Patent Grant
7563255
The invention relates generally to a drug delivery device and, more particularly, to a miniaturized, implantable drug delivery device.
The way a particular drug is administered to a recipient can significantly affect the efficacy of the drug. For example, some therapies, in order to be optimal, require that the drug be administered locally to a particular target site. Furthermore, some of those drugs need to be present at the target site for a prolonged period of time to exert maximal effect.
One approach for achieving localized drug delivery involves the injection of drug directly into the site of desired drug activity. Unfortunately, this approach may require periodic injections of drug to maintain an effective drug concentration at the target site. In order to prolong the existence at the target site, the drug may be formulated into a slow release formulation (see, for example, Langer (1998) N
Another approach for localized drug delivery includes the insertion of a catheter to direct the drug to the desired target location. The drug can be pushed along the catheter from a drug reservoir to the target site via, for example, a pump or gravity feed. Typically, this approach employs an extracorporeal pump, an extracorporeal drug reservoir, or both an extracorporeal pump and extracorporeal drug reservoir. Disadvantages can include, for example, the risk of infection at the catheter's point of entry into the recipient's body, and that because of their size the pump and/or the reservoir may compromise the mobility and life style of the recipient.
Over the years, implantable drug delivery devices have been developed to address some of the disadvantages associated with localized injection of drug or the catheter-based procedures. A variety of implantable drug delivery devices have been developed to date.
One type of implantable drug delivery device includes the osmotically driven device. A variety of osmotic drug delivery devices are known in the art. For example, one such device is available commercially from Durect Corp. (Cupertino, Calif.) under the tradename DUROS®. Similarly another device is available from ALZA Scientific Products (Mountain View, Calif.), under the tradename ALZET®. In some devices, the influx of fluid into the device causes an osmotically active agent to swell. The swelling action can then be employed to push drug initially stored in a reservoir out of the device. DUROS® pumps reportedly deliver up to 200 mg of drug at rates as low as 0.5 μL per day. However, osmotic pumps stop working when the osmotic engine in the device or drug reservoir becomes exhausted. A variety of different osmotically driven drug delivery devices are described, for example, in U.S. Pat. Nos. 4,957,494, 5,236,689 and 5,391,381.
In addition to osmotically driven drug delivery devices, a variety of mechanical and electrochemical devices have been developed to date. U.S. Pat. No. 3,692,027 describes an implantable, electromechanical drug delivery device. The device includes, within a fluid impermeable and sealed casing, a watch-type drive mechanism that drives a circular wheel. The wheel contains a plurality of cavities, all of which apparently are radially disposed in a single diametral plane about the circumference of the wheel. Once the drug-containing cavity moves into alignment with an aperture through the casing, a piston associated with the cavity ejects medicine out of the cavity and through the aperture. This type of device can be quite large in size and, therefore, may be unsuitable for implantation into small cavities within the body.
U.S. Pat. No. 6,283,949 B1 discloses an implantable drug delivery device that includes a reservoir, a dispensing chamber adjacent to the reservoir, a dispensing passage provided along an interior surface of the dispensing chamber, and an actuator for applying a moving compressive force onto the dispensing passage. As a compressive force applied by the actuator moves along the dispensing passage, drug is simultaneously ejected out of the dispensing passage into a catheter for delivery to the target site, and additional drug is drawn into the dispensing passage from the reservoir. The size of this type of device may limit its applicability when implantation into a small body cavity is desired.
U.S. Pat. Nos. 5,797,898 and 6,123,861 disclose microchip based drug delivery devices. A plurality of drug reservoirs are etched into a substrate, for example, a single microchip. Drugs then are sealed within each of the reservoirs with a seal. The seal can be either a material that degrades over time or a material that dissolves upon application of an electric potential. See also Santini et al. (1999) N
However, there is still an ongoing need in the art for reliable, miniaturized, implantable drug delivery devices that permit the localized delivery of a drug of interest over a prolonged period of time.
The invention provides a miniaturized, implantable drug delivery device for delivering, over a prolonged period of time, a drug of interest to a preselected locus in a recipient, for example, a mammal, more preferably, a human. The device is miniaturized and thus can be implanted into a small body cavity. In one application, the device can be attached to the surface of an eye for delivering a drug into the eye. When attached, the device does not affect or otherwise restrict movement of the eye.
In one aspect, the implantable drug delivery device comprises: (a) a casing defining (i) an inner volume and (ii) an aperture port passing therethrough, wherein the inner volume is in fluid flow communication with the outside of the casing; (b) a reservoir member, for example, a drum or flexible support member, disposed within the casing, wherein the reservoir member defines a cavity for receiving the drug; and (c) a seal attached to the reservoir member for sealing drug within the cavity. The device optionally may also include a puncturing member for breaking the seal to permit drug disposed within the cavity to be released into the inner volume and to exit the casing via the aperture port.
In another aspect, the implantable drug delivery device comprises (a) a casing defining an aperture port passing therethrough; (b) a rotatable drum-type reservoir member disposed within the casing and having a surface defining a plurality of cavities for receiving the drug radially disposed about the drum, wherein all the cavities do not lie in a single diametral plane; and (c) a seal attached to the drum for sealing drug within at least one cavity, which when punctured permits drug disposed within a cavity to exit the casing via the aperture port.
The reservoir member can be a rigid member or a flexible support member. In a preferred embodiment, the reservoir member is a drum or cylinder. The cavities are defined by an outer surface of the drum or cylinder, or alternatively are defined by a compliant material disposed about the outer surface of the drum or cylinder. The cavities can be arranged in a square, rectangular or helical array about the surface of the reservoir member.
The cavities of the reservoir member, after being filled with drug (in solid, liquid, or gel form) are sealed. The seal can be fabricated from a fluid degradable material, such that upon contact with a fluid, the seal solubilizes or otherwise breaks down to release the drug disposed within the cavity. Alternatively, the seal can be fabricated from a fluid-insoluble material. As a result, the device further comprises a puncturing member, for example, a mechanical or electrochemical mechanism, for breaking or puncturing the seal to release the drug. Preferred mechanical puncturing members can be fixed or moveable (for example, via rotation and/or translation) relative to the casing and/or the reservoir member. The puncturing member optionally may further comprise one or more cutting or piercing instruments. Preferred electrochemical mechanisms include seal materials fabricated from, for example, a metal, preferably, gold, that dissolve upon application of an electrical potential across the seal. Upon dissolution, the contents of the cavity are released.
In one embodiment, the device comprises a drive mechanism, for example, a magnetic drive, for moving the puncturing member, the reservoir member, or both the puncturing member and the reservoir member. The drive mechanism can be used to bring the puncturing member into contact with a cavity seal for breaking the seal.
The device of the invention can be used to administer one or more drugs to a preselected locus in a mammal. In one embodiment, one drug is loaded into the cavities. In another embodiment, two or more different drugs are loaded into the same cavity for simultaneous release. In another embodiment, one drug is loaded into one cavity and a different drug is loaded into a second, different cavity. The latter procedure permits different drugs to be released into a target location at different times.
In a preferred embodiment, the casing has an outer surface complementary in shape to a surface of a preselected tissue, for example, an eye. In one aspect, the invention provides a drug delivery device comprising: (a) a casing defining an aperture port passing therethrough and having an exterior surface complementary in shape to an outer surface of an eye; (b) a reservoir member disposed within the casing, wherein the reservoir member defines a cavity for receiving the drug; and (c) a seal attached to the reservoir member for sealing the cavity, which when broken permits drug disposed within the cavity to exit the casing through the aperture port. The device can be used to administer a drug or a plurality of drugs to the surface of an eyeball. The drug can then pass through the sclera and into the inner portion of the eye to exert its effect.
In another aspect, the devices of the invention can be used to administer a drug to the tissue of interest. The method comprises the steps of: (a) attaching the implantable drug delivery device of the invention to a preselected locus, for example, the outer surface of the eye; and (b) permitting drug disposed within the cavity to be released from the cavity and exit the casing through the aperture port. In a preferred embodiment, in step (a), the implantable drug delivery device is fixed, for example, via a suture, a tissue adhesive, or a combination thereof, to tissue in the locus, for example, the outer surface of the eye.
The foregoing and other aspects of the invention and the various features thereof may be more fully understood from the following description when read together with the accompanying drawings, in which:
In the drawings, which are not drawn to scale, like characters refer to the same or similar parts throughout the Figures.
The invention provides a miniaturized, implantable drug delivery device capable of delivering one or more drugs at defined rates to a particular target location over a prolonged period of time. The devices of the invention can be used to deliver a drug of interest into a recipient, for example, a mammal, more specifically, a human. In view of its small size, it is contemplated that the drug delivery device may be implanted using minimally invasive procedures into a small body cavity, for example, an area adjacent to an organ, for example, a heart, an area adjacent to or within brain tissue, adjacent to or in a joint, or an eye socket, which when implanted delivers one or more drugs over a prolonged period of time to tissue or body fluid surrounding the implanted device. In one embodiment, the drug delivery device is adapted for attachment to an outer surface of an eye. When attached, the device delivers drug to the surface of the eye, which then passes through the sclera and into the target tissue to ameliorate the symptoms of an ocular disorder.
Once implanted, the drug delivery device of the invention may deliver the drug of interest over a prolonged period of time into the tissue or body fluid surrounding the device thereby imparting a localized prophylactic and/or therapeutic effect. It is contemplated that the drug delivery device may administer the drug of interest over a period of weeks (for example, 1, 2, or 3 weeks), more preferably months (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 months), and most preferably years (for example, 1, 2, 3, 4, 5 years or longer).
The miniaturized drug delivery device of the invention may be more fully understood by reference to the drawings.
In one embodiment, drive mechanism 24 moves reservoir member, for example, via translation and/or rotation, so that an optional puncturing member 26 can contact and pierce or otherwise puncture seal 22 to release drug out of cavity 20. If body fluid is present within inner volume 16 of casing 12, then once seal 22 is punctured, cut, pierced, or otherwise broken, the drug can be dissolved by the body fluid in inner volume 16. The drug then leaves casing 12 via aperture port 14 by, for example, diffusive transport along a concentration gradient. In another embodiment, drive mechanism 24 moves reservoir member 18 so that cavity 20 containing the drug is moved adjacent to, and into alignment with and, therefore, into fluid flow communication with aperture port 14. If seal 22 is degradable, for example, fluid soluble, then once cavity 20 moves adjacent to, and into fluid flow communication with aperture port 14, body fluid present in aperture port 14 dissolves seal 22 to permit release of drug into the body fluid. Once released, the drug exits casing 12 via aperture port 14. In the latter embodiment, the other regions of the reservoir member 18 are protected from body fluid surrounding casing 12 by virtue of casing 12 being sealed and fluid impermeable.
The implantable drug delivery devices of the invention can be manufactured for implantation into a small cavity or space within a body. For example, the devices can be manufactured so that the device defines a total volume (i.e., via its external dimensions) of 8 cm3 or less, more preferably 4 cm3 or less, more preferably 1 cm3 or less, more preferably 0.8 cm3 or less, and most preferably 0.5 cm3 or less. Such devices may be implanted into small body cavities for delivery of drug to target regions of interest. In a preferred embodiment, the drug delivery device of the invention may be adapted to deliver drug to an eyeball, wherein the device is attached to an outer surface of the eye. In such an embodiment, the device defines a total volume of preferably 0.5 cm3 or less, by virtue of dimensions of, for example, approximately 1 cm (length), approximately 1 cm (width), and approximately 0.5 cm (height). As a result, the device may be attached to the outer surface of an eye. When the eye is disposed within the eye socket, the device may be accommodated at an extrascleral location posterior to the muscle insertions between the sclera and the Tenon's capsule. Furthermore, the device is designed such that when implanted, the eye is capable of relatively unrestricted movement.
In particular,
The device has a casing 12 defining aperture port 14 and inner volume 16. Casing 12 also has at least one exterior surface 30 complementary in shape to the outer surface of the eye 28. The eye contacting surface of the device preferably has a concave surface having a radius of curvature complementary to the radius of curvature of the eyeball. The device contains reservoir member 18 that defines at least one cavity 20 for receiving the drug of interest. Seal 22 seals the drug of interest within the cavity. The device optionally contains a puncturing member 26 to puncture, cut, pierce otherwise degrade seal 22 to release drug 32 from the sealed cavity. If the device is configured to permit entry of body fluid into inner volume 16, then the drug can dissolve into the body fluid and then pass out of casing 12 via aperture port 14 and contact the exterior surface of the eye 28. Alternatively, when the seal is fluid degradable, reservoir member 18 moves until a sealed cavity is moved into alignment, and fluid flow communication with aperture port 14. The fluid in the aperture port then degrades or otherwise dissolves the seal to release drug 32 into the fluid disposed within aperture port 14. In either embodiment, the drug, once it contacts the exterior surface of the eye, then passes through the sclera and enters the target tissue within the eye to exert its effect.
This type of device may be useful in delivering one or more drugs of interest into an eye for ameliorating the symptoms of one or more ocular disorders including, for example, (i) ocular infections, (ii) inflammatory diseases, (iii) neoplastic diseases, and (iv) degenerative disorders. In one embodiment, the drug delivery device may be useful in the treatment of certain ocular infections, for example, infections associated with the choroid, retina and cornea. Examples include, without limitation, cytomegalovirus retinitis, tuberculous choroiditis, toxoplasma retinochoroiditis and histoplasma retinochoroiditis. In another embodiment, the drug delivery device may be useful in the treatment of inflammatory diseases, for example, inflammatory disorders associated with choroid, retina, sclera, episclera, uvea, vitreous and cornea. Examples include, without limitation, sarcoidosis, diabetic retinopathy, systemic lupus erythematosus, pars planitis, birdshot retinopathy, multifocal choroiditis and panuveitis, posterior scleritis, iritis, sympathetic ophthalmia, Harada's and Vogt-Koyanagi-Harada syndrome, subretinal fibrosis and uveitis syndrome, and white dot syndromes. In another embodiment, the drug delivery device may be useful in the treatment of neoplastic diseases, for example, neoplasia of the retina, choroid, uvea, vitreous and cornea. Examples include, without limitation, choroidal melanoma, retinoblastoma, vitreous seeding from retinoblastoma, intraocular lymphoma of the choroid, retina, or vitreous; and metastatic lesions, for example, a breast adenocarcinoma. In another embodiment, the drug delivery device may be useful in the treatment of certain degenerative disorders, for example, degenerative disorders of the retina, choroid, uvea, vitreous and cornea. Examples include, for example, macular degenerations, retinitis pigmentosa, glaucoma, and macular edema secondary to retinal vascular disorders.
In addition, the device may be used to deliver one or more drugs of interest into an eye for ameliorating the symptoms of one or more ocular disorders associated with neovascularization, including, for example, (i) ocular disorders associated with choroidal neovascularization, for example, age-related macular degeneration (more specifically, the neovascular and non-neovascular forms of age-related macular degeneration), pathologic myopia, angioid streaks, choroidal ruptures, ocular histoplasmosis syndrome, multifocal choroiditis, and idiopathic choroidal neovascularization, (ii) ocular disorders associated with corneal neovascularization, including, for example, infections, burns, certain inflammatory disorders, trauma-related disorders, and immunological disorders, (iii) ocular disorders associated with iris neovascularization, including, for example, diabetes, retinal detachment, tumors, and central retinal vein occlusion, and (iv) ocular disorders associated with retinal neovascularization including, for example, diabetic retinopathy, branch retinal vein occlusion, certain inflammatory disorders, sickle cell retinopathy, and retinopathy of prematurity.
In one embodiment, the drug delivery device comprises a rotatable reservoir member disposed within the casing. The reservoir member may be rotationally coupled, either directly or indirectly (for example, via another component, for example, a drive mechanism), to the casing. In such an embodiment, the reservoir member preferably is a rotatable drum or rotatable cylinder having one or more cavities defined by an outer surface of the drum or cylinder.
Depending upon the type of seal employed, the inner volume of the casing may or may not be in fluid communication with the exterior of casing. For example, where the seal is fluid degradable (for example, fluid soluble), the casing is sealed to prevent entry of fluid into the inner volume. If not, then entry of the fluid would result in simultaneous dissolution of the water soluble seals. This may be undesirable if the reservoir member contains a plurality of fluid degradable seals, all of which would start to break down at the same by virtue of simultaneous contact with the fluid. If the seal is fluid degradable, then the casing preferably is sealed and drive mechanism 24 rotates and/or translates reservoir member 18 so that cavity 20 moves from a first position spaced apart from aperture port 14 to a second position adjacent to, and in fluid communication with aperture port 14. As a result, the fluid in aperture port 14 contacts seal 22 causing it to degrade. Once degraded, the seal is broken permitting the drug to exit the cavity 20 and pass out of casing 12 via aperture port 14.
In another embodiment, seal 22 is not degraded or otherwise dissolved on contact with body fluid. As a result, body fluid enters casing 12 and, if desirable, contacts the entire outer surface of the reservoir member 18. The device preferably contains a puncturing member for puncturing or otherwise breaking the seal. Once the seal is broken, the drug can contact, and if appropriate, dissolve or solubilize in, fluid disposed with casing 12. The drug can then exit casing 12 via aperture port 14, for example, by diffusion along a concentration gradient.
As shown in
In a preferred embodiment, drive mechanism 24, comprises a U-shaped pivotable member pivotably coupled to reservoir member 18. During operation, the pivotable member pivots about the drum, the motion of which is coupled, for example, via a ratchet and paul mechanism, to reservoir member 18 so as to positively drive reservoir member 18 in unilateral increments about its axis of rotation. The incremental rotation of reservoir member 18, in turn, positively drives rotation of puncturing member 26 via, for example, interfitting gear components 40 and 42.
U-shaped pivotable member preferably comprises one or more permanent magnets disposed within the U-shaped portion of the pivotable member (for example, two permanent magnets facing one another and each disposed on each side of the U-shape). Motion can be induced by induction of a magnetic field in the vicinity of the permanent magnets, thereby inducing their motion in one way or another. The magnetic field can be created by periodically passing current through an immobilized coil. For example, the immobilized coil may be attached to the interior of casing 12, and positioned so that at certain times, for example, when no magnetic field is generated by the coil, the U-shaped pivotable member can return to a position in which the coil is disposed within the central void defined by each arm of the U-shaped member.
In another embodiment, the drug delivery device comprises a reservoir member that is a flexible support member (see,
Each of the components and methods for making and using such components are described in more detail below.
(i) Casing
Because the device of the invention is designed for implantation into a body and to the extent that the inner volume of the casing is accessible to body fluid, the choice of material for fabricating the casing and the fluid contacting surface of the inner components of the device is important. The tissue and/or body fluid contacting portions of the drug delivery device of the invention preferably are fabricated from an inert, biocompatible material. Preferred biocompatible materials include, for example, a metal, for example, gold, titanium, titanium alloy (titanium comprising 6% aluminum and 4% vanadium), nickel titanium, stainless steel, anodized aluminum, or a polymer, for example, polyethylene, polypropylene nylon, polydimethylsiloxane, polymethylmethacrylate, or polyurethane. In addition to biocompatibility, weight, strength and impermeability are all important considerations in the choice of materials. In view of the miniature nature of the drug delivery device of the invention, because of its biocompatibility, weight, fluid impermeability, and strength-to-thickness ratio, titanium is the most preferred material for the fabrication of the casing. Furthermore, to the extent that the inner volume of the casing is accessible to body fluid, the fluid contacting surfaces of the inner components, for example, the reservoir member, the power source, and drive mechanism preferably are also fabricated from titanium.
If the tissue and/or body fluid contacting portions of the device are not fabricated from biocompatible materials, then they preferably are encapsulated within a biocompatible material, such as, polyethyleneglycol, polyvinylchloride, polycarbonate, polysulfone, polytetrafluoroethylene, parylene, titanium or the like, prior to implantation.
The particular shape of the casing may be chosen depending upon the particular application. For example, the casing may have an elliptical, circular, square, or rectangular tissue contacting surface. Furthermore, when the device is adapted for attachment to the outer surface of an eye in ocular applications, the eye contacting portion of the device preferably has a shape that is complementary (i.e., a mirror image or substantially a mirror image) to the outer surface of the eye. The casing may optionally contain one or more apertures, fenestrations or eyelets to permit the device to be immobilized to the tissue of interest, for example, via sutures or the like. Furthermore, the casing may optimally comprise a rim or flange disposed about the casing as part of or adjacent to the tissue contacting surface to assist in attaching the device to the tissue of interest.
(ii) Reservoir Member and Fabrication
The reservoir member can take a variety of configurations and is adapted to receive and store the drug or drugs of interest. The reservoir member is disposed within, and preferably is operatively coupled (either directly or indirectly) to the casing. The reservoir member preferably defines a plurality of cavities, each cavity containing a dosage unit of the same drug, one of a series of different drugs, or a mixture of different drugs. In general, the materials used to fabricate or coat the reservoir member preferably are inert, biocompatible, fluid impervious, and impermeable to the drug.
In a preferred embodiment, as shown schematically in
Movement of such a reservoir member, if desired, may vary depending upon the particular design of the drug delivery device of the invention. For example, the reservoir member may rotate and/or translate relative to the device casing and/or the puncturing member. In one embodiment, the reservoir member both rotates and translates relative to the casing. See, for example,
It is contemplated that materials useful in the fabrication of reservoir member 18 may be the same as those useful in the fabrication of the casing, as previously discussed. In a preferred embodiment, however, the reservoir member is fabricated from titanium. Furthermore, it is contemplated that the drum or cylindrical-type of reservoir member can take a variety of different forms. For example, reservoir member 18 may be solid or hollow. Hollow members are preferred when weight is a significant concern or a where a puncturing member acts on a base of the cavity to break the seal (see, for example,
The cavities may be fabricated using a variety of different techniques, the choice of which may depend, for example, upon the size of the cavity, the location and spatial relationships of the different cavities, and the mechanism used to fill each cavity with drug. For example, the cavities may be drilled or milled into the surface of the drum-type reservoir member 18. Alternatively, the cavities may be formed in a planar, compliant material, which after fabrication (and optionally after each cavity has been filled with drug and sealed) is wrapped around the surface of the drum-type reservoir member.
In another approach, the cavities may be defined by a compliant matter, which after fabrication can be wrapped around and attached to the outer surface of the drum-type reservoir member. For example,
Upon fabrication, the cavities defined by the reservoir member are filled with the drug or drugs of interest and sealed prior to use. It is contemplated that the cavities can be filled with drug and then sealed while in planar form. Alternatively, the planar sheet can be wrapped around the reservoir member, after which the cavities can be filled with drug and then sealed. Irrespective of the timing of filling and sealing of the cavities, the compliant sheet is wrapped or rolled around the surface of the reservoir member. The sheet can be attached or bonded to the reservoir member by activating the surface using, for example, an oxygen plasma for the compliant polymer sheet, or by using a glue or adhesive, such as, cyanoacrylate.
The cavities can be disposed within the planar sheet, so that when the sheet is wrapped around a cylindrical reservoir member, the cavities are disposed within a square array. Alternatively, the cavities can be disposed within the planar array slightly offset with respect to one another, so that when the sheet is wrapped around a cylindrical reservoir member, the cavities are helically disposed about the surface of the reservoir member.
In one embodiment, the reservoir member is a drum and the cavity seal is fluid degradable (see,
In another embodiment, the reservoir member is a hollow drum and the cavity seal is broken by application of pressure to the base of the cavity via a cantilever-type puncturing member (see,
In another embodiment, the reservoir member is a flexible support member that is wrapped around a spool or spindle assembly (see,
(iii) Drug and Drug Formulation
It is understood that the drug delivery device of the invention can be used to deliver one or more drugs to a particular target site. The drug can be disposed within the cavity in solid, liquid or gel form. As used herein, the term “drug” is understood to mean any natural or synthetic, organic or inorganic, physiologically or pharmacologically active substance capable of producing a localized or systemic prophylactic and/or therapeutic effect when administered to an animal. A drug includes (i) any active drug, (ii) any drug precursor or pro-drug that may be metabolized within the animal to produce an active drug, (iii) combinations of drugs, (iv) combinations of drug precursors, (v) combinations of a drug with a drug precursor, and (vi) any of the foregoing in combination with a pharmaceutically acceptable carrier, excipient or formulating agent.
The drug may include, for example, a protein (for example, an antibody or an antigen binding portion thereof), a polypeptide, a nucleic acid (for example, deoxyribonucleic acid and/or ribonucleic acid), a peptidyl nucleic acid, a polysaccharide, a fatty acid (for example, prostaglandin), an organic molecule and an inorganic molecule, that has prophylactic and/or therapeutic value, i.e., elicits a desired effect, when administered to an animal. The drug can include, for example, a hormone or synthetic hormone, an anti-infective agent (for example, an antibiotic, an anti-viral agent, and an anti-fungal agent), a chemotherapeutic agent (for example, methotrexate, chlorambucil, cyclosporine, and interferon), an autonomic drug (for example, an anticholinergic agent, adrenergic agent, adrenergic blocking agent, and a skeletal muscle relaxant), a blood formation or blood coagulation modulating agent (for example, an anti-anemia drug, coagulant and an anti-coagulant, hemorrhagic agent, and a thrombolytic agent), a cardiovascular drug (for example, a hypotensive agent, vasodilating agent, inotropic agent, β-blocker, and a sclerosing agent), a central nervous system agent (for example, an analgesic, an antipyretic, and an anti-convulsant), an immunomodulating agent (for example, etanercept, or an immunosuppresant), an anti-inflammatory agent (for example, a steroid, and interferon α), an anti-obesity agent (for example, leptin), an anti-lipemic agent (for example, an inhibitor of hydroxymethylglutaryl co-enzyme A reductase), an anti-emetic agent (for example, cisapride and metoclopramide), an anti-migraine medication (for example, imitrex), a chelating agent (for example, the iron chelator desferoxamine), and a contraceptive or fertility agent.
The drug also embraces an angiogenesis inhibitor, i.e., a compound that reduces or inhibits the formation of new blood vessels in a mammal. Angiogenesis inhibitors may be useful in the treatment of various disorders associated with neovascularization, for example, certain ocular disorders associated with neovascularization. Examples of useful angiogenesis inhibitors, include, for example, protein/peptide inhibitors of angiogenesis such as: angiostatin, a proteolytic fragment of plasminogen (O'Reilly et al. (1994) C
Other angiogenesis inhibitors include, for example, COX-2 selective inhibitors (Masferrer et al. (1998) P
Several cytokines including bioactive fragments thereof and analogs thereof have also been reported to have anti-angiogenic activity and thus may be delivered using the device of the invention. Examples include, for example, IL-12, which reportedly works through an IFN-γ-dependent mechanism (Voest et al. (1995) J. N
It is contemplated that useful angiogenesis inhibitors, if not already known, may be identified using a variety of assays well known and used in the art. Such assays include, for example, the bovine capillary endothelial cell proliferation assay, the chick chorioallantoic membrane (CAM) assay or the mouse corneal assay. However, the CAM assay is preferred (see, for example, O'Reilly et al. (1994) C
The drug also embraces a neuroprotective agent, i.e., an agent capable of retarding, reducing or minimizing the death of neuronal cells. Neuroprotective agents may be useful in the treatment of various disorders associated with neuronal cell death, for example, certain ocular disorders including, for example, macular degeneration, retinitis pigmentosa, glaucoma and diabetic retinopathy. Examples of neuroprotective agents include, for example, apoptosis inhibitors, for example, neurotrophic factors, cAMP elevating agents, and caspase inhibitors.
Exemplary neurotrophic factors include, for example, Brain Derived Growth Factor and bioactive fragments and analogs thereof (Caffe et al. (2001) I
As discussed, the device of the invention is useful in the treatment of a variety of ocular disorders. For example, the drug delivery device may deliver an anti-infective agent, such as, an antibiotic, anti-viral agent or anti-fungal agent, for the treatment of an ocular infection. Similarly, the device may deliver a steroid, for example, hydrocortisone, dexamethasone sodium phosphate or methylprednisolone acetate, for the treatment of an inflammatory disease of the eye. The device may be used to deliver a chemotherapeutic or cytotoxic agent, for example, methotrexate, chlorambucil, cyclosporine, or interferon, for the treatment of an ocular neoplasm. Furthermore, the device may be useful in delivering one or more drugs for the treatment of certain degenerative ocular disorders, for example, (i) an adrenergic agonist, such as, epinephrine (Epifrin), dipivefrin (Propine), apraclonidine (lopidine), or brimonidine (Alphgan); a β-blocker, such as, betaxolol (Betoptic) or timolol (Timoptic); a carbonic anhydrase inhibitor, such as, acetazolamide (Diamox), methazolamide (Neptazane), dorzolamide (Trusopt), or brinzolamide (Azopt); prostglandin analogues, such as, latanoprost (Xalatan), for the treatment of glaucoma, (ii) an integrin (such as, a lymphocyte function associated molecule (LFA-1), Mac-1 or p150,95) antagonist; a selectin (such as, E-selectin, P-selectin and L-selectin) antagonist; an adhesion molecule (such as, an intercellular Adhesion molecule (ICAM)-1, ICAM-2, ICAM-3) antagonist; a Platelet Endothelial Adhesion Molecule antagonist; a Vascular Cell Adhesion Molecule antagonist; a leukocyte adhesion inducing cytokine or growth factor (such as, Tumor Necrosis Factor-α, or Interleukin-1β) antagonist; a Monocyte Chemotactic Protein-1 antagonist; a VEGF antagonist, and other molecules described in PCT/US99/31215 for the treatment of diabetic retinopathy, (iii) an anti-inflammatory drug, such as, a steroid (for example, hydrocortisone, dexamethasone sodium phosphate or methylprednisolone acetate), indomethacin, naprosyn, or a VEGF antagonist for the treatment of macular edema secondary to certain retinal vascular disorders. As used herein, the antagonist may comprise, without limitation, an antibody, an antigen binding portion thereof or a biosynthetic antibody binding site that binds a particular target protein, for example, ICAM-1; an antisense molecule that hybridizes in vivo to a nucleic acid encoding a target protein or a regulatory element associated therewith, or a ribozyme, aptamer, or small molecule that binds to and/or inhibits a target protein, for example, ICAM-1, or that binds to and/or inhibits, reduces or otherwise modulates expression of nucleic acid encoding a target protein, for example, ICAM-1.
The drug or drugs of interest may be introduced into a cavity either in pure form or as a formulation, for example, in combination with a pharmaceutically acceptable carrier or encapsulated within a release system. A release system can include a matrix of a biodegradable material or a material which releases incorporated drug by diffusion. The drugs can be homogeneously or heterogeneously distributed within the release system. A variety of release systems may be useful in the practice of the invention, however, the choice of the appropriate system will depend upon rate of drug release required by a particular drug regime. Both non-degradable and degradable release systems can be used. Suitable release systems include polymers and polymeric matrices, non-polymeric matrices, or inorganic and organic excipients and diluents such as, but not limited to, calcium carbonate and sugar. Release systems may be natural or synthetic. However, synthetic release systems are preferred because generally they are more reliable, more reproducible and produce more defined release profiles. The release system material can be selected so that drugs having different molecular weights are released from a particular cavity by diffusion through or degradation of the material. Biodegradable polymers, bioerodible hydrogels, and protein delivery systems currently are preferred for drug release via diffusion or degradation.
Representative synthetic, biodegradable polymers include, for example: polyamides such as poly(amino acids) and poly(peptides); polyesters such as poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), and poly(caprolactone); poly(anhydrides); polyorthoesters; polycarbonates; and chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), copolymers and mixtures thereof. Representative synthetic, non-degradable polymers include, for example: polyethers such as poly(ethylene oxide), poly(ethylene glycol), and poly(tetramethylene oxide); vinyl polymers-polyacrylates and polymethacrylates such as methyl, ethyl, other alkyl, hydroxyethyl methacrylate, acrylic and methacrylic acids, and others such as poly(vinyl alcohol), poly(vinyl pyrolidone), and poly(vinyl acetate); poly(urethanes); cellulose and its derivatives such as alkyl, hydroxyalkyl, ethers, esters, nitrocellulose, and various cellulose acetates; polysiloxanes; and any chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), copolymers and mixtures thereof.
(iv) Cavity Filling
The drug delivery device of the invention may be used to deliver one or more drugs to a target tissue over a prolonged period of time. It is contemplated that one type of drug can be sealed within a particular cavity of the reservoir member. However, it is contemplated that a plurality of drugs may be sealed within a single cavity so that they are all released from the reservoir member at the same time. Alternatively, a first drug may be sealed within one cavity and a second, different drug may be sealed within a second, different cavity. The last approach permits two drugs to be delivered to the target site at different times.
The drug may be loaded into the cavities using conventional procedures known in the art. When the drug is in a liquid form, the cavity may be filled, for example, by a conventional micropipette system, for example, the syringe-pumped Biojet dispenser (BioDot, Inc., Irvine, Calif.). The drug may then be dried in the cavity, for example, by freeze-drying or evaporative drying. When the drug is in dry form, the cavity may be filled by, for example, dry packing.
It is understood, however, that the choice of a drug, its formulation, and loading into the different cavities of the reservoir will depend upon the particular prophylactic or therapeutic regime to be achieved.
(v) Cavity Sealing and Seal Breakage Mechanisms
After each cavity has been filled with the drug of interest, the drug then is sealed within the cavity with a seal. It is understood that the choice of seal and seal breakage mechanism are interrelated.
The seal may be integral with the reservoir member, may be a coating applied uniformly about the surface of the reservoir member, or may be formed separately from the reservoir member and then attached to the reservoir member to seal the drug within the cavity. In general, it is contemplated that two types of seals are useful in the practice of the invention. One type of seal dissolves or breaks down upon contact to a fluid. When exposed to fluid, such a seal dissolves or breaks down to permit drug disposed within the cavity to come into contact with body fluid, for example, body fluid disposed within the aperture port of the casing. The other type of seal does not dissolve or break down upon contact to a fluid. This type of seal, therefore, requires, for example, a mechanical or electrochemical procedure to break the seal and release the drug within the cavity.
When the seals are designed for dissolution or breakage upon exposure to a degrading medium, such as a body fluid, the seal preferably is fabricated from a polymeric material or a combination of polymeric materials selected to achieve a degradation rate of interest. It is possible to fabricate different seals so that they break down and release drug over different time frames. Differential drug release can be achieved using a variety of different approaches. In one approach, the seal for one cavity is fabricated from a first material and a seal for a different cavity is fabricated from a second, different material. Alternatively, the seals may be fabricated from the same material or set of materials but with modification to modulate to the rate of dissolution of one type of seal relative to another type of seal. For example, when the seal is a polymer, one approach is to adjust the level of cross-linking in, and/or thickness of one seal relative to another seal. Any combination of polymer, degree of crosslinking, or polymer thickness can be modified to obtain a specific release time of interest.
In another approach, the seal is broken down via an electrochemical process, for example, by applying an electrical potential across the seal. In this embodiment, the cavity seal comprises a thin film of conductive material patterned, for example, as an anode surrounded by cathodes in the portions of the drug reservoir surrounding the cavity. For this approach, preferred seals are fabricated from metallic materials, such as copper, gold, silver and zinc, as well as some polymers. It is contemplated, however, that such seals may be fabricated from any conductive material that oxidizes and dissolves in solution upon application of an electric potential. Preferably, the anode is the electrode where oxidation occurs. Upon application of electrical potential between the cathode and the anode, the portion of the anode sealing the drug containing cavity oxidizes and dissolves into the surrounding solution. The seal, which acts as an anode, can be fabricated from gold. The gold dissolves upon application of a potential difference of, for example, about 1 volt over each individual cavity. Positively charged gold ions in the electrode react with negatively charged ions, such as chloride ions, to create a soluble metal salt. As a result, the gold containing seal dissolves. Once the seal is sufficiently broken down or degraded, the drug then is released into fluid and can then leave the casing via the aperture port. Methods for making and using such seals are described in detail in, for example, U.S. Pat. Nos. 5,797,898 and 6,123,861, and Santini et al. (1999) N
In another approach, the cavity seal can be mechanically broken. The seals preferably are water impermeable, and preferably can be broken by cutting, piercing, puncturing, or the like. Seals that are susceptible to mechanical breakage or fracturing may be fabricated from a variety of materials including, for example, titanium, and parylene. It is contemplated that the seal may comprise a coating of material deposited uniformly about the surface of the reservoir member.
In one approach, as depicted in
In another approach, as depicted in
In another approach, as depicted in
When the reservoir member is a flexible support type member, as shown in
In another approach, as illustrated in
(vi) Drive Mechanism, Power Source and Control Systems
The drug delivery device of the invention preferably has one or more drive mechanisms to drive the reservoir member, the puncturing member, or both the reservoir member and the puncturing member. It is contemplated that a variety of different drive mechanisms may be useful in the practice of the invention. The drive mechanisms preferably can impart rotational and/or translational movement to the reservoir member and/or the puncture member. Preferred drive mechanisms include, for example, mechanical, electrical, fluidic, thermal, and magnetic systems, as well as combinations thereof.
One type of drive mechanism useful in the practice of the invention uses a self-controlled mechanical system of the type used in watch movements. Watch movements are readily available, are relatively small in size, light in weight, have a steady timing interval, and can be powered with a standard battery. A magnetic drive, for example, a step motor, presently is preferred. An exemplary magnetic drive is depicted in
Magnetic drive mechanisms that produce torque in excess of 2.0 gm-cm, have a low power demand, and can use a standard power source. An exemplary drive mechanism comprises 300 turns of 46 gauge wire, and has the dimensions of about 4 mm by about 3 mm by about 2.5 mm, and can generate 3 gm force. The wire can be manufactured from materials including, for example, copper, gold, silver, platinum, stainless steel, or other electrically conductive material. When coupled to an 8 mm ratchet mechanism, 2.5 gm force produced by the magnetic drive produces 2 gm-cm of torque. Although the drive mechanism preferably is included within the casing, it is contemplated that a similar ratchet mechanism can be driven using an external magnetic drive mechanism disposed in a site remote from the implanted drug delivery device.
Criteria for selection of a power source include small size, sufficient power capacity, the ability for integration into control circuitry, the ability to be recharged, and the length of time before recharging is necessary. One or more power sources can be incorporated directly onto the drug delivery device. The power sources contemplated for use in the drug delivery device of the invention include, for example, standard silver oxide button-cell watch batteries, other types of batteries, and inductive coils of pickups for use with external or remotely disposed devices.
Furthermore, the drug delivery device may further comprise a control mechanism, for example, a programmable control mechanism to vary the drug delivery profile. The control mechanism preferably includes an integrated circuit or microprocessor and related circuitry which controls the drive mechanism and is pre-programmed to the desired delivery profile, or is arranged with a receiver to receive, for example, radio, control signals from a programmer device located outside of the patient to allow for alterations in the delivery profile over time. In another embodiment, the control mechanism optionally comprises an input source, such as, a biosensor. The input signal from the biosensor can then be used to modify the drug delivery profile. The criteria for selection of a microprocessor include small size, low power requirement, and the ability to convert the input signal into an output signal for adjusting the rate of drug delivery. Selection of a source of input to the microprocessor such as a memory source, a signal receiver, or a biosensor depends upon the intended purpose and whether device operation is preprogrammed, controlled by remote means, or controlled by feedback from its environment (i.e., biofeedback). Useful microprocessors, related circuitry and biosensors are known in the art and so are not described in detail herein.
(vii) Applications
It is contemplated that the drug delivery device of the invention has a variety of applications. Because of their small size, the devices can be implanted into small body cavities, or areas where size is a critical feature. For example, the drug delivery device may be implanted within or immobilized adjacent to the brain for the delivery of certain drugs, for example, a chemotherapeutic agent, an anti-inflammatory drug, an angiogenesis inhibitor, a neuroprotective agent, an anti-physchotic agent, or an anti-convulsant agent, into the brain. Alternatively, the device may be implanted within or immobilized adjacent to an organ, for example, a heart, for the delivery of certain agents, for example, an angiogenesis inducer or an expression vector encoding a preselected gene, to the organ if interest. Alternatively, the device may be implanted within or immobilized adjacent to a joint for delivery of certain drugs, for example, an angiogenesis inhibitor or an anti-inflammatory agent, to the joint. Alternatively, the device may be implanted within or immobilized adjacent to the ear, for example, the middle or inner ear, for the delivery of certain agents, for example, a steroid, vasodilator, antibiotic, or pain medication, into the ear.
In a preferred embodiment, the device of the invention is particularly useful in delivering one or more drugs into an eye of a recipient thereby to treat or ameliorate the symptoms of one or more ocular disorders. It has been found that certain drugs, when applied to the outer surface of an eye, can traverse the sclera and enter the interior of the eye (see, PCT/US00/00207 and Ambati et al. (2000) I
In a preferred embodiment, the drug delivery device is attached to the outer surface of the eye. The device casing, preferably has an eye contacting surface (i) complementary in shape to the outer surface of the eye and (ii) defines an aperture port running therethrough. As a result, when drug is released from the reservoir member, it exits the casing via the aperture port and contacts the outer surface of the eye in the vicinity of the aperture port. The drug delivery device can be attached to the eye using routine surgical or medical procedures. For example, the device may be attached to the outer surface of the eye via, for example, tissue adhesive, scleral flaps, suture techniques, or a combination thereof.
When tissue adhesive is used, the adhesive is applied to the eye contacting surface of the casing, the contact surface of the eye, or both, and then the device is attached to the outer surface of the eye. A preferred tissue adhesive includes isobutyl cyanoacrylate adhesive available from Braun, Melsunger, Germany, and Ellman International, Hewlett, N.Y. In addition, tissue adhesive may be used to seal the edge of the device casing to the sclera. Also, the tissue adhesive may be used to secure scleral flaps to outer portions of the device casing.
In the scleral flap approach, partial thickness scleral flaps are created using a surgical blade, such as, a 57 Beaver blade. The flaps preferably are of a width to cover at least a portion of the outer casing of the device. In an embodiment, the tissue contacting surface of the device casing may optionally contain a rim or flange extending around the casing so that the scleral flap can be wrapped over and then attached to the rim or flange. Once the device is positioned, the scleral flaps can be sutured to each other and/or glued to the device casing using tissue adhesive.
In the suturing approach, sutures are passed through partial thickness sclera and then through correspondingly located aperture holes, eyelets or rings disposed in the device casing. Sutures preferably are preplaced if adhesive is to be used in conjunction with suturing. Sutures useful for immobilizing the device include, for example, 4-0 or 5-0 monofilament nylon, silk, mersilene or polyester. Once the device is positioned, the sutures then are permanently secured.
Furthermore, if desirable the portion of the sclera that contacts the device casing, and more preferably the portion of the sclera located adjacent to the aperture port of the casing, may be thinned prior to attachment of the device. Thinning may be accomplished using a surgical blade or a laser, for example, an Erbium YAG laser.
The desired rate of drug delivery will depend upon the age, sex, and weight of the recipient, as well as the drug and the disorder to be treated. The choice of a particular drug, the rate and mode of administration, and site of implantation are within the level of skill in the art. For example, drug may be administered at doses ranging, for example, from about 0.001 to about 500 mg/kg, more preferably from about 0.01 to about 250 mg/kg, and most preferably from about 0.1 to about 100 mg/kg. Using the device of the invention, drug is administered periodically as boluses via breakage of the various cavity seals in amounts ranging from about 0.1 μg to about 2 mg per cavity, more preferably from about 1 μg to about 1 mg per cavity, and more preferably from about 10 μg to about 0.5 mg per cavity.
To the extent that the drug delivery device of the invention becomes exhausted, for example, runs out of power and/or drug, the device may be removed. A new device may then be attached to the site of interest or the old device, once refabricated with a new power source and/or drug-containing reservoir, reimplanted at the site of interest.
The present invention may be further understood by reference to the following non-limiting examples.
A device for delivering the anti-Vascular Endothelial Growth Factor aptamer (NX1838) (see, Drolet et al. (2000) P
The drum is placed within the casing in operative association with a power source, a magnetic drive mechanism, and a rotating puncturing member having a plurality of puncture needles disposed about a surface thereof. The magnetic drive mechanism is coupled to the drum via a biased ratchet mechanism, so that when the magnetic drive mechanism is periodically activated and deactivated it incrementally rotates the drum. The drum also incrementally rotates the puncturing member via a gear mechanism preferably fabricated from interfitting titanium components. A needle disposed on the rotating puncturing member, when it contacts a cavity seal on the drug, pierces the seal to permit the release of aptamer out of the cavity. The needles on the puncturing member move in register with the cavities disposed about the surface of the incrementally rotating drum so that on a periodic basis a needle punctures the seal of a drug-containing cavity. Puncturing is repeated so that drug is sequentially released from a series of cavities to provide drug delivery over a prolonged period of time. The relative speed of rotation of the drum and puncturing member, and thus the rate of seal breakage, can be adjusted to change the rate of drug release.
Surgical implantation of the drug delivery device preferably is performed under general or local anesthesia. In one approach, a 360-degree conjunctival peritomy is performed to open the conjunctiva and Tenon's capsule. Blunt scissors then are inserted into the quadrants between the rectus muscles, and the Tenon's capsule dissected from the underlying sclera. The rectus muscles then are isolated and looped on one or more retraction sutures, which permit rotation of the globe and exposure of the quadrants.
The device preferably is inserted into an accessible quadrant, for example, the superotemporal quadrant or the inferotemporal quadrant. Placement preferably is posterior to the muscle insertions and more preferably posterior to the equator. The device is placed temporarily in the selected quadrant to allow a determination of whether the conjunctiva and Tenon's capsule cover the device. If necessary, a relaxing incision may be made in the conjunctiva away from the quadrant selected for the device.
Fixation of the device may be accomplished using one or more of a tissue adhesive, scleral flaps, or sutures. Once the device is fixed to the sclera, the muscle retraction sutures are removed and the conjunctiva and Tenon's capsule closed over the device. The conjunctiva can then be sutured at the limbus using standard procedures. When implanted, the drug delivery device is activated to permit the drug to be administered to the surface of the eye at the desired rate.
Incorporation by Reference
The disclosure of each of the patent documents and scientific articles referred to herein is expressly incorporated by reference herein.
Equivalents
The invention may be embodied in other specific forms without departing form the spirit or essential characteristics thereof. The foregoing embodiments, therefore, are to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.
This application claims priority to and the benefit of U.S. Provisional Application Serial No. 60/288,373, filed May 3, 2001; U.S. Provisional Application Serial No. 60/291,340, filed May 16, 2001; U.S. Provisional Application Serial No. 60/291,445, filed May 16, 2001; U.S. Provisional Application Serial No. 60/332,199, filed Nov. 21, 2001; U.S. Provisional Application Serial No. 60/332,200, filed Nov. 21, 2001; and U.S. Provisional Application Serial No. 60/334,177, filed Nov. 29, 2001, the disclosures of each of which are incorporated by reference herein.
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