MXPA00001941A

MXPA00001941A - Sustained release drug delivery devices

Info

Publication number: MXPA00001941A
Application number: MXPA/A/2000/001941A
Authority: MX
Inventors: Jianbing Chen; Paul Ashton
Original assignee: Control Delivery Systems Inc
Priority date: 1997-08-28
Filing date: 2000-02-24
Publication date: 2002-02-26

Abstract

A method and device for treating a mammalian organism to obtain a desired localor systemic physiological or pharmacological effect is provided. The method includes administering a sustained release drug delivery system to a mammalian organism in need of such treatment at an area wherein release of an effective agent is desired and allowing the effective agent to pass through the device in a controlled manner. The device includes an inner core or reservoir comprising the effective agent;a first coating layer, which is permeable to the passage of the effective agent;a second coating layer, which is essentially impermeable to the passage of the effective agent;and a third coating layer, which is 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 inner core;however, at least a small portion of the first coating layer or inner core is not coated with the second coating layer. The second coating layer includes an impermeable film and at least one impermeable disc. The third coating layer essentially completely covers the second coating layer and the uncoated portion of the first coating layer or inner core.

Description

DEVICES FOR SUPPLYING MEDICINAL PRODUCTS, FOR SUSTAINED RELEASE Field of Invention The present invention relates to a sustained release drug delivery device comprising an inert core or reservoir containing an agent effective to obtain a desired local or systemic physiological or pharmacological effect; a first coating that is permeable for the passage of the effective agent; a second coating containing an impermeable polymer and at least one disk essentially impermeable for the passage of the effective agent; and a third permeable coating for the passage of the effective agent. The first coating covers at least a portion of the inert core. The second coating covers at least a portion of the first coated layer and inert core; however, at least a small portion of the first coated layer or inert core is not coated with the second coated layer. The coated third layer essentially completely covers the first coated layer and the Ref: 32827 second coated layer. The portion of the first coated layer that is not coated with the second coated layer allows the agent to pass to the third coated layer thereby allowing a controlled release.

Background of the Invention Over the years, several medications have been developed to help treat a wide variety of discomforts and illnesses. However, in many cases such medications are not able to be administered either orally or intravenously without the risk of several deleterious side effects.

For example, intravenous ganciclovir (VCG) is effective in the treatment of CMV retinitis in patients with AIDS, but its toxicity in the spinal cord limits its usefulness. The incidence of neutropenia (absolute neutrophil count <1000) during intravenous GCV therapy ranges from 30 to 50%. Continuous maintenance of GCV therapy is necessary to prevent progression or recrudescence of the disease, but despite maintaining therapy, 30 to 50% of patients experience a relapse. Other problems associated with the administration of systemic GCV include the risk of the release of septicemia for permanent resident catheters and the inability to receive concurrent therapy with zidovudine (AZT) which has shown a life and prolonged improvement of immune function in patients with AIDS.

Injections of GCV int ravi treales from 200 to 400 μg administered once or twice weekly have resulted in temporary remissions of CMV retinitis in patients with AIDS. Intravitreal GCV injections can provide a higher concentration of intraocular medication than systemic therapy and reduce the incidence of neutropenia. The current treatment of CMV retinitis in patients with AIDS is clearly below optimal. Glanciclovir is a virsactant and in this way the inhibition of the disease requires maintaining the administration of medication.

Due to the risks that certain medications impose, research has developed systems to administer such medications to help in the treatment of these discomforts and diseases. Many of these systems provide a release range that reduces the occurrence of damaging side effects.

One such delivery device is an orally administered capsule or capsule containing a medicament encapsulated within several layers of a composition that dissolves for a period of time in the digestive tract, thereby allowing a gradual or slow release of the drug in the system.

Another type of device for controlling the administration of such medicaments is produced by coating a medicament with a permeable polymer material for the passage of the medicament to obtain the desired effect. Such devices are particularly suitable for treating patients in a specific local area without having to expose the patient's entire body to the medication. This is advantageous since any possible lateral effect of the medicament can be minimized.

Such systems are particularly suitable for treating discomforts affecting the eye. Advances for administering a medicament on the external surface of the eye are described in US Patent No. 4,014,335 to Arnold. Arnold describes several eye inserts that act as a reservoir or reservoir of medication to slowly release a drug in the tear film for prolonged periods of time. These inserts are made of a flexible polymeric material that is biologically inert, non-allergic, and insoluble in the tear fluid. To initiate the therapeutic programs of these devices, the ocular inserts are placed in a duct with a single hole between the sclera of the eyeball and the eyelid to administer the medication to the eye.

Devices formed of polymeric materials that are insoluble in the tear fluid maintain their shape and integrity during the course of therapy necessary to serve as a reservoir of medicament for continuously administering a medicament to the eye and surrounding tissues at a rate that is not effected. by the dissolution or erosion of the polymeric material. At the end of the desired therapeutic program, the device is removed from the single-hole conduit.

Another type of device used for the sustained release of a medicament on an external surface of the eye, described in the patent No. 3,416,530, is made with a plurality of capillary openings that communicate between the outside of the device and the generally defined inner chamber of a polymeric membrane. While these capillary openings in this construction are effective in releasing certain medicaments to the eye, considerable complexity is added to make the device since it is difficult to control the size of these openings to large-scale processing using various polymers.

Another device, described in U.S. Patent No. 3,618,604, does not involve such capillary openings, but instead provides for drug release by diffusion through a polymeric membrane. The device, in a preferred embodiment, as described in that patent, comprises a sealed container having the medicament in an interior chamber. However, as described in U.S. Patent No. 4,014,335, certain problems have been identified with such devices such as the difficulty of the task of sealing the margins of the membrane to form the container. In addition, the stresses and stresses that enter the walls of the deformation membrane during the development of these devices can cause ruptures and leaks in the reservoir.

Another such device, described in U.S. Patent No. 4,014,335, comprises a three-layer laminate having a separate and discrete first and third wall pair formed of a material insoluble in the tear fluid with one of the walls formed of a material drug release permeable to the passage of the drug and the other walls formed of a material impervious to the passage of the drug.

The aforementioned systems and devices are intended to provide sustained release of effective drugs in the treatment of patients at a desired systemic or local level to obtain certain physiological or pharmacological effects. However, there are many disadvantages associated with its use including the fact that these are often difficult to obtain the desired release rate of the drug. The need for a better delivery system is especially significant in the treatment of CMV retinitis.

Prior to developing the present invention, a novel sustained delivery delivery device was developed that ameliorates many of the aforementioned problems associated with the delivery of medication. The device, which is described in U.S. Patent No. 5,378,475, includes a first coating essentially impermeable to the passage of the effective agent and a second coating permeable to the passage of the effective agent. In the device, the first coating covers at least a portion of the inner core; however, at least a small portion of the inner core is not covered with the first coating layer. The second coating layer covers essentially completely the first coating layer and the uncovered portion of the inner core. The portion of the inner core that is not covered with the second coating layer allows the passage of the agent in the second coating layer thus allowing a controlled release.

Although the device described in U.S. Patent No. 5,378,475 solves many of the aforementioned problems concerning the delivery of medication, the devices and the method of making the devices are not without problems. In particular, suitable polymers for coating the inner core are often relatively smooth and technical difficulties in the production of uniform films can result. This is especially true when trying to coat non-spherical bodies with ends (such as cylindrical shapes). In such cases, relatively thick films should be applied to make uninterrupted coatings. In this way, the devices tend to be enlarged as necessarily as a result of the need for thickness to seal the ends of the inert core.

The problem of the size of the device is extremely important in the design of devices for implantation in limited anatomical spaces such as the eye. Large devices require more complex surgery to both implant and remove. In addition, the extra polymer requirement to perform a uniform coating reduces the potential volume of the implant and therefore limits the amount of medication that can be delivered.

As a result of the foregoing, a need remains in the art to improve the design and method of preparing devices that provide a sustained release of a drug to a patient to obtain a desired local or systemic physiological or pharmacological effect especially for ocular use. .

Brief description of the invention.

It is therefore a primary objective of the present invention to provide an appropriate device for the control and sustained release of an effective composition to obtain a desired local or systemic physiological or pharmacological effect.

The device, in one embodiment, includes an inner core or reservoir that contains an effective agent to obtain the desired effect. The device further includes a first coating layer. The first coating layer is permeable for the passage of the agent. In addition, the device includes a second coating layer that includes at least one waterproof disk and a waterproof polymer. The second coating layer is essentially impermeable for the passage of the agent and covers a portion of the first coating layer and inner core. The second coating layer blocks the passage of the agent from the inner core to those sides where the first coating layer is in contact. The excess portion of the inner core which is not blocked allows a controlled amount of the agent from the inner core to the passage in the first coating layer by means of a passage in the second coating layer, in a third coating layer. The third coating layer is permeable to the passage of the agent and essentially covers the second full coating layer. The second coating layer is placed between the inner core and the third coating layer in order to control the rate at which the agent permeates through the third coating layer.

Another object of the present invention is to provide a method for the treatment of a mammalian organism, eg, human, to obtain a desired local or systemic physiological or pharmacological effect. The method includes placing the sustained release drug delivery system in an area where release of the agent is desired and allowing the agent to pass through the third coating to the desired area of treatment.

Another object of the present invention is to provide an appropriate ocular device for direct implantation in the vitreous of the eye. Such devices of the present invention are surprisingly found to provide a sustained controlled release of various compositions for the treatment of the eye without the risk of damaging side effects.

Another object of the present invention is to maximize the amount of medicament contained in an infraocular device while minimizing its size in order to prolong the duration of the implant.

Another object of the present invention is to provide an ocular delivery system that can be applied to infraocular lenses to prevent posterior capsular opacification or inflammation.

With the above advantages as well as other objects, descriptions and aspects of the invention that will be apparent below, the nature of the invention can be understood more clearly with reference to the detailed description of the invention and the appended claims.

Brief Description of the Drawings.

Figure 1 is an enlarged view of one embodiment of the sustained release medicament delivery device showing the inner core, the first coating layer, the second coating layer and the third coating layer.

Figure 2A is an enlarged view of the impermeable polymer. Figure 2B is an enlarged view of the second coating layer including the waterproof film and the waterproof disk.

Detailed Description of the Preferred Modalities of the Invention.

More specifically, the present inventors have discovered a device and a method for the preparation thereof that is appropriate for the controlled and sustained release of an effective agent to obtain a desired local or systemic physiological or pharmacological effect. In particular, it has been found that by sealing at least one surface with a waterproof disk, the thinned coatings can be used. This has the advantage of preparing the shortest possible devices, thinned. A further advantage is that the material used to prepare the waterproof disk need not be malleable (to facilitate the coating of a curved surface); instead relatively hard materials can be used to facilitate the creation of uniform broadcast ports.

The device includes an inner core or reservoir that contains an effective agent to obtain a desired effect. The device further includes a first coating layer, a second coating layer and a third coating layer. The first coating layer that is permeable to the passage of the effective agent can completely cover the inner core. The second coating layer covers only a portion of the first coating layer and the inner core and is impervious to the passage of the agent. The third coating layer covers the entire first coating layer and the second coating layer and is permeable to the passage of the agent. The portion of the first coating layer and inner core that is not covered with the second coating layer facilitates the passage of the agent through the third coating layer. Specifically, the second coating layer is placed between the inner core and the third coating layer in such a way that they block the passage of the agent through the adjacent portions of the third coating layer in this manner by controlling the rate of passage of the agent. .

Figure 1 illustrates one embodiment of the sustained release drug delivery device of the present invention. Although the device shown in Figure 1 is cylindrical, the device can be of any shape. The device comprises an inner core or reservoir 5, a permeable coating 10 that is permeable to the passage of the agent in the core or reservoir, an impermeable coating 15 that is impermeable to the passage of the agent in the core or reservoir 5, and a permeable coating 20 which is permeable to the passage of the agent in the core or reservoir 5. The second coating includes an impermeable polymer 17 and discs 18 and 19 at the ends of the cylindrical core. Figure 1 further shows a suture tag 30.

Figures 2A and 2B only show the second coating layer and illustrate the benefits associated with the use of waterproof discs as a portion of the second layer. Figure 2A shows the thin impermeable polymer layer 17 covering the ends of the inner core. The thin coated ends 31 create a potential for the escape of the effective agent.

Figure 2B illustrates the benefits of using waterproof discs. The second coating layer contains the impermeable polymer 17 and the waterproof discs 18 and 19 at the ends of the cylindrical core. The waterproof disk 18 contains a broadcast port. The waterproof discs 18 and 19 prevent the escape of the effective agent through the thin ends 31 of the impermeable polymer.

The invention further relates to a method for the treatment of a mammalian organism to obtain a desired local or systemic physiological or pharmacological effect. The method includes administering the delivery system of sustained release medicament to the mammalian organism and allowing the agent to obtain the desired local or systemic effect to pass through the third coating to contact the mammalian organism. The term "administer", as used herein, means to place, insert, inject, implant or any other means to expose the device to the mammalian organism. The route of administration depends on a variety of factors including the type of response to treatment, type of agent and preferred place of administration.

The devices in certain embodiments can be applied to provide an effective sustained and controlled release to obtain a desired local or systemic physiological or pharmacological effect related to at least the following areas: treatment of cancerous primary tumors, (e.g., glioblastoma); chronic pain; arthritis; rheumatic conditions; hormonal deficiencies such as diabetes and dwarfism; and modification of the immune response such as in the prevention of transplant rejection and in cancer therapy. A wide variety of other disease states can also be prevented or treated using the drug delivery device of the present invention. Such disease states are known to those of ordinary skill in the art. For those not skilled in the art, reference may be made to Goodman and Gilman, The Pharmacological Basis of Therapeutics, 8th Edition, Pergamon Press, NY, 1990; and Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, PA, 1990; both of which are incorporated herein for reference.

In addition, the devices are suitable for use in the treatment of mammalian organisms infected with AIDS and opportunistic infections related to AIDS such as cytomegalovirus infections, toxoplasmosis, pneumocystis carini and intracellular avium microbacteria.

The devices are particularly suitable for the treatment of ocular conditions such as glaucoma, proliferative retinopathy, diabetic retinopathy, uveitis, and keratitis. The devices are also particularly suitable for use in an ocular device in the treatment of mammalian organisms suffering from cytomegalovirus retinitis wherein the device is surgically implanted within the vitreous of the eye.

As described above, the inner core or reservoir contains an effective agent to obtain a desired local or systemic physiological or pharmacological effect. The following classes of agents can be incorporated into the devices of the present invention: anesthetics and pain-killing agents such as lidocaine and related compounds and benzodiazepans and related compounds; anti-cancer agents such as 5-fluorourazil, adrimycin and related compounds; anti-inflammatory agents such as 6-mannose phosphate; anti-fungal agents such as fluconazole and related compounds; anti-viral agents such as trisodium fos fomonoformate, trifluorothymidine, acyclovir, ganciclovir, DDI and AZT; cell transporters / impeding movement such as colchicine, vincristine, cytochalasin B and related compounds; antiglaucoma medications such as beta blockers: timol, betaxolo atenalol, etc .; immunological response modifiers such as dipeptide muramyl and related compounds; peptides and proteins such as cyclosporin, insulin, growth hormones, insulin related to growth factor, heat shock proteins and related compounds; steroidal compounds such as dexamethasone, prednisolone and related compounds; low solubility steroids such as acetonide fluocinolone and related compounds; and carbonic anhydride inhibitors.

In addition to the above agents, other agents are suitable for administration to the eye and its surrounding tissues to produce a desired local or systemic physiological or pharmacological effect. Examples of such agents include neuroprotectors such as nimodipine and related compounds; antibiotics such as tetracycline, chlortet racicline, bacitracin, neomycin, polymyxin, gramicidin, otracycline, chloramphenicol, gentamicin, and erythromycin; antibacterials such as sulfonamides, sulface tamide, sulfametizole and sulfisoxazole; antivirals including yodoxuridine; and other antibacterial agents such as nitrofura zone and sodium propionate; anti-allergenic agents such as antazoline, tapiriline, feniramine chlorine, pyrilamine and profenpiridamine; anti-inflammatories such as hydrocortisone, hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone, medrisone, methylprednisolone, prednisolone-21-phosphate, prednisolone acetate, fluorome talone; betamethasone and triminolone; decongestants such as phenylephrine, naphazoline, and tetrahydrazoline; mioticos and anti-cholines terasa such as pilocarpine, eserin salicylate, carbachol, di-isopropyl fato fluorophos, phospholine iodide, and demecarium bromide; myriariatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamfetamine; sympathomimetics such as epinephrine; and prodrugs such as those described in Design of Prodrugs, edited by Hans Bundgaard, Elsevier Scientific Publishing Co., Amsterdam, 1985. Again, reference is made to any standard pharmaceutical textbook such as Remington's Pharmaceutical Scienes for the identification of others. agents.

Any pharmaceutically acceptable form of such compounds may be employed in the practice of the present invention, that is, the free base or a pharmaceutically acceptable salt or ester thereof. The pharmaceutically acceptable salts, for example, include sulfate, lactate, acetate, stearate, hydrochloride, tartrate, maleate and the like.

A large number of polymers can be used to construct the devices of the present invention. The only requirements are that they are inert, non-immunogenic and of the desired permeability.

Materials that may be suitable for manufacturing the device include naturally occurring or synthetic materials that are biologically compatible with bodily fluids and ocular tissues, and essentially insoluble in body fluids with the material that is brought into contact. The use of rapidly dissolving materials or highly soluble materials in eye fluids is avoided as the dissolution of the wall can affect the consistency of drug release, as well as the ability of the system to stay in place for a period of time. extended time.

Naturally or synthetically obtained materials that are biologically compatible with bodily fluids and ocular tissues and essentially insoluble in body fluids with the material contacted include, but are not limited to, polyvinyl acetate, cross-linked polyvinyl alcohol, cross-linked polyvinyl butyrate, ethylene ethylacrylate copolymer, hexylacrylate or polyethylene copolymer, polyvinyl chloride, polyvinyl acetals, plasticized ethylene vinyl acetate copolymer, polyvinyl alcohol, polyvinyl acetate, ethylene chlorovinyl copolymer, polyvinyl esters, polyvinyl butyrate , polyvinylformal, polyamides, polymethylmethacrylate, polybutylmethacrylate, plasticized polyvinyl chloride, plasticized nylon, soft plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, polytetrafluoroethylene, polyvinylidene chloride, polyacrylonitrile, poly crosslinked inylpyrrolidone, polytrifluorochloroethylene, chlorinated polyethylene, poly (1,4'-isopropylidene diphenylene carboantho), vinylidene chloride, acrylonitrile copolymer, vinyl chloride-diethyl fumarate copolymer, silicone rubbers, especially the medical grade polydimethylsiloxanes, ethylene - propylene hule, ilicone - carbonate copolymers, vinylidene chloride - vinyl chloride copolymer, vinyl chloride - acrylonitrile copolymer and vinylidene chloride - acrylonitrile copolymer.

Specifically, the second layer of the device of the present invention can be made from any of the above-listed polymers or any other polymer that is biologically compatible with bodily fluids and ocular tissues, essentially insoluble in body fluids with the material that is brought into contact and essentially impermeable to the passage of the effective agent. The term "waterproof", as used herein, means that the layer does not allow the passage of the effective agent to a range required to obtain the desired local or systemic physiological or pharmacological effect.

The second layer should be selected to be impermeable, as described above, for the passage of the inner core agent outward to the adjacent portions of the second layer of coating. The purpose is to block the passage of the agent to those portions and in this way control the release of the agent out of the medication delivery device.

The composition of the second layer, for example, the polymer, should be selected to allow the aforementioned controlled release. The preferred composition of the second layer should vary depending on such factors as the active agent, the desired rate of control and the mode of administration. The identity of the active agent is important, since the size of the molecule, for example, is critical in determining the release rate of the agent in the second layer.

The disc is essentially impermeable to the passage of the effective agent and can cover a portion of the inner core not covered by the impermeable film of the second coating layer. As shown in Figure 2B, the disk can cover the ends of the inert core and enable a thinned uniform cover of the impermeable film to be applied over the inner core which may otherwise be possible. In one embodiment, the waterproof film can completely cover the inner core and the disks. Release of the drug can occur by means of passage through a hole in the disc (see Figure 2B) or a hole in the impermeable film. The physical properties of the polymer used for the discs can be selected based on their ability to withstand subsequent process steps (such as heat curing) without undergoing deformation in the orifice. The polymer for the waterproof film can be selected based on the ease of coating the inner core. Possible materials for the disc include, Teflon, polycarbonate, polymethyl methacrylate, polyethylene alcohol, high grade vinyl ethylene acetate (content of 9% vinyl) and polyvinyl alcohol.

Since the second coating layer is essentially impermeable to the passage of the effective agent, only a portion of the inner core or reservoir and the first coating layer can be covered with the second coating layer. Depending on the desired delivery speed of the device, the second coating layer may cover only a small portion of the inner core surface area for more rapid release rates of the effective agent or may cover large portions of the inner core surface area for slower release rates of the effective agent.

At least 50% of the surface area can be coated by the second coating layer. For slower release ranges, at least 75% of the surface area can be coated. However, for slower release rates, at least 95% of the surface area can be coated.

In this way, any portion of the surface area of the first coating layer and the inner core up to but not including 100% can be coated with the second coating layer obtained along the desired rate of release of the agent.

The second coating, including the waterproof film and the waterproof disk, can be placed anywhere on the inner core and the first coating layer, including but not limited to the upper part, the bottom or any side of the first coating layer and the inner core. In addition, it may be on the top or on one side, or on the bottom and on one side, or on the top and bottom, or on opposite sides or on any combination of the top, bottom or sides.

The first and third layers of the device of the present invention must be biologically compatible with bodily fluids and ocular tissues, essentially insoluble in body fluids with the material that is in contact and permeable to the passage of the effective agent or composition to obtain the desired effect .

The effective agent is distributed in the direction of a lower chemical potential, that is, outside the surface of the device. Outside the surface of the device, equilibrium is established again. When the conditions of both sides of the third coating layer are kept constant, a constant state flow of the effective agent can be established in accordance with the Fick law of diffusion. The rate of passage of the drug through the material by diffusion generally depends on the solubility of the drug in it, as well as the thickness of the wall. This means that an appropriate selection of the materials for making the wall will depend on the particular drug to be used.

The rate of diffusion of the effective agent through a polymeric layer of the present invention can be determined by means of the cell diffusion study conducted under penetrating conditions. In cell diffusion studies carried out under penetrating conditions, the concentration of the drug in the receptor compartment is essentially zero when compared to the high concentrations in the donor compartment. Under these conditions, the rate of drug release is given by: Q / t = (D KA DC) / h where Q is the amount of drug released, t is time, D is the diffusion coefficient, K is the division coefficient, A is the surface area, DC is the difference in concentration of the drug around the membrane, and h is the thickness of the membrane.

In the case where the agent diffuses through the layer by means of pores filled with water, this is not a distribution phenomenon. In this way, K can be eliminated from the equation. Under conditions of penetration, if the release of the donor side is very slow, the DC value is essentially constant and equal to the concentration of the donor compartment. The release range will therefore depend on the surface area (A), thickness (h) and diffusivity (D) of the membrane. In the construction of the device of the present invention, the size (and therefore, the surface area) depends mainly on the size of the effective agent.

In this way, the permeability values can be obtained from the slopes of Q against the plotted time. The permeability of P, can be related to the diffusion coefficient of D, by: P = (KD) / h once the permeability is established for the coating permeable to the passage of the agent, the surface area of the agent that can be coated with the coating impervious to the passage of the agent can be determined. Thus, the available surface area is progressively reduced until the desired release rate is obtained.

Exemplary microporous materials suitable for use as a first and third coating layer, for example, are described in U.S. Patent No. 4,014,335 which is incorporated herein for full reference. These materials include cross-linked polyvinyl alcohol, polyolefin or polyvinyl chlorides or cross-linked gelatins; regenerators, insoluble, non-erodible cellulose, acylated cellulose, celluloses are esterified, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate diethylaminoacetate; polyurethanes, polycarbonates, and microporous polymers formed by co-precipitating a modified insoluble collagen of polycation and polyanion. Crosslinked polyvinyl alcohol is preferred. The third coating layer is selected for a slow release of the inner core agent in contact with a mammalian organism, for example, the human. The third coating layer is not necessary to provide gradual or controlled release of the agent in the biological environment, however, the third coating layer can advantageously be selected to also have properties or descriptions.

The devices of the present invention can be made in a wide variety of means, such as to obtain an effective amount of the agent and compress the agent to a desired shape. Once formed, the first coating layer can be applied. The first coating layer can be applied by dipping the device one or more times in a solution containing the desired polymer. Optionally, the first coating can be applied by dripping, spraying, brushing or other means of coating the outer surface of the device with the polymer solution. When a solution of polyvinyl alcohol is used to obtain the second coating layer, the desired thickness can be obtained by applying various coatings. Each coating can be dried before applying the next coating. Finally, the device can be heated to adjust the permeability of the outer coating.

The waterproof disk can be applied directly on the first layer before coating it with the impermeable polymer layer. In the case of a cylindrical core, an impermeable film may be wrapped around the core after the disks were placed at one or both ends. In this way, the second coating layer includes both the waterproof film and the waterproof discs. By sealing at least one surface with a waterproof disk, the thinned layers can be used. This has the advantage of small devices, as thin as possible than those prepared in another way.

The impermeable polymer layer should be thick enough to prevent the release of medicament around except for the uncoated area (the diffusion layer or port). Because it is desired to minimize the size of the implants, the thickness of the impermeable film layer can therefore be from 0.01 to 2 millimeters, preferably from 0.01 to less than 0.5 millimeters.

The waterproof disk must also be thick enough to prevent the release of medication around it even if a specifically prepared membrane or port is secured. Because it is desired to minimize the size of the implants, the thickness of the impermeable disc can be from 0.01 to 2 millimeters, preferably from 0.01 to less than 1 millimeter.

Once the second coating layer, including the waterproof disk (s), is applied to the device, the third coating layer can be applied. The third coating can be applied by dipping the device one or more times in a solution containing the desired polymer. Optionally, the third coating layer may be applied by dripping, spraying, brushing or otherwise to coat the outer surface of the device with the polymer solution. When a solution of polyvinyl alcohol is used to obtain the third coating layer, the desired thickness can be obtained by applying various coatings. Each coating can be dried before applying the next coating. Finally, the device can be heated to adjust the permeability of the outer coating.

The above description of how to make the devices of the present invention is merely illustrative and should not be considered as limiting the scope of the invention in any medium, such as various compositions that are known to those skilled in the art. In particular, the methods for making the device depend on the identity of the active ingredient and the selected polymers. By giving the active ingredient, the composition of the first coating, the second coating (the film and the disk), and the third coating, one skilled in the art can easily make the devices of the present invention using conventional coating techniques.

The method for the treatment of a mammalian organism to obtain a desired local or systemic physiological or pharmacological effect includes administering the sustained release drug delivery device of the present invention to the mammalian organism and allowing the agent to pass through the device to enter in direct contact with the mammalian organism.

The drug delivery system of the present invention can be administered to the mammalian organism by any means of administration known in the art. Said administration means include infraocular, oral, subcutaneous, intramuscular, int raperi tonal, intranasal, dermal and the like. In addition, one or more devices can administer once or more than one agent can be included in the inner core.

The drug delivery system of the present invention is particularly suitable for direct implantation in the vitreous of the eye and for its application to infraocular lenses.

These methods of administration and techniques for their preparation are well known to those of ordinary skill in the art. The techniques for its preparation are shown in Remington's Pharmaceutical Scienes.

The drug delivery system can be administered for a period of time and under sufficient conditions to allow treatment of the disease state concerned.

For delivery of localized medication, the devices can be surgically implanted in or near the action site. This is the case for the devices of the present invention used in the treatment of ocular conditions, primary tumors, arthritic and rheumatic conditions, and chronic pain.

For systemic delivery, the devices can be implanted subcutaneously, intramuscularly or intially. This is the case when the devices are to give sustained systemic levels and prevent premature metabolism. In addition, such devices can be administered orally.

In one embodiment of the invention, an ocular device containing ganciclovir can be prepared as the effective agent in an amount effective to prevent a replication virus. Such devices can be used to effectively fight and inhibit the reproduction of cytomegalovirus retinitis, when they are surgically implanted in the vitreous of the eye. Such devices can remain in the vitreous of the eye permanently after the treatment has been completed. The preferred amount of ganciclovir used in these devices is in the range of about 0.01 mg to about 40 mg. More preferably, such devices contain from about 15 mg to about 30 mg ganciclovir. These preferred ranges can provide sustained release of ganciclovir for a period from several hours to more than two years. The first preferred coating is polyvinyl alcohol. The preferred waterproof disk is Teflon or ethyl vinyl alcohol. The preferred waterproof polymer is ethylene vinyl acetate. The third preferred coating layer is polyvinyl alcohol. When such devices are prepared for implantation within the vitreous of the eye, it is preferred that the device does not exceed about 7 millimeters in any direction. In this way, the cylindrical device shown in Figure 1 should preferably not exceed 7 millimeters in height or 3 millimeters in diameter. The preferred thickness of the first coating layer is in the range from about 0.05 to about 0.5 millimeters. The preferred thickness of the second coating layer is in the range from 0.1 to about 1.0 millimeters. The preferred thickness of the third coating layer is in the range from about 0.1 to about 2.0 millimeters.

In another embodiment of the invention, an eye device containing nimodipine as the effective agent can be prepared. As shown in the Examples that follow, such devices can be used to provide a large sustained release term of nimodipine for several years. The preferred amount of nimodipine used in these devices is in the range of 2 to 15 mg. More preferably, such devices contain about 10-15 mg. These preferred ranges can provide a sustained release of nimodipine for a period of more than 10 years. Preferred materials include polyvinyl alcohol as the first layer, one end of the cylindrical device covered by a disk of ethylene vinyl acetate (9%) and the other discovered, ethylene vinyl acetate (19%) as the impermeable polymer layer coating the sides of the cylinder and the end sealed with the disc , and a third layer, silicone, coating the complete assembly. The preferred thickness of the first layer is in the range from 0.05 to 0.2 millimeters. The preferred thickness of the impermeable polymer layer is in the range from 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 invention, an ocular device containing fluocinolone acetonide as the effective agent can be prepared. As further shown in the Examples that follow, such devices can be used to provide a sustained release of fluocinilone acetonide for several years. The preferred amount of fluocinolone acetonide used in these devices is in the range of 2 to 15 mg. More preferably, such devices contain approximately 5 to 10 mg. These preferred ranges can provide a sustained release of the fluocinolone acetonide for a period of 3 years. The general diameter of the device is 2 millimeters and the length is 5 millimeters.

Preferred materials include polyvinyl alcohol as the first layer, one end of the cylindrical device coated with a disc of ethylene vinyl acetate (9%) and the other discovered, ethylene vinyl acetate (19%) as the impermeable polymer coating coated the sides of the cylinder and the end sealed with the disc, and a third layer, polyvinyl alcohol, coating the complete assembly. The preferred thickness of the first layer is in the range from 0.05 to 0.2 millimeters. The preferred thickness of the impermeable polymer layer is in the range from 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.

Although the embodiments described above of the invention are described in terms of preferred ranges of the effective agent amount, and the preferred thicknesses of the first and second preferred coatings, these preferences do not signify a limit of the invention. As can be readily understood by one skilled in the art, the preferred amounts, materials and dimensions depend on the method of administration, the effective agent used, the polymers used, the desired release rate and the like. Likewise, the current release ranges and duration of release depend on a variety of factors in addition to the above, such as the condition of the disease being treated, the age and condition of the patient, the route of administration, as well as the as other factors that can be readily apparent to those skilled in the art.

From the above description, one of ordinary skill in the art can easily guess the essential characteristics of the present invention, and without departing from the spirit and scope thereof, can make various changes and / or modifications of the invention to adapt it to various uses and conditions. As such, these changes and / or modifications are appropriately, equitably and intended to be, within the full range of equivalences of the following claims.

It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Having described the invention as above, the content of the following is claimed as property.

Claims

1. A method for treating a mammalian organism to obtain a desired local or systemic physiological or pharmacological effect, characterized in that it comprises: The use of a sustained release drug delivery system to a mammalian organism in need of such treatment, the drug delivery system comprises: (1) an inner core or reservoir comprising an effective amount of an agent to obtain a desired local or systemic physiological or pharmacological effect, (2) a first coating layer permeable to the passage of the agent, wherein the first coating layer covers at least a portion of the inner core, which provides control and sustained release of the agent, (3) a second coating layer, the second coating layer essentially impermeable to the passage of the agent, and the second coating layer covering at least 50% of the inner core and / or the first coating layer, wherein at least one small portion of the inner core or the first coating layer is not covered with the second coating layer and the second coating layer comprises an impermeable film and at least one impermeable disc being a material different from this or having substantially greater hardness, thickness, malleability or response to heat cure than waterproof film, and (4) a third coating layer permeable to the passage of the agent, wherein the third coating layer essentially completely covers the second coating layer and the uncovered portion of the first coating layer or inner core, by means of which the agent is able to pass through the third layer of coating in a way controlled, to treat a mammalian organism to obtain a desired physiological or pharmacological, local or systemic effect.

2. The method for the treatment of a mammalian organism as claimed in claim 1, characterized in that the third coating layer comprises polyvinyl alcohol.

3. The use as claimed in claim 2, characterized in that the second coating layer comprises ethylene vinyl acetate.

4. The use as claimed in claim 3, characterized in that the first coating layer comprises polyvinyl alcohol.

5. The use as claimed in claim 1, characterized in that the effective agent comprises fluocinolone acetonide, nimodipine or ganciclovir.

6 The use of a sistata of its supply of ms ± Lcan = r ± Q efe liberato sostoxida (1) an inner core or reservoir comprising an effective amount of an agent to obtain a desired local or systemic physiological or pharmacological effect, (2) a first coating layer permeable to the passage of the agent, wherein the first coating layer covers at least a portion of the inner core, which provides control and sustained release of the agent, (3) a second coating layer, the second coating layer essentially impermeable to the passage of the agent, and the second coating layer covering at least 50% of the inner core and / or the first coating layer, wherein at least one small portion of the inner core or the first coating layer is not covered with the second coating layer and the second coating layer comprises an impermeable film and at least one impermeable disk being a material different from this or having substantially greater hardness, thickness, malleability or response to heat curing than the impermeable film, and (4) a third coating layer permeable to the passage of the agent, wherein the third coating layer essentially completely covers the second coating layer and the uncovered portion of the first coating layer or inner core, by means of which the agent is able to pass through the third coating layer in a controlled manner, for the treatment of cytomegalovirus retinitis in a mammalian organism.

7. A method for providing a controlled and sustained administration of an effective agent to obtain a desired local or systemic physiological or pharmacological effect, characterized in that it comprises: surgically implant a delivery system of sustained release medication in the desired location, the medication delivery system comprises: (1) an inner core or reservoir comprising an effective amount of an agent to obtain a desired physiological or pharmacological effect, and (2) a first coating layer permeable to the passage of the agent, wherein the first coating layer covers at least a portion of the inner core, which provides control and sustained release of the agent, (3) a second coating layer, the second coating layer essentially impermeable to the passage of the agent, and the second coating layer covering at least 50% of the inner core and / or the first coating layer, wherein at least one small portion of the inner core or the first coating layer is not covered with the second coating layer and the second coating layer comprises an impermeable film and at least one impermeable disc being a material different from this or having substantially greater hardness, thickness, malleability or response to heat cure than waterproof film, and (4) a third coating layer permeable to the passage of the agent, wherein the third coating layer essentially completely covers the second coating layer and the uncovered portion of the first coating layer or inner core, by means of which the agent is Skillful to pass through the third coating layer in a controlled manner.

8. The method as claimed in claim 7, characterized in that the device is surgically implanted within the vitreous of the eye.

9. The method as claimed in claim 7, characterized in that the first and third coating layers comprises polyvinyl alcohol.

10. The method as claimed in claim 7, characterized in that the third coating layer is silicone.

11. The method as claimed in claim 9, characterized in that the second coating layer comprises ethylene vinyl acetate.

12. The method as claimed in claim 11, characterized in that the effective agent is ganciclovir or 5-fluorouracil.

13. The method as claimed in claim 11, characterized in that the effective agent is a steroid of low solubility.

14. The method as claimed in claim 13, characterized in that the low solubility steroid is fluocinolone acetonide.

15. The method as claimed in claim 11, characterized in that the effective agent is a neuroprotector.

16. The method as claimed in claim 15, characterized in that the neuroprotector is nimodipine.

17. A delivery system of sustained release medication, characterized in that it comprises: (A) an inner core or reservoir comprising an effective amount of an agent to obtain a desired local or systemic physiological or pharmacological effect, (B) a first coating layer permeable to the passage of the agent, wherein the first coating layer covers at least a portion of the inner core, which provides control and sustained release of the agent, (C) a second coating layer, the second coating layer impermeable to the agent's passage, and the second coating layer covering at least 50% of the inner core and / or the first coating layer, wherein at least a small portion of the inner core or the first coating layer is not covered with the second coating layer and the second coating layer comprises an impermeable film and at least one impermeable disk being a material different from this or having substantially greater hardness, thickness, malleability or response to heat cure than waterproof film, and (D) a third coating layer permeable to the passage of the agent, wherein the third coating layer essentially completely covers the second coating layer and the uncovered portion of the first coating layer or inner core.

18. The sustained release drug delivery system as claimed in claim 17, characterized in that the third coating layer comprises polyvinyl alcohol.

19. The sustained release drug delivery system as claimed in claim 18, characterized in that the second coating layer comprises ethylene vinyl acetate.

20. The sustained release drug delivery system as claimed in claim 19, characterized in that the first coating layer comprises polyvinyl alcohol.

21. The sustained release drug delivery system as claimed in claim 20, characterized in that the effective agent is ganciclovir or fluocinolone acetonide.

22. The sustained release drug delivery system as claimed in claim 17, characterized in that the effective agent is nimodipine.

23. The sustained release drug delivery system as claimed in claim 17, characterized in that the third coating layer comprises silicone.

24. The method for the treatment of a mammalian organism according to claim 1, characterized in that the impermeable film is made of a composition different from that of the impermeable disc.

25. The method for the treatment of a mammalian organism as claimed in claim 1, characterized in that the second coating layer covers the entire inner core and the first coating layer except for one opening of the diffusion port.

26. The method for the treatment of a mammalian organism as claimed in claim 1, characterized in that the impermeable disc is harder than the waterproof film.

27. The sustained release drug delivery system as claimed in claim 17, characterized in that the effective agent is a steroid.

28. The sustained release drug delivery system as claimed in claim 17, characterized in that the effective agent is a neuroprotective agent.