CA2569542C - A delivery system - Google Patents
A delivery system Download PDFInfo
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- CA2569542C CA2569542C CA2569542A CA2569542A CA2569542C CA 2569542 C CA2569542 C CA 2569542C CA 2569542 A CA2569542 A CA 2569542A CA 2569542 A CA2569542 A CA 2569542A CA 2569542 C CA2569542 C CA 2569542C
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- membrane
- active agent
- core
- therapeutically active
- delivery system
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- 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
- A61K9/08—Solutions
-
- 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
-
- 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
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- 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
- 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
-
- 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
- A61K9/0012—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
The present invention relates to a delivery system comprising a core and a membrane encasing said core, wherein said core and mem-brane consist essentially of an elastomer composition and said core comprises at least one therapeutically active agent. The delivery system is characterized in that the membrane comprises at least one regulating agent. The invention also relates to a method for controlling the release of at least one therapeutically active agent from a delivery system.
Description
A DELIVERY SYSTEM
FIELD OF THE INVENTION
The present invention relates to a delivery system comprising a core and a membrane encasing said core, wherein said core and mem-brane consist essentially of an elastomer composition and said core comprises at least one therapeutically active agent. The present in-vention also relates to a method for controlling the release of at least one therapeutically active agent from a delivery system com-1 0 prising a core and a membrane encasing said core, wherein said core and membrane consist essentially of an elastomer composition and said core comprises said at least one therapeutically active agent.
BACKGROUND OF THE INVENTION
The use of drug delivery systems for the delivery of a therapeutically active agent, which systems provide for steady release of a thera-peutically active agent to a patient's body at a controlled rate over a prolonged period of time in order to achieve a desired physiological or pharmacological effect, have proved beneficial in many therapeu-20 tic areas. A principal advantage of employing sustained-release compositions is that many therapeutically active agents would oth-erwise be rapidly metabolised or cleared from the patient's body, thus necessitating frequent administration of the therapeutically ac-tive agent to maintain a therapeutically effective concentration.
A problem often faced in controlling the release of the therapeuti-cally active agent by using a slow releasing preparation is initial burst, i.e. the release of a relatively large amount of the therapeuti-cally active agent right after the preparation has been administered or inserted to the patient. If such an initial burst occurs, the concen-I
FIELD OF THE INVENTION
The present invention relates to a delivery system comprising a core and a membrane encasing said core, wherein said core and mem-brane consist essentially of an elastomer composition and said core comprises at least one therapeutically active agent. The present in-vention also relates to a method for controlling the release of at least one therapeutically active agent from a delivery system com-1 0 prising a core and a membrane encasing said core, wherein said core and membrane consist essentially of an elastomer composition and said core comprises said at least one therapeutically active agent.
BACKGROUND OF THE INVENTION
The use of drug delivery systems for the delivery of a therapeutically active agent, which systems provide for steady release of a thera-peutically active agent to a patient's body at a controlled rate over a prolonged period of time in order to achieve a desired physiological or pharmacological effect, have proved beneficial in many therapeu-20 tic areas. A principal advantage of employing sustained-release compositions is that many therapeutically active agents would oth-erwise be rapidly metabolised or cleared from the patient's body, thus necessitating frequent administration of the therapeutically ac-tive agent to maintain a therapeutically effective concentration.
A problem often faced in controlling the release of the therapeuti-cally active agent by using a slow releasing preparation is initial burst, i.e. the release of a relatively large amount of the therapeuti-cally active agent right after the preparation has been administered or inserted to the patient. If such an initial burst occurs, the concen-I
tration of the therapeutically active agent in the blood may exceed the permissible upper limit, which may be dangerous to the patient.
Initial burst can be prevented to a certain extent by selecting the form of the therapeutically active agent and the releasing material, but a basic solution for preventing initial burst has been the subject of extensive studies. On the other hand, the concentration of a therapeutically active agent in a preparation should be as high as possible in order to achieve slow release of the therapeutically ac-tive agent over a long period of time and to be able to maintain a moderate size of the preparation.
The initial burst may be decreased or avoided by modifying the physical state of the active agent. The therapeutically active agent can be incorporated into a controlled release agent, such as poly-mer microspheres, which steadily or intermittently release the thera-peutically active agent. Examples of suitable controlled release components include microstructures, such as microparticles, nanoparticles, cyclodextrins, microcapsules, micelles and lipo-somes. The controlled release component may also include macro-structures. Suitable controlled release components also include salts of the therapeutically active agent and complexes or conju-gates in which the therapeutically active agent is operatively associ-ated with a carrier molecule.
For the liquid delivery compositions, which typically include a biode-gradable and/or bioerodable polymer or copolymer dissolved in a non-toxic organic solvent, the additional time required to release the therapeutically active agent from the controlled release component will enable the formulation to solidify into a solid implant without the initial loss of a substantial amount of the therapeutically active agent. Once formed into a solid matrix, the permeation of the thera-peutically active agent is based on the rates the therapeutically ac-tive agent is released from the controlled release component and from the implant matrix. The second mode is governed by the rate of biodegradation and/or bioerosion of the implant material.
On the other hand, in making the polymer microspheres the con-trolled release components, such as cyclodextrin, also serve as a buffer and reduce denaturing of a sensitive therapeutically active agent, e.g. when the microspheres are compressed into pellets. The buffers usually dissolve more quickly than the polymer and hereby facilitate the release of the therapeutically active agent by creating tunnels in the microspheres. Inclusion of the controlled release components can therefore also lead to an initial burst of drug re-lease after implantation.
A variety of methods for achieving low initial burst of formulations of therapeutically active agents have been described in the literature.
Such methods have mainly been focused in injection delivery sys-tems, such as microparticles, liquid polymer compositions and gel compositions.
International Patent Application WO 95/27481 Al is related to liquid polymer compositions that are useful for the delivery of therapeuti-cally active agents in vivo and permit the initial burst to be controlled more effectively than previously possible. When a liquid delivery system including a biodegradable polymer and a therapeutically ac-tive agent dissolved in a water-soluble solvent comes into contact with an aqueous medium, such as a body fluid, the solvent dissi-pates or diffuses into the aqueous medium. As the polymer precipi-tates or coagulates to form a solid matrix, the active agent is trapped or encapsulated throughout the polymeric matrix. The re-lease of the active agent then follows the general rules for the disso-lution or diffusion of a therapeutically active agent from within a polymeric matrix. The formation of the solid matrix from the liquid delivery system is, however, not instantaneous but typically occurs over a period of several hours. During this initial period, the rate of diffusion of the active agent may be much more rapid than the rate of release that occurs from the subsequently formed solid matrix.
The initial burst can be decreased by incorporating the active agent into a controlled release component and combining the controlled release component with the liquid polymer systems described for example in U.S. Patent Nos. 4,938,763, 5,278,201 and 5,278,202.
International Patent Application WO 01/08717 Al is related to im-plantable devices, where the therapeutically active agent is incorpo-rated into a controlled release agent, such as polymer micro-spheres, which steadily or intermittently release the therapeutically active agent. Various polymers can be used for encapsulating therapeutically active agents in microspheres. Preferably, the poly-mers are biocompatible and degradable when placed within human tissue. In the preparation of the microspheres, buffers, such as su-crose and cyclodextrin, can be added. Inclusion of buffers is, how-ever shown to lead to an initial burst of the active agent during, e.g., the first 24 hours after implantation.
International Patent Application WO 96/01626 Al is related to a transdermal system comprising a reservoir with the therapeutically active agent in ionized form, a pH adjusting agent and a cyclic poly-saccharide for improving the solubility of the therapeutic agent in the buffer solution. The polysaccharide may be selected from a group consisting of cyclodextrin or a derivative thereof and a cyclodextrin polymer. The reservoir wall comprises a polymer, which is substan-tially impermeable to the ionized form or the inclusion complex of the therapeutically active agent, but is permeable to water and to the unionized form of the therapeutically active agent. The therapeuti-cally active agent is able to penetrate through the reservoir wall only when the system is applied to the skin and water penetrates through the reservoir wall into the core. During these initial stages the re-lease rate of the therapeutically active agent slowly increases until the concentration of the therapeutically active agent in the reservoir wall reaches steady-state levels. The delay before steady levels are achieved in plasma can be avoided by loading the reservoir wall of a single core reservoir system with the therapeutically active agent to give a priming dose of the therapeutically active agent. The loading of the reservoir wall can cause an initial burst. The magnitude of the burst or delay in the release of the therapeutically active agent can be modified by varying the amount of the therapeutically active agent that is loaded.
A publication of J Biomater Sci Polym Ed. 1994;5(4):339-51 de-scribes controlled release systems prepared from biodegradable microparticles of poly(lactic acid-co-glycolic acid) containing beta-estradiol in the presence or absence of silicone. The release behav-iour of beta-estradiol from free microparticles as well as from mi-croparticles embedded within a silicone matrix is compared with the release behaviour shown by non-encapsulated beta-estradiol within a silicone matrix. It was found that incorporating biodegradable mi-croparticles within a silicone matrix lessens the initial burst of re-lease often seen with these types of formulations and provides a 5 controlled release of therapeutically active agent.
The above applications concentrate on injectable formulations, wherein the controlled release or regulating material and the thera-peutically active agent are located in the same phase of the delivery system.
Document US 2002/0161352 presents a vaginal ring preparation comprising a tubular base of an inert rubber, a first layer on top of it comprising a drug, a surfactant and a dispersing agent as well as a second layer of silicone rubber encapsulating said first layer on the tubular base. The dispersing agent may be for example R-type or B-type cyclodextrin. Thus this document does not disclose a core-membrane-structure wherein the therapeutically active agent is comprised in the core.
The initial burst effect, i.e. the amount of therapeutically active agent typically released in the first 24-48 hours, is non-efficient by resulting in the loss or release of a relatively large amount of the therapeuti-cally active agent. If the therapeutically active agent is not well toler-ated, this initial burst is likely to lead to side effects and may cause damage to the adjacent tissues. In any of the above cases, these ef-fects may prohibit the use of that certain formulation, if the burst ef-fect cannot be minimized.
The development of delivery systems with reduced or eliminated ini-tial burst effect would represent a significant advancement. The effi-ciency of such systems would be improved, since a greater percent-age of the active agent would remain in the device for sustained re-lease and not be lost during the initial burst. The possibility of side effects would be reduced. There is, therefore, a continuing need for controlled release systems that will facilitate the sustained release of a therapeutically active agent in a patient's body without creating an initial burst of therapeutically active agent.
Initial burst can be prevented to a certain extent by selecting the form of the therapeutically active agent and the releasing material, but a basic solution for preventing initial burst has been the subject of extensive studies. On the other hand, the concentration of a therapeutically active agent in a preparation should be as high as possible in order to achieve slow release of the therapeutically ac-tive agent over a long period of time and to be able to maintain a moderate size of the preparation.
The initial burst may be decreased or avoided by modifying the physical state of the active agent. The therapeutically active agent can be incorporated into a controlled release agent, such as poly-mer microspheres, which steadily or intermittently release the thera-peutically active agent. Examples of suitable controlled release components include microstructures, such as microparticles, nanoparticles, cyclodextrins, microcapsules, micelles and lipo-somes. The controlled release component may also include macro-structures. Suitable controlled release components also include salts of the therapeutically active agent and complexes or conju-gates in which the therapeutically active agent is operatively associ-ated with a carrier molecule.
For the liquid delivery compositions, which typically include a biode-gradable and/or bioerodable polymer or copolymer dissolved in a non-toxic organic solvent, the additional time required to release the therapeutically active agent from the controlled release component will enable the formulation to solidify into a solid implant without the initial loss of a substantial amount of the therapeutically active agent. Once formed into a solid matrix, the permeation of the thera-peutically active agent is based on the rates the therapeutically ac-tive agent is released from the controlled release component and from the implant matrix. The second mode is governed by the rate of biodegradation and/or bioerosion of the implant material.
On the other hand, in making the polymer microspheres the con-trolled release components, such as cyclodextrin, also serve as a buffer and reduce denaturing of a sensitive therapeutically active agent, e.g. when the microspheres are compressed into pellets. The buffers usually dissolve more quickly than the polymer and hereby facilitate the release of the therapeutically active agent by creating tunnels in the microspheres. Inclusion of the controlled release components can therefore also lead to an initial burst of drug re-lease after implantation.
A variety of methods for achieving low initial burst of formulations of therapeutically active agents have been described in the literature.
Such methods have mainly been focused in injection delivery sys-tems, such as microparticles, liquid polymer compositions and gel compositions.
International Patent Application WO 95/27481 Al is related to liquid polymer compositions that are useful for the delivery of therapeuti-cally active agents in vivo and permit the initial burst to be controlled more effectively than previously possible. When a liquid delivery system including a biodegradable polymer and a therapeutically ac-tive agent dissolved in a water-soluble solvent comes into contact with an aqueous medium, such as a body fluid, the solvent dissi-pates or diffuses into the aqueous medium. As the polymer precipi-tates or coagulates to form a solid matrix, the active agent is trapped or encapsulated throughout the polymeric matrix. The re-lease of the active agent then follows the general rules for the disso-lution or diffusion of a therapeutically active agent from within a polymeric matrix. The formation of the solid matrix from the liquid delivery system is, however, not instantaneous but typically occurs over a period of several hours. During this initial period, the rate of diffusion of the active agent may be much more rapid than the rate of release that occurs from the subsequently formed solid matrix.
The initial burst can be decreased by incorporating the active agent into a controlled release component and combining the controlled release component with the liquid polymer systems described for example in U.S. Patent Nos. 4,938,763, 5,278,201 and 5,278,202.
International Patent Application WO 01/08717 Al is related to im-plantable devices, where the therapeutically active agent is incorpo-rated into a controlled release agent, such as polymer micro-spheres, which steadily or intermittently release the therapeutically active agent. Various polymers can be used for encapsulating therapeutically active agents in microspheres. Preferably, the poly-mers are biocompatible and degradable when placed within human tissue. In the preparation of the microspheres, buffers, such as su-crose and cyclodextrin, can be added. Inclusion of buffers is, how-ever shown to lead to an initial burst of the active agent during, e.g., the first 24 hours after implantation.
International Patent Application WO 96/01626 Al is related to a transdermal system comprising a reservoir with the therapeutically active agent in ionized form, a pH adjusting agent and a cyclic poly-saccharide for improving the solubility of the therapeutic agent in the buffer solution. The polysaccharide may be selected from a group consisting of cyclodextrin or a derivative thereof and a cyclodextrin polymer. The reservoir wall comprises a polymer, which is substan-tially impermeable to the ionized form or the inclusion complex of the therapeutically active agent, but is permeable to water and to the unionized form of the therapeutically active agent. The therapeuti-cally active agent is able to penetrate through the reservoir wall only when the system is applied to the skin and water penetrates through the reservoir wall into the core. During these initial stages the re-lease rate of the therapeutically active agent slowly increases until the concentration of the therapeutically active agent in the reservoir wall reaches steady-state levels. The delay before steady levels are achieved in plasma can be avoided by loading the reservoir wall of a single core reservoir system with the therapeutically active agent to give a priming dose of the therapeutically active agent. The loading of the reservoir wall can cause an initial burst. The magnitude of the burst or delay in the release of the therapeutically active agent can be modified by varying the amount of the therapeutically active agent that is loaded.
A publication of J Biomater Sci Polym Ed. 1994;5(4):339-51 de-scribes controlled release systems prepared from biodegradable microparticles of poly(lactic acid-co-glycolic acid) containing beta-estradiol in the presence or absence of silicone. The release behav-iour of beta-estradiol from free microparticles as well as from mi-croparticles embedded within a silicone matrix is compared with the release behaviour shown by non-encapsulated beta-estradiol within a silicone matrix. It was found that incorporating biodegradable mi-croparticles within a silicone matrix lessens the initial burst of re-lease often seen with these types of formulations and provides a 5 controlled release of therapeutically active agent.
The above applications concentrate on injectable formulations, wherein the controlled release or regulating material and the thera-peutically active agent are located in the same phase of the delivery system.
Document US 2002/0161352 presents a vaginal ring preparation comprising a tubular base of an inert rubber, a first layer on top of it comprising a drug, a surfactant and a dispersing agent as well as a second layer of silicone rubber encapsulating said first layer on the tubular base. The dispersing agent may be for example R-type or B-type cyclodextrin. Thus this document does not disclose a core-membrane-structure wherein the therapeutically active agent is comprised in the core.
The initial burst effect, i.e. the amount of therapeutically active agent typically released in the first 24-48 hours, is non-efficient by resulting in the loss or release of a relatively large amount of the therapeuti-cally active agent. If the therapeutically active agent is not well toler-ated, this initial burst is likely to lead to side effects and may cause damage to the adjacent tissues. In any of the above cases, these ef-fects may prohibit the use of that certain formulation, if the burst ef-fect cannot be minimized.
The development of delivery systems with reduced or eliminated ini-tial burst effect would represent a significant advancement. The effi-ciency of such systems would be improved, since a greater percent-age of the active agent would remain in the device for sustained re-lease and not be lost during the initial burst. The possibility of side effects would be reduced. There is, therefore, a continuing need for controlled release systems that will facilitate the sustained release of a therapeutically active agent in a patient's body without creating an initial burst of therapeutically active agent.
OBJECT AND SUMMARY OF THE INVENTION
An object of the present invention is to provide a system and method for controlling the initial burst of therapeutically active agent from a delivery system that consists of at least one elastomer.
One object of the present invention is further to provide a system in-tended for the administration of a therapeutically active agent at a substantially constant release rate for a prolonged period of time, said system comprising a core and a membrane encasing said core, wherein said core and membrane consist essentially of an elas-tomer composition.
One object is particularly to provide a delivery system in which the release rate of the therapeutically active agent and the initial burst can easily be adjusted.
Another object of this invention is to provide a delivery system in the form of an implant, intravaginal device, intracervical or intrauterine device or transdermal patch intended for the administration of said therapeutically active agent.
Still another object is to provide a safe and flexible releasing system, which has a small cross section and which is easy to insert and convenient to wear.
Thus, the present invention concerns a delivery system and a method as described below in the independent claims.
More specifically, the invention as broadly disclosed is directed to a delivery system comprising a core and a membrane encasing said core, wherein said core and membrane consist essentially of an elastomer composition and said 6a core comprises at least one therapeutically active agent, characterized in that the membrane comprises at least one regulating agent.
In the invention as claimed, said at least one regulating agent is however more specifically selected from the group consisting of cyclodextrins and modified cyclodextrins.
A typical method according to the present invention is a method for controlling the release rate of at least one therapeutically active agent from a delivery system comprising a core and a membrane encasing said core, wherein said core and membrane consist es-sentially of an elastomer composition and said core comprises at least one therapeutically active agent. The regulation is performed by at least one regulating agent comprised in the membrane of said delivery system.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the results of example 1.
Figure 2 illustrates the results of example 2.
Figure 3 illustrates the results of example 3.
DETAILED DESCRIPTION OF THE INVENTION
The present invention concerns a delivery system and a method as described below in the independent claims. The dependent claims illustrate some embodiments of the invention.
A typical delivery system according to the present invention com-prises a core and a membrane encasing said core, wherein said core and membrane consist essentially of an elastomer composition and said core comprises at least one therapeutically active agent.
The membrane comprises at least one regulating agent.
The regulating agent is capable of forming chemical bonds, com-plexes or conjugates or binding with the therapeutically active agent molecules and immobilizing or binding them into the membrane. All of these ways of association are intended to be temporary, thus in-hibiting or lowering the release at the beginning.
In this description, the term "therapeutically active agent" is often used in singular. It is to be understood that the same given details apply when several therapeutically active agents are used.
The invention is thus based on the fact that initial burst of therapeu-tically active agent(s) can be controlled and adjusted by adding at least one regulating agent selected from certain types of com-pounds in the membrane of a delivery system that is capable of forming chemical bonds, complexes or conjugates, in which the therapeutically active agent is operatively associated with a regulat-ing agent, immobilizing or binding with the therapeutically active agent molecules first to be released, immobilizing or binding them into the membrane and thus prohibiting the burst effect. The regulat-ing agent itself can be bound into membrane material physically or chemically.
The present invention is therefore related to delivery applications for controlling the release rate of a therapeutically active agent over a prolonged period of time and starting from the beginning of therapy to achieve a low initial burst of the therapeutically active agent or no burst at all. In such applications, a release rate over a prolonged time can be adjusted by changing the formulation materials, physi-cal dimensions and therapeutically active agent load of the system.
The burst effect, where the initial release of the therapeutically ac-tive agent can be several times higher than the later achieved zero-order release, cannot, at the time of making the present invention, be fully adjusted by changing only the formulation of the device.
In the present invention the burst preventing regulating material is located in the membrane encasing the core or container comprising the therapeutically active agent. The low initial burst is achieved by a formation of chemical bonds, complexes, conjugates or weak in-termolecular bonds between the regulating agent and the molecules of the therapeutically active agent first to be released of the core material, and binding them into the membrane and thus prohibiting the burst effect. The present invention introduces a method of ad-justing burst phenomena and acquiring a negative burst effect at its best. In a negative burst effect, the release rate of the therapeuti-cally active agent is steadily accelerating from zero, reaching smoothly the normal release rate instead of being much higher at the very beginning of the release and then decreasing from there to the normal therapeutic window.
A typical method according to the present invention is a method for controlling the release rate of at least one therapeutically active agent from a delivery system comprising a core and a membrane encasing said core, wherein said core and membrane consist es-sentially of an elastomer composition and said core comprises said at least one therapeutically active agent. The regulation is per-formed by at least one regulating agent comprised in the membrane of said delivery system.
The regulating agent can be bound into the membrane elastomer physically, depending on its size difference compared to the mem-brane elastomer network, or chemically into the membrane elas-tomer chains.
The term "regulating agent" is used here to mean the burst-controlling agent, which comes into contact with the releasing thera-peutically active agent. The regulating agent can be any substance, which is capable of forming chemical bonds, complexes or conju-gates with the releasing therapeutically active agents, or capable of forming one or more host-guest associations via nonbonding inter-actions with the therapeutically active agents, e.g. via van der Waals forces, hydrogen bonding, dipole-dipole interactions or ion-paring, and can be bound into the elastomer network physically or chemi-cally directly into the polymer chains.
According to the present invention as broadly disclosed, said regulating agent is selected from the group consisting of carbohydrates, cyclodextrins and modified cyclodextrins. According to the invention as claimed, said regulating agent is however exclusively selected from the group consisting of cyclodextrins and modified cyclodextrins, and preferably from the group consisting of alpha cyclodextrins, beta cyclodextrins, gamma cyclodextrins, hydroxypropyl cyclodextrins, maltosyl 13-cyclodextrin, P-cyclodextrin sulfobutyl ether and a cyclodextrin polymer.
Other applicable regulating agents include plant extrudates such as gum arabic, seaweed extracts such as agar, guar gum, starches, fermentation gums such as dextran, animal products such as gela-9a tin, cellulose derivatives such as hydroxyalkyl celluloses, carboxy-methylcelluloses, carboxylic derivatives of cellulose, glycerol esters, mono- or polyglycerides, pectins, carrageenan, polyethylene glycol, liposomes, alginates, albumin and sorbitan fatty acid esters and crown ethers.
For pharmaceutical uses, the regulating agent should have a low toxicity profile and should preferably not be toxic. Particularly useful regulating agents are therefore cyclodextrins (a, R or y) and cyclo-dextrin derivatives.
With cyclodextrins the essential part of complex formation is the hy-drophobic cavity of the molecule, which binds hydrophobic thera-5 peutically active agents.
The control of the initial release of a therapeutically active agent can be achieved in several ways. First, the molar content of reacting agent in the membrane can be adjusted with respect to the amount of molecules of active agent released in the initial burst. Secondly, 10 the particle size of the regulating agent in the membrane elastomer can be adjusted as well, as the particle size influences the distribu-tion (more or less equal distribution) of the regulating agent in the membrane. Finally, the stability of the complex or conjugate be-tween the regulating agent and the therapeutically active agent can also be one method of controlling the initial release of the therapeu-tically active agent. The initial burst can be adjusted by changing the regulating agent, e.g. by using hydroxypropyl modified cyclodextrin instead of cyclodextrin.
With cyclodextrins, a powder form substance can be dissolved into ethanol to mix it homogeneously into the membrane polymer. In that case ethanol must be removed after mixing, by vacuum or heat de-pending on the crosslinking method of the elastomer material.
According to an embodiment of the present invention, the mem-brane comprises one regulating agent. According to another em-bodiment, the membrane comprises two regulating agents. The membrane may also comprise any other number of regulating agents, such as three, four, five, six, seven, eight or more different regulating agents. The amount of different regulating agents can be the same or different.
The formulation of the present invention is intended to mean the physical structure, i.e. size, dimensions and shape of the core and membrane parts of the system as well as the therapeutically active agent, which is loaded in the core part. The system can be an im-plant, an intravaginal ring, an intracervical device, an intrauterine system (IUS), a transdermal device or any non specified type of de-vice having an implant type structure. The system can also comprise individual parts without any membrane or core. Such parts are for example the ends of the implant, which can be sealed with any bio-compatible material without the therapeutically active agent. The system can also consist of a pharmaceutically inactive body or any separate part of the system to improve the strength of the structure or to help the insertion or attachment of the system into any point of body.
The core and the membrane encasing said core consist essentially of a same or different elastomer composition.
The elastomer composition used in the membrane is such that it al-lows the pre-determined, constant release rates of the therapeuti-cally active agent(s). The regulating agent(s) added in the mem-brane elastomer material allow the adjustment of the initial release rate, i.e. the release rate before the constant release is achieved.
The main object of the invention is thus obtained by the choice of the regulating agent(s).
The core consists essentially of an elastomer composition, that is, the core is an elastomer matrix, wherein the therapeutically active agents are dispersed. Therefore, even if the membrane encasing the core would be damaged, the therapeutically active agents would not be released in a completely uncontrolled manner causing side effects to the patient. The elastomer composition of the core is thus chosen so that the membrane primarily regulates the release of the therapeutically active agent. The release rates in general can be controlled by the membrane alone or by the membrane together with the core. It is also possible that the release rate is mainly con-trolled by the core.
The core may consist of one part comprising a therapeutically active agent as such, e.g. in liquid or crystallized form or optionally in com-bination with other therapeutically active agents. Alternatively, the core can consist of the therapeutically active agent or agents in a mixture with pharmaceutically acceptable excipients.
An object of the present invention is to provide a system and method for controlling the initial burst of therapeutically active agent from a delivery system that consists of at least one elastomer.
One object of the present invention is further to provide a system in-tended for the administration of a therapeutically active agent at a substantially constant release rate for a prolonged period of time, said system comprising a core and a membrane encasing said core, wherein said core and membrane consist essentially of an elas-tomer composition.
One object is particularly to provide a delivery system in which the release rate of the therapeutically active agent and the initial burst can easily be adjusted.
Another object of this invention is to provide a delivery system in the form of an implant, intravaginal device, intracervical or intrauterine device or transdermal patch intended for the administration of said therapeutically active agent.
Still another object is to provide a safe and flexible releasing system, which has a small cross section and which is easy to insert and convenient to wear.
Thus, the present invention concerns a delivery system and a method as described below in the independent claims.
More specifically, the invention as broadly disclosed is directed to a delivery system comprising a core and a membrane encasing said core, wherein said core and membrane consist essentially of an elastomer composition and said 6a core comprises at least one therapeutically active agent, characterized in that the membrane comprises at least one regulating agent.
In the invention as claimed, said at least one regulating agent is however more specifically selected from the group consisting of cyclodextrins and modified cyclodextrins.
A typical method according to the present invention is a method for controlling the release rate of at least one therapeutically active agent from a delivery system comprising a core and a membrane encasing said core, wherein said core and membrane consist es-sentially of an elastomer composition and said core comprises at least one therapeutically active agent. The regulation is performed by at least one regulating agent comprised in the membrane of said delivery system.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the results of example 1.
Figure 2 illustrates the results of example 2.
Figure 3 illustrates the results of example 3.
DETAILED DESCRIPTION OF THE INVENTION
The present invention concerns a delivery system and a method as described below in the independent claims. The dependent claims illustrate some embodiments of the invention.
A typical delivery system according to the present invention com-prises a core and a membrane encasing said core, wherein said core and membrane consist essentially of an elastomer composition and said core comprises at least one therapeutically active agent.
The membrane comprises at least one regulating agent.
The regulating agent is capable of forming chemical bonds, com-plexes or conjugates or binding with the therapeutically active agent molecules and immobilizing or binding them into the membrane. All of these ways of association are intended to be temporary, thus in-hibiting or lowering the release at the beginning.
In this description, the term "therapeutically active agent" is often used in singular. It is to be understood that the same given details apply when several therapeutically active agents are used.
The invention is thus based on the fact that initial burst of therapeu-tically active agent(s) can be controlled and adjusted by adding at least one regulating agent selected from certain types of com-pounds in the membrane of a delivery system that is capable of forming chemical bonds, complexes or conjugates, in which the therapeutically active agent is operatively associated with a regulat-ing agent, immobilizing or binding with the therapeutically active agent molecules first to be released, immobilizing or binding them into the membrane and thus prohibiting the burst effect. The regulat-ing agent itself can be bound into membrane material physically or chemically.
The present invention is therefore related to delivery applications for controlling the release rate of a therapeutically active agent over a prolonged period of time and starting from the beginning of therapy to achieve a low initial burst of the therapeutically active agent or no burst at all. In such applications, a release rate over a prolonged time can be adjusted by changing the formulation materials, physi-cal dimensions and therapeutically active agent load of the system.
The burst effect, where the initial release of the therapeutically ac-tive agent can be several times higher than the later achieved zero-order release, cannot, at the time of making the present invention, be fully adjusted by changing only the formulation of the device.
In the present invention the burst preventing regulating material is located in the membrane encasing the core or container comprising the therapeutically active agent. The low initial burst is achieved by a formation of chemical bonds, complexes, conjugates or weak in-termolecular bonds between the regulating agent and the molecules of the therapeutically active agent first to be released of the core material, and binding them into the membrane and thus prohibiting the burst effect. The present invention introduces a method of ad-justing burst phenomena and acquiring a negative burst effect at its best. In a negative burst effect, the release rate of the therapeuti-cally active agent is steadily accelerating from zero, reaching smoothly the normal release rate instead of being much higher at the very beginning of the release and then decreasing from there to the normal therapeutic window.
A typical method according to the present invention is a method for controlling the release rate of at least one therapeutically active agent from a delivery system comprising a core and a membrane encasing said core, wherein said core and membrane consist es-sentially of an elastomer composition and said core comprises said at least one therapeutically active agent. The regulation is per-formed by at least one regulating agent comprised in the membrane of said delivery system.
The regulating agent can be bound into the membrane elastomer physically, depending on its size difference compared to the mem-brane elastomer network, or chemically into the membrane elas-tomer chains.
The term "regulating agent" is used here to mean the burst-controlling agent, which comes into contact with the releasing thera-peutically active agent. The regulating agent can be any substance, which is capable of forming chemical bonds, complexes or conju-gates with the releasing therapeutically active agents, or capable of forming one or more host-guest associations via nonbonding inter-actions with the therapeutically active agents, e.g. via van der Waals forces, hydrogen bonding, dipole-dipole interactions or ion-paring, and can be bound into the elastomer network physically or chemi-cally directly into the polymer chains.
According to the present invention as broadly disclosed, said regulating agent is selected from the group consisting of carbohydrates, cyclodextrins and modified cyclodextrins. According to the invention as claimed, said regulating agent is however exclusively selected from the group consisting of cyclodextrins and modified cyclodextrins, and preferably from the group consisting of alpha cyclodextrins, beta cyclodextrins, gamma cyclodextrins, hydroxypropyl cyclodextrins, maltosyl 13-cyclodextrin, P-cyclodextrin sulfobutyl ether and a cyclodextrin polymer.
Other applicable regulating agents include plant extrudates such as gum arabic, seaweed extracts such as agar, guar gum, starches, fermentation gums such as dextran, animal products such as gela-9a tin, cellulose derivatives such as hydroxyalkyl celluloses, carboxy-methylcelluloses, carboxylic derivatives of cellulose, glycerol esters, mono- or polyglycerides, pectins, carrageenan, polyethylene glycol, liposomes, alginates, albumin and sorbitan fatty acid esters and crown ethers.
For pharmaceutical uses, the regulating agent should have a low toxicity profile and should preferably not be toxic. Particularly useful regulating agents are therefore cyclodextrins (a, R or y) and cyclo-dextrin derivatives.
With cyclodextrins the essential part of complex formation is the hy-drophobic cavity of the molecule, which binds hydrophobic thera-5 peutically active agents.
The control of the initial release of a therapeutically active agent can be achieved in several ways. First, the molar content of reacting agent in the membrane can be adjusted with respect to the amount of molecules of active agent released in the initial burst. Secondly, 10 the particle size of the regulating agent in the membrane elastomer can be adjusted as well, as the particle size influences the distribu-tion (more or less equal distribution) of the regulating agent in the membrane. Finally, the stability of the complex or conjugate be-tween the regulating agent and the therapeutically active agent can also be one method of controlling the initial release of the therapeu-tically active agent. The initial burst can be adjusted by changing the regulating agent, e.g. by using hydroxypropyl modified cyclodextrin instead of cyclodextrin.
With cyclodextrins, a powder form substance can be dissolved into ethanol to mix it homogeneously into the membrane polymer. In that case ethanol must be removed after mixing, by vacuum or heat de-pending on the crosslinking method of the elastomer material.
According to an embodiment of the present invention, the mem-brane comprises one regulating agent. According to another em-bodiment, the membrane comprises two regulating agents. The membrane may also comprise any other number of regulating agents, such as three, four, five, six, seven, eight or more different regulating agents. The amount of different regulating agents can be the same or different.
The formulation of the present invention is intended to mean the physical structure, i.e. size, dimensions and shape of the core and membrane parts of the system as well as the therapeutically active agent, which is loaded in the core part. The system can be an im-plant, an intravaginal ring, an intracervical device, an intrauterine system (IUS), a transdermal device or any non specified type of de-vice having an implant type structure. The system can also comprise individual parts without any membrane or core. Such parts are for example the ends of the implant, which can be sealed with any bio-compatible material without the therapeutically active agent. The system can also consist of a pharmaceutically inactive body or any separate part of the system to improve the strength of the structure or to help the insertion or attachment of the system into any point of body.
The core and the membrane encasing said core consist essentially of a same or different elastomer composition.
The elastomer composition used in the membrane is such that it al-lows the pre-determined, constant release rates of the therapeuti-cally active agent(s). The regulating agent(s) added in the mem-brane elastomer material allow the adjustment of the initial release rate, i.e. the release rate before the constant release is achieved.
The main object of the invention is thus obtained by the choice of the regulating agent(s).
The core consists essentially of an elastomer composition, that is, the core is an elastomer matrix, wherein the therapeutically active agents are dispersed. Therefore, even if the membrane encasing the core would be damaged, the therapeutically active agents would not be released in a completely uncontrolled manner causing side effects to the patient. The elastomer composition of the core is thus chosen so that the membrane primarily regulates the release of the therapeutically active agent. The release rates in general can be controlled by the membrane alone or by the membrane together with the core. It is also possible that the release rate is mainly con-trolled by the core.
The core may consist of one part comprising a therapeutically active agent as such, e.g. in liquid or crystallized form or optionally in com-bination with other therapeutically active agents. Alternatively, the core can consist of the therapeutically active agent or agents in a mixture with pharmaceutically acceptable excipients.
According to another embodiment of the invention, the core consists of at least two parts each part comprising at least one therapeuti-cally active agent. The elastomer compositions of said parts are chosen according to the release rates desired and can be the same or different in each part. According to the embodiment in which the core consists of two or more parts, the parts may be either posi-tioned next to each other or in such a way that one part of a core encases at least partly another part of the core. Any combination of structure is naturally possible and within the scope of the invention.
If several parts of core are used, the different parts may or may not be separated from each other by a separation membrane.
The membrane may consist of one or more layers, such as one, two three, four, five, six or seven layers. According to an embodiment of the invention, the membrane consists of at least two layers, each layer having a certain thickness. The thickness of the layers may be the same or different and the elastomer compositions used in each layer may also be the same or different. The membranes encasing each above-mentioned part of the core may also be identical or dif-ferent in either the elastomer composition or the structure of the membrane (one or several layers). The combination of different lay-ers of membrane either in thickness or in material or both gives a further possibility for controlling the release rates of the therapeuti-cally active agents.
Depending on the application used for the delivery of a therapeuti-cally active agent and the number of therapeutically active agents, one or more regulating agents can be used, as discussed above.
The regulating agents can be in the same membrane but they can also be placed into separate parts of the membrane and/or in sepa-rate layers of the membrane.
Elastomer compositions mentioned above, namely the elastomer compositions of the core, the membrane and the possible separa-tion membrane, can be the same or different and may stand for one single elastomer, or the elastomer composition may be made up of elastomers that are interlaced, one inside the other. The term "elas-tomer" is intended to mean at least partly amorphous polymer or a mixture of polymers, the deformation of which caused by the strain is reversible, i.e. the elastomer's shape recovers to a certain level after the strain.
In principle any elastomer can be used as a carrier as long as it is biocompatible. However, the release kinetics of a therapeutically ac-tive agent from an elastomeric delivery system depend on the mo-lecular weight, solubility, diffusivity and charge of the therapeutically active agent as well as the characteristics of the elastomer, the per-centage of the loading of the therapeutically active agent, the dis-tance the therapeutically active agent must diffuse through the de-vice body to reach its surface and the characteristics of any matrix or membrane.
Examples of commonly used polymeric materials include, but are not limited to, polysiloxanes, ethylene/vinyl acetate copolymers (EVA), and copolymers of dimethylsiloxanes and methylvinylsilox-anes. The structural integrity of the material may be enhanced by the addition of a particulate material such as silica or diatomaceous earth. The elastomers can also be mixed with other additives to ad-just elastomer's hydrophilic or hydrophobic properties while taking into account that they need to be biocompatible and harmless to the patient.
According to a preferable embodiment, the core is made of a silox-ane based elastomer composition comprising at least one elastomer and possibly a non-crosslinked polymer.
The elastomer composition may also be selected from the group consisting of - an elastomer composition comprising poly(dimethylsiloxane) (PDMS), - an elastomer composition comprising a siloxane-based elas-tomer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units, - an elastomer composition comprising poly(alkylene oxide) groups, said poly(alkylene oxide) groups being present as alkoxy-terminated grafts or blocks linked to the polysiloxane units by silicon-carbon bonds or as a mixture of these forms, and - a combination of at least two thereof.
According to an embodiment of the invention, in the siloxane-based elastomer I to approximately 50 % of the substituents attached to the Si-atoms of the siloxane units are 3,3,3-trifluoropropyl groups.
The percentage of the substituents that are 3,3,3-trifluoropropyl groups can be for example 5-40 %, 10-35 %, 1-29 % or 15-49.5 %.
According to another embodiment of the invention, the poly(alkylene oxide) groups mentioned above are poly(ethylene oxide) (PEO) groups.
The methods for the preparation of these elastomers are given in the applicant's other patents and patent applications.
Different types of systems The system can be any system suitable for delivery of the therapeu-tically active agent at a controlled rate over a prolonged period of time. Thus, the system can take a wide variety of shapes and forms for administering the therapeutically active agent at controlled rates to different areas of the body. The invention can be applied to any type of formulation as long as they consist of a membrane control-ling the release of a therapeutically active agent and a core contain-ing the therapeutically active agent. The invention includes external and internal drug delivery systems, such as transdermal patches, implants for releasing a therapeutically active agent in the body tis-sues, intravaginal rings, intracervical and intrauterine devices.
According to a preferred embodiment, the device is an implant for subcutaneous use, an intravaginal ring or an intrauterine system (IUS). According to the most preferred embodiments, the device is an implant for subcutaneous use or an intrauterine system.
The manufacturing of such systems is discussed below, even though it is well known in the art. The shape and size of the system may also be freely chosen by the person skilled in the art. It is also evident that the systems according to the invention may be applied to humans as well as to animals. When the delivery system is for example an intrauterine system, it may further comprise a body forming the structure of the system, which can be made of any bio-compatible material. In this case, the core-membrane structure of the system is hollow so that it can be positioned over the body of the system. The body may have various forms, e.g. the form of T, S or 5 7.
The therapeutically active agent The variety of different therapeutically active agents can be used in conjunction with the invention. Therapeutically active agents can be mixed as such with above materials or they may be used in liquid 10 form mixed with suitable diluents such as polyethylene glycol (PEG).
The amount of the therapeutically active agent incorporated in the delivery system varies depending on the particular therapeutically active agent, the desired therapeutic effect and the time for which the system is expected to provide therapy. Since a variety of de-15 vices with varying sizes and shapes can be formulated for adminis-tering dosages for different therapeutical areas, there is no critical upper limit on the amount of therapeutically active agent incorpo-rated in the device. The lower limit depends on the activity of the therapeutically active agent and the expected release time. A per-son skilled in the art is readily able to determine the amount of the therapeutically active agent needed for each specific application of the delivery system.
Preferably, the amount of therapeutically active agent in the core varies between almost zero to 70 wt-%, when it is mixed into the elastomer, the preferred amount being between 20 - 60 wt-%. Other possible ranges of the amount of the therapeutically active agent are0,5-70wt-%, 5-65wt-%, 10-50wt-%, 25-70wt-%, 50-60 wt-% and 40 - 50 wt-%. The core can also consist of pure therapeu-tically active agent, which however is not recommended due to a risk of system breakage.
Manufacture of implants The implants according to this invention can be manufactured in ac-cordance with standard techniques. The therapeutically active agent is mixed with the core matrix elastomer, such as polydimethylsilox-ane (PDMS), or the components forming the elastomer composition as defined above, processed to the desired shape by molding, cast-ing, extrusion, or other appropriate methods. The membrane layer can be applied onto the core according to known methods, such as by mechanical stretching, swelling in a suitable solvent, such as cyclohexane, diglyme, isopropanol, or mixture of solvents, or dip-ping. Reference is made to the patents US 3,832,252, US 3,854,480 and 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 con-taining 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 im-plant is necessary.
Intravaginal ring and the medicated cores used in intrauterine and intracervical systems represent one application of an implant and can be manufactured by using similar techniques.
Intrauterine and intracervical systems The intrauterine system can be made according to well-known tech-nology. A preferable intrauterine system (IUS) or intracervical sys-tem 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 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.
In medicated intrauterine systems the therapeutically active agent intended to be released is in a core or a reservoir adjusted-around the body. The core or reservoir preferably consists of the elastomer matrix with the therapeutically active agent dispersed therein. The matrix is encased in a membrane that is made of an elastomer.
The reservoir adjusted around the stem of the T-shaped body can be manufactured by using methods described above for the manu-facture of implants. Alternatively, the matrix can first be applied onto the stem after which the matrix is encased by a membrane. The elastomer composition of the matrix and membrane of the reservoir can be the same or different.
The invention is further illustrated by the following, non-limiting ex-amples.
EXPERIMENTAL PART
The release rate of the therapeutically active substance from the device was measured in vitro as follows:
The devices (implant, intravaginal ring, intracervical or intrauterine system) were attached into a stainless steel holder in vertical posi-tion and the holders with the devices were placed into glass bottles containing 75 ml of a dissolution medium, a 1 wt-% hydroxypropyl cyclodextrin solution. The glass bottles were shaked in shaking wa-terbath 100 rpm at 37 C. The dissolution medium was withdrawn and replaced by a fresh dissolution medium at predetermined time intervals, and the amount of the released substance was analysed by using standard HPLC methods. The concentration of the dissolu-tion medium and the moment of change (withdrawal and replace-ment) of medium were selected, so that sink-conditions were main-tained during the test.
Example 1 Danazol in intravaginal ring The ability to control the initial burst effect was demonstrated with danazol, a synthetic androgen hormone (17alpha)-pregna-2,4-dien-20-yn[2,3-d]isoxazol-17-oI, by using an intravaginal ring (IVR) appli-cation in vitro for up to 32 days. Hydroxypropyl 3-cyclodextrin (HPBCD) was used as the regulating agent. Three different implants with different hydroxypropyl [i-cyclodextrin (HPBCD) contents in the membrane were made and the results were compared to corre-sponding implants without any added HPBCD. All the implants con-sisted of a core containing the therapeutically active agent and a re-lease rate-controlling membrane encasing the core. The core and the membrane silicone elastomer rods were manufactured by extru-sion and the implant compositions were made by swelling the mem-brane in propanol, as explained above. The content of the therapeu-tically active agent was 20 wt-% (weight percent) in the core and the micronized hormone was mixed into the elastomer with a mixer be-fore extrusion. The diameters of the IVR rings were ca. 50 - 55 mm and the periphery of the cross section ca. 9 - 10 mm, the thick-nesses of the membranes were 0.25, 0.35 and 0.7 mm and the HPBCD contents of the membrane were 0.17 wt-%, 1.7 wt-% and 7.7 wt-% respectively.
The results are shown in Figure 1 for the daily in vitro release rate per core area ( g / (d*mm2), shown as the y axis and days shown in the x-axis), wherein the empty triangles represent the results for 0.17 wt-% HPBCD-content in the membrane with 0.7 mm wall thick-ness. The empty squares illustrate the results for 1.7 wt-% HPBCD-content in the membrane with 0.35 mm wall thickness and the stars show the results for 7.7 wt-% HPBCD-content in the membrane with 0.25 mm wall thickness. The full triangles represent the comparative results for a membrane with wall thickness of 0.3 mm and the full squares illustrate the comparative results for a membrane with wall thickness of 0.9 mm.
As seen in Figure 1, HPBCD modification results in a significant im-provement of reducing the initial burst of danazol from silicone based application. The initial burst effect found with all the HPBCD
modified samples shows a negative initial burst effect.. According to Figure 1, the initial burst without the modification is five to ten times that found for modified samples and three to five times that found for the release rate in two weeks dissolution. The results show that without any regulating agent the magnitude of the initial burst is several times the release rate in the stable phase and the initial burst cannot be merely reduced by changing the formulation of the samples.
The release rate of the therapeutically active agent with HPBCD
modified implants shows a slightly increasing trend for the first two weeks until it achieves a zenith point, where the release rate is at the maximum level. After that point the release rate of the therapeu-tically active agent presents a normal decreasing release profile as seen in the reference samples. For example thecurve of empty tri-angles, with 0.17 w-% HPBCD content and 0.7 mm membrane wall, compared to an ordinary ring with 0.9 mm wall, shows that the re-lease rate of the therapeutically active agent stays equal in two and half week release. However, according to the results the release rate seems to be higher, when HPBCD is added into the membrane.
Example 2 Gestodene implant The present invention was also tested with an implant containing gestodene, a synthetic progestogene hormone. The implant core and membrane rods were made with extrusion and the implant composition was made by swelling the membrane in propanol. The outer diameter of the implant core was 2.5 - 3.0 mm and the length 40 - 48 mm. The content of the therapeutically active agent in the core was 65 wt-%. The membrane thickness was 0.25 mm, inner diameter 2.35 - 2.65 mm, outer diameter was 3.0 - 3.25 mm and length 10 mm longer than the elastomer core. The HPBCD content of the implant membrane was 4 wt-%. The membrane was made of PEO-b-PDMS (15 wt-%) and PDMS (85 wt-%).
The results are shown in Figure 2 as the release rate of the thera-peutically active agent ( g/d, shown in y-axis) versus time (days, shown in x-axis), wherein the squares represent the results for the Reference 1, the losanges represent the results for an implant hav-ing a HPBCD-containing membrane and the triangles illustrate the results for Reference 2. Reference 1 comprises a core having an outer diameter of 2.5 mm and a length of 40 mm, and a membrane, the thickness of which is 0.25 mm. The implant having a membrane containing I wt-% HPBCD has a core with an outer diameter of 3.03 mm and a length of 44 mm, and the membrane wall of 0.25 mm.
Reference 2 comprises a core having an outer diameter of 2.8 mm, a length of 48 mm and the membrane with a wall of 0.25 mm.
Referring to Figure 2, the release rate profiles of gestodene are smoother than previously presented for danazol in Example 1 as the total decrease of release was only 30 % in 14 days with both refer-ence samples. However, the cyclodextrin modification smoothed the release rates from the implants and the maximum decrease of re-lease was only ca. 6 % in two weeks. In addition to that, cyclodextrin modification seemed to stabilise the release rate of the therapeuti-cally active agent after the initial burst, as the total decrease of the gestodene release was from the second to the third week only 0.5 %, while for the reference samples the decrease was 8.4 % and 11 5 %.
Example 3 Fluorinated antiprogestin (FAP) in intrauterine system (IUS) HPBCD modification was tested with a fluorinated antiprogestin de-rivative (FAP, 11-(4-Acetylphenyl)-17-hydroxy-17-(1,1,2,2,2-10 pentafluoroethyl) estra-4, 9-dien-3-one) in intrauterine (IUS) system.
Two samples of I and 4 wt-% of HPBCD content in the membrane were prepared by combining with swelling separately extruded membrane and core elastomer rods over the IUS T-frame. The swelling agent was isopropanol.
15 The content of the therapeutically active agent in the core elastomer was 65 wt-% and the outer diameter of the core was 2.88 - 2.92 mm and length 21.0 - 21.1 mm. The membrane was 3 mm longer than the core and the thickness of the membrane was 0,25 mm. Figure 3 presents the release rate of the therapeutically active agent ( g/d, 20 shown in the y-axis) from two FAP containing intrauterine systems as a function of time (days, shown in the x-axis) compared to a ref-erence sample. Indeed, the squares represent the results for the reference sample, the losanges illustrate the results for the cyclo-dextrin modified membrane, when the amount of cyclodextrin was 1 wt-% and the triangles represent the results for the cyclodextrin modified membrane, when the amount of cyclodextrin was 4 wt-%.
According to Figure 3, the initial burst is decreased with both cyclo-dextrin-modified membranes. When the amount of cyclodextrin was 1 wt-%, there is still some burst effect remaining. In addition to that, the release rate profile of the therapeutically active agent is higher for both cyclodextrin modified samples than for the reference sam-ple and the level of the release rate is higher, when the amount of cyclodextrin in the membrane was 4 wt-%. However, with FAP the profile, i.e. the shape of the curve, of the release rate after two days is similar for the reference and modified samples.
If several parts of core are used, the different parts may or may not be separated from each other by a separation membrane.
The membrane may consist of one or more layers, such as one, two three, four, five, six or seven layers. According to an embodiment of the invention, the membrane consists of at least two layers, each layer having a certain thickness. The thickness of the layers may be the same or different and the elastomer compositions used in each layer may also be the same or different. The membranes encasing each above-mentioned part of the core may also be identical or dif-ferent in either the elastomer composition or the structure of the membrane (one or several layers). The combination of different lay-ers of membrane either in thickness or in material or both gives a further possibility for controlling the release rates of the therapeuti-cally active agents.
Depending on the application used for the delivery of a therapeuti-cally active agent and the number of therapeutically active agents, one or more regulating agents can be used, as discussed above.
The regulating agents can be in the same membrane but they can also be placed into separate parts of the membrane and/or in sepa-rate layers of the membrane.
Elastomer compositions mentioned above, namely the elastomer compositions of the core, the membrane and the possible separa-tion membrane, can be the same or different and may stand for one single elastomer, or the elastomer composition may be made up of elastomers that are interlaced, one inside the other. The term "elas-tomer" is intended to mean at least partly amorphous polymer or a mixture of polymers, the deformation of which caused by the strain is reversible, i.e. the elastomer's shape recovers to a certain level after the strain.
In principle any elastomer can be used as a carrier as long as it is biocompatible. However, the release kinetics of a therapeutically ac-tive agent from an elastomeric delivery system depend on the mo-lecular weight, solubility, diffusivity and charge of the therapeutically active agent as well as the characteristics of the elastomer, the per-centage of the loading of the therapeutically active agent, the dis-tance the therapeutically active agent must diffuse through the de-vice body to reach its surface and the characteristics of any matrix or membrane.
Examples of commonly used polymeric materials include, but are not limited to, polysiloxanes, ethylene/vinyl acetate copolymers (EVA), and copolymers of dimethylsiloxanes and methylvinylsilox-anes. The structural integrity of the material may be enhanced by the addition of a particulate material such as silica or diatomaceous earth. The elastomers can also be mixed with other additives to ad-just elastomer's hydrophilic or hydrophobic properties while taking into account that they need to be biocompatible and harmless to the patient.
According to a preferable embodiment, the core is made of a silox-ane based elastomer composition comprising at least one elastomer and possibly a non-crosslinked polymer.
The elastomer composition may also be selected from the group consisting of - an elastomer composition comprising poly(dimethylsiloxane) (PDMS), - an elastomer composition comprising a siloxane-based elas-tomer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units, - an elastomer composition comprising poly(alkylene oxide) groups, said poly(alkylene oxide) groups being present as alkoxy-terminated grafts or blocks linked to the polysiloxane units by silicon-carbon bonds or as a mixture of these forms, and - a combination of at least two thereof.
According to an embodiment of the invention, in the siloxane-based elastomer I to approximately 50 % of the substituents attached to the Si-atoms of the siloxane units are 3,3,3-trifluoropropyl groups.
The percentage of the substituents that are 3,3,3-trifluoropropyl groups can be for example 5-40 %, 10-35 %, 1-29 % or 15-49.5 %.
According to another embodiment of the invention, the poly(alkylene oxide) groups mentioned above are poly(ethylene oxide) (PEO) groups.
The methods for the preparation of these elastomers are given in the applicant's other patents and patent applications.
Different types of systems The system can be any system suitable for delivery of the therapeu-tically active agent at a controlled rate over a prolonged period of time. Thus, the system can take a wide variety of shapes and forms for administering the therapeutically active agent at controlled rates to different areas of the body. The invention can be applied to any type of formulation as long as they consist of a membrane control-ling the release of a therapeutically active agent and a core contain-ing the therapeutically active agent. The invention includes external and internal drug delivery systems, such as transdermal patches, implants for releasing a therapeutically active agent in the body tis-sues, intravaginal rings, intracervical and intrauterine devices.
According to a preferred embodiment, the device is an implant for subcutaneous use, an intravaginal ring or an intrauterine system (IUS). According to the most preferred embodiments, the device is an implant for subcutaneous use or an intrauterine system.
The manufacturing of such systems is discussed below, even though it is well known in the art. The shape and size of the system may also be freely chosen by the person skilled in the art. It is also evident that the systems according to the invention may be applied to humans as well as to animals. When the delivery system is for example an intrauterine system, it may further comprise a body forming the structure of the system, which can be made of any bio-compatible material. In this case, the core-membrane structure of the system is hollow so that it can be positioned over the body of the system. The body may have various forms, e.g. the form of T, S or 5 7.
The therapeutically active agent The variety of different therapeutically active agents can be used in conjunction with the invention. Therapeutically active agents can be mixed as such with above materials or they may be used in liquid 10 form mixed with suitable diluents such as polyethylene glycol (PEG).
The amount of the therapeutically active agent incorporated in the delivery system varies depending on the particular therapeutically active agent, the desired therapeutic effect and the time for which the system is expected to provide therapy. Since a variety of de-15 vices with varying sizes and shapes can be formulated for adminis-tering dosages for different therapeutical areas, there is no critical upper limit on the amount of therapeutically active agent incorpo-rated in the device. The lower limit depends on the activity of the therapeutically active agent and the expected release time. A per-son skilled in the art is readily able to determine the amount of the therapeutically active agent needed for each specific application of the delivery system.
Preferably, the amount of therapeutically active agent in the core varies between almost zero to 70 wt-%, when it is mixed into the elastomer, the preferred amount being between 20 - 60 wt-%. Other possible ranges of the amount of the therapeutically active agent are0,5-70wt-%, 5-65wt-%, 10-50wt-%, 25-70wt-%, 50-60 wt-% and 40 - 50 wt-%. The core can also consist of pure therapeu-tically active agent, which however is not recommended due to a risk of system breakage.
Manufacture of implants The implants according to this invention can be manufactured in ac-cordance with standard techniques. The therapeutically active agent is mixed with the core matrix elastomer, such as polydimethylsilox-ane (PDMS), or the components forming the elastomer composition as defined above, processed to the desired shape by molding, cast-ing, extrusion, or other appropriate methods. The membrane layer can be applied onto the core according to known methods, such as by mechanical stretching, swelling in a suitable solvent, such as cyclohexane, diglyme, isopropanol, or mixture of solvents, or dip-ping. Reference is made to the patents US 3,832,252, US 3,854,480 and 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 con-taining 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 im-plant is necessary.
Intravaginal ring and the medicated cores used in intrauterine and intracervical systems represent one application of an implant and can be manufactured by using similar techniques.
Intrauterine and intracervical systems The intrauterine system can be made according to well-known tech-nology. A preferable intrauterine system (IUS) or intracervical sys-tem 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 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.
In medicated intrauterine systems the therapeutically active agent intended to be released is in a core or a reservoir adjusted-around the body. The core or reservoir preferably consists of the elastomer matrix with the therapeutically active agent dispersed therein. The matrix is encased in a membrane that is made of an elastomer.
The reservoir adjusted around the stem of the T-shaped body can be manufactured by using methods described above for the manu-facture of implants. Alternatively, the matrix can first be applied onto the stem after which the matrix is encased by a membrane. The elastomer composition of the matrix and membrane of the reservoir can be the same or different.
The invention is further illustrated by the following, non-limiting ex-amples.
EXPERIMENTAL PART
The release rate of the therapeutically active substance from the device was measured in vitro as follows:
The devices (implant, intravaginal ring, intracervical or intrauterine system) were attached into a stainless steel holder in vertical posi-tion and the holders with the devices were placed into glass bottles containing 75 ml of a dissolution medium, a 1 wt-% hydroxypropyl cyclodextrin solution. The glass bottles were shaked in shaking wa-terbath 100 rpm at 37 C. The dissolution medium was withdrawn and replaced by a fresh dissolution medium at predetermined time intervals, and the amount of the released substance was analysed by using standard HPLC methods. The concentration of the dissolu-tion medium and the moment of change (withdrawal and replace-ment) of medium were selected, so that sink-conditions were main-tained during the test.
Example 1 Danazol in intravaginal ring The ability to control the initial burst effect was demonstrated with danazol, a synthetic androgen hormone (17alpha)-pregna-2,4-dien-20-yn[2,3-d]isoxazol-17-oI, by using an intravaginal ring (IVR) appli-cation in vitro for up to 32 days. Hydroxypropyl 3-cyclodextrin (HPBCD) was used as the regulating agent. Three different implants with different hydroxypropyl [i-cyclodextrin (HPBCD) contents in the membrane were made and the results were compared to corre-sponding implants without any added HPBCD. All the implants con-sisted of a core containing the therapeutically active agent and a re-lease rate-controlling membrane encasing the core. The core and the membrane silicone elastomer rods were manufactured by extru-sion and the implant compositions were made by swelling the mem-brane in propanol, as explained above. The content of the therapeu-tically active agent was 20 wt-% (weight percent) in the core and the micronized hormone was mixed into the elastomer with a mixer be-fore extrusion. The diameters of the IVR rings were ca. 50 - 55 mm and the periphery of the cross section ca. 9 - 10 mm, the thick-nesses of the membranes were 0.25, 0.35 and 0.7 mm and the HPBCD contents of the membrane were 0.17 wt-%, 1.7 wt-% and 7.7 wt-% respectively.
The results are shown in Figure 1 for the daily in vitro release rate per core area ( g / (d*mm2), shown as the y axis and days shown in the x-axis), wherein the empty triangles represent the results for 0.17 wt-% HPBCD-content in the membrane with 0.7 mm wall thick-ness. The empty squares illustrate the results for 1.7 wt-% HPBCD-content in the membrane with 0.35 mm wall thickness and the stars show the results for 7.7 wt-% HPBCD-content in the membrane with 0.25 mm wall thickness. The full triangles represent the comparative results for a membrane with wall thickness of 0.3 mm and the full squares illustrate the comparative results for a membrane with wall thickness of 0.9 mm.
As seen in Figure 1, HPBCD modification results in a significant im-provement of reducing the initial burst of danazol from silicone based application. The initial burst effect found with all the HPBCD
modified samples shows a negative initial burst effect.. According to Figure 1, the initial burst without the modification is five to ten times that found for modified samples and three to five times that found for the release rate in two weeks dissolution. The results show that without any regulating agent the magnitude of the initial burst is several times the release rate in the stable phase and the initial burst cannot be merely reduced by changing the formulation of the samples.
The release rate of the therapeutically active agent with HPBCD
modified implants shows a slightly increasing trend for the first two weeks until it achieves a zenith point, where the release rate is at the maximum level. After that point the release rate of the therapeu-tically active agent presents a normal decreasing release profile as seen in the reference samples. For example thecurve of empty tri-angles, with 0.17 w-% HPBCD content and 0.7 mm membrane wall, compared to an ordinary ring with 0.9 mm wall, shows that the re-lease rate of the therapeutically active agent stays equal in two and half week release. However, according to the results the release rate seems to be higher, when HPBCD is added into the membrane.
Example 2 Gestodene implant The present invention was also tested with an implant containing gestodene, a synthetic progestogene hormone. The implant core and membrane rods were made with extrusion and the implant composition was made by swelling the membrane in propanol. The outer diameter of the implant core was 2.5 - 3.0 mm and the length 40 - 48 mm. The content of the therapeutically active agent in the core was 65 wt-%. The membrane thickness was 0.25 mm, inner diameter 2.35 - 2.65 mm, outer diameter was 3.0 - 3.25 mm and length 10 mm longer than the elastomer core. The HPBCD content of the implant membrane was 4 wt-%. The membrane was made of PEO-b-PDMS (15 wt-%) and PDMS (85 wt-%).
The results are shown in Figure 2 as the release rate of the thera-peutically active agent ( g/d, shown in y-axis) versus time (days, shown in x-axis), wherein the squares represent the results for the Reference 1, the losanges represent the results for an implant hav-ing a HPBCD-containing membrane and the triangles illustrate the results for Reference 2. Reference 1 comprises a core having an outer diameter of 2.5 mm and a length of 40 mm, and a membrane, the thickness of which is 0.25 mm. The implant having a membrane containing I wt-% HPBCD has a core with an outer diameter of 3.03 mm and a length of 44 mm, and the membrane wall of 0.25 mm.
Reference 2 comprises a core having an outer diameter of 2.8 mm, a length of 48 mm and the membrane with a wall of 0.25 mm.
Referring to Figure 2, the release rate profiles of gestodene are smoother than previously presented for danazol in Example 1 as the total decrease of release was only 30 % in 14 days with both refer-ence samples. However, the cyclodextrin modification smoothed the release rates from the implants and the maximum decrease of re-lease was only ca. 6 % in two weeks. In addition to that, cyclodextrin modification seemed to stabilise the release rate of the therapeuti-cally active agent after the initial burst, as the total decrease of the gestodene release was from the second to the third week only 0.5 %, while for the reference samples the decrease was 8.4 % and 11 5 %.
Example 3 Fluorinated antiprogestin (FAP) in intrauterine system (IUS) HPBCD modification was tested with a fluorinated antiprogestin de-rivative (FAP, 11-(4-Acetylphenyl)-17-hydroxy-17-(1,1,2,2,2-10 pentafluoroethyl) estra-4, 9-dien-3-one) in intrauterine (IUS) system.
Two samples of I and 4 wt-% of HPBCD content in the membrane were prepared by combining with swelling separately extruded membrane and core elastomer rods over the IUS T-frame. The swelling agent was isopropanol.
15 The content of the therapeutically active agent in the core elastomer was 65 wt-% and the outer diameter of the core was 2.88 - 2.92 mm and length 21.0 - 21.1 mm. The membrane was 3 mm longer than the core and the thickness of the membrane was 0,25 mm. Figure 3 presents the release rate of the therapeutically active agent ( g/d, 20 shown in the y-axis) from two FAP containing intrauterine systems as a function of time (days, shown in the x-axis) compared to a ref-erence sample. Indeed, the squares represent the results for the reference sample, the losanges illustrate the results for the cyclo-dextrin modified membrane, when the amount of cyclodextrin was 1 wt-% and the triangles represent the results for the cyclodextrin modified membrane, when the amount of cyclodextrin was 4 wt-%.
According to Figure 3, the initial burst is decreased with both cyclo-dextrin-modified membranes. When the amount of cyclodextrin was 1 wt-%, there is still some burst effect remaining. In addition to that, the release rate profile of the therapeutically active agent is higher for both cyclodextrin modified samples than for the reference sam-ple and the level of the release rate is higher, when the amount of cyclodextrin in the membrane was 4 wt-%. However, with FAP the profile, i.e. the shape of the curve, of the release rate after two days is similar for the reference and modified samples.
Claims (8)
1. A delivery system comprising a core and a membrane encasing said core, wherein said core and membrane consist essentially of an elastomer composition and said core comprises at least one therapeutically active agent, characterized in that the membrane comprises at least one regulating agent selected from the group consisting of cyclodextrins and modified cyclodextrins.
2. The delivery system according to claim 1, characterized in that said regulating agent is selected from the group consisting of alpha cyclodextrins, beta cyclodextrins, gamma cyclodextrins, hydroxypropyl cyclodextrins, maltosyl .beta.-cyclodextrin and .beta.-cyclodextrin sulfobutyl.
3. The delivery system according to claim 1 or 2, characterized in that the membrane comprises one regulating agent.
4. The delivery system according to claim 1 or 2, characterized in that the membrane comprises two regulating agents.
5. The delivery system according to claim 4, characterized in that said regulating agents are present in separate parts of said membrane.
6. The delivery system according to claim 4 or 5, characterized in that said regulating agents are present in separate layers of said membrane.
7. The delivery system according to any one of claims 1 to 6, characterized in that said delivery system is selected from the group consisting of transdermal patches, implants for releasing a therapeutically active agent in the body tissues, intravaginal rings, intracervical and intrauterine devices.
8. A method for controlling the release of at least one therapeutically active agent from a delivery system comprising a core and a membrane encasing said core, wherein said core and membrane consist essentially of an elastomer composition and said core comprises said at least one therapeutically active agent, characterized in that said regulation is performed by at least one regulating agent comprised in the membrane of said delivery system, said at least one regulating agent being selected from the group consisting of cyclodextrins and modified cyclodextrins.
Applications Claiming Priority (3)
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| EP04396049.1 | 2004-07-13 | ||
| EP04396049A EP1629844B2 (en) | 2004-07-13 | 2004-07-13 | A longterm delivery system with controlled initial burst |
| PCT/FI2005/000314 WO2006005794A1 (en) | 2004-07-13 | 2005-07-05 | A delivery system |
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| CA2569542A1 CA2569542A1 (en) | 2006-01-19 |
| CA2569542C true CA2569542C (en) | 2012-10-09 |
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| CA2569542A Expired - Fee Related CA2569542C (en) | 2004-07-13 | 2005-07-05 | A delivery system |
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| EP (1) | EP1629844B2 (en) |
| JP (1) | JP4881861B2 (en) |
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| ATE372772T1 (en) | 2004-07-13 | 2007-09-15 | Schering Oy | RETARDED RELEASE SYSTEM WITH CONTROLLED INITIAL RELEASE |
| ES2432556T3 (en) * | 2004-08-04 | 2013-12-04 | Evonik Corporation | Methods for manufacturing supply devices and their devices |
| US8124601B2 (en) * | 2007-11-21 | 2012-02-28 | Bristol-Myers Squibb Company | Compounds for the treatment of Hepatitis C |
| EP2222281B1 (en) | 2007-12-20 | 2018-12-05 | Evonik Corporation | Process for preparing microparticles having a low residual solvent volume |
| US20100158980A1 (en) * | 2008-12-18 | 2010-06-24 | Casey Kopczynski | Drug delivery devices for delivery of therapeutic agents |
| US8580294B2 (en) | 2010-10-19 | 2013-11-12 | International Partnership For Microbicides | Platinum-catalyzed intravaginal rings |
| WO2013013172A1 (en) * | 2011-07-20 | 2013-01-24 | The University Of Utah Research Foundation | Intravaginal devices for drug delivery |
| KR102067472B1 (en) | 2012-01-18 | 2020-01-20 | 월드와이드 이노베이티브 헬쓰케어, 인코포레이티드 | Kit and method of modifiable occlusive skin dressing |
| AR089765A1 (en) | 2012-01-23 | 2014-09-17 | Bayer Oy | A SYSTEM FOR THE SUPPLY OF A PHARMACO |
| US10137031B2 (en) | 2013-11-14 | 2018-11-27 | International Partnership For Microbicides, Inc. | Combination therapy intravaginal rings |
| CN105310974B (en) * | 2014-08-01 | 2019-08-23 | 山东绿叶制药有限公司 | The implant of rotigotine and its derivative or its pharmaceutical salts |
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| US3832252A (en) | 1970-09-29 | 1974-08-27 | T Higuchi | Method of making a drug-delivery device |
| NZ217844A (en) * | 1985-10-11 | 1989-10-27 | Sumitomo Pharma | A sustained release pharmaceutical composition containing silicone elastomer and an albumin |
| ES2054784T3 (en) † | 1987-08-08 | 1994-08-16 | Akzo Nv | A METHOD FOR THE MANUFACTURE OF AN IMPLANT. |
| US4938763B1 (en) | 1988-10-03 | 1995-07-04 | Atrix Lab Inc | Biodegradable in-situ forming implants and method of producing the same |
| RU2088166C1 (en) | 1993-08-10 | 1997-08-27 | Педдер Валерий Викторович | Method and device for carrying out contraception |
| PT754032E (en) | 1994-04-08 | 2002-05-31 | Atrix Lab Inc | LIQUID COMPOSITIONS FOR DIFFUSE |
| US5492947A (en) * | 1994-06-23 | 1996-02-20 | Aspen Research Corporation | Barrier material comprising a thermoplastic and a compatible cyclodextrin derivative |
| GB2290964A (en) | 1994-07-08 | 1996-01-17 | Arto Olavi Urtti | Transdermal drug delivery system |
| FI97947C (en) | 1994-09-27 | 1997-03-25 | Leiras Oy | Process for the preparation of a pharmaceutical composition |
| GB9522403D0 (en) † | 1995-11-01 | 1996-01-03 | Hoechst Roussel Ltd | Intravaginal drug delivery device |
| US6416778B1 (en) * | 1997-01-24 | 2002-07-09 | Femmepharma | Pharmaceutical preparations and methods for their regional administration |
| US6039968A (en) * | 1997-06-24 | 2000-03-21 | Hoechst Marion Roussel | Intravaginal drug delivery device |
| NZ330596A (en) * | 1998-06-05 | 2001-02-23 | Dec Res | Intravaginal devices allowing for increased uptake of active ingredients |
| WO1999061062A1 (en) † | 1998-05-29 | 1999-12-02 | Massachusetts Institute Of Technology | Cyclodextrin complexes |
| CA2380111A1 (en) | 1999-08-03 | 2001-02-08 | Smith & Nephew, Inc. | Controlled release implantable devices |
| EP1248596B1 (en) * | 2000-01-11 | 2007-03-07 | Roland Bodmeier | Implantation kit comprising a support phase and a solvent |
| US6299894B1 (en) * | 2000-05-10 | 2001-10-09 | Leiras Oy | Drug delivery device, especially for the delivery of gestodene |
| AU2002210580A1 (en) * | 2000-10-20 | 2002-04-29 | Leiras Oy | Drug delivery system |
| NZ528377A (en) | 2001-03-27 | 2005-05-27 | Galen Chemicals Ltd | Intravaginal drug delivery devices for the administration of an antimicrobial agent |
| CN1210079C (en) | 2001-04-25 | 2005-07-13 | 上海市计划生育科学研究所 | Medicine for vaginal ring and its application |
| PL367961A1 (en) * | 2001-08-31 | 2005-03-07 | Schering Oy | Drug delivery system |
| US8404272B2 (en) | 2003-06-26 | 2013-03-26 | Poly-Med, Inc. | Fiber-reinforced composite rings for intravaginal controlled drug delivery |
| CN1822815B (en) † | 2003-07-10 | 2012-04-11 | 沃纳奇尔科特(爱尔兰)有限公司 | Intravaginal drug delivery devices |
| CA2559224C (en) † | 2004-03-24 | 2011-12-13 | N.V. Organon | Drug delivery system based on polyethylene vinylacetate copolymers |
| ATE372772T1 (en) | 2004-07-13 | 2007-09-15 | Schering Oy | RETARDED RELEASE SYSTEM WITH CONTROLLED INITIAL RELEASE |
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2004
- 2004-07-13 AT AT04396049T patent/ATE372772T1/en active
- 2004-07-13 EP EP04396049A patent/EP1629844B2/en active Active
- 2004-07-13 ES ES04396049T patent/ES2293193T5/en active Active
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- 2004-07-13 DE DE602004008912T patent/DE602004008912T3/en active Active
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- 2005-07-05 NZ NZ551823A patent/NZ551823A/en not_active IP Right Cessation
- 2005-07-05 CN CNA2005800232239A patent/CN1984639A/en active Pending
- 2005-07-05 US US11/631,873 patent/US7850986B2/en not_active Expired - Fee Related
- 2005-07-05 JP JP2007520845A patent/JP4881861B2/en not_active Expired - Fee Related
- 2005-07-05 AU AU2005261682A patent/AU2005261682B2/en not_active Ceased
- 2005-07-05 KR KR1020077000571A patent/KR20070035032A/en not_active Application Discontinuation
- 2005-07-05 MX MX2007000433A patent/MX2007000433A/en active IP Right Grant
- 2005-07-05 CA CA2569542A patent/CA2569542C/en not_active Expired - Fee Related
- 2005-07-05 RU RU2006145900/15A patent/RU2412693C2/en not_active IP Right Cessation
- 2005-07-05 WO PCT/FI2005/000314 patent/WO2006005794A1/en active Application Filing
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