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WO2001085132A1 - Dispositifs d'administration de medicaments, notamment de levonorgestrel - Google Patents

Dispositifs d'administration de medicaments, notamment de levonorgestrel Download PDF

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Publication number
WO2001085132A1
WO2001085132A1 PCT/FI2001/000406 FI0100406W WO0185132A1 WO 2001085132 A1 WO2001085132 A1 WO 2001085132A1 FI 0100406 W FI0100406 W FI 0100406W WO 0185132 A1 WO0185132 A1 WO 0185132A1
Authority
WO
WIPO (PCT)
Prior art keywords
elastomer
siloxane
polymer
active agent
trifluoropropyl
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/FI2001/000406
Other languages
English (en)
Inventor
Tommi Markkula
Juha Ala-Sorvari
Harri Jukarainen
Jarkko Ruohonen
Matti Lehtinen
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.)
Bayer Oy
Original Assignee
Leiras Oy
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 Leiras Oy filed Critical Leiras Oy
Priority to AU2001258442A priority Critical patent/AU2001258442A1/en
Publication of WO2001085132A1 publication Critical patent/WO2001085132A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/568—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 positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—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 positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • 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
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms

Definitions

  • This invention relates to a drug delivery device, particularly to a device intended for administration of levonorgestrel, at a substantially constant rate for a prolonged period of time.
  • Polysiloxanes such as poly(dimethylsiloxane) (PDMS), are highly suitable for use as a membrane or a matrix regulating the permeation of drugs in various drug forms, in particular in implants and mtra-uterine systems (IUS). Polysiloxanes are physiologically inert, and a wide group of drugs are capable of penetrating polysiloxane membranes, which also have the required mechanical properties.
  • PDMS poly(dimethylsiloxane)
  • IUS mtra-uterine systems
  • the object of this invention is to provide a drug delivery device, particularly a device intended for administration of levonorgestrel, at a substantially constant rate for a prolonged period of time.
  • the object is particularly to provide a device with which the drug release rate can easily be adjusted.
  • the invention concerns a delivery device for the controlled release of the therapeutically active agent levonorgestrel, over a prolonged period of time, at a release rate of 0,1-200 ⁇ g/day, said device comprising
  • the elastomer is a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units, and the release rate of said therapeutically active agent of said delivery device is regulated by the amount of said 3,3,3-trifluoropropyl groups.
  • the device according to the invention can for example be an implant, an intrauterine device, an intravaginal device or an intracervical device.
  • the release rate of the active agent in an intrauterine device is 0,1-200 ⁇ g/day, preferably 0,5-100 ⁇ g/day, more preferably 0,5-50 ⁇ g/day and most preferably 0,5-20 ⁇ g/day.
  • the release rate of the active agent in an implant is 0,1-200 ⁇ g/day, preferably 0,5-150 ⁇ g/day and more preferably 1-100 ⁇ g/day.
  • the elastomer suitable for use in the device according to this invention is a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units.
  • siloxane-based elastomer shall be understood to cover elastomers made of poly(disubstituted siloxanes) where the substituents mainly are lower alkyl, preferably alkyl groups of 1 to 6 carbon atoms, or phenyl groups, wherein said alkyl or phenyl can be substituted or unsubstituted.
  • a widely used and preferred polymer of this kind is poly(dimethylsiloxane) (PDMS).
  • a certain amount of the substituents attached to the Si-atoms of the siloxane units in the elastomer shall be 3,3,3- trifluoropropyl groups.
  • the elastomer can be based on one single crosslinked siloxane-based polymer, such as a poly(dialkyl siloxane) where a certain amount of the alkyl groups at the Si-atoms are replaced by 3,3,3- trifluoropropyl groups.
  • a preferred example of such polymers is poly(3,3,3- trifluoropropyl methyl siloxane) the structure of which is shown as Compound I below.
  • a polymer of this kind in which approximately 50 % of the methyl substituents at the Si-atoms are replaced by 3,3,3-trifiuoropropyl groups, is commercially available.
  • the term "approximately 50 %” means that the degree of 3,3,3-trifluoropropyl substitution is in fact somewhat below 50 %, because the polymer must contain a certain amount (about 0.15 % of the substituents) of crosslinkable groups such as vinyl or vinyl-terminated groups. Similar polymers having lower substitution degree of 3,3,3-trifluoropropyl groups can easily be synthetised.
  • the retarding effect of the 3,3,3-trifluoropropyl groups on the permeation of drugs across a membrane of the elastomer is dependent on the amount of these groups. Furthermore, the effect is highly dependent on the drug used. If the elastomer is made of one single polymer only, it would be necessary to prepare and use polymers with different amounts of 3,3,3-trifluoropropyl groups for different drugs.
  • elastomers for several different drugs are needed, is to crosslink a mixture comprising a) a non-fluorosubstituted siloxane-based polymer and b) a fluorosubstituted siloxane-based polymer, where said polymer comprises 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units.
  • the first ingredient of the mixture, the non-fluorosubstituted polymer can be any poly(disubstituted siloxane) where the substituents mainly are lower alkyl, preferably alkyl groups of 1 to 6 carbon atoms, or phenyl groups, wherein said alkyl or phenyl can be substituted or unsubstituted.
  • the substituents are most preferably alkyl groups of 1 to 6 carbon atoms.
  • a preferred non-fluorosubstituted polymer is PDMS.
  • the second ingredient of the mixture, the fluoro-substituted polymer can for example be a poly(dialkyl siloxane) where a certain amount of the alkyl groups at the Si- atoms are replaced by 3,3,3-trifluoropropyl groups.
  • a preferred example of such polymers is poly(3,3,3-trifluoropropyl methyl siloxane) as mentioned above.
  • a particularly preferable polymer of this kind is a polymer having as high amount of 3,3,3-trifluoropropyl substituents as possible, such as the commercially available polymer, in which approximately 50 % of the methyl substituents at the Si-atoms are replaced by 3,3,3-trifluoropropyl groups.
  • An elastomer with great permeation retarding effect can be achieved by using exclusively or mainly the aforementioned polymer. Elastomers with less retarding influence on the permeation of the drug can be obtained by using mixtures with increasing amounts of the non-fluorosubstituted siloxane-based polymer.
  • the elastomer should preferably comprise a filler, such as amorphous silica, in order to give a sufficient strength for the membrane made from said elastomer.
  • the elastomer is prepared by crosslinking, in the presence of a catalyst, a vinyl-functional polysiloxane component and a silicon hydride-functional crosslinking agent.
  • crosslinking is meant the addition reaction of the silicon hydride- functional crosslinking agent with the carbon-carbon double bond of the vinyl-functional polysiloxane component.
  • the elastomer is prepared by crosslinking the polymer in the presence of a peroxide catalyst.
  • vinyl-functionar polysiloxane shall be understood to cover polysiloxanes substituted with vinyl groups or with vinyl-terminated groups.
  • the "vinyl-functional polysiloxane component" and the “polysiloxane component” to be crosslinked shall also be understood to cover copolymers with polysiloxanes having vinyl substituents or vinylterminated substituents.
  • the amounts of the components are preferably selected so that the ratio of the molar amounts of the silicon hydrides to the double bonds is at least 1.
  • the elastomer for use in this invention can be made by crosslinking one single fluorosubstituted siloxane-based polymer, or by crosslinking a mixture of a non-fluorosubstituted siloxane-based polymer and a fluorosubstituted siloxane-based polymer.
  • the term "vinyl-functional polysiloxane component" can thus be a mixture comprising a non- fluorosubstituted siloxane-based polymer and a fluorosubstituted siloxane- based polymer, where said polymer comprises 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units.
  • the "vinyl- functional polysiloxane component” can be a single fluorosubstituted siloxane-based polymer, where said polymer comprises 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units.
  • a so-called compatibiliser can be mixed with the above- mentioned components.
  • the compatibiliser is typically a block copolymer of a non-fluorosubstituted polymer and a fluorosubstituted polymer.
  • the silicon hydride-functional crosslinking agent is preferably a hydride- functional polysiloxane that may be straight chain, branched or cyclic.
  • the hydride-functional siloxane crosslinking agent may also contain trifluoropropyl groups.
  • the fluorosubstituted siloxane-based polymer is preferably a PDMS polymer where approximately 50 % of the methyl groups in said PDMS are replaced by 3,3,3-trifluoropropyl groups.
  • a filler such as amorphous silica, is preferably added to the vinyl-functional component before the crosslinking.
  • a polymer component can be a mixture comprising a non-fluorosubstituted siloxane-based polymer and a fluorosubstituted siloxane-based polymer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units.
  • this polymer component can be a single fluorosubstituted siloxane-based polymer, where said polymer comprises 3,3,3-trifluoropropyl groups attached to the Si- atoms of the siloxane units.
  • the catalyst to be used in the crosslinking is preferably a noble metal catalyst, most commonly a platinum complex in alcohol, xylene, divinyl siloxane or cyclic vinyl siloxane.
  • An especially suitable catalyst is a Pt(0)-divinyl- tetramethyl disiloxane complex.
  • the therapeutically active agent is selected from the therapeutically active agent.
  • the preferred therapeutically active agent used in the device according to the invention is levonorgestrel, (-)-13-Ethyl-17 hydroxy-18, 19-dinor-17 ⁇ -pregn- 4-en-20-yn-3-one, the structure of which is shown as Compound II.
  • Compound II is levonorgestrel, (-)-13-Ethyl-17 hydroxy-18, 19-dinor-17 ⁇ -pregn- 4-en-20-yn-3-one, the structure of which is shown as Compound II.
  • the implants according to this invention can be manufactured in accordance with standard techniques.
  • the therapeutically active agent is mixed with the core matrix polymer, processed to the desired shape by molding, casting, extrusion, or other appropriate methods.
  • the membrane layer can be applied onto the core according to known methods such as by mechanical stretching, swelling or dipping.
  • US-patents US 3,832,252, US 3,854,480, US 4,957,119 An especially suitable method for preparation of the implants is disclosed in the Finnish patent FI 97947.
  • This patent discloses an extrusion technology where prefabricated rods containing the active ingredient are coated by an outer membrane. Each such rod is, for example, followed by another rod without any active ingredient. The formed string is cut at the rods that contain no active agent. In this way, no special sealing of the ends of the implant is necessary.
  • the intra-uterine device can be made according to well known technology, a preferable intra-uterine device (IUS, intrauterine system), intra-vaginal device or intra-cervical device in common use is a T-shaped body made of plastic material such as polyethene.
  • the body consists of an elongate member (stem) having at one end a transverse member comprising two wings.
  • the elongate member and the transverse member form a substantially T-shaped piece when the device is positioned in the uterus.
  • the device has an attached thread long enough to protrude out of the cervical canal when the device is in position in the uterus.
  • IUS:s releasing drugs have a drug reservoir adjusted around the elongate member.
  • This drug reservoir is preferably a matrix which consists of the elastomer matrix with the active agent(s) dispersed therein.
  • the matrix is encased in a membrane.
  • the membrane is usually made of an elastomer.
  • the drug reservoir adjusted around the stem of the T-shaped body can be manufactured as the implant as described above.
  • the matrix can first be applied onto the step after which the matrix is encased by a membrane.
  • the matrix and membrane of the drug reservoir on the IUS can be made of the same elastomer as the implants described above.
  • the implants consisted of three parts: a core, a membrane and adhesive end- caps.
  • the end-caps were inert and their function was only minimal in a sense of controlling the release of the active agent.
  • the core consisted of elastomer mixed with the active agent.
  • the membrane was made from elastomer that controlled the release rate of the active agent.
  • the therapeutically active agent used in the examples was levonorgestrel (LNG), of purity over 99 m-%, manufactured by Schering AG.
  • silica-filled poly(trifluoropropylmethylsiloxane-co- vinylmethylsiloxane) content of trifluoropropyl-rnethylsiloxane units 99,7 mol-%; i.e. degree of trifluoropropyl substitution 50 %) and 1.2 parts by weight of dibentsoylperoxide-polydimethylsiloxane paste (50 % of dichlorobenzoylperoxide) were mixed with a 2-roll mill. The mixture was extruded into a tube-like form with a wall thickness of 0,2 mm and cured by heat.
  • the release rate of the drug from the implant was measured in vitro as follows:
  • the implants were attached into a stainless steel holder in vertical position and the holders with the implants were placed into glass bottles containing 75 ml of a dissolution medium.
  • the glass bottles were shaked in shaking waterbath 100 rpm at 37 °C.
  • the dissolution medium was withdrawn and replaced by a fresh dissolution medium at predetermined time intervals, and the released drug was analysed by HPLC.
  • the concentration of the dissolution medium and the moment of change (withdrawal and replacement) of medium were selected so that sink-conditions were maintained during the test.
  • 30% of the substituents of siloxane groups in the membrane were 3,3,3- trifluoropropyl groups.
  • the core and membrane were prepared according to the example 1, except that in the membrane, the content of trifluoropropyl-methylsiloxane units of poly(trifluoropropylmethylsiloxane-co-vinylmethylsiloxane) was 60 mol-%; i.e. the degree of trifluoropropyl substitution was 30 %.
  • the implant was prepared according to example 1.
  • the drug release test was performed according to example 1 and the results are shown in Figure 1 as the daily in vitro release rate of levonorgestrel.
  • the implant was made from PDMS and it did not contain 3,3,3- trifluoropropyl groups.
  • the core and membrane were prepared according to the example 1, except that in the membrane, silica-filled poly(dimethylsiloxane-co- vinylmeth lsiloxane) was used instead of silica-filled poly (trifluoropropylmethylsiloxane-co- vinylmethylsiloxane) .
  • the implant was prepared according to example 1.
  • the drug release test was performed according to example 1 and the results are shown in Figure 1 as the daily in vitro release rate of levonorgestrel.
  • Figure 1 shows the daily in vitro release rate of levonorgestrel from the three implants according to examples 1-3.
  • the square marked curve refers to example 1, the round marked curve to example 2 and the triangle marked curve to comparative example 3.
  • the examples thus demonstrate clearly the retarding effect caused by the 3,3,3-trifluoropropyl substitution of the membrane polymer.

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  • Health & Medical Sciences (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)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dispositif d'administration permettant de libérer lentement un agent thérapeutiquement actif lévonorgestrel, sur une longue durée, à un taux de libération de 0,1-200 νg/jour. Ce dispositif comporte un noyau contenant au moins un agent thérapeutiquement actif et une membrane renfermant ce noyau, laquelle membrane est constituée d'un élastomère. Selon l'invention, il s'agit d'un élastomère à base de siloxane contenant des groupes 3,3,3-trifluoropropyle fixés sur les atomes de silicium des unités siloxane et le taux de libération de l'agent thérapeutiquement actif de ce dispositif d'administration est régulé par la quantité des groupes 3,3,3-trifluoropropyle.
PCT/FI2001/000406 2000-05-10 2001-04-27 Dispositifs d'administration de medicaments, notamment de levonorgestrel Ceased WO2001085132A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001258442A AU2001258442A1 (en) 2000-05-10 2001-04-27 Drug delivery device, especially for the delivery of levonorgestrel

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US56802800A 2000-05-10 2000-05-10
US09/568,028 2000-05-10

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WO2001085132A1 true WO2001085132A1 (fr) 2001-11-15

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009029958A3 (fr) * 2007-08-30 2009-06-04 Sunstorm Res Corp Dispositif de distribution implantable
US7862552B2 (en) 2005-05-09 2011-01-04 Boston Scientific Scimed, Inc. Medical devices for treating urological and uterine conditions
CN103041455A (zh) * 2013-01-10 2013-04-17 扬州大学临床医学院 生物可降解纳米载药缓释宫内节育器及其制备方法
EP2585011A4 (fr) * 2010-06-22 2014-10-15 Teva Womens Health Inc Dispositifs intra-vaginaux comportant des agents cholinolytiques, et leurs procédés de fabrication
USD718435S1 (en) 2012-05-30 2014-11-25 Medicines360 Intrauterine insertion device
CN106546706A (zh) * 2015-09-21 2017-03-29 上海复旦张江生物医药股份有限公司 pH梯度主动载药法制备的脂质体药物的体外释放测试方法
CN106546705A (zh) * 2015-09-21 2017-03-29 上海复旦张江生物医药股份有限公司 一种脂质体药物体外释放的测试方法
US10028858B2 (en) 2011-07-11 2018-07-24 Medicines360 Intrauterine systems, IUD insertion devices, and related methods and kits therefor
US10500381B2 (en) 2012-01-23 2019-12-10 Bayer Oy Drug delivery system

Citations (3)

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US6056976A (en) * 1998-11-12 2000-05-02 Leiras Oy Elastomer, its preparation and use
WO2000028968A1 (fr) * 1998-11-12 2000-05-25 Leiras Oy Dispositif d'administration de medicaments, en particulier des progestatifs et des oestrogenes
WO2000028967A1 (fr) * 1998-11-12 2000-05-25 Leiras Oy Dispositif d'administration de medicaments, en particulier des androgenes

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US6056976A (en) * 1998-11-12 2000-05-02 Leiras Oy Elastomer, its preparation and use
WO2000028968A1 (fr) * 1998-11-12 2000-05-25 Leiras Oy Dispositif d'administration de medicaments, en particulier des progestatifs et des oestrogenes
WO2000028967A1 (fr) * 1998-11-12 2000-05-25 Leiras Oy Dispositif d'administration de medicaments, en particulier des androgenes

Non-Patent Citations (2)

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Title
KATHERINE L. ULMAN ET AL.: "Drug permeability of modified silicone polymers. I. Silicone-organic block copolymers", JOURNAL OF CONTROLLED RELEASE, vol. 10, 1989, pages 251 - 260, XP002948824 *
YING SUN ET AL.: "Effect of polymer composition on steroid permeation: membrane permeation kinetics of androgens and progestins", JOURNAL OF CONTROLLED RELEASE, vol. 5, 1987, pages 69 - 78, XP002948823 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7862552B2 (en) 2005-05-09 2011-01-04 Boston Scientific Scimed, Inc. Medical devices for treating urological and uterine conditions
WO2009029958A3 (fr) * 2007-08-30 2009-06-04 Sunstorm Res Corp Dispositif de distribution implantable
EP2585011A4 (fr) * 2010-06-22 2014-10-15 Teva Womens Health Inc Dispositifs intra-vaginaux comportant des agents cholinolytiques, et leurs procédés de fabrication
US10028858B2 (en) 2011-07-11 2018-07-24 Medicines360 Intrauterine systems, IUD insertion devices, and related methods and kits therefor
US11090186B2 (en) 2011-07-11 2021-08-17 Medicines360 Methods for using intrauterine systems and IUD insertion devices
US12004992B2 (en) 2011-07-11 2024-06-11 Medicines360 Kits for intrauterine systems and IUD insertion devices
US12427053B2 (en) 2011-07-11 2025-09-30 Medicines360 IUD insertion devices with a rotatable string controller and methods
US10500381B2 (en) 2012-01-23 2019-12-10 Bayer Oy Drug delivery system
USD718435S1 (en) 2012-05-30 2014-11-25 Medicines360 Intrauterine insertion device
CN103041455A (zh) * 2013-01-10 2013-04-17 扬州大学临床医学院 生物可降解纳米载药缓释宫内节育器及其制备方法
CN106546706A (zh) * 2015-09-21 2017-03-29 上海复旦张江生物医药股份有限公司 pH梯度主动载药法制备的脂质体药物的体外释放测试方法
CN106546705A (zh) * 2015-09-21 2017-03-29 上海复旦张江生物医药股份有限公司 一种脂质体药物体外释放的测试方法

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