A surgically implantable and sealable delivery device that upon contact of its contents via an interface window or port therein with an organ or tissue exposes a therapeutic agent to the organ or tissue surface, allowing a controlled, selective and unidirectional diffusion of the agent into the tissue or organ. The device protects adjacent organs or tissue structures from unnecessary high levels of the delivered agent. Novel methods to deliver chemotherapeutics or bioactive agents to mammalian organs or tissues through a surgically implanted device by the way of a selective and protected diffusion mechanism are disclosed as well as method to achieve the sealing properties of the device.

SUMMARY OF THE INVENTION

In an embodiment, an implantable and sealable drug delivery system is provided, that provides local sustained release of a therapeutic agent or agents directly and selectively to a mammalian internal organ, tissue or system. A preferred embodiment comprises an isolated drug reservoir that solely delivers the agent through an interface that can be selectively exposed with the targeted structure. The control over the interface is achieved by a sealing mechanism provided by a sealing base and methods described therefore.

A simple and novel method of providing local or systemic therapeutic levels through a direct, unidirectional and protected delivery of agents to a mammalian organ, tissue or system is also disclosed. Devices of the present invention can deliver therapeutic agents to specific tissues surrounded by internal body fluids in a preferential manner, exposing only the targeted sites to high therapeutic levels of the agent for a prolonged period of time, and avoiding undesired toxic effects to adjacent structures.

In an embodiment, the drug reservoir is isolated from adjacent structures and fluids by an outer layer of polymer impermeable to the carried therapeutic agent. A delivery port or interface window is provided in the housing of the device for providing targeted release of a drug contained therein. The interface window is sealed to the tissue surface by a surrounding sealing base associated to designed structures to assure the hermetical seal necessary for the control of the interface diffusion mechanism. The delivery port or interface window may be covered by a structural layer that is permeable to the therapeutic agent contained within the device reservoir, or by a layer that is biodegradable. In certain instances, the therapeutic agent is contained in a slow release formulation that does not require that the delivery port or interface window be covered during implantation, so that a portion of the agent bolus in the device reservoir is directly contacted with the target tissue. In an embodiment, the device housing includes an attachment mechanism for attaching the device to a target tissue. This is provided by a series of structures that in combination allow a hermetical seal between the system and the targeted tissue.

This invention can provide therapeutic or prophylactic levels of therapeutic or physiological agents to mammalian organs, tissues or systems. This invention to provide sustained levels of physiological or therapeutic agents to artificial organs, cell cultures, cell or tissue scaffolds and transplanted organs or tissues. This invention can be used to implant through minimally invasive procedures a foldable, elastic, flexible or expandable drug delivery device to provide selective delivery of therapeutic or physiological agents to mammalian organs, tissues or systems, through a sustained and protected release of an agent, assuring an unidirectional diffusion through the target interface, and avoiding dissipation of the agent to adjacent structures. The invention can also provide to a mammalian organ or tissue a selective delivery of sensitizers, magnetic or radioactive agents that will offer benefits in treating or diagnosing those structures. The present invention may be better understood by reference to the figures and further detailed description below.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the present invention involves a new method of selectively deliver therapeutic agents to mammalian organs, tissues or systems through a surgically implantable and hermetically sealable device system that provides a sustained and protected release of an agent, assuring an unidirectional diffusion through the target interface, and avoiding dissipation of the agent to adjacent structures.

The invention was based on unexpected findings that agents can be safely and predictably delivered at therapeutic or prophylactic levels to specific tissues, even in a local context, through the control of the organ surface exposed to an agent as well as by control of the agent's exposure to the internal body tissues and fluids. This can be achieved by maintaining the organ interface permeable to the agent through osmotic agents, physical, chemical or biological treatment, and by isolating and localizing the interface area of exchange through a sealing mechanism.

The control of the agent exposed to the targeted tissue can be obtained by using drug-associated polymers, osmotic agents and by preferably by coating the drug reservoir with a non-drug-permeable polymer, wherein the drug to which the polymer is not permeable is the active agent(s)), avoiding dissipation and toxic effects of the agents to adjacent structures and fluids, and higher availability to the targeted structure. This is proportioned by a series of structures designed to maintain a hermetically sealed contact between the device and the target tissue.

The inventors found that this system can offer a tremendous advantage over the conventional way the drugs are delivered to tissues or organs, allowing even agents never considered for clinical use due to non-specificity and toxicity to be reconsidered for use. This enables new agents to be developed based on this alternative of drug delivery technology.

This invention allows new therapeutic modalities, such as organ transplantation, tissue regeneration techniques, artificial organs or tissue implantation, to be developed. This will provide a therapeutic and physiologic support to any new technology that will depend on biological local incorporation or maintaining in an internal body portion.

Drug within the reservoir can be associated or mixed with another agent, a polymer or an osmotic agent. Layers of drug can be provided, wherein a first drug is delivered, followed by a second drug. A multi-compartmental reservoir is also designed having an inner wall separating the cavities. The body BI comprises the construction of a wall dividing the cavities. Preferentially the dividing wall slightly extends beyond the corresponding height to the curvature of the sclera or the surface to isolate the compartments at the interface level. It minimizes the possibility of mixture and interaction between the agents before they reach the target surface.

The interface window may have be coated and/or contain an enhancer of tissue diffusion, such as an enzyme. Collagenases, prostaglandin analogues, matrix metalloproteinases, hyluronidases are enzymes that can modify the diffusion properties of the sclera or tissue surface. The coating process is preferentially done when compressing the solid drug or during the drug preparation and mixture with its polymer or vehicle. If it requires a steady and sustained effect it can be dispersed throughout the reservoir or restricted to the internal surface to be place in contact with the sclera. Depending on the stability and interaction between the enhancer and the active therapeutic agent a layer of the enhancer may be incorporated to the internal surface of the reservoir. Preferentially it is made using a biodegradable material such as a collagen biomaterial, gelatin, glycolic acid, cellulose and lactic acid. Alternatively it can be made of any material that does not interfere directly in the release rate of the agent from the reservoir and its exposure to the target tissue. In other words, it is not the material carrying the enhancer expected to play a direct role in the diffusion rate, but the action of enhancer on the target surface. We refer to this layer as a functional layer for containing an agent or enhancer that will affect the diffusion rate and lately the pharmacokinetics of the given therapeutic agent.

An internal layer of a rapidly biodegradable polymer, preferentially a gelatin, hialuronic acid, methyl-cellulose, poly-glycolic, poly-lactic is envisioned to be built for allowing liquid, powder and viscous agents to be held in the reservoir it gets stable on the target surface. This process is preferentially accomplished by interpositioning the layer between the sealing base and the adhesive layer, in its more inner aspect, still allowing a strong adhesion between the adhesive layer and the sealing base in its most peripheral aspect. A tunnel surrounding the interface window is also envisioned to allow the entrapment of the layer in the tunnel using silicone or any material of the same class of the sealing base or the device to build a ring to be fitted in the tunnel by mechanical apposition or adhesive attachment.

The interface window, where the reservoir is exposed to the target tissue is surrounded by a sealing base that may be a continuation of the polymer composing the external wall or may constitute a different polymer incorporated to previous one by mechanical attachment or use of adhesives. The internal surface of the sealing base may also be composed by a different part, said sealing part, that once is mechanically incorporated to the main part, said the core device, can entrap a layer of polymer necessary to hold a liquid or viscous suspension in the reservoir avoiding premature exposure or leakage, or to stabilize the above described layer of enhancer carrier. The process is envisioned as a sandwich-like apposition still respecting the window area that will lately determine the interface between the drug reservoir and the target surface. The sealing part will then have the incorporated characteristics described above for the sealing base in order to allow hermetical sealing between the device and the exposed tissue.

Materials useful in constructing the device include but are not limited to poly-ethylene, silicone, hydrogels, poly-orthoester, poly-glycolic acid, poly-lactic acid, poly-caprolactone, polyvinyl-alcohol, polyvinyl-pylirridone, and any derivatives thereof, and biopolymers, such as hyaluronic acid, fibrin, methyl-cellulose, collagen, gelatin, or any derivatives might be used in other parts of the device.

Preferably, the device allows and protects the preferential flow of the therapeutic agent across the targeted interface. This is accomplished by using design structures to allow a hermetical sealing of the device to the target surface. Such unidirectional flow will be made possible by means of an external surface impermeable to the drug. Whether the external will be permeable or not to the external body fluids, will depend on the characteristics of the drug(s) and carrier polymer, as well as to the need for a dissolving agent to regulate the release of the drug from the reservoir. Such a mechanism of drug release may be as simple as the dissolution of the pure drug/polymer contained in the reservoir by the incoming fluids, or using an osmotic agent to regulate the water inflow and dissolution rate of the drug, before it permeates the targeted surface.

As mentioned before the embodiment incorporates a series of structures to allow a hermetical sealing to the target surface. The first is the sealing base, which consists on the primary way of achieving sealing. The extended surface beyond the interface window is aimed to increase the sealing contact area, whether or not it is coated with an adhesive layer. The sealing base preferentially follows the same curvature of the target surface, although a slightly more curved base is envisioned to maximize the contact, particularly when flexible materials are used. The combination of one or more or more of the other characteristics to ameliorate the sealing affect, said accessory sealing structures, will provide the characteristics for accomplishing the controlled and protected drug delivery.

The first accessory is described as a buckle suture stabilizer or suture stabilizer. This is a built bump, lane or tunnel on the external surface to prevent the suture to slide out of the implant once it buckles the device in apposition to the tissue. One or more can be built depending on the size and position of the device in relation to the target surface. Preferentially those suture stabilizers are made of the same material for the outer surface during the molding process. Alternatively, it can be incorporated to the device later on the process using different materials.

The second accessory is described as a buckling band tunnel or trail. It consists of a depression on the outer surface, crossing its diameter, to allow an encircling element to be place and provide a sealing apposition between the device and the target tissue. Preferentially it is built on the device external surface during the molding process.

The third accessory is described as a multiple holes base where a sewing suture should be applied to seal the base of the device. The holes again are preferentially created during the molding process for the sealing base. Alternatively a flexible material can be used as sealing base with a linear surrounding thinning to allow the suture to be performed by an automatic apparatus.

The above mentioned methods for creating a hermetical seal between the drug delivery device are essentials in diminishing the interference of surrounding fluid and tissues in the diffusion mechanism provided by the drug-tissue interface. Moreover, they play a significant role in avoiding unnecessary exposure of surrounding tissues to toxic effects of the pharmaceutical agents.

Fluid transport before drug dissolution occurs is possible through two distinct mechanisms. The first is across the organ surface through an osmotic or pressure gradient driven diffusion. The second is across the outer wall polymer mainly driven by an osmotic gradient between the reservoir and the outside tissue as well as the characteristics of the polymer.

Among the factors related to the permeation of agents through biological membranes, the surface contact area, concentration of the agent in the donor side and the molecular weight of the drug are balanced to provide the tissue with the desired levels of the agent in the specific regions. Other factors taken in account are the membrane properties and pharmacokinetics of the drug in the tissue. Those, despite being biological, can be altered through physical, chemical or biological methods, before the exposure to the therapeutic agent and device. In other words, the bioavailability and pharmacokinetics of the permeating agents are expected to be different through this proposed route, and will be helpful in establishing the appropriate combination of the compounds.

It is envisioned that the system of the present invention has numerous variations. For example, the device can carry an enhancer agent, preferentially, but not limited to an enzyme and a protein, such as albumin. The external surface can be composed by a polymer non-permeable to the carried agent, preferentially formed but not restricted to a silicone, poly-glycolic acid, poly-lactic acid, hyaluronate derivatives, polyvinyl alcohol, acrylate, methacrylate, cellulose, collagen, metals, any derivatives or associations of the above mentioned polymers or others that retain characteristics of non-permeability to the carried agent.

The external surface of the device may include a refilling port preferentially made of, but not restricted to a self-sealing material, such as silicone rubber. It is envisioned that in using a multiple compartmental device, multiple refilling ports are also built in the device. These structures are built on the external surface communicating the exterior environment to the interior of the reservoir. To be recognized after the surgical procedure the port is stained by a biocompatible, radiosensitive, echogenic marker or dye. Alternatively, its is also extended beyond the outer surface of the device and place in a more accessible part of the body.

The device may be foldable or flexible to allow insertion through small incisions, and to conform and tightly fit to irregular organs surfaces.

The invention includes methods for selective administration to a mammalian organ, tissue or system desired levels of a therapeutic agent through a controlled drug permeation across a target device interface. The interface with the tissue can be directly with drug contained within the device reservoir or through a biodegradable polymer, preferentially composed of but not restricted to gelatin, caprolactone, hyaluronic acid, cellulose, poly-glycolic acid, poly-lactic acid, and derivatives thereof. These compounds and/or compositions may be pressure, heat, photo, or chemically sensitive.

The active agents may be in an encapsulated form, such as liposomes or microspheres.

Thus, the present invention includes a method of local, protected and sustained delivery of therapeutic agents directly through a targeted tissue surface in a unidirectional way, avoiding dissipation of the agent to surrounding tissues and fluid, after surgical implantation into a mammalian organism. The method involves placing the drug-loaded device interface window in contact with the targeted tissue. The method includes sealing the device to the target tissue by way of adhesives, buckling or suturing or the combination of any of those. To build the adhesive layer it preferentially uses but is not limited to a hydrogel, hyaluronate and fibrin adhesive. It is incorporated to the sealing base by the use of a film or layer containing adhesive in its both sides, or by the pre-application of the adhesive to the internal side of the sealing base. For holding the adhesive in place multiple cavities, single cavity or a channel system along the internal surface of the sealing base are preferentially used. Such sealing structures are made preferentially during the molding process of the device. After placement of the adhesive in contact to the base, a film may be placed in contact to the adhesive layer. Preferentially the film is non-reactive with the adhesive used and can peeled off before the implantation procedure. The use of an exposed sealing base, presenting the structures mentioned above to hold the adhesive in place allows also its application right before the implantation procedure, particularly if a biological adhesive such as fibrin sealant is desired to be used.

The device may be interfaced with an artificial organ, a synthetic or biological platform for cells or biological agents, a scaffold for tissue or cell regeneration, and/or a transplanted tissue or organ.

The method of the present invention can achieve local or systemic, physiological or pharmacological effects in a mammalian organism, by using a surgically implantable device that delivers an agent directly and preferentially through its interface with the targeted tissue or organ, keeping the rest of its surface non-permeable to the carried agent.

The therapeutic agent may be a prophylactic agent. The system or device may carry an osmotic agent.

The effect or diffusion of the agent may be started or enhanced after the implantation procedure through the use of a secondary agent, whether it is chemical, physical or biological.

Some non-limiting examples of diseases for which the present inventions may be used include, myocardial ischemic disease, hepatic cancers, hepatic metastasis of colon cancers, gall bladder tumors, adrenal tumors, neuroblastomas, and kidney and pancreatic cancers. The device of the present invention can be loaded with the desired active agent (i.e., drug(s) and/or prodrug(s)) and can be implanted and attached to an anatomical or histological surface. For example, the device can be glued to the pericardium surface to deliver an agent to the pericardial space, allowing the drug in the reservoir to diffuse to the whole myocardium. It can also, through an opening of the pericardium, be glued directly to the myocardium (note that the pericardium is a sac, mostly acellular, but is delineated from other structures by a histopathological and anatomical surface, and the myocardium which is mostly cellular, is also delineated by the pericardium by surface, which is ultimately the muscle cell, but there is still a distinguished surface). It is preferred that the device not be implanted inside the myocardium to deliver drug to a deeper layer of the muscle or a specific group of cells, as it is preferred that such invasive techniques be minimized. Hence, it is preferred that the devices, when implanted, not degrade the histological structure of the tissue that will be treated (the target).

In an embodiment, the present invention has numerous applications in ophthalmology, with the eye providing several locations where loaded devices may be applied. Preferentially, in Ophthalmology, the device is used to be in placed in contact to the sclera. Alternatively, between the outer layer of the eye, known as the sclera, and the vitreous there is suprachoroidal space (accessible through a scleral incision) or even the subretinal space. For the subretinal space, either a choroidal incision or a retinotomy could be made to allow the insertion of the implant. Diseases in ophthalmology that may be treated with the present inventions and other ophthalmic applications of the present invention include but are not limited to intraocular tumors, e.g. retinoblastoma, melanoma, macular degeneration, delivery to the posterior pole (e.g., choroidal and RPE layers) of growth factors, antiangiogenic factors, photosensitizers (which may be subject to application of laser), gene vectors, etc. The present invention may be applied to glaucoma by delivering antiglaucoma drug(s) via the device to the cilliary body directly through the sclera. The present invention may also be applied to retinitis pigmentosa, to deliver growth factors or to deliver immunosupressive agents to protect a retina or RPE graft, without an intraocular surgical procedure that would jeopardize the graft.

The present invention is designed for implantation, rather than for external body surface or buccal applications. The present invention makes possible the targeting of specific tissues within the body or eye, and takes into account that many drugs are more specific and toxic to certain groups of cells than others. In situations where the surrounding target tissue can be harmed by the applied drug, the present invention provides a superior solution by focusing the drug on the target tissue.

In addition to treating localized diseases, the present invention can be used to provide systemic benefits. Using a system of the present invention to deliver growth factors to the pancreas of a diabetic patient can change the context of the systemic disease. Application of appropriate agents using the system of the present invention to an inoperable liver affected by a colonic metastatic carcinoma can reduce the size of the tumor and make it ressectable. In addition to cures, the present invention can also be used for treatments aimed to improve the quality of life of patients, or improve their cost-effectiveness. The local delivery of cytotoxic agents by the device to a tumor expanding and compressing the esophagus can make a difference in the patient's quality of life preventing more complex interventions, such as a surgical ressection. Thus, even palliative care is facilitated by the present invention. The invention is particularly useful in tumor treatments when the tumor or effected organ has a distinguishable surface to which can be sealed the interface window incorporated in a drug delivery device of the present invention.

The method of delivering the loaded drug delivery devices of the present invention may involve a variety of implantation techniques either manually or through an injector. The devices may be implanted under direct visualization or under indirect visualization techniques, such as ultra-sound, MRI, CT-scan guided, laparoscopy, etc.

 

Claim 1 of 72 Claims

1. An implantable delivery device for delivery of at least a first therapeutic agent into a target tissue, comprising: a housing, said housing comprising a reservoir with a release port for release of at least a first therapeutic agent into a target tissue, said reservoir having at least a first wall that is substantially impermeable to a first therapeutic agent to be placed therein, a sealing base for sealing said release port to a target tissue, wherein when said release port is sealed to a target tissue a first therapeutic agent in said reservoir is substantially prohibited from release by said device other than through said release port into the target tissue, and an attachment mechanism to facilitate sealing of said release port to a target tissue, said attachment mechanism comprising at least one member of the group consisting of a sufficient amount of an adhesive for adhering said sealing base to a target tissue wherein said adhesive is held within at least one cavity or channel within said sealing base, and at least one stabilizer on said first wall for engaging a buckling band or suture for sealably engaging said device with a target tissue.
 

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.