WO2002032433A1 - Systeme d'administration de medicament - Google Patents

Systeme d'administration de medicament Download PDF

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Publication number
WO2002032433A1
WO2002032433A1 PCT/FI2001/000879 FI0100879W WO0232433A1 WO 2002032433 A1 WO2002032433 A1 WO 2002032433A1 FI 0100879 W FI0100879 W FI 0100879W WO 0232433 A1 WO0232433 A1 WO 0232433A1
Authority
WO
WIPO (PCT)
Prior art keywords
active agent
elastomer
therapeutically active
siloxane
poly
Prior art date
Application number
PCT/FI2001/000879
Other languages
English (en)
Inventor
Harri Jukarainen
Timo Haapakumpu
Juha Ala-Sorvari
Jarkko Ruohonen
Matti Lehtinen
Original Assignee
Leiras Oy
Lehtinen, Pirkko
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, Lehtinen, Pirkko filed Critical Leiras Oy
Priority to AU2002210580A priority Critical patent/AU2002210580A1/en
Publication of WO2002032433A1 publication Critical patent/WO2002032433A1/fr

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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
    • 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
    • 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
    • A61K9/0039—Devices retained in the uterus for a prolonged period, e.g. intrauterine devices for contraception
    • 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
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes

Definitions

  • This invention relates to a drug delivery system, particularly to a system intended for administration of ll ⁇ -(4-Acetylphenyl)-17 ⁇ -hydroxy-17 ⁇ - (l,l,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one, 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 drags in various drug forms, in particular in implants and intra-uterine systems (IUS), also known as intra-uterine devices (IUD).
  • IUS intra-uterine systems
  • IUD intra-uterine devices
  • Polysiloxanes are physiologically inert, and a wide group of drugs are capable of penetrating polysiloxane membranes, which also have the required mechanical properties.
  • Contraceptive subcutaneous implants are known in the art and they are described e.g. in US patents 4,957,119, 5,088,505, 5,035,891, 5,565,443 and 5,633,000.
  • the commercially available NORPLANT ® system is an implant having a core containing the synthetic progestin, levonorgestrel as the active substance, and where the core is surrounded by a membrane of a siloxane elastomer of poly(dimethylsiloxane).
  • a special preparation of this kind is JADELLE ® in which the core is a poly(dimethylsiloxane) based matrix with levonorgestrel dispersed therein.
  • the membrane is an elastomer made from PDMS and silica filler, which, besides giving necessary strength properties to the membrane, also retards the permeation of the active agent through the membrane.
  • the object of this invention is to provide a drug delivery system, particularly a system intended for administration of ll ⁇ -(4-Acetylphenyl)-17 ⁇ -hydroxy- 17 -(l,l,2,2,2- ⁇ entafluoroethyl)estra-4,9-dien-3-one, at a substantially constant rate for a prolonged period of time.
  • the object is particularly to provide a system with which the drug release rate can easily be adjusted.
  • the invention concerns a delivery system for the controlled release of the therapeutically active agent ll ⁇ -(4-Acetylphenyl)-17 ⁇ -hydroxy-17 ⁇ - (l,l,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one, over a prolonged period of time, said system comprising a core comprising at least said therapeutically active agent, and a membrane encasing said core wherein said membrane is made of an elastomer chosen from the group consisting of a siloxane-based elastomer and a composition comprising at least a siloxane-based elastomer.
  • the release rate of said therapeutically active agent is 0,1-200 ⁇ g/day.
  • Figure 1 shows the daily in vitro release of l l ⁇ -(4-Acetylphenyl)-17 ⁇ - hydroxy- 17 ⁇ -( 1 , 1 ,2,2,2-pentafluoroethyl)es tra-4,9-dien-3-one from the implants described in Example 1.
  • Figure 2 shows the daily in vitro release of ll ⁇ -(4-Acetylphenyl)-17 ⁇ - hydroxy- 17(X-( 1 , 1 ,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one from the intrauterine systems described in Example 2.
  • the system according to the invention can for example be an implant, an intrauterine system, an intravaginal system or an intracervical system.
  • the release rate of the active agent in an intrauterine system is 0,1-200 ⁇ g/day, preferably 0,5-50 ⁇ g/day, more preferably 1-30 ⁇ 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 1-200 ⁇ g/day.
  • the elastomer suitable for use in the system according to this invention is chosen from the group consisting of a siloxane-based elastomer and a composition comprising at least a siloxane-based elastomer.
  • 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).
  • said elastomer is a composition comprising poly(alkylene oxide) groups which are present in the elastomer as alkoxy-terminated grafts of polysiloxane units, or as blocks, said grafts or blocks being linked to the polysiloxane units by silicon-carbon bonds, or as a mixture of these forms.
  • the composition comprising at least a siloxane-based elastomer may be made up of two networks that are interlaced, one inside the other.
  • the first network comprises poly(alkylene oxide) groups so that the poly(alkylene oxide) groups are present in the said network either as alkoxy-terminated grafts of polysiloxane units or as blocks, the said grafts or blocks being linked to the polysiloxane units by silicon- carbon bonds.
  • the poly(alkylene oxides) may also be present as a blend of the options mentioned.
  • the second network may be a siloxane-based elastomer, suitably a poly(dimethyl siloxane)-based elastomer.
  • Said second network may possibly also comprise poly(alkylene oxide) groups.
  • These poly(alkylene - oxide) groups may also be present either as alkoxy-terminated grafts of poly- (dimethyl siloxane) units or as blocks, the said grafts or blocks being linked to the poly(dimethyl siloxane) units by silicon-carbon bonds.
  • the poly(alkylene oxides) may also in this elastomer be present as a blend of the options mentioned above.
  • the composition comprising at least a siloxane-based elastomer may be a blend which comprises a siloxane-based elastomer, which is, for example, made up of PDMS, and at least one linear polysiloxane copolymer which comprises poly(alkylene oxide) groups.
  • the poly(alkylene oxide) groups are present in the said polymer either as alkoxy-terminated grafts of polysiloxane units or as blocks, the said grafts or blocks being linked to the polysiloxane units by silicon-carbon bonds.
  • the poly(alkylene oxide) groups may, of course, also be present in the polymer as a blend of the forms mentioned.
  • the siloxane-based elastomer may comprise ⁇ oly(alkylene oxide) groups, in which case these ⁇ oly(alkylene oxide) groups are present in the elastomer either as alkoxy- terminated grafts of polysiloxane units or as blocks, the said blocks or grafts being linked to the polysiloxane units by silicon-carbon bonds.
  • the ⁇ oly(alkylene oxide) groups may also be present as a blend of the forms mentioned.
  • the poly(alkylene oxide) groups of the elastomer composition may suitably be, for example, poly(ethylene oxide) groups (PEO groups).
  • the polysiloxane units of the elastomer composition are preferably groups having the formula
  • alkyl or phenyl groups which are the same or different and which are a lower alkyl group, or a phenyl group, in which case the said alkyl or phenyl groups may be substituted or unsubstituted, or alkoxy-terminated ⁇ oly(alkylene oxide) groups having the formula R 3 -0-(CRH-CH 2 -0) m -alk, where alk is a lower alkyl group, suitably methyl, R is hydrogen or a lower alkyl, m is 1-30, and R 3 is a linear or branched C 2 - C 6 alkylene group,
  • q 1-3000.
  • lower alkyl stands here and generally in the description for - C 6 alkyl groups.
  • R' and R" groups are suitably a lower alkyl group, preferably methyl.
  • poly(alkylene oxide) group means that said group comprises at least two alkyl ether groups successively connected to each other.
  • the poly(alkylene oxide) groups are present in the elastomer in the form of poly(alkylene oxide) blocks having the formula
  • R is hydrogen, a lower alkyl or a phenyl
  • R ! is hydrogen or a lower alkyl
  • y is 2-6
  • m is 1-30.
  • 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.
  • a filler such as amorphous silica
  • the novel elastomer composition comprising at least a siloxane-based elastomer is prepared by crosslinking, in the presence of a catalyst, a vinyl-functional polymer component and a hydride-functional siloxane component.
  • crosslinking is meant the addition reaction of the hydride-functional siloxane component with the carbon-carbon double bond of the vinyl- functional polymer component.
  • the amounts of the components are preferably selected so that the ratio of the molar amounts of the reactive hydrides and the reactive double bonds is at least 1.
  • the elastomer composition comprising at least a siloxane-based elastomer is prepared by crosslinking the polymer in the presence of a peroxide catalyst.
  • a peroxide catalyst In this case the vinyl and methyl groups react with each other and form carbon-carbon bonds.
  • a crosslink may also be formed between two methyl groups or between two vinyl groups.
  • the vinyl-functional polymer component may be any vinyl-functional polymer component.
  • R' and R" are the same or different, and are a lower alkyl group, or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted, and where some of the substituents R' and/or R" have been substituted for by vinyl groups, and r is 1-27000, or
  • - A -(SiR'R'O) q SiR'R"-, where R' and R" are the same or different and are a lower alkyl group, or a phenyl, in which case the said alkyl or phenyl group may be substituted or unsubstituted;
  • - B is a poly(alkylene oxide) having the formula
  • CH 2 CR 1 COO(CRHCH 2 0) m COCR 1 HCH 2 -
  • R is hydrogen, a lower alkyl or phenyl
  • Ri is hydrogen or a lower alkyl
  • R 3 and R are the same or different and are linear or branched C 2 - C 6 alkylene groups
  • R 11 is a linear or branched C 2 - C 6 alkenyl group
  • m is 1-30
  • q is 1- 3000
  • x is 0-100, or
  • R' and R" are the same or different and are a lower alkyl group, or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted, and where some of the substituents R' and/or R" have been substituted for by vinyl groups, and r is 1-27000, and
  • R' is a lower alkyl group, or an alkoxy- terminated poly(alkylene oxide) group having the formula
  • alk is a lower alkyl group, suitably methyl
  • R is hydrogen or a lower alkyl group
  • R is a linear or branched
  • R' is a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted
  • R" is a lower alkyl or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted
  • p is 1-5000, or
  • R 11 and R 12 are the same or different linear or branched C 2 - C 6 alkenyl groups, R is hydrogen or a lower alkyl, and m is 1-30, or
  • SiR'RO(SiRRO) r (SiR'RO) p SiR'R"-R' it should be noted that the formula is a kind of gross formula, in which the repeat units in successive parentheses may appear in any order in relation to one another.
  • the hydride-functional component may be
  • a hydride-functional siloxane which may be linear, star shaped, branched or cyclic, or
  • R' and R" are the same or different and are a lower alkyl group or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted;
  • B is a poly(alkylene oxide) having the formula
  • R is hydrogen, a lower alkyl or a phenyl
  • Ri is hydrogen or a lower alkyl
  • R 3 and R 4 are the same or different and are linear or branched C 2 - C 6 alkyl groups
  • m is 1-30
  • q is 1-3000
  • x is 0-100, or
  • the hydride-functional siloxane copolymer may be linear, in which case its formula is
  • R' and R" are the same or different and are a lower alkyl group, or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted, and where some of the substituents R' and/or R" have been substituted for by hydrogen, and r is 1-27000.
  • the vinyl-functional polymer component may contain a filler, suitably silica.
  • the catalyst to be used in the crosslinking is suitably a noble metal catalyst, most commonly a platinum complex in alcohol, xylene, vinyl siloxane or cyclic vinyl siloxane.
  • An especially suitable catalyst is a Pt(0)-divinyl- tetramethyl disiloxane complex.
  • the elastomer composition comprising at least a siloxane-based elastomer made up of two networks is prepared so that initially a first network is formed, whereafter a second network is formed by crosslinking in the presence of the first network. Thus the second network will penetrate through the first network, forming an interpenetrating network.
  • the elastomer composition comprising at least a siloxane-based elastomer which comprises an elastomer and a linear polymer is prepared, for example, by blending a vinyl-functional polymer component, a hydride-functional component, and a polymer which has no vinyl or hydride groups.
  • the vinyl-functional polymer component and the hydride- functional component form an elastomer, but the polymer component which does not contain the said functional groups will not take part in the crosslinking reaction but will remain, in a non-crosslinked form, inside the elastomer.
  • 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 moulding, 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 system can be made according to well-known technology.
  • a preferable intra-uterine system (IUS, intrauterine system), intra-vaginal system or intra-cervical system in common use is a T-shaped body made of plastic material such as polyethylene.
  • 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 system is positioned in the uterus.
  • the system has an attached thread long enough to protrude out of the cervical canal when the system 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 that 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 drag reservoir on the IUS can be made of the same elastomer as the implants described above.
  • the therapeutically active agent l l ⁇ -(4-Acetylphenyl)-17 ⁇ - hydroxy- 17 ⁇ -( 1 , 1 ,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one is called "drug”. Further, “parts” stand for parts per weight.
  • the release rate of the drug from the implants and the IUS were measured in vitro as follows: the implants/IUS 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.
  • siloxane membrane corresponds to a commercial silica-filled poly(dimethylsiloxane) membrane and it was prepared as follows:
  • the membrane tubes (length 50 mm) were swelled with cyclohexane and the cores were inserted into the membrane. Cyclohexane was allowed to evaporate and ends were closed with a silicone adhesive. After 24 hours the ends were cut to give 2 mm end-caps. This implant corresponds to system 1 in
  • the implant was prepared as in Example 1 a) and corresponds to system 2 in Figure 1.
  • Example 2 The core was prepared as in Example 1 b).
  • the implant was prepared as in Example 1 a) and corresponds to system 3 in Figure 1.
  • Example 2 The core was prepared as in Example 1 b).
  • the implant was prepared as in Example 1 a) and corresponds to system 3 in Figure 1.
  • Example 2
  • the intrauterine system (IUS) described in this Example consists of three parts: a core with the drug in a polymer matrix, a membrane covering the core and a T-shaped body of polyethylene onto which the core surrounded by the membrane is applied.
  • the membrane was the same as described in Example 1 a) above.
  • the IUS contains two different elastomer composition types.
  • the partial amounts of the different elastomer composition types of the membrane and the core were the same as in Example lb).
  • the content of the drag was 40 % (weight/weight), based on HPLC assay.
  • the IUS was prepared as in Example 2 a) and corresponds to system 5 in Figure 2. c) Drug containing IUS based on the use of PEO-PDMS
  • the IUS contains two different elastomer composition types.
  • the partial amounts of different composition types of the membrane and the core were the same as in Example 1 c).
  • the content of the drag was 40 % (weight/weight), based on HPLC assay.
  • the IUS was prepared as in Example 2 a) and corresponds to system 6 in Figure 2.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
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  • Veterinary Medicine (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
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  • Dermatology (AREA)
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Abstract

La présente invention concerne un système d'administration permettant la libération lente d'un agent à activité thérapeutique, le 11b-(4-Acétylphényl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroéthyl)estra-4,9-diene-3-un pendant un laps de temps prolongé. Ce système comprend un noyau contenant au moins l'agent thérapeutique susmentionné, et une membrane enveloppant le noyau. La membrane est composée d'un élastomère choisi dans le groupe comprenant au moins un élastomère à base de siloxane et une composition contenant au moins un élastomère à base de siloxane. La présente invention se caractérise en ce que la vitesse de libération de l'agent à activité thérapeutique est de 0,1 à 200 νg/jour.
PCT/FI2001/000879 2000-10-20 2001-10-11 Systeme d'administration de medicament WO2002032433A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002210580A AU2002210580A1 (en) 2000-10-20 2001-10-11 Drug delivery system

Applications Claiming Priority (2)

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US69222400A 2000-10-20 2000-10-20
US09/692,224 2000-10-20

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Publication Number Publication Date
WO2002032433A1 true WO2002032433A1 (fr) 2002-04-25

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006005794A1 (fr) * 2004-07-13 2006-01-19 Schering Oy Systeme de liberation
US7862552B2 (en) 2005-05-09 2011-01-04 Boston Scientific Scimed, Inc. Medical devices for treating urological and uterine conditions
WO2013110856A1 (fr) * 2012-01-23 2013-08-01 Bayer Oy Système d'administration de médicament
WO2019063382A1 (fr) * 2017-09-27 2019-04-04 Bayer Oy Procédé de modification de la libération d'un agent thérapeutiquement actif à partir d'une matrice élastomère

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000550A1 (fr) * 1998-06-30 2000-01-06 Leiras Oy Membrane ou matrice permettant de reguler la vitesse de permeation des medicaments
US6063395A (en) * 1998-11-12 2000-05-16 Leiras Oy Drug delivery device especially for the delivery of progestins and estrogens
WO2001047490A1 (fr) * 1999-12-23 2001-07-05 Leiras Oy Dispositifs destines a l'administration de medicaments dotes de proprietes antiprogestatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000000550A1 (fr) * 1998-06-30 2000-01-06 Leiras Oy Membrane ou matrice permettant de reguler la vitesse de permeation des medicaments
US6063395A (en) * 1998-11-12 2000-05-16 Leiras Oy Drug delivery device especially for the delivery of progestins and estrogens
WO2001047490A1 (fr) * 1999-12-23 2001-07-05 Leiras Oy Dispositifs destines a l'administration de medicaments dotes de proprietes antiprogestatives

Non-Patent Citations (1)

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Title
FUHRMANN ET AL.: "Synthesis and biological activity of a novel, highly potent progesterone receptor antagonist", J. MED. CHEM., vol. 43, 2000, pages 5010 - 5016, XP001064233 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006005794A1 (fr) * 2004-07-13 2006-01-19 Schering Oy Systeme de liberation
US7850986B2 (en) 2004-07-13 2010-12-14 Schering Oy Delivery system
US7862552B2 (en) 2005-05-09 2011-01-04 Boston Scientific Scimed, Inc. Medical devices for treating urological and uterine conditions
WO2013110856A1 (fr) * 2012-01-23 2013-08-01 Bayer Oy Système d'administration de médicament
JP2015504083A (ja) * 2012-01-23 2015-02-05 バイエル・オーイュー 薬剤送達システム
AU2013213514B2 (en) * 2012-01-23 2017-07-13 Bayer Oy A drug delivery system
TWI626951B (zh) * 2012-01-23 2018-06-21 拜耳股份有限公司 藥物遞送系統
EA032208B1 (ru) * 2012-01-23 2019-04-30 Байер Ой Система доставки лекарств
US10500381B2 (en) 2012-01-23 2019-12-10 Bayer Oy Drug delivery system
WO2019063382A1 (fr) * 2017-09-27 2019-04-04 Bayer Oy Procédé de modification de la libération d'un agent thérapeutiquement actif à partir d'une matrice élastomère
US11666552B2 (en) 2017-09-27 2023-06-06 Bayer Oy Method for modifying release of a therapeutically active agent from an elastomeric matrix

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