Abstract:
This invention relates to a reusable drug delivery device, preferably a device that is placed or implanted in the eye to release a pharmaceutically active agent to the eye. The device utilizes a rigid box-like holder and cap and can be reused once the active has completely diffused from the core or upon completion of a research study.

Description:
CROSS REFERENCE  
       [0001]     This application claims the benefit of Provisional Patent Application No. 60/638,481 filed Dec. 22, 2004 and is incorporated herein by reference. 
     
    
     FIELD OF THE INVENTION  
       [0002]     This invention relates to a reusable drug delivery device, preferably a device that is placed or implanted in the eye to release a pharmaceutically active agent to the eye. The device utilizes a rigid box-like holder and cap and can be reused once the active has completely diffused from the core or upon completion of a research study.  
       BACKGROUND OF THE INVENTION  
       [0003]     Various drugs have been developed to assist in the treatment of a wide variety of ailments and diseases. However, in many instances, such drugs cannot be effectively administered orally or intravenously without the risk of detrimental side effects. Additionally, it is often desired to administer a drug locally, i.e., to the area of the body requiring treatment. Further, it may be desired to administer a drug locally in a sustained release manner, so that relatively small doses of the drug are exposed to the area of the body requiring treatment over an extended period of time.  
         [0004]     Accordingly, various sustained release drug delivery devices have been proposed for placing in the eye for treating various eye diseases. Examples are found in the following patents, the disclosures of which are incorporated herein by reference: US 2002/0086051A1 (Viscasillas); US 2002/0106395A1 (Brubaker); US 2002/0110591A1 (Brubaker et al.); US 2002/0110592A1 (Brubaker et al.); US 2002/0110635A1 (Brubaker et al.); U.S. Pat. No. 5,378,475 (Smith et al.); U.S. Pat. No. 5,773,019 (Ashton et al.); U.S. Pat. No. 5,902,598 (Chen et al.); U.S. Pat. No. 6,001,386 (Ashton et al.); U.S. Pat. No. 6,375,972 (Guo et al.); U.S. patent application Ser. No. 10/403,421 (Drug Delivery Device, filed Mar. 28, 2003) (Mosack et al.); and U.S. patent application Ser. No. 10/610,063 (Drug Delivery Device, filed Jun. 30, 2003) (Mosack).  
         [0005]     Many of these devices include an inner drug core having a pharmaceutically active agent, and some type of holder for the drug core made of an impermeable material such as silicone or other hydrophobic materials. The holder includes one or more openings for passage of the pharmaceutically active agent through the impermeable material to eye tissue. Many of these devices include at least one layer of material permeable to the active agent, such as polyvinyl alcohol (PVA).  
         [0006]     The prior art devices have been designed for single use and may require a complicated assembly process. This can provide difficulty in controlling certain studies that require relatively exact reproducibility. Moreover, it may be desirable to test a drug core in a laboratory environment with a device that does not require a complicated assembly process. Additionally, there remains a need for a device that is micromachined to fine tolerances that provides for improved accuracy of clinical research. Therefore there remains a need for reusable drug delivery devices for implantation in the eye. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0007]      FIG. 1  is a top plan view of a first embodiment of a drug delivery device of this invention.  
         [0008]      FIG. 2  is a side plan view of the device of  FIG. 1 .  
         [0009]      FIG. 3  is a perspective view of the device of  FIG. 1 .  
         [0010]      FIG. 4  is a top plan view of the cap of a drug delivery device.  
         [0011]      FIG. 5  is a side cross-section view of the cap of  FIG. 4 .  
         [0012]      FIG. 6  is a perspective view of the cap of  FIG. 4 .  
         [0013]      FIG. 7  is an exploded view of one embodiment of the device of this invention.  
         [0014]      FIG. 8  is a perspective view of the assembled device of this invention.  
         [0015]      FIG. 9  is a side cross-section view of the device showing the drug core. 
     
    
     SUMMARY OF THE INVENTION  
       [0016]     According to a first embodiment, this invention relates to a reusable drug delivery device. The reusable drug delivery device comprises a holder and a cap; the holder being capable of holding a drug core and as an anchoring mechanism for implantation, the holder being made of a material capable of being micromachined, stamped or formed and having an outside surface configured to reversibly receive a cap. A second embodiment of the invention comprises an anchoring mechanism for implantation thereby providing a unitary drug holder and anchoring mechanism for implantation and being made of a material capable of being micromachined, stamped, or formed. The anchoring mechanism for implantation (e.g., suture tab) contains a suture hole at one end of the device or other means for holding the device in place once implanted-.  
       DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
       [0017]      FIG. 1  is a top plan view of an embodiment of the base  1  of the device  50 . The base  1  is generally elongate with a suture hole  2  at an end opposite the box-like holder  3  for the drug core (not shown). Suture hole  2  preferably comprises chamfered edges to avoid tearing of any suture material that may be used with the device. Holder  3  has an inside dimension  5  that is wide enough to hold the drug core and any optional coating(s). Holder  3  also has an outer side surface  6  that allows it to reversibly receive a cap  11 . The structural relationship between outer side surface  6  and cap  11  will be explained further on in the description.  
         [0018]      FIG. 2  is a side plan view of the device of  FIG. 1 . As shown in  FIG. 2 , the ends of base  1  can be curved  7 ,  8  to avoid sharp edges that may undesirably interact with tissue upon implantation.  FIG. 3  is a perspective view of the device of  FIG. 1 .  
         [0019]      FIG. 4  is a top plan view of the cap  11  to be used with the base  1  of  FIGS. 1-3 . The cap  11  has an opening  12  to allow to release of the active found in drug core (not shown). Cap  11  also comprises a surface portion  13  that is impermeable to the agent. As indicated above, the cap  11  has an inner side surface  14  that reversibly engages with the outer side surface  6  of the holder  3  of the base  1 . This inner side surface  14  is more easily seen in  FIG. 5  which is a side cross-sectional view of cap  11 . Cap  11  has an outer side surface  15  that is chamfered  16  at the shoulder where it joins the top surface  13  of the cap. As shown in  FIG. 5 , various internal shapes may be formed to accommodate the drug core (not shown) so long as inner side surface  14  is configured to removably engage with outer side surface  6  of the holder  3 . By reversibly engage we mean that the cap  11  and holder  3  are able to form a seal that can be released when desired. The seal is accomplished through mechanical means such as a friction fit.  
         [0020]      FIG. 6  is a perspective view of cap  11  showing opening  12  in the top surface portion  13  of cap  11 . Also shown is the exterior side wall  15  of cap  11 .  
         [0021]      FIG. 7  is an exploded perspective view of the complete device  50  better showing how the top surface  20  of holder  3  is sized and configured to tightly engage with the inside bottom surface  21  of cap  11  to form a seal. In this embodiment, sealing is obtained not just through engagement of outer side surface  6  of the holder  3  with inner side surface  14  of cap  11  but also through engagement of top surface  20  of holder  3  with inside bottom surface  21  of cap  11 .  
         [0022]      FIG. 8  is a perspective view of the assembled device  50 .  
         [0023]      FIG. 9  is a side cross-sectional view of device  50  showing core  25  comprising a pharmaceutically active agent  26  contained in a matrix  27 . The core  25  may optionally comprise a coating  28  which can assist in providing desirable release kinetics.  
         [0024]     Although the embodiment shown utilizes a friction fit to allow the cap  11  to be removably attached to the holder  3  other engagements means are also envisioned. For example, outer side surface  15  and inner side surface  14  may be threaded to allow cap  11  to be screwed onto holder  3 . Other engagement means would include threaded, pressed, locking or, in the absence of engagement means, sealed with an impermeable material. Also, although the preferred embodiment contains an elongated base with an opening to serve as a suture tab, this feature is not necessary for the successful operation of the device.  
         [0025]     The active agent may include any compound, composition of matter, or mixture thereof that can be delivered from the device to produce a beneficial and useful result to the eye, especially an agent effective in obtaining a desired local or systemic physiological or pharmacological effect. Examples of such agents include: anesthetics and pain killing agents such as lidocaine and related compounds and benzodiazepam and related compounds; benzodiazepine receptor agonists such as abecamil; GABA receptor modulators such as baclofen, muscimol and benzodiazepines; anti-cancer agents such as 5-fluorouracil, adriamycin and related compounds; anti-fungal agents such as fluconazole and related compounds; anti-viral agents such as trisodium phosphomonoformate, trifluorothymidine, acyclovir, ganciclovir, DDI and AZT; cell transport/mobility agents impeding such as colchicine, vincristine, cytochalasin B and related compounds; antiglaucoma drugs such as beta-blockers: timolol, betaxolol, atenalol, etc; antihypertensives; decongestants such as phenylephrine, naphazoline, and tetrahydrazoline; immunological response modifiers such as muramyl dipeptide and related compounds; peptides and proteins such as cyclosporin, insulin, growth hormones, insulin related growth factor, heat shock proteins and related compounds; steroidal compounds such as dexamethasone, prednisolone and related compounds; low solubility steroids such as fluocinolone acetonide and related compounds; carbonic anhydrase inhibitors; diagnostic agents; antiapoptosis agents; gene therapy agents; sequestering agents; reductants such as glutathione; antipermeability agents; antisense compounds; antiproliferative agents; antibody conjugates; antidepressants; bloodflow enhancers; antiasthmatic drugs; antiparasitic agents; non-steroidal antiinflammatory agents such as ibuprofen; nutrients and vitamins: enzyme inhibitors: antioxidants; anticataract drugs; aldose reductase inhibitors; cytoprotectants; cytokines, cytokine inhibitors and cytokine protectants; uv blockers; mast cell stabilizers; and antineovascular agents such as antiangiogenic agents like matrix metalloprotease inhibitors.  
         [0026]     Examples of such agents also include: neuroprotectants such as nimodipine and related compounds; antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamycin, and erythromycin; antiinfectives; antibacterials such as sulfonamides, sulfacetamide, sulfamethizole, sulfisoxazole; nitrofurazone, and sodium propionate; antiallergenics such as antazoline, methapyriline, chlorpheniramine, pyrilamine and prophenpyridamine; antiinflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrysone, methyiprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, betamethasone and triminolone; miotics and anti-cholinesterase such as pilocarpine, eseridine salicylate, carbachol, diisopropyl fluorophosphate, phospholine iodine, and demecarium bromide; mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine; sympathomimetics such as epinephrine; and prodrugs such as those described in Design of Prodrugs, edited by Hans Bundgaard, Elsevier Scientific Publishing Co., Amsterdam, 1985. In addition to the above agents, other agents suitable for treating, managing, or diagnosing conditions in a mammalian organism may be placed in the inner core and administered using the sustained release drug delivery devices of the current invention. Once again, reference may be made to any standard pharmaceutical textbook such as Remington&#39;s Pharmaceutical Sciences for the identity of other agents.  
         [0027]     Any pharmaceutically acceptable form of such a compound may be employed in the practice of the present invention, i.e., the free base or a pharmaceutically acceptable salt or ester thereof. Pharmaceutically acceptable salts, for instance, include sulfate, lactate, acetate, stearate, hydrochloride, tartrate, maleate and the like.  
         [0028]     Active agent  26  may be mixed with a matrix material  27 . Preferably, matrix material is a polymeric material that is compatible with body fluids and the eye. Additionally, matrix material should be permeable to passage of the active agent therethrough, particularly when the device  50  is exposed to body fluids. For this embodiment, the matrix material is PVA. Also, in this embodiment, inner drug core may be coated  28  with a coating of additional matrix material which may be the same or different from material mixed with the active agent. For the illustrated embodiment, the coating employed is also PVA.  
         [0029]     In addition to the illustrated materials, a wide variety of materials may be used to construct the devices of the present invention. The only requirements are that they are inert, non-immunogenic, of the desired permeability, and capable of being micro-machined. Materials that may be suitable for fabricating the device include naturally occurring or synthetic materials that are biologically compatible with body fluids and body tissues, and essentially insoluble in the body fluids with which the material will come in contact and capable of being micro-machined. The use of rapidly dissolving materials, materials highly soluble in body fluids, or highly flexible materials are to be avoided since dissolution of the wall would affect the constancy of the drug release, as well as the capability of the device  50  to remain in place for a prolonged period of time and flexible materials may be difficult to machine.  
         [0030]     Naturally occurring or synthetic materials that are biologically compatible with body fluids and eye tissues and essentially insoluble in body fluids which the material will come in contact include, but are not limited to metal, polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linked polyvinyl butyrate, ethylene ethylacrylate copolymer, polyethyl hexylacrylate, polyvinyl chloride, polyvinyl acetals, plasiticized ethylene vinylacetate copolymer, polyvinyl alcohol, polyvinyl acetate, ethylene vinylchloride copolymer, polyvinyl esters, polyvinylbutyrate, polyvinylformal, polyamides, polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinyl chloride, plasticized nylon, plasticized soft nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, polyvinylidene chloride, polyacrylonitrile, cross-linked polyvinylpyrrolidone, polytrifluorochloroethylene, chlorinated polyethylene, poly(1,4′-isopropylidene diphenylene carbonate), vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethyl fumerate copolymer, butadiene/styrene copolymers, silicone rubbers, especially the medical grade polydimethylsiloxanes, ethylene-propylene rubber, silicone-carbonate copolymers, vinylidene chloride-vinyl chloride copolymer, vinyl chloride-acrylonitrile copolymer and vinylidene chloride-acrylonitride copolymer.  
         [0031]     A device of the type shown in  FIGS. 1-9  may be manufactured as follows. Standard micromachining techniques such as milling, lathing, etching, etc. are applied to the material used to form device  50 . Such techniques are within the purview of one of ordinary skill in the art.  
         [0032]     It will be appreciated the dimensions of the device can vary with the size of the device, the size of the inner drug core, and the holder that surrounds the core or reservoir. The physical size of the device should be selected so that it does not interfere with physiological functions at the implantation site of the mammalian organism. The targeted disease states, type of mammalian organism, location of administration, and agents or agent administered are among the factors which would affect the desired size of the sustained release drug delivery device. However, because the device is intended for placement in the eye, the device is relatively small in size. Generally, it is preferred that the device, excluding the suture tab, has a maximum height, width and length each no greater than 10 mm, more preferably no greater than 5 mm, and most preferably no greater than 3 mm.  
         [0033]     It should be understood that the preferred device comprises a suture tab. However, a suture tab is not necessary for therapeutic operation of the device.  
         [0034]     The device is typically provided to the end user in a sealed sterilized package, for example, by gamma irradiation, for example, such as is disclosed in U.S. patent application Ser. No. 10/183,804, the contents of which are incorporated by reference herein.  
         [0035]     The examples and illustrated embodiments demonstrate some of the sustained release drug delivery device designs for the present invention. However, it is to be understood that these examples are for illustrative purposes only and do not purport to be wholly definitive as to the conditions and scope. While the invention has been described in connection with various preferred embodiments, numerous variations will be apparent to a person of ordinary skill in the art given the present description, without departing from the spirit of the invention and the scope of the appended claims.