• 专利附录
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    • 专利摘要:
    Provided are methods and apparatus for the treatment of mammalian organisms to achieve the desired local or systemic physiological or pharmacological effects. The method includes administering a sustained release drug delivery system to a mammalian organism in need of treatment in a region in which release of the effective agent is desired, and allowing the effective agent to pass through the device in a controlled manner. The device may comprise an inner core or reservoir containing an effective agent; A first coating layer permeable to passage of an effective agent; A second coating layer that is essentially impermeable to passage of the effective agent; And a third coating layer permeable to the passage of the effective agent. The first coating layer covers at least a portion of the inner core. The second coating layer covers at least a portion of the first coating layer and the inner core, but at least a small portion of the first coating layer or the inner core is not coated with the second coating layer. The second coating layer comprises an impermeable membrane and one or more impermeable disks. The third coating layer essentially completely covers the second coating layer and the uncoated portion of the first coating layer or the inner core.
    公开号:KR20010023358A
    申请号:KR1020007001996
    申请日:1998-08-28
    公开日:2001-03-26
    发明作者:지안빙 첸；폴 애쉬톤
    申请人:폴 애쉬톤；콘트롤 딜리버리 시스템즈, 인크.；
    IPC主号:
    专利说明:

    Sustained Release Drug Delivery Devices
    Over the years, a variety of drugs have been developed to help treat a wide variety of ailments and diseases. In many cases, however, the drugs could not be administered orally or intravenously without the risk of various adverse side effects.
    For example, intravenous gancyclovir (GCV) is effective in the treatment of CMV retinitis in AIDS patients, but bone marrow toxicity limits its usefulness. The incidence of neutropenia (absolute neutrophil count <1000) during intravenous GCV treatment ranges from 30 to 50%. Ongoing maintenance of GCV treatment is necessary to prevent the progression or recurrence of the disease, but in spite of maintenance of treatment, 30-50% of patients will experience relapse during treatment. Other problems associated with systemic GCV administration include the risk of sepsis associated with permanent indwelling catheter and the inability to receive concurrent treatment with zivudine (AZT), which has been shown to improve immune function and prolong life in AIDS patients. .
    Intravitreal GCV infusions of 200-400 μg administered once or twice weekly resulted in transient remission of CMV retinitis in AIDS patients. Intravitreal GCV infusion can provide higher intraocular drug concentrations than systemic treatment and can reduce the incidence of neutropenia. Current treatment of CMV retinitis in AIDS patients is clearly suboptimal. Gancyclovir is virus propagation inhibitory and disease inhibition therefore requires continued drug administration.
    Because of the risks of certain drugs, researchers have developed systems for the administration of these drugs to help treat these diseases and disorders. Many of these systems provide release rates that reduce the occurrence of harmful side effects.
    One such delivery device is a pill or capsule for oral administration that contains a drug encapsulated in various layers of the composition that dissolve over a period of time in the digestive tract to allow gradual or slow release of the drug into the system.
    Another type of device for controlling the administration of the drug is made by coating the drug with a polymeric material permeable to the passage of the drug to achieve the desired effect. The device is particularly suitable for treating a patient in certain local areas without exposing the patient's entire body to the drug. This is advantageous because any possible side effects of the drug can be minimized.
    The system is particularly suitable for treating diseases affecting the eye. Advances for administering drugs to the outer surface of the eye are described in Arnold, US Pat. No. 4,014,335. Arnold describes various eye implants that act as deposits or drug reservoirs for the slow release of drugs into the tear film for extended periods of time. These inserts are made of a flexible polymeric material that is biologically inert, non-allergenic, and insoluble in tears. To initiate the treatment program for these devices, an eye insert is placed in the blind space between the eyelid and the eye sclera for drug administration to the eye.
    A device made of a polymeric material insoluble in tear fluid has its form and integrity during the necessary course of treatment so that the drug can be continuously administered to the eye and surrounding tissue at a rate that is not affected by dissolution or erosion of the polymeric material. Used as a repository. At the end of the desired treatment program, the device is removed from the blind.
    Another type of device used for the sustained release of drugs to the outer surface of the eye, described in US Pat. No. 3,416,530, is made with a plurality of capillary openings that communicate between the outside of the device and an inner chamber generally formed from a polymer membrane. . While these capillary openings of this structure are effective in releasing certain drugs into the eye, they add significant complexity to the manufacture of devices because of the difficulty in controlling the size of these openings when produced at large scale using a variety of polymers.
    Other devices described in US Pat. No. 3,618,604 do not include the capillary openings, but instead provide release of the drug by diffusion through the polymer membrane. As disclosed in this patent, the device of the preferred embodiment includes a sealed container containing the drug in an inner chamber. Nevertheless, as described in US Pat. No. 4,014,335, certain problems have been identified in connection with the device, such as the difficult task and task of sealing the edges of the membrane to manufacture the container. In addition, stresses and strains introduced into the membrane walls from deformation during the manufacture of these devices can rupture the reservoir causing leaks.
    Another such device described in US Pat. No. 4,014,335 has a pair of separate discontinuous first and third walls of insoluble material in the tear fluid, wherein one of the walls is permeable to the passage of the drug. It consists of an emissive material and the remaining walls comprise a three layer stack, made of a material that is impermeable to the passage of the drug.
    The above systems and devices are intended to provide sustained release of the drug effective to treat the patient at the desired local or systemic level in order to obtain certain physiological or pharmacological effects. However, there are many disadvantages associated with their use, including the fact that it is often difficult to obtain the desired release rate of the drugs. The need for a better release system is particularly important in the treatment of CMV retinitis.
    Prior to the development of the present invention, novel sustained release delivery devices have been developed that improve many of the above problems associated with drug delivery. The device described in US Pat. No. 5,378,475 includes a first coating that is essentially impermeable to the passage of the effective drug and a second coating that is permeable to the passage of the effective drug. In the apparatus, the first coating covers at least a portion of the inner core, but at least a small portion of the inner core is not coated with the first coating layer. The second coating layer essentially completely covers the uncoated portion of the first coating layer and the inner core. A portion of the inner core not coated with the second coating layer allows passage of the medicament into the second coating layer to allow controlled release.
    Although the device described in US Pat. No. 5,378,475 solves many of the above-mentioned problems with drug delivery, the device and its manufacturing method are not without problems. Specifically, polymers suitable for coating the inner core are mainly relatively soft, which can lead to technical difficulties in producing a uniform film. It is particularly difficult when trying to coat non-spherical bodies (eg cylindrical) with edges. In this case, a relatively thick film must be applied to achieve an unbroken coating. Thus, the device tends to be larger than necessary because of the thickness required to seal the ends of the inner core.
    The issue of device size is of paramount importance in the design of devices for implantation into limited anatomical spaces such as the eye. Larger devices require more complex surgery both when implanted and removed. In addition, the extra polymer needed to achieve a uniform coating reduces the potential volume of implantation and thus limits the amount of drug that can be delivered.
    As a result of the above, there is still a need in the art to improve the design and manufacture of devices that provide delayed release of drugs to patients in order to achieve the desired local or systemic physiological or pharmacological effects, especially for intraocular purposes.
    <Summary of invention>
    Accordingly, it is a primary object of the present invention to provide a device suitable for controlled release and delayed release of a composition which is effective for obtaining the desired physiological or pharmacological effects of local or systemic.
    In one embodiment the device comprises an inner core or reservoir containing a medicament effective to achieve the desired effect. The device further includes a first coating layer. The first coating layer is transparent to the passage of the medicament. The device also includes a second coating layer comprising at least one impermeable disc and one impermeable polymer. The second coating layer is essentially impermeable to passage of the medicament and covers a portion of the first coating layer and the inner core. The second coating layer blocks the passage of the medicament from the inner core in contact with the first coating layer. The remaining portion of the unblocked inner core allows a controlled amount of medicament to pass from the inner core through the passage in the second coating layer to the first coating layer and to the third coating layer. The third coating layer is transparent to the passage of the medicament and essentially covers the entire second coating layer. The second coating layer is positioned between the inner core and the third coating layer to control the rate at which the drug is permeated through the third coating layer.
    Another object of the present invention is to provide a method for treating a mammalian organism, for example a human, in order to obtain the desired physiological or pharmacological effects of local or systemic. The method includes placing a sustained release drug delivery system in an area where release of the drug is desired and allowing the drug to pass through the third coating to the desired treatment area.
    Another object of the present invention is to provide a guide device suitable for implantation directly into the vitreous body of the eye. The devices of the present invention have been surprisingly found to provide controlled and delayed release of various compositions to treat the eye without the risk of harmful side effects.
    Another object of the present invention is to maximize the amount of drug contained in the intraocular device while minimizing the size to prolong the implantation period.
    Another object of the present invention is to provide an intraocular delivery system that can be applied to an intraocular lens to prevent inflammation or posterior capsular opacity.
    In addition to the above, as well as other objects, advantages, features and embodiments of the present invention which will become apparent below, the features of the present invention are more clearly understood by reference to the detailed description of the invention and the appended claims. Could be.
    The present invention comprises an internal core or reservoir containing a medicament effective for obtaining a desired local or systemic physiological or pharmacological effect; A first coating permeable to the passage of an effective agent; A second coating containing at least one impermeable disc and an impermeable polymer that is essentially impermeable to passage of an effective medicament; And a third coating that is permeable for passage of an effective drug. The first coating covers at least a portion of the inner core. The second coating covers at least a portion of the first coating layer and the inner core, but at least a small portion of the first coating layer or the inner core is not coated with the second coating layer. The third coating layer essentially completely covers the first coating layer and the second coating layer. A portion of the first coating layer that is not coated with the second coating layer allows passage of the medicament into the third coating layer, thus allowing controlled release.
    1 is an enlarged view of one embodiment of a sustained release drug delivery device showing an inner core, a first coating layer, a second coating layer, and a third coating layer.
    2A is an enlarged view of an impermeable polymer. 2B is an enlarged view of a second coating layer comprising an impermeable membrane and an impermeable disc.
    More specifically, the inventors have found devices and methods for their preparation that are suitable for controlled release and delayed release of a medicament effective to achieve the desired local or systemic physiological or pharmacological effects. In particular, it has been found that thinner coatings can be used by sealing at least one surface with an impermeable disc. This has the advantage that thinner, shorter devices can be manufactured than was otherwise possible. An additional advantage is that the material used to make the impervious disk does not have to be flexible (to facilitate the covering of the curved surface), so instead of using a relatively hard material it is possible to create a uniform diffuser. It can be done easily.
    The device includes an inner core or reservoir containing a medicament effective in obtaining the desired effect. The apparatus further includes a first coating layer, a second coating layer and a third coating layer. The first coating layer permeable to the passage of the effective agent may completely cover the inner core. The second coating layer covers only a portion of the first coating layer and the inner core and is impermeable to the passage of the medicament. The third coating layer covers the entirety of the first coating layer and the second coating layer and is transparent to the passage of the medicament. The first coating layer and the inner core portion not coated with the second coating layer facilitate the passage of the medicament through the third coating layer. Specifically, the second coating layer is positioned between the inner core and the third coating layer to prevent the drug from passing through the adjacent third coating layer portion to adjust the rate of passage of the drug.
    1 illustrates one embodiment of a sustained release drug delivery device of the present invention. The device shown in FIG. 1 is cylindrical, but the device can be of any shape. The apparatus comprises an inner core or reservoir (5), a permeable coating (10) permeable to passage of a medicament in the core or reservoir, an impermeable coating (15) and a core impermeable to passage of the medicament in the core or reservoir (5). Or a permeable coating 20 permeable to the passage of the medicament in the reservoir 5. The second coating comprises an impermeable polymer 17 and discs 18 and 19 at the cylindrical core end. 1 further shows a suture tag 30.
    2A and 2B show only the second coating layer and illustrate the advantages associated with using an impermeable disc as part of the second coating layer. 2A shows an impermeable polymer layer 17 which thinly coats the edges of the inner core. The thinly coated edge 31 creates the possibility for leakage of the effective drug.
    2B illustrates the advantages of using an opaque disc. The second coating layer contains the impermeable polymer 17 and the impermeable discs 18 and 19 at the ends of the cylindrical core. The impermeable disc 18 contains a diffuser. The impermeable discs 18 and 19 prevent leakage of the effective agent through the thin edges 31 of the impermeable polymer.
    The invention also relates to a method of treating a mammalian organism for obtaining the desired physiological or pharmacological effects of local or systemic. The method includes administering a sustained release drug delivery system to the mammalian organism and allowing a medicament effective to achieve the desired local or systemic effect through the third coating to contact the mammalian organism. As used herein, the term administration refers to positioning, insertion, infusion, implantation or any other means for exposing a device to a mammalian organism. The route of administration depends on various factors, including the type of response or treatment, the type of drug, and the site of administration desired.
    Devices of certain embodiments include at least the following areas: primary tumors of cancer (eg, glioblastoma); Chronic pain; arthritis; Rheumatic diseases; Medicaments effective to achieve desirable local or systemic physiological or pharmacological effects on the treatment of hormone deficiencies such as diabetes and dwarfism, and on the modification of immune responses, eg on the prevention of graft rejection and on the treatment of cancer. It can be applied in providing controlled and delayed release. Various other disease states can also be prevented or treated using the drug delivery device of the present invention. Such disease states are known by those of ordinary skill in the art. If not a person of ordinary skill in the art, Goodman and Gilman, The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, NY, 1990, and references cited herein by reference See Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA, 1990.
    The device is also suitable for use in the treatment of mammalian organisms infected with AIDS and AIDS related opportunistic infections, such as cytomegalovirus infection, Toxoplasma disease, pneumocystis carni and mycobacterium abium cells.
    This device is particularly suitable for the treatment of eye diseases such as glaucoma, proliferative vitreoretinopathy, diabetic retinopathy, uveitis and keratitis. The device is also particularly suitable for use as an intraocular device in the treatment of mammalian organisms with cytomegalovirus retinitis, in which the device is surgically implanted into the vitreous body of the eye.
    As noted above, the inner core or reservoir contains a medicament effective to achieve the desired physiological or pharmacological effects of the topical or systemic. Agents of the following groups may be incorporated into the devices of the present invention: anesthetics and analgesics, such as lidocaine and related compounds and benzodiazepam and related compounds; Anticancer agents such as 5-fluorouracil, adriamycin and related compounds; Anti-inflammatory agents such as 6-mannose phosphate; Antifungal agents such as fluconazole and related compounds; Antiviral agents, for example trisodium phosphomonoformate, trifluorothymidine, acyclovir, gancyclovir, DDI and AZT; Cell transport / motility blockers such as colchicine, vincristine, cytocalin B and related compounds; Antiglaucoma drugs such as beta-blockers; Timolol, betaxolo athenalol and the like; Immunological response modifiers such as muramyl dipeptides and related compounds; Peptides and proteins such as cyclosporin, insulin, growth hormone, insulin related growth factors, heat shock proteins and related compounds; Steroidal compounds such as dexamethasone, prednisolone and related compounds; Low solubility steroids such as fluorocinolone acetonide and related compounds; And carbon anhydrous inhibitors.
    In addition to the agents described above, other agents are also suitable for administration to the eye and surrounding tissues to produce a physiological or pharmacological beneficial effect of the topical or systemic. Examples of such agents include neuroprotective agents such as nimodipine and related compounds; Antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidine, oxytetracycline, chloramphenicol, gentamicin and erythromycin; Antibacterial agents such as sulfonamide, sulfacetamide, sulfamethiazole and sulfisoxazole; Antiviral agents such as idocuridine; And other antibacterial agents such as nitrofurazone and sodium propionate; Anti-allergic agents such as antazoline, metapyriline, chlorpheniramine, pyrylamine and propenpyridamine; Anti-inflammatory agents such as hydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate, fluorocinolone, medridone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluorometallon, betamethasone and triminolone; Decongestants such as phenylephrine, napazoline and tetrahydrazoline; Pupil diminishing agents and anticholinesterases such as pilocarpine, esserine salicylate, carbacol, di-isopropyl fluorophosphate, phospholine iodine and demecarium bromide; Shandong pharmaceuticals such as atropine sulfate, cyclopentholate, homatropin, scopolamine, tropicamide, eucartropin and hydroxyamphetamine; Sympathetic stimulants such as epinephrine; And prodrugs, such as those described in Design of Prodrugs, edited by Hans Bundgaard, Elsevier Scientific Publishing Co., Amsterdam, 1985. Once again, reference may be made to any standard pharmaceutical textbook, for example Remington's Pharmaceutical Sciences, for the identification of other drugs.
    Any pharmaceutically acceptable form of such compounds, ie their free bases or pharmaceutically acceptable salts or esters, can be used in the practice of the present invention. Examples of pharmaceutically acceptable salts include sulfate, lactate, acetate, stearate, hydrochloride, tartrate, maleate and the like.
    A large number of polymers can be used to construct the device of the present invention. The only requirement is that they be inert, non-immunogenic and have the desired permeability.
    Materials that may be suitable for the manufacture of devices include natural or synthetic materials that are biologically compatible with tears and ocular tissues and are essentially insoluble in the body fluids to which the materials will come into contact. The use of rapidly dissolving substances or highly soluble substances in the ophthalmic solution should be avoided because the dissolution of the walls will affect not only the constant release of the drug but also the capacity of the system to remain in place for an extended period of time.
    Natural or synthetic materials that are biologically compatible with tear and ocular tissues and are essentially insoluble in the body fluids to which the materials will come into contact include polyvinyl acetate, crosslinked polyvinyl alcohol, crosslinked polyvinyl butyrate, ethylene ethylacrylate Copolymer, polyethyl hexyl acrylate, polyvinyl chloride, polyvinyl acetal, plasticized ethylene vinyl acetate copolymer, polyvinyl alcohol, polyvinyl acetate, ethylene vinyl chloride copolymer, polyvinyl ester, polyvinyl butyrate, polyvinyl for Equine, Polyamide, Polymethylmethacrylate, Polybutylmethacrylate, Plasticized Polyvinyl Chloride, Plasticized Nylon, Plasticized Soft Nylon, Plasticized Polyethylene Terephthalate, Natural Rubber, Polyisoprene, Polyisobutylene, Poly Butadiene, polyethylene, polytetrafluoro Tylene, polyvinylidene chloride, polyacrylonitrile, crosslinked polyvinylpyrrolidone, polytrifluorochloroethylene, chlorinated polyethylene, poly (1,4'-isopropylidene diphenylene carbonate), vinylidene chloride , Acrylonitrile copolymers, vinyl chloride-diethyl fumeral copolymers, silicone rubbers, in particular medicinal polydimethylsiloxanes, ethylene-propylene rubbers, silicone-carbonate copolymers, vinylidene chloride-vinyl chloride copolymers, vinyl chloride- Acrylonitrile copolymers and vinylidene chloride-acrylonitrile copolymers include, but are not limited to these.
    Specifically, the second layer of the device of the present invention is biologically compatible with any of the polymers described above or with lacrimal fluid and ocular tissue, is essentially insoluble in the body fluids to which the substance will come into contact and is essential for the passage of effective agents. Can be made of any other polymer that is impermeable. As used herein, the term “impermeable” means that the layer does not enable passage of the effective agent at a rate necessary to achieve the desired local or systemic physiological or pharmacological effect.
    The second layer should be chosen to be impermeable to passage of the medicament from the inner core to the adjacent portion of the second coating layer, as described above. The purpose is to block the passage of the medicament to the portion described above and thus to control the release of the medicament from the drug delivery device.
    The composition of the second layer, for example the polymer, should be chosen to enable controlled release as described above. The preferred composition of the second layer will vary depending on factors such as the active agent, the desired rate of control and the mode of administration. Identity of the active agent is important because, for example, the size of the molecule is critical to determining the rate of release of the drug into the second layer.
    The disk is essentially impermeable to passage of the effective medicament and can cover the inner core portion that is not covered by the impermeable membrane of the second coating layer. As shown in Figure 2B, the disk can cover the edges of the inner core and allow a coating of a thinner and more uniform impermeable film to be applied on the inner core than was otherwise possible. In one embodiment, the impermeable membrane can completely cover the inner core and the disk. Drug release may occur via the passage through the hole in the disc (see also 2B) or through the hole in the impermeable membrane. The physical properties of the polymer used in the disc can be selected based on their ability to withstand subsequent processing steps (eg, thermal curing) without causing deformation of the holes. The polymer for the impermeable membrane can be selected based on the ease of coating of the inner core. Possible materials for the disc include Teflon, polycarbonate, polymethyl methacrylate, polyethylene alcohol, high grade ethylene vinyl acetate (9% vinyl content) and polyvinyl alcohol.
    Since the second coating layer is essentially impermeable to passage of the effective medicament, only a portion of the inner core or reservoir and the first coating layer may be coated with the second coating layer. Depending on the desired delivery rate of the device, the second coating layer coats only a small portion of the surface area of the inner core for faster release rates of the effective medicament or a larger portion of the inner core for slower release rates of the effective medicament. can do.
    At least 50% of the surface area may be coated by the second coating layer. For slower release rates, more than 75% of the surface area can be coated. For even slower release rates, more than 95% of the surface area can be coated.
    Thus, as long as the release rate of the desired medicament is obtained, any portion of the surface area up to about 100% but not including 100% of the first coating layer and the inner core may be coated with the second coating layer.
    The second coating comprising the impermeable membrane and the impermeable disc is located at any position on the first coating layer and the inner core, including but not limited to the top, bottom and any side of the first coating layer and the inner core. can do. It may also be located on the top and one side, or on the bottom and one side, or on the top and bottom or opposite side or on any combination of top, bottom or sides.
    The first and third layers of the device of the present invention must be biologically compatible with body fluids and ocular tissues, and are essentially insoluble in the body fluids to which the substance will come in contact and permeable to the passage of a medicament or composition effective to achieve the desired effect. .
    The effective agent diffuses in the lower chemical potential direction, ie towards the outer surface of the device. Equilibrium is again at the outer surface of the device. When the conditions on both sides of the third coating layer remain constant, the steady state flux of the active agent is achieved according to the law of diffusion of Pick's. The rate of passage of the drug through the material by diffusion generally depends on the solubility of the drug therein, as well as the thickness of the wall. This means that the choice of the appropriate material for producing the wall will depend on the specific drug used.
    The rate of diffusion of the effective agent through the polymeric layer of the present invention can be determined through diffusion cell studies conducted under sinking conditions. In diffuse cell studies conducted under sinking conditions, the concentration of drug in the receptor compartment is essentially zero as compared to the high concentration in the donor compartment. Under these conditions, the drug release rate is represented by the following equation.
    Q / t = (D · K · A · DC) / h
    Where Q is the amount of drug released, t is time, D is the diffusion coefficient, K is the partition coefficient, A is the surface, DC is the difference in concentration of the drug across the membrane, and h is the thickness of the membrane. .
    If the drug diffuses through the layer through the water filled pores, there is no distribution. Thus, K can be removed from the equation. Under sinking conditions, when the emission from the donor side is very slow, the DC value is essentially constant and equal to the concentration of the donor compartment. Thus, the release rate will depend on the surface area (A), the thickness (h) and the diffusivity (D) of the film. In the construction of the device of the present invention, the size (ie surface area) depends mainly on the size of the effective drug.
    Thus, the transmittance value can be obtained from the slope of the Q versus time plot. The transmittance P may be related to the diffusion coefficient D by Equation 2 below.
    P = (KD) / h
    Once permeability is obtained for a coating that is permeable to the passage of the medicament, the surface area of the medicament that should be coated with the coating that is opaque to the passage of the medicament can be determined. This is done by gradually decreasing the available surface area until the desired release rate is obtained.
    Exemplary microporous materials suitable for use as the first and third coating layers are described, for example, in US Pat. No. 4,014,335, which is incorporated herein by reference. These materials include crosslinked polyvinyl alcohols, polyolefins or polyvinyl chlorides or crosslinked gelatins; Regenerated insoluble, noncorrosive cellulose, acrylated cellulose, esterified cellulose, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate diethyl-aminoacetate; Polyurethanes, polycarbonates, and microporous polymers formed by coprecipitation of poly cations and poly anion-modified insoluble collagen. Crosslinked polyvinyl alcohol is preferred. The third coating layer is selected to cause delayed release of the medicament from the inner core to contact the mammalian organism, for example a human. The third coating layer need not provide for gradual release or control of the medicament into the biological environment, but it is advantageous to select the third coating layer to also have the above characteristics or characteristics.
    The device of the invention can be produced in various ways, for example by taking an effective amount of a medicament and compressing the medicament into the desired form. Once formed, the first coating layer can be applied. The first coating layer may be applied by dipping the device one or more times in a solution containing the desired polymer. Optionally, the first coating layer may be applied to the polymer solution by dipping, spraying, brushing or other means of coating the outer surface of the device. When using the polyvinyl alcohol solution to obtain the second coating layer, the desired thickness can be obtained by applying the coating several times. Each coating can be dried before applying the next coating. Finally, the device can be heated to control the permeability of the outer coating.
    The impermeable disc can be applied directly over the first layer before being coated with the impermeable polymer layer. In the case of a cylindrical core, the impermeable membrane can be wound around the core after the disk has been applied to one or both ends. Thus, the second coating layer includes both an impermeable membrane and an impermeable disc. By sealing at least one surface with an impermeable disk, thinner layers can be used. This has the advantage that thinner and shorter devices can be manufactured than would otherwise be possible.
    The impermeable polymer layer should be thick enough to prevent release of the drug through it except for the uncovered area (diffusion layer or diffuser). Since it is desirable to minimize the size of the implant, the thickness of the impermeable membrane layer may be less than 0.01 to 2 millimeters, preferably less than 0.01 to 0.5 millimeters.
    The impermeable disc should also be thick enough to prevent release of the drug through it except through specifically prepared membranes or spheres. Since it is desirable to minimize the size of the implant, the thickness of the impermeable disc may be 0.01 to 2 millimeters, preferably less than 0.01 to 1 millimeter.
    Once the second coating layer, including the impermeable disk (s), is applied to the device, the third coating layer can be applied. The third coating layer can be applied by immersing the device one or more times in a solution containing the desired polymer. Optionally, the third coating layer may be applied to the polymer solution by dipping, spraying, brushing or other means of coating the outer surface of the device. When using polyvinyl alcohol solution to obtain the third coating layer, the preferred thickness can be obtained by applying the coating several times. Each coating can be dried before applying the next coating. Finally, the device can be heated to control the permeability of the outer coating.
    The foregoing description of the method of making the device of the present invention is exemplary only, and various compositions should not be considered as limiting the scope of the present invention in any way, as is known to those skilled in the art. In particular, the method of making the device depends on the identity of the selected polymer and the active agent. Given the composition of the active agent, the first coating, the second coating (membrane and disk) and the third coating, one of ordinary skill in the art can easily manufacture the device of the present invention using conventional coating techniques. .
    A method of treating a mammalian organism to achieve the desired local or systemic physiological or pharmacological effect is achieved by administering the sustained release drug delivery device of the present invention to a mammalian organism, wherein the medicament is passed through the device and directly with the mammalian organism. It includes making contact.
    The drug delivery system of the present invention can be administered to a mammalian organism via any route of administration known in the art. Examples of the administration route include intraocular, oral, subcutaneous, intramuscular, intraperitoneal, intranasal, and skin. In addition, one or more devices may be administered at one time or one or more agents may be included in the inner core.
    The drug delivery system of the present invention is particularly suitable for application to intraocular lenses and for direct implantation of the eye into the vitreous body.
    Their administration methods and preparation techniques are known by those skilled in the art. Their preparation techniques are described in Remington's Pharmaceutical Sciences.
    The drug delivery system can be administered for a sufficient time under conditions that allow for the treatment of the disease of interest.
    For localized drug delivery, the device can be surgically implanted at or near the site of action. This is the case where the device of the present invention has been used for the treatment of intraocular diseases, primary tumors, rheumatic and arthritis diseases and chronic pain.
    For alleviation of the whole body, the device can be implanted subcutaneously, intramuscularly or intraperitoneally. This is where the device provides continuous systemic levels and to avoid premature metabolism. The device may also be administered orally.
    In one embodiment of the present invention, an intraocular device can be prepared which contains ganciclovir as an effective agent in an amount effective to prevent the replication of the virus. The device may be used to effectively eradicate or inhibit regeneration of cytomegalovirus retinitis when surgically implanted into the vitreous of the eye. The device may remain in vitreous permanently after treatment is complete. Preferred amounts of gancyclovir used in these devices range from about 0.01 mg to about 40 mg. More preferably, the device contains about 15 mg to about 30 mg of gancyclovir. These preferred ranges can provide delayed release of gancyclovir over a period spanning several hours to two years. Preferred first coating layer is polyvinyl alcohol. Preferred impermeable discs are teflon or ethyl vinyl alcohol. Preferred impermeable polymers are ethylene vinyl acetate. Preferred third coating layer is polyvinyl alcohol. When the device is made for implantation into the vitreous body of the eye, the device preferably does not exceed about 7 millimeters in any direction. Thus, the cylindrical device shown in FIG. 1 preferably does not exceed 7 millimeters in height or exceed 3 millimeters in diameter. Preferred thicknesses of the first coating layer range from about 0.05 to about 0.5 millimeters. Preferred thicknesses of the second coating layer range from about 0.1 to about 1.0 millimeters. Preferred thicknesses of the third coating layer range from about 0.1 to about 2.0 millimeters.
    In another embodiment of the present invention, an intraocular device containing nimodipine as an effective agent may be prepared. As further shown in the examples below, the devices can be used to provide prolonged release of nimodipine for several years. Preferred amounts of nimodipine used in these devices range from 2 to 15 mg. More preferably, the device contains approximately 10-15 mg. These preferred ranges can provide delayed release of nimodipine for periods of more than 10 years. Preferred materials include polyvinyl alcohol as the first coating layer, wherein one end of the cylindrical device is covered with a disc of ethylene vinyl acetate (9%) and the other is not covered, and the disk-sealed end and the cylindrical faces are covered. Ethylene vinyl acetate (19%) as the impermeable polymer layer, and the third layer covering the entire assembly comprises silicon. Preferred thicknesses of the first layer range from 0.05 to 0.2 millimeters. The preferred thickness of the impermeable polymer layer is 0.05 to 0.15 millimeters, preferably 0.75 millimeters. The preferred thickness of the disc is in the range of 0.05 to 2 millimeters and the preferred thickness of the third layer is in the range of 0.1 to 0.5 millimeters.
    In another embodiment of the present invention, an intraocular device containing fluorocinolone acetonide can be prepared as an effective agent. As further shown in the examples below, the devices can be used to provide delayed release of fluorocinolone acetonide for several years. Preferred amounts of fluorocinolone acetonide used in these devices range from 2 to 15 mg. More preferably, the device contains approximately 5-10 mg. These preferred ranges can provide delayed release of fluorocinolone acetonide over a three year period. The total diameter of the device is 2 millimeters and the length is 5 millimeters.
    Preferred materials include polyvinyl alcohol as the first coating layer, wherein one end of the cylindrical device is covered with a disc of ethylene vinyl acetate (9%) and the other is not covered, and the disk-sealed end and the cylindrical faces are covered. Ethylene vinyl acetate (19%) as the impermeable polymer layer, and the third layer covering the entire assembly comprises polyvinyl alcohol. Preferred thicknesses of the first layer range from 0.05 to 0.2 millimeters. The preferred thickness of the impermeable polymer layer is 0.05 to 0.15 millimeters, preferably 0.75 millimeters. The preferred thickness of the disc is in the range of 0.05 to 2 millimeters and the preferred thickness of the third layer is in the range of 0.1 to 0.5 millimeters.
    While the foregoing embodiments of the invention have been described in terms of preferred ranges of amounts of effective medicament, and preferred thicknesses of the preferred first and second coatings, these do not limit the invention in any sense. As will be readily appreciated by one of ordinary skill in the art, the preferred amounts, materials, and dimensions depend on the method of administration, the effective agent used, the polymer used, the desired release rate, and the like. Likewise, the actual release rate and duration of release may be determined by various factors other than those described above, such as the disease state to be treated, the age and condition of the patient, the route of administration, as well as other factors readily apparent to those of ordinary skill in the art. Depends on
    From the foregoing description, one of ordinary skill in the art can readily identify the essential features of the present invention and can adapt the present invention to adapt it to uses and conditions of the present invention without departing from the spirit and scope of the invention. And / or may be modified. As such, these changes and / or modifications are appropriately intended to be within the full scope of equivalents of the following claims.
    权利要求:
    Claims (23)
    [1" claim-type="Currently amended] (1) an internal core or reservoir containing an effective amount of a medicament to achieve the desired local or systemic physiological or pharmacological effect,
    (2) a first coating layer permeable to the passage of the medicament, covering at least a portion of the inner core,
    (3) at least a small portion of the inner core or the first coating layer covers at least a portion of the inner core and the first coating layer so as not to be coated with the second coating layer, and comprises an impermeable membrane and one or more impermeable disks. A second coating layer that is essentially impermeable to passage and
    (4) permeable to passage of the medicament, essentially covering the second and first uncoated portions of the first and / or inner cores to allow the medicament to pass through the third coating in a controlled manner. Third coating layer
    A method of treating a mammalian organism for obtaining a desired local or systemic physiological or pharmacological effect, comprising administering a sustained release drug delivery system comprising a mammalian organism in need thereof.
    [2" claim-type="Currently amended] The method of claim 1, wherein the third coating layer comprises polyvinyl alcohol.
    [3" claim-type="Currently amended] The method of claim 2, wherein the second coating layer comprises ethylene vinyl acetate.
    [4" claim-type="Currently amended] 4. The method of claim 3, wherein the first coating layer comprises polyvinyl alcohol.
    [5" claim-type="Currently amended] The method of claim 1, wherein the effective agent comprises fluorocinolone acetonide, nimodipine or gancyclovir.
    [6" claim-type="Currently amended] (1) an internal core or reservoir comprising an effective amount of gancyclovir effective to achieve the desired local or systemic physiological or pharmacological effect,
    (2) a first coating layer permeable to the passage of the medicament, essentially completely covering the inner core,
    (3) said intercyclo, at least a small portion of the inner core or the first coating layer covering at least a portion of the inner core and the first coating layer so as not to be coated with the second coating layer and comprising an impermeable membrane and one or more impermeable disks; A second coating layer that is essentially impermeable to passage of the vir and
    (4) passage of the gancyclovir, essentially covering completely the uncoated portion of the second coating layer and the first coating layer or inner core to allow the gancyclovir to pass through the third coating layer in a controlled manner. Third coating layer permeable to
    A method for treating cytomegalovirus retinitis in a mammalian organism comprising administering a sustained release drug delivery system comprising a mammalian organism in need thereof.
    [7" claim-type="Currently amended] (1) an internal core or reservoir containing an effective amount of a medicament effective to achieve the desired physiological or pharmacological effect,
    (2) a first coating layer permeable to the passage of the medicament, covering at least a portion of the inner core,
    (3) at least a small portion of the inner core or the first coating layer covers at least a portion of the inner core and the first coating layer so as not to be coated with the second coating layer, and comprises an impermeable membrane and one or more impermeable disks. A second coating layer that is essentially impermeable to passage and
    (4) permeable to passage of the medicament, essentially covering the second and first uncoated portions of the first and / or inner cores to allow the medicament to pass through the third coating in a controlled manner. Third coating layer
    A method of providing controlled and sustained administration of a medicament effective to achieve a desired local or systemic physiological or pharmacological effect, comprising surgically implanting a sustained release drug delivery system comprising a.
    [8" claim-type="Currently amended] 8. The method of claim 7, wherein the device is surgically implanted into the vitreous of the eye.
    [9" claim-type="Currently amended] 8. The method of claim 7, wherein said first and third coating layers comprise polyvinyl alcohol.
    [10" claim-type="Currently amended] 8. The method of claim 7, wherein said third coating layer is silicon.
    [11" claim-type="Currently amended] The method of claim 9, wherein the second coating layer comprises ethylene vinyl acetate.
    [12" claim-type="Currently amended] The method of claim 11, wherein the active agent is gancyclovir or 5-fluorouracil.
    [13" claim-type="Currently amended] The method of claim 11, wherein the effective agent is a low solubility steroid.
    [14" claim-type="Currently amended] The method of claim 13, wherein the low solubility steroid is fluorocinolone acetonide.
    [15" claim-type="Currently amended] The method of claim 11, wherein the effective agent is a neuroprotective agent.
    [16" claim-type="Currently amended] The method of claim 15, wherein said neuroprotective agent is nimodipine.
    [17" claim-type="Currently amended] (A) an internal core or reservoir containing an effective amount of a medicament effective to achieve the desired local or systemic physiological or pharmacological effect,
    (B) a first coating layer permeable to the passage of the medicament, covering at least a portion of the inner core,
    (C) at least a small portion of the inner core or the first coating layer covers at least a portion of the inner core and the first coating layer so as not to be coated with the second coating layer and comprises an impermeable membrane and one or more impermeable disks. A second coating layer impermeable to passage of and
    (D) a third coating layer permeable to the passage of the effective agent, essentially completely covering the second coating layer and the first coating layer or the uncoated portion of the inner core.
    Sustained release drug delivery system comprising a.
    [18" claim-type="Currently amended] 18. The sustained release drug delivery system according to claim 17, wherein the third coating layer comprises polyvinyl alcohol.
    [19" claim-type="Currently amended] The sustained release drug delivery system according to claim 18, wherein the second coating layer comprises ethylene vinyl acetate.
    [20" claim-type="Currently amended] 20. The sustained release drug delivery system according to claim 19, wherein the first coating layer comprises polyvinyl alcohol.
    [21" claim-type="Currently amended] 21. A sustained release drug delivery system according to claim 20, wherein said effective agent is gancyclovir or fluorocinolone acetonide.
    [22" claim-type="Currently amended] 18. The sustained release drug delivery system according to claim 17, wherein the effective agent is nimodipine.
    [23" claim-type="Currently amended] 18. The sustained release drug delivery system according to claim 17, wherein the third coating layer comprises silicone.
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    HK1035135A1|2009-09-25|
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    CZ302339B6|2011-03-23|
    BR9811381A|2000-08-29|
    TWI222884B|2004-11-01|
    YU11100A|2002-12-10|
    AU9029198A|1999-03-22|
    US5902598A|1999-05-11|
    CZ2000604A3|2000-09-13|
    CN1283992A|2001-02-14|
    PL344039A1|2001-09-24|
    EP1009388A1|2000-06-21|
    JP2010168388A|2010-08-05|
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    IL134568D0|2001-04-30|
    AR017026A1|2001-08-22|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1997-08-28|Priority to US08/919,221
    1997-08-28|Priority to US08/919,221
    1998-08-28|Application filed by 폴 애쉬톤, 콘트롤 딜리버리 시스템즈, 인크.
    1998-08-28|Priority to PCT/US1998/017342
    2001-03-26|Publication of KR20010023358A
    优先权:
    申请号 | 申请日 | 专利标题
    US08/919,221|US5902598A|1997-08-28|1997-08-28|Sustained release drug delivery devices|
    US08/919,221|1997-08-28|
    PCT/US1998/017342|WO1999011244A1|1997-08-28|1998-08-28|Sustained release drug delivery devices|
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