected within weekly intervals.
- the sample as collected before the placement of the implant serves to confirm the non-existence of circulating estradiol. ovarectomy placement
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- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Dermatology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
La présente invention a trait à une composition hormonale à libération différée, à l'utilisation de la composition, à un dispositif de libération différée d'hormones, à un procédé de fabrication de dispositif de libération différée d'hormones et à des procédés pour le traitement de conditions ou de dysfonctionnements. La présente invention a trait à une composition hormonale à libération différée dans l'organisme humain, plus particulièrement à une composition biocompatible non biodégradable comprenant une matrice à base de polymère choisi parmi le groupe de polyorganosiloxanes ou d'éthylène-acétate de vinyle réticulé par rayonnement ionisant dans laquelle est dispersée une hormone. Dans d'autres modes de réalisation, la présente invention a trait à l'utilisation de ladite composition pour obtenir un dispositif de libération différée d'hormones, au procédé pour la fabrication dudit dispositif et à un procédé pour le traitement de conditions ou de dysfonctionnement de l'organisme humain.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| MX2007002845A MX2007002845A (es) | 2004-09-09 | 2005-09-09 | Composiciones de hormonas de liberacion prolongada sobre la base de poliorganosiloxanos o etilenvinilacetato y su respectivo proceso para su manufactura. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BRPI0406247-7 | 2004-09-09 | ||
| BR406247 | 2004-09-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2006026844A1 true WO2006026844A1 (fr) | 2006-03-16 |
Family
ID=36036036
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/BR2005/000183 WO2006026844A1 (fr) | 2004-09-09 | 2005-09-09 | Composition hormonale a liberation differee a base de polyorganosiloxanes ou d'ethylene-acetate de vinyle, son procede de fabrication |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2006026844A1 (fr) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9220692B2 (en) | 2010-05-05 | 2015-12-29 | Teva Women's Health, Inc. | Methods of reducing symptoms in subjects using single dosage forms with tapering release rates |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4012497A (en) * | 1974-09-24 | 1977-03-15 | Schering Aktiengesellschaft | Drug excipient of silicone rubber |
| EP0970704A1 (fr) * | 1998-07-02 | 2000-01-12 | The Population Council, Inc. | Implant avec un noyau en silicone pour une libération prolongée d'androgène |
| US20040009222A1 (en) * | 2002-05-07 | 2004-01-15 | Control Delivery Systems, Inc. | Processes for forming a drug delivery device |
-
2005
- 2005-09-09 WO PCT/BR2005/000183 patent/WO2006026844A1/fr active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4012497A (en) * | 1974-09-24 | 1977-03-15 | Schering Aktiengesellschaft | Drug excipient of silicone rubber |
| EP0970704A1 (fr) * | 1998-07-02 | 2000-01-12 | The Population Council, Inc. | Implant avec un noyau en silicone pour une libération prolongée d'androgène |
| US20040009222A1 (en) * | 2002-05-07 | 2004-01-15 | Control Delivery Systems, Inc. | Processes for forming a drug delivery device |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9220692B2 (en) | 2010-05-05 | 2015-12-29 | Teva Women's Health, Inc. | Methods of reducing symptoms in subjects using single dosage forms with tapering release rates |
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