Source: https://patents.google.com/patent/US9078900B2/en
Timestamp: 2018-04-19 21:53:49
Document Index: 355918883

Matched Legal Cases: ['Application No. 61', 'Application No. 61', 'Application No. 2009298637', 'Application No. 2009298711', 'Application No. 200980142114', 'Application No. 200980142350', 'Application No. 200980142114', 'Application No. 2011', 'Application No. 211952', 'Application No. 09', 'Application No. 09', 'Application No. 14172031', 'Application No. 08010973', 'Application No. 2011', 'Application No. 211954', 'Application No. 2011', 'Application No. 2011', 'Application No. 2009', 'Application No. 200980142350', 'Application No. 200980142113', 'Application No. 09', 'Application No. 2011117328', 'Application No. 211953', 'Application No. 2011', 'Application No. 2011', 'Application No. 2011117327', 'Application No. 200980142114', 'Application No. 211593', 'Application No. 200980142113']

US9078900B2 - Implantable device for the delivery of risperidone and methods of use thereof - Google Patents
Implantable device for the delivery of risperidone and methods of use thereof Download PDF
US9078900B2
US9078900B2 US12569558 US56955809A US9078900B2 US 9078900 B2 US9078900 B2 US 9078900B2 US 12569558 US12569558 US 12569558 US 56955809 A US56955809 A US 56955809A US 9078900 B2 US9078900 B2 US 9078900B2
US12569558
US20100080835A1 (en )
BRAEBURN PHARMACEUTICALS BVBA SPRL
This invention is related to the use of polyurethane-based polymer as a drug delivery device to deliver biologically active risperidone at a constant rate for an extended period of time and methods of manufactures thereof. The device is very biocompatible and biostable, and is useful as an implant in patients (humans and animals) for the delivery of risperidone to tissues or organs.
This application claims priority to U.S. Provisional Application No. 61/101,548 filed Sep. 30, 2008, and U.S. Provisional Application No. 61/117,448 filed Nov. 24, 2008, the entire disclosures of which are incorporated herein by reference.
Described herein are methods and compositions based on the unexpected discovery that solid formulations comprising one or more active agents can be used at the core of a polyurethane implantable device such that the active agent is released in a controlled-release, zero-order manner from the implantable device. The active agents and polyurethane coating can be selected based on various physical parameters, and then the release rate of the active from the implantable device can be optimized to a clinically relevant release rate based on clinical and/or in vitro trials.
One embodiment is directed to a method for delivering a formulation comprising an effective amount of risperidone to a subject, comprising: implanting an implantable device into the subject, wherein the implantable device comprises risperidone or a formulation thereof substantially surrounded by a polyurethane-based polymer. In a particular embodiment, the polyurethane-based polymer is formed from one or more polyols, wherein the general polyol structure is selected from the group consisting of
—[O—(CH2)n]x—O—;
O—(CH2—CH2—CH2—CH2)x—O—; and
O—[(CH2)6—CO3]n—(CH2)—O—.
For the compositions and methods described herein, the values for n and x are integer values of between about 1 and about 1,000,000; of between about 2 and about 500,000; of between about 5 and about 250,000; and of between about 10 and about 100,000. In a particular embodiment, the polyol comprises —[O—(CH2)n]x—O—, wherein the polyurethane-based polymer has an equilibrium water content of between about 5% and about 200%, e.g., of at least about 15%. In a particular embodiment, risperidone is released at a zero-order rate of about 149 μg/day per square centimeter of the surface area of the implantable device. In a particular embodiment, the polyol comprises O—(CH2—CH2—CH2—CH2)x—O—, wherein the polyurethane-base polymer has a flex modulus of between about 1000 and about 92,000 psi, e.g., of about 2,300 psi. In a particular embodiment, risperidone is released at a zero-order rate of about 146 μg/day per square centimeter of the surface area of the implantable device. In a particular embodiment, the polyol comprises O—[(CH2)6—CO3]n—(CH2)—O—, wherein the polyurethane-based polymer has a flex modulus of between about 620 and about 92,000 psi, e.g., of about 620 psi. In a particular embodiment, risperidone is released at a zero-order rate of about 40 μg/day per square centimeter of the surface area of the implantable device.
One embodiment is directed to a drug delivery device for the controlled release of risperidone over an extended period of time to produce local or systemic pharmacological effects, comprising: a) a polyurethane-based polymer formed to define a hollow space; and b) a solid drug formulation comprising a formulation comprising risperidone and optionally one or more pharmaceutically acceptable carriers, wherein the solid drug formulation is contained in the hollow space, and wherein the device provides a desired release rate of risperidone from the device after implantation. In a particular embodiment, the drug delivery device is conditioned and primed under conditions chosen to be consistent with the water solubility characteristics of the at least one active agent. In a particular embodiment, the pharmaceutically acceptable carrier is stearic acid. In a particular embodiment, the polyurethane-based polymer is formed from one or more polyols, wherein the general polyol structure is selected from the group consisting of:
In a particular embodiment, the polyol comprises —[O—(CH2)n]x—O—, wherein the polyurethane-based polymer has an equilibrium water content of between about 5% and about 43%, e.g., of at least about 15%. In a particular embodiment, risperidone is released at a zero-order rate of about 149 μg/day per square centimeter of the surface area of the implantable device. In a particular embodiment, the polyol comprises O—(CH2—CH2—CH2—CH2)x—O—, wherein the polyurethane-base polymer has a flex modulus of between about 1000 and about 92,000 psi, e.g., of about 2,300 psi. In a particular embodiment, risperidone is released at a zero-order rate of about 146 μg/day per square centimeter of the surface area of the implantable device. In a particular embodiment, the polyol comprises O—[(CH2)6—CO3]n—(CH2)—O—, wherein the polyurethane-based polymer has a flex modulus of between about 620 and about 92,000 psi, e.g., of about 620 psi. In a particular embodiment, risperidone is released at a zero-order rate of about 40 μg/day per square centimeter of the surface area of the implantable device. In a particular embodiment, appropriate conditioning and priming parameters can be selected to establish the desired delivery rates of the at least one active agent, wherein the priming parameters are time, temperature, conditioning medium and priming medium.
FIG. 4 is a graph of the release rate of risperidone from Carbothane® PC-3575A polyurethane implants (Flex Modulus 620 psi) prepared from tubing sections representing the beginning, middle and end of a coil of tubing as part of an assessment of the uniformity of the material within a particular lot. Samples were evaluated weekly for one year. All implants were of equivalent geometry and drug load.
FIG. 5 is a graph of the release rate of risperidone from Carbothane® PC-3575A polyurethane implants (Flex Modulus 620 psi) as part of an assessment of the effect using saline versus aqueous hydroxypropyl betacellulose solution (15% in phosphate buffered saline) as the elution media. Samples were evaluated weekly for 11 weeks. All implants were of equivalent geometry and drug load.
FIGS. 6A and 6B are graphs comparing the release rates of risperidone from Carbothane® PC-3595A polyurethane implants (Flex modulus 4500 psi) to Tecophilic® HP-60D-20 polyurethane implants (EWC, 14.9%) as part of the evaluation of the release of the active from either hydrophilic and hydrophobic polyurethane materials. Samples were evaluated weekly for 22 weeks for the Carbothane® implant. Samples were evaluated weekly for 15 weeks for the Tecophilic® implant. All implants were of equivalent geometry and drug load. FIG. 11B is a graph of the release rate of risperidone from Tecophilic® HP-60D-20 polyurethane implants (EWC, 14.9%) alone, sampled weekly for 15 weeks.
FIG. 7 is a graph comparing the release rates of risperidone from Tecoflex® EG-80A polyurethane implants (Flex Modulus 1000 psi) and two grades of Tecophilic® polyurethane implants, HP-60D-35 and HP-60D-60 (EWC, 23.6% and 30.8%, respectively). All were sampled weekly for 10 weeks. All implants were of equivalent geometry and drug load.
FIG. 8 is a graph of the release rate of risperidone from Carbothane® PC-3575A polyurethane implants (Flex Modulus 620 psi) that served as in vitro controls for implants used in the beagle dog study described in Example 8. The in vitro elution study of these implants was initiated on the date of implantation of the subject implants as part of an assessment of in vivo-in vitro correlation.
FIG. 9 is a graph of the in vivo plasma concentration of risperidone in the beagle dog study described in Example 8. The lower plot represents the average plasma concentration achieved in dogs implanted with one Carbothane® PC-3575A polyurethane implant (Flex Modulus 620 psi). The upper plot represents the average plasma concentration achieved in dogs implanted with two Carbothane® PC-3575A polyurethane implants (Flex Modulus 620 psi).
FIG. 10 is a graph showing the in vitro release of risperidone from Tecoflex® and Carbothane® implants. The pellets comprising the risperidone formulation had a diameter of 3.5 mm, a length of about 4.5 mm and a weight of 5.4 mg. The implant had a reservoir length of about 39-40 mm, a wall thickness of 0.2 mm, and internal diameter of 3.6 mm and an overall length of about 45 mm.
FIG. 11 is a graph showing the in vivo release of risperidone from Tecoflex® and Carbothane® implants, as compared to a control. The pellets comprising the risperidone formulation had a diameter of 3.5 mm, a length of about 4.5 mm and a weight of 5.4 mg. The implant had a reservoir length of about 39-40 mm, a wall thickness of 0.2 mm, and internal diameter of 3.6 mm and an overall length of about 45 mm.
To take the advantage of the excellent properties of polyurethane-based polymers, the present invention is directed to the use of polyurethane-based polymers as drug delivery devices for releasing drugs at controlled rates for an extended period of time to produce local or systemic pharmacological effects. The drug delivery device can comprise a cylindrically shaped reservoir surrounded by polyurethane-based polymer that controls the delivery rate of the drug inside the reservoir. The reservoir contains a formulation, e.g., a solid formulation, comprising one or more active ingredients and, optionally, pharmaceutically acceptable carriers. The carriers are formulated to facilitate the diffusion of the active ingredients through the polymer and to ensure the stability of the drugs inside the reservoir.
A polyurethane is any polymer consisting of a chain of organic units joined by urethane links. Polyurethane polymers are formed by reacting a monomer containing at least two isocyanate functional groups with another monomer containing at least two alcohol groups in the presence of a catalyst. Polyurethane formulations cover a wide range of stiffness, hardness, and densities.
Tecoflex® polyurethanes, Tecogel® polyurethanes and Tecophilic® polyurethanes are cycloaliphatic polymers and are of the types produced from polyether-based polyols. For the Tecoflex® polyurethanes, the general structure of the polyol segment is represented as,
whereby an increase in “x” represents a increase in flexibility (decreased “Flex Modulus”; “FM”), yielding FM ranging from about 1000-92,000 psi. From the standpoint of drug release from these materials, the release of a relatively hydrophobic API decreases as the FM increases. For the compositions and methods described herein, the values for x are integer values of between about 1 and about 1,000,000; of between about 2 and about 500,000; of between about 5 and about 250,000; and of between about 10 and about 100,000. In still other embodiments, x may range from about 2-500, about 2-100, about 5-50, and 10-30.
For the Tecophilic® (hydrophilic) or Tecogel® polyurethanes, the general structure of the polyol segment is represented as,
whereby increases in “n” and “x” represent variations in hydrophilicity, and yield equilibrium water contents (% EWC) ranging from about 5%-200%. For the compositions and methods described herein, the values for n and x are integer values of between about 1 and about 1,000,000; of between about 2 and about 500,000; of between about 5 and about 250,000; and of between about 10 and about 100,000. In still other embodiments, n and x may have the same or different values, with those values ranging from about 2-500, about 2-100, about 5-50, and 10-30. From the standpoint of drug release from these materials, the release of a relatively hydrophilic API increases as the % EWC increases.
whereby an increase in “n” represents a increase in flexibility (decreased FM), yielding FM ranging from about 620-92,000 psi. For the compositions and methods described herein, the values for n are integer values of between about 1 and about 1,000,000; of between about 2 and about 500,000; of between about 5 and about 250,000; and of between about 10 and about 100,000. In still other embodiments, n may range from about 2-500, about 2-100, about 5-50, and 10-30. From the standpoint of drug release from these materials, the release of a relatively hydrophobic API will decrease as the FM increases.
Chain extenders and cross linkers are low molecular weight hydroxyl- and amine-terminated compounds that play an important role in the polymer morphology of polyurethane fibers, elastomers, adhesives and certain integral skin and microcellular foams. Examples of chain extenders include, for example, ethylene glycol, 1,4-butanediol (1,4-BDO or BDO), 1,6-hexanediol, cyclohexane dimethanol and hydroquinone bis(2-hydroxyethyl)ether (HQEE). All of these glycols form polyurethanes that phase separate well, form well-defined hard segment domains, and are melt processable. They are all suitable for thermoplastic polyurethanes with the exception of ethylene glycol, since its derived bis-phenyl urethane undergoes unfavorable degradation at high hard segment levels. Tecophilic®, Tecoflex® and Carbothane® polyurethanes all incorporate the use of 1,4-butanediol as the chain extender.
ⅆ M ⅆ t = 2 ⁢ ⁢ π ⁢ hp ⁢ ⁢ Δ ⁢ ⁢ C ln ⁡ ( r o / r i )
The permeability coefficient is primarily regulated by the hydrophilicity or hydrophobicity of the polymer, the structure of the polymer, and the interaction of drug and the polymer. Once the polymer and the active ingredient are selected, p is a constant, h, ro, and ri are fixed and kept constant once the cylindrically shaped device is produced. ΔC is maintained constant.
To keep the geometry of the device as precise as possible, the device, e.g., a cylindrically shaped device, can be manufactured through precision extrusion or precision molding process for thermoplastic polyurethane polymers, and reaction injection molding or spin casting process for thermosetting polyurethane polymers.
A person skilled in the art would understand that the conditioning and priming step of the drug delivery device is affected by the medium in which the device is placed. A hydrophilic drug can be conditioned and primed, for example, in an aqueous solution, e.g., in a saline solution. The temperature used to condition and prime the drug delivery device can vary across a wide range of temperatures, e.g., about 37° C.
The delivery of risperidone can be useful, for example, to treat schizophrenia, manic states, bipolar disorder, irritability, autism, obsessive-compulsive disorder, severe treatment-resistant depression with or without psychotic features, Tourette syndrome, disruptive behavior disorders in children; and eating disorders. Risperidone belongs to a class of anti-psychotic drugs known as “atypical neuroleptics”. It is a strong dopamine antagonist. It has a high affinity for D2 dopaminergic receptors. It has actions at several 5-HT (serotonin) receptor subtypes. These are 5-HT2C, linked to weight gain, 5-HT2A, linked to its antipsychotic action and relief of some of the extrapyramidal side effects experienced with the “typical neuroleptics” through action at 5-HT1A. The latter action leads to an increased release of dopamine from mesocortical neurons in the brain. Effective levels of risperidone in the blood are known and established and can range, for example, about 0.1 to about 10 ng/ml, from about 0.5 to about 8 ng/ml or about 1.0 to about 5 ng/ml range.
One of skill in the art would be able to tailor risperidone release by altering a variety of implant factors. For example, as shown in the Examples, different classes of polyurethanes lead to different release rates of risperidone. Additionally, within classes of polyurethanes, the EWC and/or flex modulus of the polyurethane can be varied to achieve different risperidone release rates. Further still, one of skill in the art could vary the size of the implant to increase or decrease the surface area of the implant, thereby varying the release rate of risperidone from the implant. Such alterations lead to release rates in the physiologically-relevant range, e.g., of about 0.001 to about 15 mg/day, from about 0.1 to about 15 mg/day, from about 1 to about 12.5 mg/day, from about 7.5 to about 12.5 mg/day or at about 12.5 mg/day. Release rate from implants can also be varied, for example, by adjusting the amount and nature of excipients contained in the risperidone formulation.
Implants that achieve physiological release rates of risperidone can vary in size, depending on, for example, the nature of the polyurethane used. A cylindrical implant, for example, can have a range of internal diameters from about 1 mm to about 10 mm, from about 1.5 mm to about 5 mm, from about 1.8 mm to about 3.6 mm, about 3.6 mm or about 1.8 mm. An implant can range in length from about, for example, 5 mm to about 100 mm, from about 7.5 mm to about 50 mm, from about 10 mm to about 40 mm, from about 15 mm to about 30 mm, about 37 mm, about 40 mm or about 15.24 mm.
Different functional groups can be introduced into the polyurethane polymer chains through the modification of the backbones of polyols depending on the properties desired. Where the device is used for the delivery of water soluble drugs, hydrophilic pendant groups such as ionic, carboxyl, ether, and hydroxyl groups are incorporated into the polyols to increase the hydrophilicity of the polymer (e.g., U.S. Pat. Nos. 4,743,673 and 5,354,835). Where the device is used for the delivery of hydrophobic drugs, hydrophobic pendant groups such as alkyl, siloxane groups are incorporated into the polyols to increase the hydrophobicity of the polymer (e.g., U.S. Pat. No. 6,313,254). The release rates of the actives can also be controlled by the hydrophilicity/hydrophobicity of the polyurethane polymers.
Tables 2A-C show release rates of risperidone from three different classes of polyurethane compounds (Tecophilic®, Tecoflex® and Carbothane®). The release rates have been normalized to surface area of the implant, thereby adjusting for slight differences in the size of the various implantable devices. Risperidone is considered to be hydrophobic (not very water-soluble), as indicated by the Log P value; for the purposes of the data provided, a Log P value of greater than about 2.0 is considered to be not readily soluble in aqueous solution. The polyurethanes were selected to have varying affinities for water soluble active agents and varying flexibility (as indicated by the variation in flex modulus).
For applications of the polyurethanes useful for the devices and methods described herein, the polyurethane exhibits physical properties suitable for the risperidone formulation to be delivered. Polyurethanes are available or can be prepared, for example, with a range of EWCs or flex moduli (Table 2). Tables 2A-C show normalized release rates for various active ingredients from polyurethane compounds. Tables 2D-F show the non-normalized release rates for the same active ingredients, together with implant composition.
27.9 mg API 29.8 mg API 29.7 mg API
Example 3 Elution of Risperidone from Polyurethane Implantable Devices
FIGS. 5-10 are graphs showing elution profiles of risperidone from various implantable devices over varying periods of time.
Release rates were obtained for risperidone from Carbothane® PC-3575A polyurethane implants (F.M. 620 psi) prepared from tubing sections representing the beginning, middle and end of a coil of tubing as part of an assessment of the uniformity of the material within a particular lot (FIG. 5). Samples were evaluated weekly for one year. All implants were of equivalent geometry and drug load.
Release rates were obtained for risperidone from Carbothane® PC-3575A polyurethane implants (F.M. 620 psi) as part of an assessment of the effect using saline versus aqueous hydroxypropyl betacellulose solution (15% in phosphate buffered saline) as the elution media (FIG. 6). Samples were evaluated weekly for 11 weeks. All implants were of equivalent geometry and drug load.
Release rates were compared for risperidone from Carbothane® PC-3595A polyurethane implants (F.M. 4500 psi) and Tecophilic® HP-60D-20 polyurethane implants (EWC 14.9%) as part of the evaluation of the release of the active from either hydrophilic and hydrophobic polyurethane materials (FIGS. 7A and 7B). Samples were evaluated weekly for 22 weeks for the Carbothane® implant. Samples were evaluated weekly for 15 weeks for the Tecophilic® implant. All implants were of equivalent geometry and drug load.
Release rates were compared for risperidone from Tecoflex® EG-80A polyurethane implants (F.M. 1000 psi) and two grades of Tecophilic® polyurethane implants, HP-60D-35 and HP-60D-60 (EWC, 23.6% and 30.8%, respectively) (FIG. 8). All were sampled weekly for 10 weeks. All implants were of equivalent geometry and drug load.
Release rates were obtained for risperidone from Carbothane® PC-3575A polyurethane implants (F.M. 620 psi) that served as in vitro controls for implants used in the beagle dog study described in Example 4. The in vitro elution study of these implants was initiated on the date of implantation of the subject implants as part of an assessment of in vivo-in vitro correlation.
Example 4 Evaluation of Polyurethane Subcutaneous Implant Devices Containing Risperidone in Beagle Dogs
This study determines the blood levels of risperidone from one or two implants and the duration of time the implants release the drug. Polyurethane-based implantable devices comprising a pellet comprising risperidone were implanted into beagles to determine release rates of risperidone in vivo. The results of the sample analysis are summarized in Table 3 and FIG. 10. Risperidone is still present at a high level in the dog plasma at the end of the third month. The study was conducted in accordance with WCFP's standard operating procedures (SOPs), the protocol, and any protocol amendments. All procedure were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Center, National Academy Press, Washington, D.C., 1996), and approved by the Institutional Animal Care and Use Committee in WCFP.
Age at Initiation of Treatment: 6˜9 months
No. of Animals Dose rate Total Dose
Group Dose Route Male (mcg/day) (mg)
1 Subcutaneous 3 130 23 (single
implant implant)
2 Subcutaneous 3 260 46 (double
implant implants)
Animals were fasted at least four hours prior to blood sampling. Since blood sampling was done in the morning, food was withheld overnight. Blood samples were drawn using a 20 G needle and collected directly into the 5 mL tubes containing sodium heparin and maintained chilled until centrifugation. Samples were then centrifuged at 5000 RPM for 5 minutes at 4° C. The separated plasma was then be transferred into two 3 mL cryo tubes. The samples were labeled with the actual date the sample was taken, the corresponding study day, the dog identification and the duplicate sample designator (either A or B). Samples were kept at −20° C. until ready for analysis.
On two consecutive days, prior to implantation of the delivery device, baseline blood samples were taken. In addition, daily blood samples were taken during the first week and weekly blood samples were taken for the three months following implantation. Two 5 mL blood samples were drawn at each time from each dog. Blood samples were drawn from the cephalic veins primarily; with the saphenous or jugular used as a backup. For both the single and double implant groups, blood samples were drawn at appropriate times as outlined in Table 3 below. Analysis required at least 2 mL of plasma, which required no less than 10 mL of blood drawn for each sample. Analysis of plasma concentrations of risperidone was performed using an LC/MS assay developed for this compound. A single assay was be run for each sample. Samples were collected, held at the appropriate condition and analyzed in batches.
Group 1(single implant) Group 2(double implants) Group 1 Group 2
FIG. 9 is a graph of the in vivo plasma concentration of risperidone in the beagle dog study. The lower plot represents the average plasma concentration achieved in dogs implanted with one Carbothane® PC-3575A polyurethane implant (F.M. 620 psi). The upper plot represents the average plasma concentration achieved in dogs implanted with two Carbothane® PC-3575A polyurethane implants (F.M. 620 psi).
Example 5 Evaluation of Polyurethane Subcutaneous Implant Devices Containing Risperidone in Beagle Dogs
Expanding on the data presented in Example 4, this study determines the blood levels of risperidone from one or two larger implants and the duration of time the implants release the drug. Polyurethane-based implantable devices comprising a pellet comprising risperidone were implanted into beagles to determine release rates of risperidone in vivo. The results of the larger implant data are summarized in FIG. 10 (in vitro elution profile) and FIG. 11 (elution in beagle dogs).
The pellets comprising the risperidone formulation used for this study had a diameter of 3.5 mm, a length of about 4.5 mm and a weight of 5.4 mg. The implant had a reservoir length of about 39-40 mm, a wall thickness of 0.2 mm, and internal diameter of 3.6 mm and an overall length of about 45 mm. initially contained about 80 mg of risperidone and are designed to deliver approximately 130 mcg/day for 3 months.
1. A drug delivery device for the controlled release of risperidone over an extended period of time to produce local or systemic pharmacological effects, comprising:
a) a polyurethane-based polymer formed to define a hollow space; and
a solid drug formulation consisting essentially of a formulation consisting essentially of risperidone and optionally one or more pharmaceutically acceptable carriers,
wherein the solid drug formulation is contained in the hollow space, and wherein the device provides a pre-determined release rate of risperidone from the device after implantation and wherein the polyurethane-based polymer is formed from one or more polyols, wherein the general polyol structure is selected from the group consisting of:
2. The drug delivery device of claim 1, wherein the drug delivery device is conditioned and primed under conditions chosen to be consistent with the water solubility characteristics of the risperidone.
3. The drug delivery device of claim 2 including one or more pharmaceutically acceptable carriers, and wherein the pharmaceutically acceptable carrier is stearic acid.
4. The drug delivery device of claim 1, wherein the polyol comprises —[)—(CH2)n]x—O—, and wherein the polyurethane-based polymer has an equilibrium water content of between about 5% and about 200%.
5. The drug delivery device of claim 4, wherein the polyurethane-based polymer has an equilibrium water content of at least about 15%.
6. The drug delivery device of claim 1, wherein risperidone is released at a zero-order rate of about 149 μg/day per square centimeter of the surface area of the implantable device.
7. The drug delivery device of claim 1, wherein the polyol comprises O—(CH2—CH2—CH2—CH2)x—O—, and wherein the polyurethane-base polymer has a flex modulus of between about 1000 and about 92,000 psi.
8. The drug delivery device of claim 7, wherein the polyurethane-based polymer has a flex modulus of about 2,300 psi.
9. The drug delivery device of claim 7, wherein risperidone is released at a zero-order rate of about 146 μg/day per square centimeter of the surface area of the implantable device.
10. The drug delivery device of claim 1, wherein the polyol comprises O—[(CH2)6—CO3]n—(CH2)—O—, and wherein the polyurethane-based polymer has a flex modulus of between about 620 and about 92,000 psi.
11. The drug delivery device of claim 10, wherein the polyurethane-based polymer has a flex modulus of about 620 psi.
12. The drug delivery device of claim 10, wherein risperidone is released at a zero-order rate of about 40 μg/day per square centimeter of the surface area of the implantable device.
13. The drug delivery device of claim 1, wherein appropriate conditioning and priming parameters are selected to establish the predetermined delivery rates of the risperidone, wherein the priming parameters are time, temperature, conditioning medium and priming medium.
14. The drug delivery device of claim 7, wherein the polyurethane-based polymer has a flex modulus of about 1000 psi.
15. The drug delivery device of claim 1 including the one or more pharmaceutically acceptable carriers, and wherein the one or more pharmaceutically acceptable carriers comprise stearic acid.
16. The drug delivery device of claim 7 including the one or more pharmaceutically acceptable carriers, and wherein the one or more pharmaceutically acceptable carriers comprise stearic acid.
17. The drug delivery device of claim 16, wherein the stearic acid comprises about 2 wt % of the solid drug formulation.
18. The drug delivery device of claim 17, wherein the polyurethane-based polymer has a flex modulus of about 1000 psi.
19. The drug delivery device of claim 1, with an internal diameter of about 3.6 mm.
20. The drug delivery device of claim 1, which has a length of about 7.5 mm to about 50 mm.
21. The drug delivery device of claim 7, which has a length of about 7.5 mm to about 50 mm.
22. The drug delivery device of claim 1, which has a length of about 45 mm.
23. The drug delivery device of claim 1, wherein the polyurethane-based polymer formed to define a hollow space has a wall thickness of 0.2 mm.
24. The drug delivery device of claim 1, wherein the device provides a pre-determined release rate of risperidone of between about 0.001 mg/day to about 15 mg/day from the device after implantation.
25. The drug delivery device of claim 7, wherein the device provides a pre-determined release rate of risperidone of between about 0.001 mg/day to about 15 mg/day from the device after implantation.
26. The drug delivery device of claim 1, wherein the general polyol structure is: —[O—(CH2)n]x—O—.
27. The drug delivery device of claim 12, wherein the general polyol structure is: O—(CH2—CH2—CH2—CH2)x—O—.
28. The drug delivery device of claim 1, wherein the general polyol structure is: O—[(CH2)6—CO3]n—(CH2)—O—.
29. A method for delivering an effective amount of risperidone to a subject, comprising implanting the drug delivery device of claim 1 into the subject.
30. The method of claim 29, wherein the polyol comprises —[O—(CH2)n]x—O—,and wherein the polyurethane-based polymer has an equilibrium water content of between about 5% and about 200%.
31. The method of claim 30, wherein the polyurethane-based polymer has an equilibrium water content of at least about 15%.
32. The method of claim 29, wherein risperidone is released at a zero-order rate of about 149 μg/day per square centimeter of the surface area of the implantable device.
33. The method of claim 29, wherein the polyol comprises O—(CH2—CH2—CH2—CH2)x—O—, and wherein the polyurethane-base polymer has a flex modulus of between about 1000 and about 92,000 psi.
34. The method of claim 33, wherein the polyurethane-based polymer has a flex modulus of about 2,300 psi.
35. The method of claim 33, wherein risperidone is released at a zero-order rate of about 146 μg/day per square centimeter of the surface area of the implantable device.
36. The method of claim 29, wherein the polyol comprises O—[(CH2)6—CO3]n—(CH2)—O—, and wherein the polyurethane-based polymer has a flex modulus of between about 620 and about 92,000 psi.
37. The method of claim 36, wherein the polyurethane-based polymer has a flex modulus of about 620 psi.
38. The method of claim 36, wherein risperidone is released at a zero-order rate of about 40 μg/day per square centimeter of the surface area of the implantable device.
US12569558 2008-09-30 2009-09-29 Implantable device for the delivery of risperidone and methods of use thereof Active 2030-01-30 US9078900B2 (en)
US12569558 US9078900B2 (en) 2008-09-30 2009-09-29 Implantable device for the delivery of risperidone and methods of use thereof
US14735588 US20160030337A1 (en) 2008-09-30 2015-06-10 Implantable device for the delivery of risperidone and methods of use thereof
US14735588 Continuation US20160030337A1 (en) 2008-09-30 2015-06-10 Implantable device for the delivery of risperidone and methods of use thereof
US20100080835A1 true US20100080835A1 (en) 2010-04-01
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