Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-05-10
2001-10-09
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S449000, C424S430000, C424S486000, C424S473000
Reexamination Certificate
active
06299894
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a drug delivery device, particularly to a device intended for administration of gestodene, at a substantially constant rate for a prolonged period of time.
BACKGROUND OF THE INVENTION
The publications and other materials used herein to illuminate the background of the invention, and in particular, the cases to provide additional details respecting the practice, are incorporated by reference.
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 intra-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.
It is known from the literature that the adding of poly(ethylene oxide) groups, i.e. PEO groups, to a PDMS polymer may increase the perneation of drugs. Publication KL Ullman et al., Journal of Controlled Release 10 (1989) 251-260, describes membranes prepared from a block copolymer which contains PEO and PDMS and the penetration of various steroids through these membranes. It is further known that membranes based on modified PDMS polymers, in which a certain amount of the methyl substituents at the Si-atoms are replaced by trifluoropropyl groups, decrease the permeation of drugs. The publication Ying Sun et al., Journal of Controlled Release, 5 (1987) 69-78, describes the effect on membranes prepared from PDMS, trifluoropropyl substituted PDMS and PDMS/PEO/PMMA (where PMMA is poly(methylmethacrylate)) on the permeation of androgenic and progestenic steroids. The study shows that the permeation for both groups of steroids was lower for the membrane made of trifluoropropyl substituted PDMS than for that made of unmodified PDMS. The publication does not, however, disclose any elastomer made of trifluoropropyl substituted PDMS.
OBJECTS AND SUMMARY OF THE INVENTION
The object of this invention is to provide a drug delivery device, particularly a device intended for administration of gestodene, 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.
Thus, the invention concerns a delivery device for the controlled release of the therapeutically active agent gestodene, over a prolonged period of time, at a release rate of 0,1-300 &mgr;g/day, said device comprising
a core comprising at least said therapeutically active agent, and
a membrane encasing said core wherein said membrane is made of an elastomer.
According to the invention, 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.
DETAILED DESCRIPTION OF THE INVENTION
The device according to the invention can for example be an implant, an intrauterine device, an intravaginal device or an intracervical device. According to one embodiment of the invention, the release rate of the active agent in an intrauterine device is 0,1-300 &mgr;g/day, preferably 0,5-100 &mgr;g/day, more preferably 0,5-50 &mgr;g/day and most preferably 0,5-30 &mgr;g/day. According to another embodiment of the invention, the release rate of the active agent in an implant is 0,1-300 &mgr;g/day, preferably 0,5-200 &mgr;g/day and more preferably 1-100 &mgr;g/day.
Description of the Elastomer
The elastomer suitable for use in the device according to this invention, particularly for use in the membrane of the device, is a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units.
The term “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).
According to the invention, 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. Such an elastomer can be achieved in different ways. According to one embodiment, 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-trifluoropropyl 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.
According to another embodiment, which is particularly preferred if suitable 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 nonfluorosubstituted 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.
General Description of the Method for the Preparation of the Elastomer
According to one embodiment, the elastomer is prepared by crosslinking, in the presence of a catalyst, a vinyl-functional polysiloxane component and a silicon hydride-functional crosslinking agent.
By crosslinking is meant the addition reaction of the silicon hydride-functional crosslinkng agent with the carbon-carbon double bond of the vinyl-functional polysiloxane component.
According
Ala-Sorvari Juha
Jukarainen Harri
Lehtinen Matti
Markkula Tommi
Ruohonen Jarkko
Joynes Robert M.
Leiras Oy
Lydon James C.
Page Thurman K.
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