MXPA05007289A - Method and device for minimally invasive implantation of biomaterial. - Google Patents

Abstract

A minimally invasive method of placing a delivery device substantially adjacent to vascular tissue and a device for use with such a method are disclosed. The delivery device may be a flexible biological construct with a flexible tethering means. The delivery device may be percutaneously inserted near vascular tissue such as, for example, peritoneal tissue. When the delivery device has been inserted, the tether may be used to pull the delivery device toward the vascular tissue and secure the device thereto. Contact between the front surface of the delivery device and the vascular tissue may be maintained by making and keeping the tether substantially taut. The delivery device may serve accomplish sustained delivery of active agents.

Description

METHOD AND DEVICE FOR IMPLEMENTATION OF BIOMATERIAL WITH MINIMAL INVASION BACKGROUND OF THE INVENTION The present invention relates generally to the implantation of biomaterial, and is particularly directed to a method and a device that accomplishes the same with minimal invasion. Specifically, the present invention relates to a biomaterial for delivery of active agent and methods for long-term delivery of a prophylactic or therapeutic agent by implantation of the active agent delivery biomaterial. Many of the known implantation methods involve the use of a punching means to propel the implant towards a cannula or similar tubular implement in the body. Said punching involves the use of a pushing tool, such as a rod or wire, which must be inserted into the tubular implement behind the implant to achieve the punching. Other possible implantation methods include the extension of a second tubular implement capped to the hole of a first tubular implement within the body; wherein the second tubular implement contains the implant and releases the implant when the extension of the second tubular implement reveals an opening in the side of the second tubular implement through which the implant can fall into the body. The vascular nature of the peritoneal wall is well known in the art. Although the technique has taught the implantation of matepals on or near the peritoneal tissue, these teachings have focused on the structural preparation or prevention of ruptured hemiaries. Therefore, the technique lacks implementation teachings in or near peritoneal tissue for sustained supply of materials for non-hemiarial purposes. Although the art has taught the implantation of cellular capsules for the sustained delivery of neuroactive substances into the central nervous system, said implantation means are relatively inflexible, and their utility is substantially limited to the central nervous system. A relatively inflexible implant would not fully take advantage of the vascular nature of tissue such as peritoneal tissue if implanted in or near said tissue, since a relatively inflexible implant would not maximize the surface contact between the implant and the vascular tissue. The maximum surface-to-surface contact increase serves to achieve a more efficient direct exchange of biomaterials between an implant and vascular tissue. There is a strong need for the elimination of undesirable physiological and economic problems with long-term drug therapy, while maintaining the therapeutic advantageous properties of the treatment. Due to the risks imposed by certain drugs, researchers have developed systems to administer such drugs to help in the treatment of illnesses and diseases. The systems have been designed to greatly reduce and control the rate of release of incorporated drugs. However, these systems do not achieve the surprising and unexpected results obtained by the present invention. Therefore, there is a need for a minimally invasive method to place and maintain a relatively flexible implant within the body, substantially adjacent to vascular tissue, and an implant device capable of sustained delivery of therapeutic or prophylactic materials or other active agents.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to devices and methods for the delivery of active agents in a subject. The active agent formulation can be stored within an active agent delivery system (e.g., contained in a system delivery layer or a reservoir within the controlled active agent delivery system). The active agent formulation may comprise an amount of active agent sufficient for the treatment and is stable at body temperatures (e.g., without unacceptable degradation) for the entire pre-selected treatment period. The active agent delivery systems can safely store the active agent formulation (eg, without dose release), provide sufficient protection against bodily processes to avoid unacceptable degradation of the formulation, and release the active agent formulation in a controlled manner at a therapeutically effective rate to the subject. During use, the active agent delivery system can be implanted in the subject's body at an implantation site, and the active agent formulation can be released from the active agent delivery system to a delivery site within, for example, the peritoneal or abdominal wall. Once released at the delivery site, the active agent formulation can enter the subject through vascularized tissue. The present invention can allow a patient greater flexibility of lifestyle, freedom of movement and the ability to perform physical activity in a more natural and comfortable way. The present invention can eliminate the need for frequent injections and the pain associated with multiple daily needle injections, skin irritation, mental anguish suffered by patients having difficulty with control or maintenance of the physiological parameters corresponding to their clinical condition. In one embodiment, the invention comprises an active agent delivery device comprising a tied delivery device and a minimally invasive method for positioning said active agent delivery device substantially adjacent to vascular tissue. The implantation of said device can provide a sustained supply of therapeutic, prophylactic materials and / or many other types of materials. In general, the active agent delivery device can be placed within, for example, the abdominal space, within the omentum, within the peritoneal cavity, a space formed when the parietal and visceral layers of the peritoneum, or between the parietal peritoneum and the abdominal wall. Other sites suitable for placement are possible. The contemplated implantation techniques include an approach that places the active agent delivery device within the peritoneal space through the use of a puncture wound. It may be desirable to use surgical techniques that allow access to the peritoneal cavity, where a small wound exposes the cavity. After dissection of the peritoneum, an active agent delivery device, as described herein, can be inserted into the space. After allowing a certain degree of placement, if necessary, the wound can be closed. The active agent delivery device can include a biological construct and a mooring means. The delivery device can be substantially flexible and / or have an adhesive front. The clamping means can be made of a substantially flexible material capable of anchoring the delivery device in substantially flat contact with the vascularized tissue. The delivery device can be inserted percutaneously near vascular tissue such as, for example, peritoneal tissue. When the delivery device is inserted, the lashing means can be used to pull the delivery device toward the vascular tissue, such that the upper surface of the active agent delivery of the delivery device comes into contact with the vascular tissue. . The contact between the active agent delivery surface and the delivery device and the vascular tissue can be maintained by making and maintaining a substantially taut mooring means. In an alternative embodiment, an adhesive on the active agent delivery surface of the delivery device capable of substantially adhering to the vascular tissue can be used to keep the delivery device substantially in contact with the vascularized tissue. Any generally tubular or similar implement may be used to insert and / or deploy the delivery device. The insert attachment can be composed of an internal and an external tube, wherein the delivery device is placed inside the inner tube. The side of the inner tube may have an opening in which the delivery device may be placed when the inner tube is extended out of the outer tube. Where one end of the lashing means of the delivery device is fixed to the delivery device, the other end of the lashing means can be fixed within the closed distal end of the inner tube. The inner tube can be retracted towards the external tube before implantation. After a trocar is inserted into the subject, with the insertion implement placed inside the trocar cannula, the inner tube can be extended into the body of the subject. When the extension of the inner tube results in exposure of the opening in the side of the inner tube to the body cavity, the delivery device can be deployed within the body of the subject. After the delivery device is deployed, the inner tube can again be substantially retracted into the outer tube, without cutting the tie-down means. Then, the trocar can be removed from the body, along with the insertion implement. After the distal end of the insert attachment has been removed, the strap can be seen and manipulated. The lashing means can be cut from the insert attachment and manipulated to hold the delivery device in place. The inventors of the present invention have discovered a device that is suitable for controlled and sustained release of an effective agent to obtain a desired local or systemic physiological or pharmacological effect. The device includes an implantable active agent delivery system comprising an effective amount of at least one active agent that, once implanted, the device can provide a continuous supply of the agent or agents to internal regions of the body without requiring additional invasive penetrations. in these regions. Instead, the device can remain in the body and serve as a continuous source of the agent or agents. The device according to the present invention allows the prolonged constant release of active agents during a specific period of months (e.g., 1 month, 2 months, 3 months, 6 months) or years (e.g., 1 year, 5 years, 10 years, 20 years) until the agent is used substantially. The types of substances that can be delivered through the delivery device may include drugs (thrombolytics, platelet inhibitors, anti-restenotic agents, beta-blockers, ion channel antagonists, positive or negative ionotropic agents, antiarrhythmics, antibiotics, analgesics , chemotherapeutic agents, other antineoplastic agents, etc.), natural or recombinant proteins (e.g., angiogenic proteins such as vascular endothelial growth factor (VEGF), fibroblast growth factors (FGF), epidermal growth factor (EGF) ), platelet derived growth factor (PDGF), nerve cell growth factor (NGF) or hepatocyte growth factor (HGF)), cells or cell preparations (e.g., stem cells, other progenitor cells, myocytes , myoblasts, pancreatic islet cells, dopamine-secreting cells, etc.), genes or gene therapy preparations (e.g., viral vectors containing genes for gene therapy applications, genetic material for electrophoretic transmission in cells, plasmids, viral vectors, genetically modified cells, naked DNA, etc.), contrast media or dyes for matrix formation, radiolabelled diagnostic materials or drugs or other traceable substances, mixtures of any of the foregoing, alone, in solution or in combination with any substance or delivery matrix (e.g., polymer matrices used to inhibit or slow down the distribution or spread of a substance far from your original injection site), dialysis solutions or microdialysis solutions, and / or any other type of substances or combinations thereof that can be introduced through the delivery device for therapeutic purposes, image formation, diagnosis or other. In various aspects, the active agent can be delivered at a low dose rate, e.g., up to about 0.01 micrograms / hr, OJO micrograms / hr, 0.25 micrograms / hr, 1 microgram / hour, or 5, 10, 25 , 50, 75, 100, 150 or generally up to about 200 micrograms / hr. The specific ranges of amount of active agent delivered may vary depending, for example, on potency. In an illustrative embodiment, a drug formulation is delivered at a low volume rate, eg, a volume regime of about 0.01 microliters / day to about 2 ml / day. The delivery of a formulation may be substantially continuous or pulsed, and may be during a preselected administration period ranging from a few hours to years. In another embodiment, the formulation is delivered at a volume rate of about 1 ml per day to about 150 ml per day. In another embodiment, the formulation supply is substantially continuous. The brief description of the above invention is not intended to describe each embodiment or each implementation of the present invention. Advantages and achievements, together with a more complete understanding of the invention, will become apparent and will be appreciated by referring to the following detailed description and claims taken along with the accompanying drawings. Throughout this document, all temperatures are given in degrees centigrade, and all percentages are in percent by weight unless otherwise indicated. The following are definitions of terms used in the specification. The initial definition provided for a group or term here applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which this invention is directed. Although any methods, devices and materials similar or equivalent to those described herein can be used in the practice or test of the invention, preferred methods, devices and materials are now described. All publications mentioned herein are incorporated by reference for the purpose of describing and breaking down the compositions and methodologies that are described in publications that may be used in connection with the presently described invention. The publications described herein are provided solely for description before the date of submission of the present application. Nothing here should be considered as an admission that the invention has no right to precede said description by virtue of the previous invention.

BRIEF DESTRUCTION OF THE DRAWINGS The accompanying drawings incorporated in the specification and forming part thereof illustrate various aspects of the present invention, and together with the description serve to explain the principles of the invention. In the drawings: Figure 1 is a view of a delivery device within the abdomen in accordance with the embodiment of the invention. Figure 2 is a view of a delivery device introduced into an abdomen through a cannula in accordance with an embodiment of the invention ..}. Figure 3 is a view of an insert attachment with a delivery device in accordance with an embodiment of the invention. Figure 4 shows an insertion implement in a cannula at the entrance to an abdomen in accordance with an embodiment of the invention. Figure 5 shows the insertion implement in a cannula of figure 4 after entering an abdomen in accordance with an embodiment of the invention. Figure 6 shows the extension of the internal tube of the insertion implement in a cannula of figure 4 according to one embodiment of the invention. Figure 7 shows a delivery device that descends from the insertion implement in a cannula of figure 4 in accordance with a modality of the invention. Figure 8 shows the insertion implement in a cannula of figure 4 that is removed from the abdomen in accordance with an embodiment of the invention. Figure 9 shows a clip attached to a fastened delivery device to hold it in place on the abdomen in accordance with one embodiment of the invention. Figure 10 shows a cross-sectional view of a delivery device and the distal end of an insert attachment in accordance with an embodiment of the present invention. Figure 11 is an insert delivery and attachment device of Figure 8 with the delivery device detached from the inner tube of the insert attachment according to one embodiment of the invention. Figure 12 illustrates an embodiment of the delivery device with biological material extending to the outer diameter of the inner tube of the insert attachment. Figure 13 illustrates one embodiment of the delivery device with a flexible substrate that describes an arc in the outer diameter of the inner tube of the insert attachment. Figure 14 is a delivery device of Figure 13 deployed and that assumes a substantially flat shape in accordance with an embodiment of the invention. Figure 15 is a cross section of a mode in which the delivery device has a reservoir. Figure 16 is a cross section of the embodiment of Figure 15. Reference will now be made in detail to the present preferred embodiment of the invention, an example of which is illustrated in the accompanying drawings. Alternative modalities will also be described.

DETAILED DESCRIPTION OF THE INVENTION Before breaking down and describing the method of the present invention for making transdermal and mucosal delivery devices, and / or other delivery devices, it should be understood that this invention is not limited to the particular process steps and materials hereby they are described, since such procedural steps and materials may vary somewhat. It should also be understood that the terminology used herein is used for the purpose of describing particular embodiments only and should not be limiting since the scope of the present invention will be limited only by the appended claims. It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an" and "the", "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to a laminate structure containing "a drug" includes a mixture of two or more drugs; the reference to "an adhesive" includes the reference to two or more of those adhesives; and the reference to "an increment" includes the reference to a mixture of two or more increments. In describing and claiming the present invention, the following terminology will be used in accordance with the claims set forth below. As used herein, the term "active agent" includes, without limitation, any substance that is desired to be incorporated into the delivery system of the present invention for sustained and controlled delivery and / or delivery. An active agent can be in any condition, including liquids, solutions, pastes, solids and the like. The active agent can be a pharmaceutically active agent, such as an active agent and / or diagnostic substance for human or veterinary use. In general, "active agents" refer, without limitation, to any composition that can be used for the benefit of a mammalian species. Said agents can take the form of, for example, ions, macromolecules, small organic molecules, peptides, proteins or polypeptides, oligonucleotides and oligosaccharides. The term "active agent delivery device" means an implantable device capable of delivering a therapeutically effective amount of an active agent from a biomaterial and includes a device comprising an implantable device that includes a strap. The term "active agent delivery device" can be used interchangeably with the term "implant device" or "implant". As used herein, the term "active gel", "gellficated drug", "drug in gel form", and the like include a drug in which a gelling agent is dispersed to obtain selected flow or surface tension properties for application to laminated patches. Therefore, an active gel is a liquid drug in a viscous but fluidizable state, and can be a colloidal / biphasic or dissolved mixture of the liquid drug and a gelling agent. The liquid drug means either a drug that is itself a liquid suspended or dispersed in a selected solvent or vehicle. Said solvent would be a liquid, such as ethanol, water and the like, or a low viscosity semi-solid which can be extruded, such as low molecular weight polymer, waxes, petroleum jelly and the like. An active gel may also include enhancers that may be added to the formulation to facilitate transport of the drug into the body. The active gel may also include a combination of drugs, gelling agents, enhancers, preservatives, antioxidants, anti-irritants, solubilizing agents and the like. The term "gel" means applying to the functional nature of the thickened drug component whether or not the technical definition of a gel is met. The term "administer" is intended to include introducing the delivery system or device of the present invention into a subject. When the administration is for the purpose of treatment, the administration may be for prophylactic or therapeutic purposes. When provided prophylactically, the substance is provided in anticipation of any symptoms. The prophylactic administration of the substance can serve to prevent or attenuate any subsequent symptoms. When provided therapeutically, the substance is provided in (or soon after) the onset of a symptom. The therapeutic administration of this substance can serve to attenuate any real symptom. As used herein, the term "biomaterial" includes biocompatible material that comprises one or more active agents in a form suitable for delivery within a subject in a therapeutically acceptable amount. "Increase of supply", "increase of penetration" or "increase of permeation" as used herein, refers to an increase in quantity and / or rate of supply of a compound that is delivered in and through one or more layers of an epithelial or endothelial tissue. A delivery implement can be observed by measuring the speed and / or quantity of the compound passing through one or more layers of animal or human tissue. The increase in supply may also imply an increase in the depth in the fabric to which the compound is supplied, and / or to the degree of supply for one or more types of epithelial tissue or tissue cells. Such measurements are easily obtained, for example, by using a diffusion cell apparatus as described in U.S.A. 5,891, 462. "Delivery site", as used herein, means including an area of the body to which the active agent is supplied to enter the systemic circulation eg, a site that allows systemic access of active agent delivered to the site. Illustrative delivery sites compatible with the systemic delivery of active agent include, but are not necessarily limited to, sites of peritoneum and omentum. The supply can be transepithelial or through the epithelial tissue. An "epithelial tissue" is the basic tissue that covers surface areas of the surface, spaces and cavities of the body. The epithelial tissues are composed mainly of epithelial cells that are linked to each other and the rest in an extracellular matrix (basement membrane) that is typically produced by the cells. As used herein, the term "drug" or "active agent" or any other similar term means any chemical or biological material or compound suitable for administration by the methods taught in the present invention, which induces a desired biological or pharmacological effect, which may include but is not limited to (1) affecting living processes, (2) having a prophylactic effect on the organism and preventing an unwanted biological effect such as preventing an infection, (3) alleviating a condition caused by an illness, for example, relieving pain and inflammation caused as a result of illness, and / or (4) either alleviating, reducing or completely eliminating the disease from the organism. The effect may be local, such as providing a local anesthetic effect, or it may be systemic. The invention is not directed to novel drugs or new classes of active agents. Rather, it is limited to devices and methods for making devices for delivery of drugs or agents that exist in the art or that can subsequently be established as drugs or active agents and that are suitable for delivery by the present invention. Such substances include broad classes of compounds normally supplied to the body, including through body surfaces and membranes. In general, this includes but is not limited to: anti-infectives such as antibiotics, antiviral agents; analgesics and analgesic combinations; anorexics; anthelmintics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents; antimigraine preparations; antinausea; antineoplastics; antiparkinsonian drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergic; sympathycimetics; xanthine derivatives; cardiovascular preparations including potassium and sodium channel blockers, beta-blockers, alpha-blockers, and antiarrhythmics; antihypertensive; diuretics and antidiuretics; vasodilators including general, peripheral and cerebral coronaries; stimulants of the central nervous system; vasoconstrictors; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressants, muscle relaxants; parasimpáticolíticos; psychostimulants; sedatives; tranquilizers and nicotine and acid addition salts thereof.

The change in either the resistance (the diffusion coefficient) or the driving force (the gradient for diffusion) can increase the flow of a drug through the muscle tissue. The flow can be increased by using so-called penetration or chemical enhancers. Chemical increments are composed of two main categories of components, that is, compounds that alter cell cover and solvents or binary systems that contain both compounds that alter cell cover and solvents. The term "formulation" means any drug together with a pharmaceutically acceptable excipient or carrier such as a solvent such as water, saline regulated in its pH with phosphate or another acceptable substance. A formulation can include one or more active agents, and also encompasses one or more carrier materials as is known in the art. The term "implantation site" is used to refer to a site on or within the body of a subject in which an active agent delivery device may be introduced. This includes but is not limited to a function or opening in the epidermis through which a delivery device can be inserted. An "implantation site" can usually be close to a "supply site". For example, an "implantation site" can refer to an opening in the external surface of a subject, while the "delivery site" refers to an area generally adjacent to or close to the opening on an internal surface of the subject.

The term "macromolecule" as used herein, refers to large molecules (MW greater than 1000 daltons) illustrated by, but not limited to, peptides, proteins, oligonucleotides and polynucleotides of biological or synthetic origin. "Small organic molecule" refers to an agent containing carbon having a molecular weight (MW) less than or equal to 1000 daltons. The term "peptide", as used herein, refers to a compound made from a single chain of D- or L-amino acids or a mixture of D- and L-amino acids joined by peptide bonds. Generally, the peptides contain at least two amino acid residues and are less than about 50 amino acids in length. The term "protein" refers to a compound that is formed by linearly linked amino acids linked by peptide bonds, but unlike peptides, has a well-defined conformation. Proteins, unlike peptides, generally consist of chains of 50 or more amino acids. "Polypeptide" as used herein, refers to a polymer of at least two amino acid residues and that contains one or more peptide bonds. "Polypeptides" encompass peptides and proteins regardless of whether the polypeptide has a well-defined conformation. "Pattern" or "temporary" as used in the context of active agent delivery means the supply of active agent in a pattern, generally a substantially regular pattern, during a preselected period (e.g., other than another period). associated with, for example, a bolus injection). The "standard" or "temporary" active agent supply means encompassing the delivery of active agent at a regimen or range of regimens (e.g., amount of active agent per unit time, or volume of active agent formulation per unit of time). unit of time) in increments, decreases, substantially constant or pulsatile, and also encompasses the supply that is continuous or substantially continuous, or chronic. By "substantially continuous", as used in, for example, in the context of "substantially continuous infusion" or "substantially continuous supply", means that it refers to the supply of active agent in a manner that is substantially uninterrupted for a preselected period. of active agent supply (other than a period associated with, for example, a bolus injection). In addition, the "substantially continuous" active agent supply may also encompass the delivery of active agent at a regimen or range of regimens (e.g., amount of an active agent unit time or volume of active agent formulation for a unit time). ) substantially constant, preselected which is substantially uninterrupted for a preselected period of active agent delivery. The term "substrate", as used herein, means including a lower layer of the active agent delivery device. The substrate may provide the simple structural backing and / or may have one or more other functions. For example, the substrate may include other operable agents to be useful for the subject and / or the active agent and / or the material containing the active agent. The use of the term "substrate" should not be read as a limitation of the invention for a delivery device comprising a plurality of layers, since the delivery device may comprise a single layer. The terms "subject", "individual" and "patient", used interchangeably herein, refer to any subject, generally, by way of example only, a mammal (e.g., human, canine, feline, equine, bovine, Ursino, Actino, porcine, ungulate, etc.), to which an active agent can be supplied. As used herein, the terms "sustained release" and "controlled release" indicate an extension of the duration of release and / or duration of action of an active agent and are well understood in the art and are designed to be interchangeable, unless otherwise indicated. Sustained release, for example, can be a period of at least 12 hours, at least 24 hours, at least two weeks, at least one month, at least three months or more. The term "systemic delivery" means that it encompasses all parenteral delivery routes that allow the active agent to enter the systemic circulation, e.g., intravenous, intraarterial, intramuscular, subcutaneous, intraadipose tissue, intralymphatic, etc. The term "therapeutically effective amount" means an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent, effective to facilitate a desired therapeutic effect. The precise desired therapeutic effect will vary in accordance with the condition to be treated, the formulation to be administered and a variety of other factors that are appreciated by those skilled in the art. As used herein the term "biocompatible" includes any material that is compatible with living tissue or a living system not to be toxic or harmful and does not cause immunological rejection. "Biocompatibility" includes the tendency of a material to be biocompatible. As used herein, the term "biocompatible" refers collectively to both the intact delivery device and its contents. Specifically, it relates to the ability of the implanted intact delivery device and its contents to avoid detrimental effects of the various protective systems of the body and to remain functional for a significant period. In addition to avoiding protective responses against the immune system or fibrotic foreign body response, "biocompatible" also implies that no specific undesirable cytotoxic or systemic effects are caused by the delivery device and its contents so as to interfere with the desired functioning of the delivery device. supply or its content. The biocompatibility of the device is produced by a combination of factors. Important for biocompatibility and continuous functionality are the morphology of the delivery device, the hydrophobic character and the absence of undesirable substances either on the surface of the same or leachable supply device thereof. Therefore, planed surfaces, folds, interlayers or other forms or structures that induce a response of foreign bodies are avoided. The dispensing device forming materials are sufficiently pure so that unwanted substances are not leached from the materials of the delivery device itself. In addition, after preparation of the delivery device, treatment of the external surface of the delivery device with fluids or materials (eg, serum) that can adhere to or be absorbed by the delivery device and subsequently alter the biocompatibility of the supply device are avoided. First, the materials used to form the delivery device are selected substances based on their ability to be compatible with and accepted by the implanted delivery device receiver tissues. Substances that are not harmful to the recipient or to the isolated biologically active agent are used. Second, the substances used in the preparation of the biocompatible delivery device are either free of leachable pyrogenic substances or otherwise immunogenic, noxious, irritant substances or are exhaustively purified to remove said harmful substances. Subsequently, and throughout the manufacture and maintenance of the delivery device before implantation, great care is taken to avoid adulteration or contamination of the delivery device with substances that would adversely affect its biocompatibility. Third, the outer configuration of the delivery device including its texture is formed in such a way as to provide an optimum interface with the tissues of the recipient after implantation. This parameter will be defined in part by the implementation site. For example, if the delivery device will be in the peritoneal cavity of the receiver, its surface would be smooth. However, if it were embedded in the soft tissue of the recipient, its surface could be moderately rough or grainy. A determining factor will be whether it is desirable to allow the receptor cells to bind to the external surface of the delivery device or if such binding should be avoided. An open-textured or sponge-shaped surface can promote the internal growth of capillary beds, while a smooth surface may not stimulate excessive overgrowth by fibroblasts. Excessive overgrowth by fibroblasts should be avoided, except where capillary growth has occurred, as it can result in the deposition of a poorly permeable nasal membrane around the delivery device and prevent the isolated cells from making contact with the recipient's body . It has also been found that certain geometries of the delivery device specifically induce fibrotic responses of foreign bodies and should be avoided. Therefore, the delivery devices should not contain structures having interlayers such as planed surfaces or creases. In general, opposing supply device surfaces or edges of either the same or adjacent delivery devices would be at least 1 mm, preferably more than 2 mm, and most preferably more than 5 mm. Preferred embodiments include cylinders, "U" shaped cylinders, and flat sheets or sandwich type structures. The surrounding or peripheral region (liner) of the biocompatible delivery device may optionally include substances that reduce or prevent the local inflammatory response to the implanted delivery device, and / or generate or promote a suitable local environment for implanted cells or tissues. As used herein, the term "bioabsorbable" includes the ability of a material to be finally absorbed by the body. Preferably, this absorption occurs without adverse effects on the body. As used herein, the term "shape memory" includes the ability of a material to return to the preformed shape. Referring now to the drawings in detail, wherein similar numbers indicate the same elements in all views, Figure 3 shows an insert attachment 11 operable to implant an object in the body. The delivery device 10 may be a cell or tissue matrix such as that described in the US patent. No. 4,902,295 to Walthall et al., Or any other biomaterial capable of delivering a drug or other therapeutic, prophylactic, or other material. The delivery device 10 can be suspended from a strap 12, which can be attached to a tube 14. The strap 12 would not adversely affect the operation of the delivery device 10 or the biocompatibility of the delivery device 10. The insert attachment 11 includes an inner tube 14 and an outer tube 16. The inner tube 14 has a portion removed, creating a cavity 18 for receiving the delivery device 10. The inner tube 14 is slidable through the outer tube 16. The external tube tip of the tube Inner 14 may be blunt, rounded, or pointed, depending on the fabric structure in which the acceptable amount of secondary damage will penetrate and / or other considerations. The inserting implement 11 may have a handle 13 which, when tightened, causes the inner tube 14 to extend distally away from the distal edge of the outer tube 16. Figure 3 illustrates the handle 13 completely crushed and therefore the tube inner 14 extends far enough to expose cavity 18, allowing supply device 10 to fall therefrom. When the inner tube 14 is extended from the outer tube 16, the delivery device 10 is suspended from a strap 12. When the inner tube 14 is retracted into the outer tube 16 before implantation, the delivery device 10 is retained within the cavity 18 by the outer tube 16. A seal, such as a lip rub seal, could be used between the inner and outer tubes to seal the gas within the abdomen while the implement of insertion 11 is in use. In a preferred embodiment, the delivery device 10 is an encapted belt that contains biologically active agents. In that embodiment, the delivery device 10 includes a membrane 32 containing the biologically active agent, with a belt 12, or rod, extending therefrom. The strap 12 is of sufficient length to go from the membrane 32, at the treatment site 5, to an external location near the insertion site 2, and may be an extension of the cell carrier. The abdomen 20 can be insufflated during the implantation procedure using, for example, a Veress needle. A trocar, such as one created by Ethicon Endosurgery, in Cincinnati, Ohio, can be used to penetrate the abdomen 20 and / or serve as a vehicle for the insertion implement 11 and / or to serve as a vehicle for the delivery device 10. The distal end of the insert attachment 11 may be introduced into the abdomen 20 in a variety of ways. For example, a cannula 22, such as that of a trocar, can be placed in the insertion site 2 with a plug inserted therein to prevent material from entering the cannula 22 during insertion. After the cannula / obturator combination is inserted into the abdomen 20 at the insertion site 2, the obturator is removed, leaving the cannula 22 in the abdomen 20. Once the obturator has been removed, the cannula 22 can receive the Insert Attachment 11, which generally has a predetermined shape to slidably fit within the central hole of the cannula 22, loosely. FIG. 5 illustrates a trocar with insert attachment 11 inserted inside its cannula 22 in the abdomen 20 of a subject. The use of a handle 13 advances the inner tube 14 distally into the outer tube 16.

Alternatively, where the insert attachment 11 is capped at its distal end as shown in Figure 3, the insert attachment 11 can act as the obturator to eliminate the steps of removing a obturator from the cannula 22 and subsequently inserting the implement. 11 in the cannula 22 after the cannula 22 has entered the abdomen 20. Figure 4 shows the insertion implement 11 loaded in the cannula 22 of a trocar ready to be used in the abdomen 20 of a subject, although the device can be use to implant objects in other parts of the body of a subject. When the insertion implement 11 is used as a stopper, the insertion implement will be loaded into the cannula 22 before penetration into the insertion site 2. In this way, the insertion implement 11 can be introduced into the abdomen 20 with the simultaneous insertion of the trocar with the insertion implement 11. Figure 5 illustrates a trocar with an insertion implement 11 inserted inside the cannula 22 in the abdomen 20 of a subject. The use of a handle 13 advances the inner tube 14 distally into the inner tube 16. Alternatively, the insertion implement 11 can be inserted into an insertion site 2 without the use of a separate cannula 22. When the distal end of the implement 11 insertion has been introduced into the abdomen 20 through the cannula 22, such as that of a trocar, the distal end of the insertion implement 11 can also be extended from the cannula 22 as shown in figure 6. The tube internal 14 extends distally from the outer tube 16. A portion of the inner tube 14 and the delivery device 10 is still inside the outer tube 16, whereby the outer tube 16 will secure the delivery device 10 within the cavity 18 of the inner tube 16. Prior to the extension of inner tube 14, abdomen 20 can be insufflated. This insufflation may assist in the deployment of the delivery device 10 from the cavity 18 of the inner tube 14. As shown in Figure 7, the inner tube 14 may extend distally within the abdomen 20. The delivery device 10 may then fall from the inner tube 14, or alternatively, could be ejected from inner tube 14 by a spring or other deployment means. A fluid material or other material can be used to serve as a lubricant in the inner tube 14 to assist in the deployment of the delivery device 10. The delivery device 10 is then suspended from a belt 12. After deployment of the delivery device 10, the inner tube 14 can be substantially retracted folded proximally inside the outer tube 16. The proximal retraction of the inner tube 14 can be temporarily stopped in such a way that the strap 12 is not separated when piercing it between the lip of the cavity 18 in the inner tube 14 and the distal lip of outer tube 16. As shown in Fig. 8, the combination of cannula 22 and inserter attachment 11 can then be pulled proximally through the wall of the abdomen 20. Alternatively, after that the delivery device 10 has been unfolded, the combination of the cannula 22 and the insertion implement 11 can be pulled proximally through s of the wall of the abdomen 20 without retracting the inner tube 14 back to the outer tube 16. In other words, the inner tube 14 can be left completely or substantially extended at the time when the combination of the cannula 22 and the implement of Insert 11 is pulled proximally through the wall of the abdomen 20. Figure 9 shows the delivery device 10 preloaded against the inner wall of the abdomen 20. It could be placed, for example, against the peritoneal wall by pulling the proximal end of the strap 12 proximally. Once the strap 12 is substantially tensioned, the strap 12 can be tied in place with a clip 23. Alternatively, the strap 12 can be attached to the abdomen 20 or otherwise tied using a suture or other means known in the art. After the strap 12 is attached, it can be detached from the inner tube 14. As an optional final step, a lid can be used to seal the insertion site 12 to prevent the introduction of foreign material through the insertion site 2. In a preferred form of the inventive method, the strap 12 allows the delivery device 10 to be retrieved from the treatment site 12. The delivery device 10 can now have the advantage of the vascular tissue of the interior of the abdomen 20. The vascularization of the delivery 10 may occur to feed the delivery device 10 with blood or to produce exchange of any medication within the delivery device 10. Against the vascular tissue, the delivery device 10 may deliver drugs or therapeutic and / or prophylactic materials into the tissue vascular. The amount or rate of delivery of agent through and / or within tissues is sometimes quantified in terms of the amount of compound passing through a predetermined area of tissue, which is a defined area of intact, unbroken, living tissue. That area will generally be in the range of about 5 cm2 to about 100 cm2, more usually in the range of about 10 cm2 to about 100 cm2, most usually even in the range of about 20 cm2 to about 60 cm2. As will be appreciated by those skilled in the art, other ranges are possible. Figure 10 shows a cross-sectional view of the dlstal end of the insertion implement 11. The delivery device 10 is inside the inner tube 14. The delivery device 10 could be a biological construction, such as one described in the US patent. No. 4,902,295 to Walthall et al., Or could be an elastic or sponge-shaped biomaterial impregnated with useful pharmaceutical compounds or other materials. A softer material could be retained with a substrate 24 in the form of, for example, an impregnable and biocompatible plastic, such as a polylactic acid or any other biocompatible and implantable material suitable for such use. Figure 11 illustrates the delivery device 10 detached from the inner tube 14 and suspended by a strap 12. The strap 12 can connect to both the delivery device 10 and the distal end of the inner tube 14 using, for example, a ball joint and receptacle to allow free maneuverability of the belt 12 while still fixing the parts. The strap 12 can also be fixed to the delivery device 10 and the far end! of the inner tube 14 using any other methods available and known to those skilled in the art. Figure 12 shows a cross section taken through a longitudinal axis of the inner tube 14. In one embodiment of the delivery device 10, the biomaterial 26 could extend to the external diameter of the inner tube 14, to create a flat interface surface between the biomaterial 26 and the peritoneal wall of the abdomen 20. Figure 13 shows an alternative embodiment in which a substrate 24 follows the curvature of the inner tube 14, whereby the biomaterial 26 is enclosed. The substrate 24 follows a precise path of the outer diameter of the inner tube 14. This substrate 24 can further be composed of or supported by a biocompatible elastic material having configuration memory, such that the delivery device 10 is substantially flattened as it unfolds. in the body of a subject, while it is nevertheless flexible enough to maximize surface contact with vascular tissue. The possible types of elastic materials having shape memory and methods for using them in a patch implantation context are described in Seid in the US patent. No. 5, 254.133. Other materials that have shape memory can be used. Figure 14 illustrates the delivery device 10 of Figure 13 deployed or before being loaded on the insertion implement 11. The material of the substrate 24 and the biomaterial 26 is sufficiently flexible to assume a substantially flat position when deployed, thereby after implantation the biomaterial 26 rests substantially on the peritoneal wall of the abdomen 20 maximizing contact between the surface of the biomaterial 26 and the peritoneal wall of the abdomen 20. In the figures, the delivery device 10 generally has the shape of a rod However, it should be appreciated that the delivery device 10 can have any shape that can accommodate the source of biologically active agent, or cells that release active agents, without causing extraordinary trauma to the patient during implantation. The present delivery device 10 can be formed in a wide variety of suitable shapes and combinations of materials. One consideration in the selection of a particular configuration for the delivery device when cells are present may be the access of oxygen and nutrients to isolated cells or tissues, and the passage of waste metabolites, toxins and secreted products from the delivery device. . The delivery device 10 of the present invention can provide, at least in one dimension, a sufficiently close proximity of any cells isolated in the nucleus to the surrounding tissues of the recipient, including the bloodstream of the recipient, in order to maintain viability and function of the isolated cells. In general, the delivery device 10 can have a maximum surface depth to depth of no greater than 5 mm in at least one dimension, with a maximum depth of 500 microns being preferred. Other depths may be used without departing from the scope of the present invention. One or more delivery devices 10 may be required to produce a desired effect or effects on the receiver. Various alternative embodiments of implantable delivery devices 10 are shown. However, it will be appreciated that there are even more alternative embodiments of implantable delivery device 10 that are possible and within the scope of the present invention, but are not shown in the figures. . In one embodiment, the implantable delivery device 10 of the present invention is of sufficient durability size to complete recovery after implantation. To contrast with recoverable microcapsules, which have a typical maximum practical volume of the order of one microliter, the preferred delivery device 10 of the present invention is called "macrocapsules". Said macrocapsules may have a core of a preferably minimum volume of about 1 to 10 microliters and depending on the use more easily manufactured to have a value in excess of 100 microllters. Other volumes are possible without departing from the present invention. The delivery device 10, shown with further detail in Figures 13, 14, 15 and 16, includes biomaterial 26 filled with a secretory cell, preferably a cell that produces biologically active agents. In one embodiment, the delivery device 10 further includes a permeable, semipermeable or permselective membrane surrounding the biomaterial 26. The strap 12 may be generally constructed of a waterproof membrane material or may be coated with a material that makes the strap waterproof . In one embodiment, an impermeable protective barrier material can coat a portion of an outer membrane of biomaterial 26. The illustrative protective barrier material includes polyethylene oxides, polypropylene oxides, silicon, hydrogels, and derivatives and mixtures thereof. It should be appreciated that the semipermeable membrane 32 may have alternative shapes that will accommodate the biomaterial 26. Alternatively, the delivery device can comprise a substantially solid formation of biomaterial without the need for any additional substrate and / or membranes, if said biomaterial is of sufficient stiffness and strength to maintain a shape sufficient to maintain contact with the tissues of the subject. The optional support structure 24, together with the biomaterial layer (s) 26 forms a three-dimensional structure that can promote tissue growth and neovascularization for drug delivery. It should be noted that the support structure 24, together with any optional membrane layers, can be composed of single or multiple layers of biocompatible materials, including, but not limited to hydrogels, poll (2-hydroxyethyl) methacrylate, (pHEMA), hydroxyethyl methacrylate (HEMA), polyacrylonitrile-polyvinyl chloride polymers (PAN-PVC), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polypropylene, high density polyethylene, polyurethane, polyester (Dacron), polyvinyl chloride, alcohol polyvinyl, acrylic copolymers, polysulfone, nylon, polyvinyl difluoride, polyanhydrides, silicone, polycarbonate, cellulose acetate, mixed ester-cellulose, collagen, firbina, poly (l-lysine), poly (L-lactic acid), hydroxyethyl methacrylate , protein polymers, peptide polymers, hydroxyapatite, alumina, zirconia, carbon fiber, aluminum, calcium phosphate, titanium, titanium alloy, nintinol, ace Stainless steel and CoCr alloy. An outer membrane can be a polymer material and can include a surfactant, an anti-inflammatory agent, angiogenic factors and / or an antioxidant. The specific type of polymer, surfactant or other additive may depend on the material to be encapsulated and the configuration of the extrusion apparatus. Illustrative antiinflammatory agents include but are not limited to corticosteroids such as cortisone and ACTH, dexamethasone, cortisol, interleukin-1 and its receptor antagonists, and antibodies to TGF-beta, to interleukin-1 (I L-1) and to interferon -gamma. Exemplary surfactants include but are not limited to Triton-X 100 from Sigma Chemicals, and Pluronics P65, P32 and P18. Illustrative antioxidants include, but are not limited in any way to vitamin C (ascorbic acid) and vitamin E. Illustrative angiogenic factors include but are not limited in any way to fibroblast growth factor and nerve growth factor. Optional membranes can be modified to additionally optimize the drug delivery, such as by the addition of polyethylene oxide (PEO), heparin, albumin, tissue growth factors, angiogenic growth factors, and other interstitial tissue matrix substances. , anti-inflammatory drugs and anti-rejection medications that promote and maintain healthy vascular tissue throughout the interconnecting pore structure, while minimizing the deposition of matrix, fibrin or collagen proteins within the internal pore structure. Angiogenic growth factors that can be used in membranes include but are not limited to basic fibroblast growth factor (bFGF), (also known as heparin-binding growth factor II and fibroblast growth factor II), factor of acid fibroblast growth (aFGF), (also known as heparin-binding growth factor I and fibroblast growth factor I), vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor BB ( PDEGF-BB), angiopoietin-1, transforming growth factor beta (TGF-Beta), transforming growth factor alpha (TGF-alpha), hepatocyte growth factor, tumor necrosis factor-alpha (TNF-alpha), angiogenin , interleukin-8 (I L-8), hypoxia-l inducible factor (HIF-I), angiotensin-converting enzyme (ACE) inhibitor, Quinaprilat, angiotropin, thrombospondin, KGHK peptide, low oxygen tension, lactic acid, insulin and growth hormone. Extracellular matrix proteins (ECM) placed within the outer membrane of the biomaterial structure provide cellular support, cell polarity, cell targeting signals and cell adhesion sites to increase the internal growth of vascular tissue and angiogenesis. In the event that the supply of active agents, e.g., cells that secrete said factors, is spent, a delivery device 10 can be removed and replaced. The recovery of an implanted delivery device 10 can be achieved by pulling it from the treatment site 5 by its strap 12. One way of effecting the removal is to use a pair of forceps after exposing the strap 12 when removing a lid. Other devices and / or recovery methods may be used. The cap can be placed directly under the epithelial tissues of the patient. The delivery device 10 can be replaced by a new insert in the event that additional therapy is required. The cells encapsulated within a delivery device 10 can also be recovered if the cells stop producing the biologically active agent, expire or are no longer needed to correct and / or prevent a particular dysfunction. A permeable portion (e.g., membrane) of the delivery device 10 is implanted at or near the target treatment site 5, while an impermeable portion can confine an active agent or agents to within the limits of the insert. A permeable portion can include a polymeric material having pores of a particular size (i.e., having a particular molecular weight cutoff) that excludes some molecules from passing through it, while allowing the passage of others.

In this way, the diffusion of desired elements from the delivery device 10 to the treatment site is allowed, while the passage of deleterious elements such as viruses and various proteases is effectively impeded. For example, delivery devices with pores having a molecular weight exclusion of about 50 kD to about 300 kD may be useful, with those having pores with a molecular weight cutoff of about 25 kD to about 200 kD being particularly preferred. . Other configurations and / or pore dimensions are possible without departing from the scope of the present invention. The delivery device 10 may be composed of any biocompatible material having a desired pore size and which is composed of materials that do not limit the activity of the substance embedded therein. Hydrophilic matrices such as, by way of example only, hydrogels (e.g., hydroxyethyl methacrylate, polyanhydrides, polyvinyl alcohol and polyvinylpyrrolidone) and hydrophobic matrices such as ethylene-vinyl acetate may be particularly useful. In one embodiment, the implantable delivery device of the present invention is of sufficient size and durability to complete recovery after implantation. The delivery device 10 can provide any biologically active agent that satisfies the subject's deficiency or remedies the dysfunction. Alternatively, the device may provide an active analogue, active fragment or active derivative of an active agent or agents, and / or may include a precursor which, after processing, provides the same activity as the factor in the appropriate place in vivo. The delivery device 10 can also include a factor agonist. Other agents may include insulin, factor VIII, trophic factors such as erythropoietin and growth hormone, biological response modifiers such as lymphokines and cytokines, enzymes and antibody-secreting cell antibodies. In addition, the capsule may contain multiple types of cells and cells, tissue and / or other appropriate substance or substances. An illustrative form of the delivery device 10 is a smooth seamless supply device 10 manufactured by the coextrusion of a polymeric casting solution and a biomaterial solution. In this approach, a multi-orifice extruder nozzle is used with the polymer solution extruded from the outer bore and the active agent co-extruded from an internal bore. In addition to containing active agent (or tissue cells of the type described above), the active agent may include nutrients, such as fetal, equine or porcine bovine serum. Any cells that secrete the biologically active agent that is therapeutic for a disease of the subject can be incorporated into the system of the invention. In addition or alternatively, cells that secrete a biologically active agent that is prophylactic for a disease of the subject can be incorporated into the system of the invention. Various "growth factors" that have the ability to stimulate cell growth, cell differentiation and / or factor secretion can be implanted with the active agent secreting cells to ensure the successful delivery of the desired agent or desired factor in the site of treatment. These treatment factors can be specific for a cell type or have a generalized effect on a number of different tissues. In the case of neurotransmitter-producing cells such as neurons, growth factors can act to maintain neurotransmitter production, as well as to promote the maintenance and growth of the cells. Alternatively, the growth factors can keep the nerve cells in a differentiated state. Useful cell growth factors include nerve growth factor (NGF), an arrangement of fibroblast growth factors (FGF), platelet-derived growth factor (PDGF), brain-derived neurotrophic factor (BDNF) and epidermal growth factor (EGF), and ciliary growth factor, among many. In addition, effectors of several membrane receptors such as glutamate and nicotine may also be useful. In addition, any cells that have been engineered to express the desired active agent, growth factor and / or their agonists, precursors, derivatives, analogs or fragments thereof, or other active agents having similar effector activities may also be useful in the practice of this invention. Therefore, in such an approach, the gene encoding the active agent or its analog or precursor can be either isolated from a cell line or constructed by DNA manipulation. The gene can then be incorporated into a plasmid which, in turn, can be transfected into a cell, such as a fibroblast, for expression (See, e.g., Sambrook, et al., Molecular Cloning (1989), incorporated here by reference for further discussion of cloning delivery devices and genetic manipulation procedures). Cells expressing the biologically active agent or factor can be grown in vitro until an adequate density is achieved. Fig. 15 is a cross-sectional view of an alternative embodiment of the delivery device 10 in which the biomaterial 26 is near a substance 28 within a reservoir 29. In Fig. 15, a polymeric reservoir supply device 10 that contains active agent secreting cells is attached to the belt 12. The substance 28 could be, for example, a nutrient-rich material to allow the cells within the delivery device 10 to survive until the vascularization of the delivery device 10 occurs. The nutrient-rich material could be, for example, fetal, equine or porcine bovine serum, or any other material suitable for the purpose. The openings 30 are adjacent to the substance 28 to allow it to make contact with the biomaterial 26. Alternatively, the substance 28 may be a non-nutrient-rich material having any suitable purpose. Figure 16 shows a cross-sectional view taken through the longitudinal axis of the inner tube 14 of the embodiment of Figure 15. In the embodiment of Figure 16, the strap 12 can be a tube that can be used to fill a reservoir 29. The tank 29 could be filled by other means, such as injection. The strap 12, after implantation, can be capped to maintain a separation between the peritoneum and areas outside the body. In a preferred embodiment, the delivery device 10 used is a PAN / PVC thermoplastic capsule with a liquid core and cell, having a wall thickness greater than 25 microns, although a thickness of 25 microns or less can also be used . The core may also contain a hydrogel matrix or the like. The hydrogel matrix can be any commercially available three-dimensional network of hydrophilic polymers that are covalently or ionically crosslinked. Any method of preparing a thermoplastic capsule, including preparing hollow fibers followed by filling with the cells and plugging and sealing using heat sealing can be used. Alternatively, the capsules can be formed by co-extrusion through a spinner of multiple lumens. When the biologically active agent within the core of the biocompatible delivery device 10 comprises cells, the core is preferably constructed to provide a suitable local environment for the continued viability and function of the isolated cell therein. The present delivery device 10 can be used to encapsulate a wide variety of cells or tissues, spanning the range from anchor-dependent cells, completely differentiated or primary tissues, through incompletely differentiated fetal or neonatal tissues, to cells or transformed cell lines independent of anchorage. Unless otherwise specified, the term "cells" means cells in any form, including but not limited to cells retained in tissue, clusters of cells and individually isolated cells. The implants of the delivery device 10 and contents thereof can retain functionality for more than three months in vivo and in many cases for longer than one year. In addition, the delivery device 10 of the present invention can be prepared in a size sufficient to deliver an entire therapeutic and / or prophylactic dose of a substance from a single or a few (less than 10) implanted delivery devices and easily recoverable. The core of the delivery device 10 can be constructed to provide a suitable local environment for the particular cells isolated therein. In some embodiments, the core comprises a liquid medium sufficient to maintain the cells. Liquid nuclei are particularly suitable for maintaining transformed cells. In other embodiments, the core comprises a gel matrix that immobilizes and distributes the cells, thereby reducing the formation of dense cell clumps. The gel matrix may be composed of, by way of example only, hydrogel or extracellular matrix components. Suitably, the core can be composed of a matrix formed by a hydrogel, which can stabilize the position of the cells in groups of cells. The term "hydrogel" here refers to a three-dimensional network of interlaced hydrophilic polymers. The network may be in the form of a gel substantially composed of water, preferably but not limited to gels that are greater than 90% water. Interlinked hydrogels can also be considered solid because they do not flow or deform without appreciable applied shear stress. Compositions that form hydrogels can fall into three classes for the purpose of this application. The first class carries a net negative charge and is typified by alginate. The second class carries a net positive charge and is typified by extracellular matrix components such as collagen and laminin. Examples of commercially available extracellular matrix components include Matrigel and Vitrogen. The third class is net neutral in charge. An example of a net neutral hydrogel is highly entangled polyethylene oxide or polyvinyl alcohol. Nuclei made from a hydrogel matrix may be particularly suitable for maintaining cells or tissues that tend to form agglomerates or aggregates, such as cells in islets of Langerhans, or adrenal chromaffin cells. The matrix may be of sufficient viscosity to maintain the dispersion of the cells within the matrix. Optionally, the core of the present delivery device may contain substances that support or promote the function of the isolated cells. These substances can include natural and / or synthetic nutrient sources, extracellular matrix components (ECM), growth factors or growth regulating substances, and / or a population of feeder or accessory cells or O2 carriers such as hemoglobins and fluorocarbons. In addition, a population of feeder or accessory cells may be co-isolated within the delivery device. For example, hepatocytes can be co-isolated with endothelial accessory cells. Other embodiments and additions to the delivery device and delivery methods are possible. Some are described below. A delivery device 10 could include a marker to allow non-invasive location of a delivery device 10 after implantation. Contrast material could be incorporated into the delivery device 10 to create the marker. The material could be, for example, gadolinium, an opaque material or microbubbles. The contrast materials could be different in different delivery devices 10 to identify the delivery devices 10 for tracking manufacturing numbers, or the type of delivery device 10. The delivery devices 10 could then be differentiated by medicament or cells containing , manufacturing time, type of use or other reasons for which they want differentiation. Where the delivery device 10 is composed of cells or a protected cell matrix, the constituent cells can be allogeneic or xenogenic. In one embodiment, the cells are progenitor cells, e.g., stem cells and other pluripotent cells. The insertion implement 11 could consist only of an Inner tube 14 without an external tube 16 if the cannula 22 of a trocar is used as an external tube. In general, methods for implantation or otherwise placing of active agent delivery devices 10 to deliver an active agent are well known in the art. In general, the placement of the active agent delivery device 10 can be achieved using methods and tools that are well known in the art, and can be performed under aseptic conditions with at least some local or general anesthesia administered to the subject. The removal and / or placement of active agent delivery devices 10 can also be achieved using tools and methods that are readily available. In one embodiment of the present invention, the delivery device 10 can be inserted into an abdomen 20 or other suitable site without the use of the insert attachment 11. By way of example only, an opening can be created at the insertion site 2. by any method and / or suitable device. The delivery device 10 can then be simply inserted manually, or with the aid of any suitable device. Figure 1 illustrates a delivery device 10 within an abdomen 20 without an insertion implement 11 or other device. As shown in Figure 2, the delivery device 10 can be inserted through a cannula 22 without the use of the insertion implement 11 shown in Figure 3. In one form of the method of the invention, before inserting the device 10, the central hole of the cannula 22 is filled with a physiologically compatible solution, such as sterile saline solution. The delivery device 10 is then inserted over the cannula 22, and the solution acts as a lubricant to ensure passage of the vehicle to the distal end of the cannula 22. In this embodiment, the insert increase 11 shown in Figure 3 is not uses. After insertion of the delivery device 10 into the cannula 22, a guide can be inserted to assist in positioning the delivery device 10 at the distal end of the cannula 22. The guide can be either the same obturator as that which a different obturator, a guide wire or the like was initially placed inside the cannula 22. The guide can be positioned above the delivery device 10 within the cannula 22 and the delivery device 10 can be gently pushed into its position at the distal end of the cannula 22. Finally, the cannula 22 is removed from the site of treatment 5. If a guide device or other device is used in the previous step to position the delivery device 10, generally that device is removed in addition to the cannula 22. As with the obturator, the cannula 22 can be removed either by the cannula assembly 22 or manually. The final result may be placing the delivery device 10 in the treatment site 5. The system of the invention, useful for practicing the method of the invention as described above, may include a cannula 22, at least one obturator , and a biological delivery device 10. Each of these is substantially as described above. The inclusion of a strap 12 of the biocompatible delivery device 10 should not affect the performance of the delivery or its biocompatibility. The full length of the illustrative delivery device 10, including strap 12, can be 2-10 cm. However, other lengths may be used without departing from the present invention. The delivery device 10 can also be attached to vascular tissue other than the peritoneum. For example, the delivery device 10 could be implanted on the omentum. In a device fixed in this manner, the delivery device 10 could be suspended from a strap 12 after the delivery device 10 enters the abdominal cavity. The delivery device 10 could then be fixed to the omentum and a belt 12 could alternatively be detached or remain fixed to provide a port towards the exterior of the body. The strap 12 may also include a collagen plug or similar means to prevent tissue hernia adjacent to the perforated tract created during implantation. A preventive system for closing a percutaneous perforation with a collagen plug is described in Kensey et al., In the U.S. patent. No. 5,531, 759. As used herein, a belt 12 can serve as a flexible link between a fastening fabric and the delivery device 10. The flexible belts 12 for securing the delivery device 10 to a substrate can satisfy two important requirements: (1) the need to provide immobilization of the delivery device 10 and tension the delivery device 10 against vascularized tissues so that the effector molecules of the active agent of the biomaterial 26 exert an effect, and (2) biocompatibility of materials used for immobilization. Examples of water soluble biocompatible polymers that can serve as belts 12 include polymers such as synthetic polymers such as polyethylene oxide (PEO), polyvinyl alcohol, polyhydroxyethyl methacrylate, polyacrylamide, and natural polymers such as hyaluronic acid, chondroitin sulfate, carboxymethyl cellulose and starch. The length of a belt 12 can be limited only by the mechanical strength of the used belt 12 and the desired stability of a tied biomaterial 26. It is expected that the stronger belts 12 can be made longer than the weaker belts. It may be desirable that the length and strength of the belt 12 can be matched to give a desired half-life to the belt 12, prior to a throughput, and thus adjust the half-life of the biomaterial action. The minimum length of the belt 12 also depends on the nature of the belt 12. A more flexible belt 12 can work well, even if the length of the belt 12 is relatively short, while a stiffer belt 12 may need to be longer to allow an effective connection between the biomaterial 26 and the tissues. By way of example but not limitation, the belts 12 can have any length between 5 and 500 mm. Within this preferred range, it is contemplated that length ranges with different lower limits, such as 1, 2, 10, 15, 25, 30, 50 and 100 mm, may have useful characteristics. Other belt lengths 12 are possible without departing from the present invention. In one embodiment, delivery device 10 comprises a backing substrate having biomaterial 26 on one side. The backing substrates 24 can have any useful shape including, but not limited to, fibers, non-woven fibers, shaped polymers, particles, sheets, sponge or membrane. There may be two basic types of backing substrates 24 on which the active agents are preferably moored. One class includes biocompatible materials that are not biodegradable, such as, by way of example only, polystyrenes, polyethylene-vinyl acetates, polypropylenes, polymethacrylates, polyacrylates, polyethylenes, polyethylene oxides, glass, polysilicates, polycarbonates, polytetrafluoroethylene, fluorocarbons, nylon , silicon, rubber and stainless steel alloys. The other kind of materials does not include, but is not limited to, biocompatible biodegradable materials such as polyanhydrides, polyglycolic acid, polyhydroxy acids such as polylactic acid, polyglycolic acid and polylactic acid glycolic acid copolymers, polyorthoesters, polyhydroxybutyrate, polyphosphazenes, polypropyl fumarate and biodegradable polyurethanes, proteins such as collagen and polyamino acids and polysaccharides such as glycosaminoglycans, alginate and caragenan, bone powder or hydroxyapatite and combinations thereof.

The biodegradability of a substrate 24 can be used to regulate the length of time an active agent stimulates growth and to allow replacement of implanted substrate 24 with new tissue. For this purpose, the substrate 24 with moored active agents can be considered a scaffold on which a new tissue can be formed. As such, a degradable scaffold can be decomposed as tissue replacement proceeds. Once released from the substrate 26, an active agent can be internalized or can diffuse away from the target cells. Such planned degradation can be especially useful in the context of implanted compositions, used to stimulate tissue replacement, by limiting the amount of tissue growth and by eliminating the need to remove the tissue scaffold. For implantation in the body, the preferred degradation times are typically less than one year, very typically in the range of weeks to months. Other degradation times are possible without departing from the present invention. In some embodiments, the attachment of substrate 24 cells can be increased by coating the substrate 24 with compounds such as extracellular membrane components, basement membrane components, agar, agarose, gelatin, gum arabic, collagen types I, II, 111, IV and V, fibronectin, laminin, glycosaminoglycans, mixtures thereof, and other materials known to those skilled in the cell culture art. The strap 12 and / or the substrate 24 can be made of a bioabsorbable material such as, by way of example only, the materials described by Tormala et al., In the U.S. patent. No. 5,406, 498. In another embodiment, the passive sustained release active agent drug delivery system comprises a matrix comprising a polymer and an active agent. Preferably, the active agent is present in a concentration of at least about 5% by weight based on the weight of the matrix. Other concentrations are possible without departing from the present invention. In another embodiment, the matrix further comprises a penetration promoter. In another embodiment, the active agent delivery system comprises a patch suitable for adhering to tissue, the patch having a reservoir containing a matrix. In another embodiment, the patch comprises (a) an impermeable backing layer; (b) an active agent layer element having a hollow space; and (c) an upper surface having a microporous or semipermeable membrane. In addition, this may comprise an adhesive layer on the upper surface to adhere to the tissues. The reservoir can be formed by a hollow space between the cover layer and the membrane. Generally, the membrane comprises an inert polymer. The reservoir may comprise an open-pored foam, a closed-pored foam, a fabric layer or a mat layer. Optionally, the matrix is self-adhesive. The microporous or semipermeable membrane may consist of an inert polymer, for example polypropylene, polyvinyl acetate or silicone.

In another embodiment, the passive active agent drug delivery system comprises: (a) an impermeable backing layer; and (b) a matrix layer containing active agent; wherein the active substance in the active agent-containing layer comprises a prodrug form or an active form of at least one active agent; optionally a penetration promoter; and a matrix polymer. A method is also provided for the administration of passive sustained release of an active form or of a prodrug of active agent to a subject in need of treatment, the method comprising contacting the patient's tissue with a sustained release device as described herein. .

Supply of active agents The present invention provides compositions and methods that affect the transfer of compounds, including drugs and other biologically active agents, in and through tissues, e.g., one or more layers of an epithelial or animal endothelial tissue. These methods involve contacting the tissue with an active agent delivery device 10 that includes the compound of interest. The methods and compositions are useful for the delivery of drugs and other biologically active molecules, and also for the delivery of diagnostic imaging molecules. The methods and compositions of the invention can be particularly useful for the delivery of compounds that require trans-epithelial or trans-endothelial transport to exhibit their biological effects, and that by themselves, are incapable, or only poorly capable, of exhibiting activity. biological The delivery devices 10 and methods of the invention provide significant advantages over previously available methods to obtain delivery of compounds of interest in the tissue. The compositions and methods of the present invention may have particular utility in the area of human and veterinary therapeutics. In general, the doses administered may be effective to deliver picomolar to micromolar concentrations of the therapeutic composition to the effector site. The appropriate doses and concentrations may depend on factors such as the therapeutic composition or drug, the intended delivery site and the route of administration, all of which may be derived empirically according to methods well known in the art. Additional study guidance can be obtained using experimental animal models to assess the dose, as is known in the art. The administration of the compounds of the invention with a suitable pharmaceutical excipient, as necessary, can be carried out by any of the accepted modes of administration. Suitable administration sites therefore include but are not limited to peritoneum and omentum. The formulations may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as, for example, tablets, pills, capsules, powders, solutions, suspensions, emulsions, suppositories, retention enemas, creams, ointments, lotions, aerosols or the like, preferably in unit dosage forms suitable for simple administration of precise doses. The active agents can be provided in any of a variety of formulations within the biomaterial compatible with the transmucosal / transepithelial delivery, provided that said formulation is stable (i.e., not subject to degradation at an unacceptable amount at body temperature). The concentration of active agents in the formulation can vary from about 0.1% by weight to about 80 or even 100% by weight. The active agents can be provided in any suitable form to be carried out by the drug delivery device controlled and released for distribution, eg, solid, semi-solid, gel, liquid, suspension, emulsion, osmotic dose formulation, dosage formulation by diffusion, wear-resistant formulation, etc. The compositions may include a conventional pharmaceutical carrier or excipient and may also include other medicinal agents, vehicles, adjuvants and the like. Preferably, the composition will be from about 5% to 95% by weight of a compound or compounds of the invention, wherein the remainder consists of suitable pharmaceutical excipients. Other compositions are possible without departing from the present invention. Suitable excipients can be adjusted to the particular composition and route of administration by methods well known in the art. In some embodiments, the composition may contain, among other things, any of the following: a diluent such as lactose, sucrose, dicalcium phosphate and the like; a disintegrant such as starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as a starch, acacia gum, polyvinyl pyrrolidone, gelatin, cellulose and derivatives thereof. If desired, the composition to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH regulating agents, such as, for example, sodium acetate, sorbitan monolaurate, or sodium oleate. triethanolamine. The methods for preparing such dosage forms are known or will be apparent to those skilled in the art; for example, see Remington's Pharmaceutical Sciences, mentioned above, and similar publications. The composition to be administered may, in any case, contain an amount of the prodrug and / or active compound (s) in a pharmaceutically effective amount for the relief of the condition being treated when administered in accordance with the teachings of this invention. In general, the compounds of the invention are administered in a therapeutically effective amount, i.e., a dose sufficient to effect treatment, which may vary depending on the individual and condition being treated. By way of example only, a therapeutically effective daily dose may be from OJ to 100 mg / kg of body weight per day of drug. Many conditions can respond to the administration of a total dose of between about 1 and about 30 mg / kg of body weight per day, or between about 70 mg and 2100 mg per day for a 70 kg person. Other doses may be administered without departing from the present invention. The delivery devices 10 of the invention make it possible to provide biologically active and diagnostic agents in vascularized tissue within the body of a subject. This ability to deliver active agents in a sustained long-term delivery method can greatly increase the efficacy of compounds such as antibacterials, antifungals, antivirals, antiproliferatives, immunosuppressants, vitamins, analgesics, hormones and the like. In general, administration of active compounds according to the invention may be sustained release for several hours (e.g., 2 hours, 12 hours, or 24 hours to 48 hours or more), up to several days (v. ., 2 to 5 days or more), up to several months or years. Typically, the supply may be continued for a period ranging from about 1 month to about 12 months or more. The active compounds can be administered to an individual for a period of, for example, from about 2 hours to about 72 hours, from about 4 hours to about 36 hours, from about 12 hours to about 24 hours, from about 2 days to about 30. days, from about 5 days to about 20 days, from about 7 days or more, from about 10 days or more, from about 100 days or more, from about 1 week to about 4 weeks, from about 1 month to about 24 months, from about 2 months to about 12 months, from about 3 months to about 9 months, about 1 month or more, about 2 months or more, or about 6 months or more; or other time intervals, including increment intervals, within these ranges, as necessary. Cytotoxic and immunosuppressive drugs may constitute an additional class of drugs for which the delivery devices 10 of the invention may be useful. These agents are commonly used to treat hyperproliferative diseases such as psoriasis, as well as for immune diseases such as dermatosis bullosa and leukocytoclastic vasculitis. Examples of such compounds include but are not limited to, antimetabolites such as methotrexate, azathioprine, fluorouracil, hydroxyurea, 6-thiocuanine, mycophenolate, chlorambucil, vinicristin, vinbiasrin and dactinomycin. Other examples include alkylating agents such as cyclophosphamide, mechloroethamine hydrochloride, carmustine, taxol, tacrolimus and vinblastine are additional examples of useful biological agents, such as dapsone and sulfasalazine. Ascomycins such as cyclosporin, FK506 (tacrolimus), and rapamycin (e.g., U.S. Patent No. 5,912,253) and analogs of said compounds are of particular interest (e.g., Mollinson et al., Current Pharm. 4 (5): 367-380 (1988); US patents Nos. 5,612,350; 5,599,927; 5,604,294; 5,990,131; 5.561, 140; 5,859,031; 5,925,649; 5,994,299; 6,004,973 and 5,508,397). Cyclosporins include cyclosporin A, B, C, D, G and M. See, e.g., US patents. Nos. 6,007,840; and 6,004,973. Another aspect of the invention comprises the provision of anticancer compositions of taxane and taxoid, which are particularly useful for inhibiting the growth of cancer cells. The delivery devices 10 may be useful for the treatment of conditions such as lupus erythematosus (both discoid and systemic), cutaneous dermatomyositis, porphyria cutanea tarda and light polymorphous rash. Agents useful for the treatment of such conditions include, for example, quinine, chloroquine, hydroxychloroquine, and quinacrine. The delivery devices 10 of the invention may also be useful for the transdermal delivery of anti-infective agents. For example, antibacterial, antifungal and antiviral agents can be used with delivery devices 10. Antibacterial agents may be useful for treating conditions such as acne, skin infections and the like. Antifungal agents can be used to treat tinea corporis, tinea pedis, onychomycosis, candidiasis, tinea versicolor and the like. Examples of antifungal agents include but are not limited to, azole antifungals such as itraconazole, miconazole and fluconazole. Examples of antivirals include but are not limited to, acyclovir, famciclovir and valacyclovir. Such agents may be useful for treating viral diseases, e.g., herpes. Another example of a biologically active agent for which the delivery devices 10 of the invention may be desirable are antihistamines. These agents are useful for treating conditions such as pruritus due to urticaria, atopic dermatitis, contact dermatitis, psoriasis and many others. Examples of said reagents include, for example, terfenadine, astemizole, lorotadine, cetiricin, acrivastin, temelastin, cimetidine, ranitidine, famotidine, nizatidine and the like. Tricyclic antidepressants can also be delivered using the delivery devices 10 of the invention. Pain relief agents and local anesthetics constitute another class of compounds for which the delivery devices 10 of the invention can increase treatment. Lidocaine, bupivacaine, novocaine, procaine, tetracaine, benzocaine, cocaine and opiates, are among others the compounds that can be used with delivery devices 10 of the invention. In one embodiment, the active agent formulation comprises a cardiac drug that includes but is not limited to: angiogenic factors, growth factors, calcium channel blockers, antihypertensive agents, inotropic agents, antiatherogenic agents, anticoagulants, beta-blockers, antiarrhythmic agents , anti-inflammatory agents, sympathomimetic agents, phosphodiesterase inhibitors, diuretics, vasodilators, thrombolytic agents, cardiac glycosides, antibiotics, antiviral agents, antifungal agents, agents that inhibit protozoa, antineoplastic agents and steroids. The term "antiarrhythmic agent" or "antiarrhythmic agent" refers to any drug for treating a disorder of speed, rhythm or conduction of electrical impulses within the heart. The term "angiogenic agent" (or "angiogenic factor") means any compound that promotes growth of new blood vessels. Angiogenic factors include, but are not limited to, a fibroblast growth factor, e.g., basic fibroblast growth factor (bFGF), and acid fibroblast growth factor, e.g., FGF-1, FGF. -2, FGF-3, FGF-4, recombinant human FGF (U.S. Patent No. 5,604,293); a vascular endothelial cell growth factor (VEGF), including but not limited to VEGF-1, VEGF-2, VEGF-D (U.S. Patent No. 6,235,713); transforming growth factor alpha; transforming growth factor beta; platelet-derived growth factor; a mitogenic endothelial growth factor; a platelet activating factor; tumor necrosis factor alpha; angiogenin; a prostaglandin, including but not limited to PGE1, PGE2; placenta growth factor; GCSF (granulocyte colony stimulating factor); HGF (hepatocyte growth factor); IL-8 permeability factor; epidermal growth factor; substance P; bradykinin; angiogenin; Angiotensin II; proliferin; growth factor similar to insulin-1; nicotinamide; a nitric oxide synthase stimulator; estrogen including, but not limited to, estradiol (E2), estriol (E3), and 17-beta estradiol; and similar. Angiogenic factors further include functional derivative analogs of any of the aforementioned angiogenic factors. Derivatives include angiogenic polypeptide factors that have an amino acid sequence that differs from the native or wild type amino acid sequence, including conservative amino acid differences (e.g., serine / threonine substitutions, asparagine / glutamine, alanine / valine, leucine / isoleucine, phenylalanine / tryptophan, lysine / arginine, aspartic acid / glutamic acid); truncations; insertions; deletions; and the like, which do not adversely affect substantially and which may increase the angiogenic property of the angiogenic factor. Angiogenic factors include factors modified by modifications of polyethylene glycol; acylation acetylation; glycosylation; and similar. An angiogenic factor may also be a polynucleotide that encodes the angiogenic polypeptide factor. Said polynucleotide may be a naked polynucleotide or it may be incorporated into a vector, such as a viral vector system such as an adenovirus, adeno-associated virus or lentivirus systems. Antibiotics are among the biologically active agents that may be useful when used with delivery devices 10 of the invention, particularly those that act on invasive bacteria, such as Shigella, Salmonella, and Yersinia. Such compounds include, for example, norfloxacin, ciprofloxacin, trimethoprim, sulfametyloxazole, and the like.

The antineoplastic agents can also be supplied by the delivery devices 10 of the invention. These include, for example, cisplatin, methotrexate, taxol, fluorouracil, mercaptopurine, donorubicin, bleomycin, and the like. The delivery devices 10 may also be useful for delivering biologically active and diagnostic agents through the cerebrovascular barrier. The agents may be useful for the treatment of ischemia (e.g., using an antiapoptotic drug), as well as for delivering neurotransmitters and other agents for the treatment of various conditions such as schizophrenia, Parkinson's disease, pain, (v. ., morphine, the opiates). The 5-hydroxytryptamine receptor antagonist is useful for the treatment of conditions such as migraine headaches and anxiety. The delivery devices 10 may also be useful for delivering biologically active agents by controlled delivery and / or sustained release and are capable of inducing or promoting a feeling of satiety in a subject. In general, in order to induce satiety, the active agent is selected from the group consisting of nutrients and pharmacological agents. The nutrients are usually selected from the group consisting of food, amino acids, peptides, proteins, lipids, carbohydrates, vitamins and minerals. Protein sources include, but are not limited to, milk, soy, rice, meat (e.g., animal), vegetable (e.g., beet, pea, potato), ßß egg (egg albumen), gelatin and fish. Suitable intact proteins include, but are not limited to, soy-based protein, milk-based protein, casein protein, whey protein, rice protein, beef collagen, pea protein, potato protein and mixtures thereof. Protein hydrolysates also include but are not limited to, soy protein hydrolyzate, casein protein hydrolyzate, whey protein hydrolyzate, rice protein hydrolyzate, potato protein hydrolyzate, fish protein hydrolyzate, egg albumen hydrolyzate, gelatin protein hydrolyzate, a combination of animal and vegetable protein hydrolysates, and mixtures thereof. Hydrolysed proteins (protein hydrolysates) are proteins that have been hydrolysed or broken down into short peptide fragments and amino acids. Flavored proteins include extensively hydrolysed protein hydrolysates prepared from proteins of animal and plant origin treated with acid or enzyme, such as, casein hydrolyzate, whey hydrolyzate, casein hydrolyzate / whey, soy hydrolyzate, and mixtures thereof. By "extensively hydrolyzed" protein hydrolysates is meant that the intact protein is hydrolyzed into peptide fragments whereby a majority of peptide fragments have a molecular weight less than 1000 Daltons. Most preferably, at least about 75% (preferably at least about 95%) of the peptide fragments have a molecular weight of less than about 1000 Daltons. The amino acids can be one or more of aspartic acid, alanine, arginine, asparagine, cysteine, glycine, glutamic acid, glutamine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. Preferred amino acids are L-phenylalanine, L-tryptophan, L-tyrosine, L-cystine, L-taurine, L-methionine, L-arginine and L-carnitine. The most preferred amino acids are L-phenylalanine and L-tryptophan. Suitable food materials, amino acids, peptides, proteins, lipids, carbohydrates, vitamins and minerals can vary widely and are well known to those skilled in the art of manufacturing pediatric formulas. Carbohydrates useful in the present invention include mono-, di- and polysaccharides. Preferred saccharides include e.g., glucose, fructose, mannose, galactose, sucrose, maltose, lactose, maltodextrins and glucose polymers. Preferably, the carbohydrate is maltose. Suitable carbohydrates may therefore include, but are not limited to, hydrolyzed, intact, naturally and / or chemically modified starches, maize, tapioca, rice or potato in waxy or non-waxy forms; and sugars. Suitable vitamins include but are not limited to vitamins A, E, C, D, K, the B vitamins, pantothenic acid, thiamine, niacin, niacinamide, riboflavin, iron, and biotin. Minerals include but are not limited to calcium, chromium, phosphorus, sodium, chlorine, magnesium, manganese, iron, copper, zinc, selenium and iodine. You can also use salts. Suitable salts include but are not limited to sodium, potassium, magnesium and calcium. Suitable lipids include but are not limited to coconut oil, soybean oil, corn oil, olive oil, safflower oil, high oleic acid safflower oil, MCT oil (medium chain triglycerides), oil of sunflower, sunflower oil with high content of oleic acid, palm oil, palm olein, canola oil, lipid sources of arachidonic acid and docosahexaneoic acid and mixtures thereof. Lipid sources of arachidonic acid and docosahexaneoic acid include but are not limited to marine oil, egg yolk oil and mushroom oil. Depending on the desired results, the active agent may include an active lipid; a serotonin, serotonin agonist, or serotonin reuptake inhibitor; peptide YY or a functional analog of peptide YY; peptide related to calcitonin gene (CGRP) or a functional analogue of CGRP; an adrenergic agonist; an opioid agonist; a combination of any of these; or an antagonist of a serotonin receptor, peptide receptor YY, CGRP receptor; adrenoceptor and / or opioid receptor; and / or glucagon-like peptide 1 (GLP1). Preferably, in order to induce a feeling of satiety in the subject, the active agent is one or more agents selected from the group of an active lipid; a serotonin, serotonin agonist, or serotonin reuptake inhibitor; peptide YY or a functional analog of peptide YY; GLP1 peptides and GLP1 analogs, peptide related to calcitonin gene or functional analogue; CGRP or a functional analog of CGRP; an adrenergic agonist; an opioid agonist; or a combination of any of these, which is delivered in an amount and under such conditions that the cholinergic bowel-fugal pathway, at least one prevertebral ganglionic pathway, the neural adrenergic efferent pathway, the serotonergic interneuron and / or the opioid interneuron are activated by them. Serotonin or 5-hydroxytriptamine (5-HT) is preferably used at a dose of 0.005-0.75 mg / kg of body mass. Serotonin reuptake inhibitors include Prozac or Zoloft. Serotonin receptor antagonists include 5-HT3, 5HT1P, 5-HT1A, 5-HT2, and / or 5-HT4 receptor antagonists. Examples include ondansetron or granisetron, 5HT3 receptor antagonists (preferred dose range 0.04-5 mg / kg), deramciclan, or alosetron. The 5-HT4 receptor antagonists are preferably used at a dose of 0.05-500 picomoles / kg. Peptide YY (PYY) and its functional analogues are preferably supplied at a dose of 0.5-500 picomoles / kg. Functional analogs of PYY include PYY (22-36), BIM-43004 (Liu, CD, et al., J. Surg. Res. 59 (1): 80-84

[1995]), BIM-43073D, BIM- 43004C (Litvak, DA e al al, Dig. Dis. Sci. 44 (3): 643-48

[1999]). Other examples are also known in the art (e.g., U.S. Patent No. 5,604,203). PYY receptor antagonists preferably include antagonists of Y4 / PP1, Y5 or Y5JPP2 / Y2, and most preferably Y1 or Y2 (e.g., U.S. Patent No. 5,912,227). Other examples include BIBP3226, CGP71683A (King, P.J. et al., J. Neurochem. 73 (2): 641-46

[1999]). Adrenergic agonists include norepinephrine. Adrenergic or adrenoceptor antagonists include β-adrenoceptor antagonists, including propranolol and atenolol. Preferably they are used at a dose of 0.05-2 mg / kg. Opioid agonists include delta opioid agonists (preferred dose range is 0.05-50 mg / kg, most preferred is 0.05-25 mg / kg; action opioid agonists k (preferred dose range is 0.005-100 micrograms / kg); μ action agonists (preferred dose range is 0.05-25 μg / kg); and epsilon-action agonists. Opioid receptor antagonists include μ-action opioid antagonists (preferably used at a dose range of 0.05-5 micrograms / kg); opioid receptor antagonists k (preferably used at a dose of 0.05-30 mg / kg); Opioid receptor antagonists? (preferably used at a dose of 0.05-200 micrograms / kg); and opioid receptor antagonists e. Examples of useful opioid receptor antagonists include naloxone, naltexone, methylnaltrexone, nalmefene, H2186, H3116 or fedotozine, ie, (+) - 1-1 [3,4,5-trimethoxy) benzyloxymethyl] -1-phenyl-N , N-dimethylpropylamine. Other useful opioid receptor antagonists are known (e.g., U.S. Patent No. 4,987,136). In one embodiment, the active agent is one or more active lipids.

As used herein, "active lipid" embraces a digested or substantially digested molecule having a structure and function substantially similar to a hydrolyzed end product of fat digestion. Examples of hydrolyzed end products are molecules such as diglycerides, monoglycerides, glycerol and most preferably free fatty acids or salts thereof. In a preferred embodiment, the active agent is an active lipid comprising a saturated or unsaturated fatty acid. The fatty acids contemplated by the invention include fatty acids having between 4 and 24 carbon atoms. Examples of fatty acids contemplated for use in the practice of the present invention include capric acid, capric acid, capric acid, lauric acid, myristic acid, oleic acid, palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenic acid, acid trans-hexadecanoic; elaidic acid, columbinic acid, arachidonic acid, behenic acid, eicosenoic acid, erucic acid, bresidic acid, ketoleic acid, nervonic acid, Mead's acid, arachidonic acid, tinmodonic acid, clupanodonic acid, decosahexanoic acid and the like. In a preferred embodiment, the active lipid comprises one or more of oleic acid, dodecanoic acid and glycerol monooleate. Also preferred are lipids in the form of pharmaceutically acceptable salts of hydrolyzed fats, including salts of fatty acids. Sodium or potassium salts are preferred, but salts formed with other pharmaceutically acceptable cations are also useful. Useful examples include sodium or potassium salts of caprolate, caprulate, caprate, laurate, myristate, oleate, palmitate, stearate, palmitolate, linolate, linolenate, trans-hexadecanoate, elaidate, columbinate, arachididate, behenate, eicosenate, erucate, bresidate, ketoleate , nervonate, arquidonate, timnodonate, clupanodonate, decosahexanoate and the like. In a preferred embodiment, the active lipid comprises an oleate and / or dodecanoate salt. Sodium dodecanoate or sodium dodecylsulfate are also preferred active ingredients. The delivery devices of the invention are also useful for delivering diagnostic matrix and contrast agents in and through one or more layers of epithelial and / or endothelial tissue. Examples of diagnostic agents include substances that are labeled with radioactivity, such as 99 mTc glucoheptonate, or substances used in magnetic resonance imaging (MRI) methods such as gadolinium-doped chelating agents (e.g., Gd) -DTPA). Other examples of diagnostic agents include marker genes that encode proteins that are readily detectable when expressed in a cell (including but not limited to beta-galactosidase, green fluorescent protein, luciferase, and the like). A wide variety of markers can be used, such as radionuclides, fluorine, enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, ligands (particularly haptens), etc.

The small organic molecule therapeutics can be advantageously delivered as described herein, through an epithelial or endothelial tissue. For example, the delivery of highly charged agents, such as levodopa (L-3,4-dihydroxy-phenylalanine; L-DOPA) may benefit by binding to delivery devices as described herein. Peptoids and peptidomimetic agents (e.g., Langston (1997) DDT2: 255; Giannis et al. (1997) Advances Drug Res. 29: 1) are also contemplated. Also, the invention is advantageous for delivering small organic molecules that have low solubilities in aqueous liquids, such as serum and aqueous saline. Therefore, compounds whose therapeutic efficiencies are limited by their low solubilities may be administered in higher doses according to the present invention, and may be more effective due to the higher levels of absorption by the cells. The devices and methods of the invention are particularly suitable for transporting in and through one or more layers of an epithelial or endothelial tissue for a number of macromolecules, including but not limited to proteins, nucleic acids, polysaccharides and analogs thereof. Exemplary nucleic acids include oligonucleotides and polynucleotides formed of DNA and RNA, and analogs thereof, which have selected sequences designed to hybridize to complementary targets (e.g., antisense sequences for single-chain or double-stranded targets), or to express nucleic acid transcripts or proteins encoded by the sequences. Such molecules can be used in a variety of therapeutic regimens, including enzyme replacement therapy, gene therapy and antisense therapy, for example. Another class of macromolecules that can be transported through one or more layers of an epithelial or endothelial tissue is illustrated by way of example by proteins and in particular enzymes. Therapeutic proteins include but are not limited to replacement enzymes. Therapeutic enzymes include but are not limited to alglucerase, for use in the treatment of deficiency of glucocerebrosidase lysozomal (Gaucher's disease), alpha-L-iduronidase, for use in the treatment of mucopolysaccharidosis 1, alpha-N-acetylglucosamidase, to be used in the treatment of Sanfilippo B syndrome, lipase, for use in the treatment of pancreatic insufficiency, adenosine deaminase, for use in the treatment of severe combined immunodeficiency syndrome, and triosephosphate isomerase, for use in the treatment of neuromuscular dysfunction associated with triosaphosphate isomerase deficiency . In another embodiment, the invention is useful for the delivery of immunospecific antibodies or fragments of antibody to the cytosol to interfere with deleterious biological processes such as microbial infection. Peptides to be delivered by the methods described herein include, but should not be limited to, effector polypeptides, receptor fragments, and the like. Examples include peptides that have phosphorylation sites used by protein-mediating intracellular signals. Examples of such proteins include but are not limited to protein kinase C, RAF-1, p21Ras, NF-kappaB, C-JUN, and cytoplasmic tails of membrane receptors such as IL-4 receptor, CD28, CTLA-4, V7 , and MHC class I and class II antigens. In addition to the above ingredients, the therapeutic composition of the invention may generally contain various pharmaceutically acceptable additives as well as a pharmaceutically acceptable carrier or base necessary for the dispersion of said substances. Such additives include but are not limited to pH control agents, such as arginine, sodium hydroxide, glycine, hydrochloric acid, citric acid, etc., local anesthetics represented by benzyl alcohol, isotonizing agents such as sodium chloride, mannitol, sorbitol, etc., absorption inhibitors such as Tween 80, etc., solubilizers such as cyclodextrins and derivatives thereof, stabilizers such as serum albumin, etc., and reducing agents such as glutathione, etc. Since a variety of proteolytic enzymes are present in the administration environment, there are cases in which a protease inhibitor can be advantageously incorporated into the composition of the invention to prevent degradation of the physiologically active peptide or protein and thereby ensure a increased bioavailability. The aforementioned protease inhibitor includes but is not limited to gabaxate, mesylate, a1-antitrypsin, aprotinin, leupepsin, a2-macroglobulin, pepstatin and egg white or soybean trypsin inhibitor. These inhibitors can be used alone or in combination. The inhibitor of 7 The protease can be incorporated into the hydrophilic polymer, coated on the surface of the dosage form to be brought into contact with the tissue or incorporated into a surface surface phase. The therapeutic composition of the present invention can be further complemented with an absorption promoter that aids in the absorption and diffusion of the physiologically active peptide or protein. The absorption promoter may be any promoter that is pharmaceutically acceptable. Thus, sodium salicylate and salicylic acid derivatives (acetyl salicylate, choline salicylate, salicylamide, etc.), amino acids and salts thereof (e.g., monoaminocarboxylic acids such as glycine, alanine, etc.) can be mentioned. phenylalanine, proline, hydroxyproline, etc., hydroxy amino acids such as serine, etc., acidic amino acids such as aspartic acid, glutamic acid, etc., and basic amino acids such as lysine, etc., including their alkali metal or alkali metal salts earth), N-acetylamino acids (N-acetylalanine, N-acetylphenylalanine, N-acetylserine, N-acetylglycine, N-acetyl-lysine, N-acetylglutamic acid, N-acetylproline, N-acetylhydroxyproline, etc.) and their salts (alkali metal salts and alkaline earth metal salts), substances which are generally used as emulsifiers (e.g., sodium oleylphosphate, sodium lauryl phosphate, sodium laurisulfate, sodium myristyl sulfate, polyoxyethylene alkyl ethers, you are polyoxyethylene alkyl, etc.), caproic acid, lactic acid, malic acid and citric acid and alkali metal salts thereof, pyrrolidonecarboxylic acids, esters of alkylpyrrolidonecarboxylic acid, N-alkyl pyrrolidones, acyl proline esters, etc. Although the mechanism of absorption promotion can vary with different absorption promoters, the one suitable for long-term administration can be selected according to each combination of the physiologically active peptide or protein and other ingredients. The aforementioned additives can be dispersed in the pharmaceutically acceptable base or vehicle. The basis for the therapeutic composition of the present invention may be a hydrophilic compound having an ability to disperse the peptide and said additives. The molecular weight of said hydrophilic compound is preferably, but not limited to, not less than 1,000, most preferably not less than 10,000, and most preferably not less than 100,000. The compound may be a pharmaceutically acceptable substance and may typically include but not be limited to the following compounds. Therefore, polycarboxylic acid copolymers or salts thereof or carboxylic anhydrides (e.g., maleic anhydride) with other monomers (e.g., methyl (meth) acrylate, acrylic acid, etc.), polymers hydrophilic vinyls such as polyvinyl acetate, polyvinyl alcohol, polyvinylpyrrolidone, etc., cellulose derivatives such as hydroxymethylcellulose, hydroxypropylcellulose, etc., and natural polymers such as chitosan, collagen, sodium alginate, gelatin, hyaluronic acid, etc., and non-toxic metal salts thereof. In addition, synthetic fatty acid esters such as polyglycerin fatty acid esters, sucrose fatty acid esters, etc. can also be mentioned.

The hydrophilic polymers can be used alone or in combination and partial crystallization, ionic bonding, entanglement or the like can impart necessary structural integrity. Any of these hydrophilic polymers can be molded into a film and the fabric applied. As the base for use in the present invention, a synthetic biodegradable polymer can be used as a suspension base containing the active agent. The biodegradable polymer may typically include but are not limited to polylactic acid, poii acid copolymer (lactic-glycolic acid), polyhydroxybutyric acid, poly (hydroxybutyric acid-glycolic acid) copolymer, and mixtures thereof. These biodegradable polymers can be molded into a film or tablet to be applied to vascular tissue. For the peptides, the physiologically acceptable peptide is dispersed in said base in dosage form in the manner known per se. The release of the active peptide from a dosage form can be by diffusion, disintegration of said biodegradable polymer or the associated formulation of water channels. A possible additional mechanism is that when the glass transition temperature of said biodegradable polymer is close to or is lower than the body temperature, the biodegradable polymer applied to the living body softens to cause release of the physiologically active peptide at an accelerated diffusion rate. . An additional absorption promotion can be ensured by an ingenious combination of biodegradable polymer and cytidine nucleotide derivative. The pharmaceutical composition of the present invention may contain a hydrophilic low molecular weight compound. Said hydrophilic low molecular weight compound can provide continuous massages through which the physiologically active peptide or protein soluble in water can diffuse through the base to the surface of the body where it is absorbed. The passages can be microscopic or macroscopic, that is, the entire dose form can serve as a passage. The hydrophilic low molecular weight compound can be any compound that absorbs moisture from the tissue or atmosphere of administration and dissolves the water-soluble active peptide. The molecular weight of said hydrophilic low molecular weight compound is typically but not limited to no greater than 10,000 and preferably no greater than 3,000. Thus, as polyol compounds there may be mentioned oligo-, di- and monosaccharides such as sucrose, mannitol, lactose, L-arabinose, D-erythrose, D-ribose, D-xylose, D-mannose, D-galactose, lactulose, cellobiose, gentibious, etc. As other polyol compounds, glycerin and polyethylene glycol (average molecular weight of 200-3000) can be mentioned. Other examples of said hydrophilic low molecular weight compound include N-methylpyrrolidone, alcohols (e.g., oligovinyl alcohol, ethanol, ethylene glycol, propylene glycol, etc.). These hydrophilic low molecular weight compounds are used alone or in combination.

The aforementioned hydrophilic polymer, biodegradable polymer, hydrophilic low molecular weight compound, absorption promoter, protease inhibitor and additives are preferably selected in accordance with the amino acid composition of the active peptide, the steric structure thereof and / or other factors. The amount of peptide or physiological protein in the compositions of this invention is typically an amount that provides an effective amount of the peptide or protein to produce the physiological activity for which the peptide or protein is being administered. The amount of the physiologically active peptide or protein to be contained in the therapeutic composition of the present invention can be selected according to the activity of the particular substance and its therapeutically effective dose but in consideration of the fact that the bioavailability of any substance active can never be 100%, ie the administered dose of the active peptide is not completely absorbed, it may be preferable to incorporate a quantity slightly larger than the desired dose.

Active agent producing cells An alternate implantable active agent delivery system comprises (a) a delivery device 10 comprising a carrier and eukaryotic cells that produce at least one therapeutic agent.

Optionally, the delivery device 10 may include a stimulating element operatively coupled to the delivery device 10 to stimulate the release of the therapeutic agent from the delivery device 10. In another embodiment, the delivery device 10 further comprises a detection element for monitoring at least one physiological property of a patient in which the system is implanted and communicating with the stimulating element to stimulate the release of the therapeutic agent from the delivery device 10. The vehicle can be selected from a group comprising stents, grafts vascular, stent grafts, synthetic patches, infusion cuffs and catheters. Eukaryotic cells can reside within a polymeric composition. The implantable system may also include a polymer composition capable of being dehydrated and rehydrated. In one embodiment, the polymer composition can be selected from a group consisting of fibrins, collagens, alginates, polylactic acids, polyglycolic acids, celluloses, hyaluronic acids, polyurethanes, silicones, polycarbonates, blends and copolymers thereof. In one embodiment, eukaryotic cells are selected from a group consisting of endothelial cells, fibroblasts and mixtures thereof. Generally, cells can be autologous, but they do not have to be autologous. Preferably, the cells are genetically engineered. In general, the delivery device further comprises a containment vehicle in which the cells are located. Cells suitable for use in the present invention include a wide variety of eukaryotic cells that produce therapeutic agents, or can be engineered to produce therapeutic agents. Ideally, said cells are also capable of secreting those agents, particularly under the application of a stimulus, such as an electrical stimulus and / or other stimulus. Cells suitable for use in the present invention typically include mesenchymal or mesodermal cells, including but not limited to endothelial cells and fibroblasts, whether they are autologous or allogeneic, genetically engineered or not genetically engineered. Mixtures of said cells can also be used. Suitable cells also include progenitor cells, e.g., stem cells and other pluripotent cells. Endothelial cells and fibroblasts are preferred because they have been shown to be suitable for use in ex vivo gene transfer. Ex vivo gene transfer (also referred to here as ex vivo gene therapy) is a process by which cells are removed from the body using well-known techniques, genetically engineered, usually through transduction or transfection of nucleic acid to cells in vitro, and then returned to the body for therapeutic purposes. This contrasts with gene therapy in vivo, wherein a gene transfer vector is administered to the patient resulting in gene transfer to cells and tissues in the intact patient. The ex vivo techniques are well known to one skilled in the art.

Ex vivo gene therapy is an effective approach because the target cells that are to be used in the method can be manipulated as necessary to optimize the efficiency of gene transfer and thus the effectiveness of the overall procedure. However, the ex wVo approach can only be used for those types of cells that can be easily recovered from the body, cultured ex vivo and then returned to the body. Such cells include blood and bone marrow cells, hepatocytes of the liver, skin fibroblasts, muscle myoblasts and vascular endothelial cells. Therefore, endothelial cells and fibroblasts, which can be efficiently infected by retroviral vectors in vitro, and then transplanted back to the host to achieve gene transfer in vivo, are particularly preferred for use in the present invention. Autologous endothelial cells may be particularly desirable. Vascular endothelial cells have been removed from a patient and transduced ex vivo with a retroviral vector designed for β-galactosidase expression as a reporter gene, as described in Nabel et al., Science, 244, 1342-1344 (1989). These genetically engineered cells can be reintroduced into the patient. In one embodiment of the present invention, endothelial cells are obtained from a patient and grown in cell culture. During proliferation in cell culture, they are infected with a genetically engineered retrovirus, which integrates the gene so that the drug is locally delivered to the chromosomes of endothelial cells. This can be achieved, for example, in accordance with the teachings of the U.S. patent. No. 5,674, 722. For the treatment of coronary artery disease (CAD), candidate genes include, for example, the gene encoding the plasminogen activator of wild-type tissue and the gene encoding protein C. There is a a wide variety of methods that can be used to deliver nucleic acid to eukaryotic cells if they are modified to secrete a desired agent. These are well known to those skilled in the art. The desired nucleic acid can be inserted into an appropriately supplied vehicle, such as, for example, an expression plasmid, cosmid, YAC vector and the like. There are a number of viruses, live or inactive, including recombinant viruses that can also be used. A retrovirus can be genetically modified to deliver any of a variety of genes. Adenoviruses have been used in a variety of experiments to deliver nucleic acid capable of directing and expressing protein in a cell. Illustrative nucleic acids that can function as a nucleic acid for incorporation into cells include, but are not limited to, nucleic acid that operably encodes a protein, polypeptide or peptide to deliver a therapeutic effect to a cell. The nucleic acid can include an entire gene or a portion of a gene. Illustrative genes include but are not limited to the active form of nitric oxide synthase (a protein known to relax blood vessels and prevent clots) and prostaglandin H synthase (to repair an endogenous platelet aggregation inhibitor) and vasoconstriction after injury to the endothelium) and insulin-producing genes. There are a variety of disorders that can be treated using the systems and devices of this invention. Examples of such disorders include but are not limited to diabetes and insulin-related diseases (target pancreatic islet cells), damage associated with myocardial infarction or aneurysms (fibroblast growth factor or transforming growth factor targets, and a protease, respectively ), atherosclerosis (target high density lipoprotein), and hypercoagulable states (target tissue plasminogen activator). The gene sequence of the nucleic acid supplied by the virus, including nucleic acid encoding proteins, polypeptide or peptide may be available from a variety of sources including GenBank (Los Alamos National Laboratories, Los Alamos, N. Mex.), databases of EMBL (Heidelberg, Germany) and University of Wisconsin Biotechnology Center, (Madison, Wis), published journals, patents and patent publications. All of these sources can be resources easily accessible to those skilled in the art. The gene sequence can be obtained from cells that contain the nucleic acid fragment (usually DNA) when a sequence of genes is known. The nucleic acid can be obtained either by digestion with restriction endonuclease and isolation of a gene fragment, or by polymerase chain reaction (PCR) using oligonucleotides as primers to either amplify cDNA copies of mRNA from cells expressing the gene of interest or to amplify cDNA copies of a gene from gene expression libraries that are commercially available. Older oligonucleotides or DNA fragments can be prepared by known nucleic acid synthesis techniques and from commercial suppliers of custom oligonucleotides such as Amitof Biotech Inc. (Boston, Mass.), Or the like. Those skilled in the art will recognize that a variety of commercial kits are available to obtain mRNA cDNAs (sources including but not limited to Stratagene, La Jolla, Calif. And Invitrogen, San Diego, Calif.). Similarly, a variety of commercial gene expression libraries are available to those skilled in the art including libraries available from Stratagene and the like. General methods for cloning, a polymerase chain reaction and vector assembly are available from Sambrook, et al. eds. (Molecular Cloning: A Laboratory Manual, 1989 Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.) and Innis et al., Eds. (PCR Strategies, 1995, Academic Press, New York, N.Y.). In a further embodiment, the present invention provides an implantable bioartificial active secretion system for providing a physiological secretion necessary for functionality of a physiological activity of a host living being. The system first includes a housing having an inlet with an opening external thereto and an outlet with an external opening therefrom. This housing may be at least partially implantable within the host such that the inlet and outlet openings may be placed in fluid communication with tissue fluid from the host and the tissue fluid may be received in the housing and subsequently supplied from the host. accommodation. A chamber may be disposed within the housing between the inlet and outlet and in communication therewith, and may contain a plurality of living, physiologically active, secretory cells autonomously operable to produce physiological secretion. In a further embodiment, disposed within the housing is a pump apparatus that periodically operates to bring initial tissue fluid through the inlet from the host for contact with the physiologically active cells within the chamber for collection and regulation of physiological secretion , and to supply resulting tissue fluid that has physiological secretion through it into and into the host. Finally, input and output filter systems in operational communication with the external openings of the inlet and outlet may have openings therethrough to impede the passage of immune system cells, immunoglobulins and components of the host complement system. The tissue fluid taken to be in contact with the living secretory cells may generally reflect host requirements for the particular physiological secretion. Therefore, in the treatment of diabetes for example, the peritoneal fluid can be taken since it is known that the peritoneal fluid reflects glucose levels in the blood, so the peritoneal fluid makes contact with secretory cells that are beta pancreatic cells, which produce insulin for peritoneal fluid absorption and return to target regulating these glucose levels. The secretory cells are preferably encapsulated with a permeable medium through which the cell nutrient as well as cellular metabolic waste can pass and also through which physiological secretion can pass, but through which cells of the immune system can not pass without the probability that these cells pass through the input filter. The encapsulation increases the charge density of the cells and their surface interaction with the fluid. Depending on the specific application, the life cycle of the secretory cells can often also be up to approximately two years, after which time replacement cells are introduced. A pumping apparatus preferably includes a plurality of elasticised pumping tubes, activated and deactivated in peristaltic form, sequentially arranged for peristaltic movement within which the initial tissue fluid and the tissue fluid containing the physiological secretion through of the device can be included. Pumping in peristaltic form can be achieved electromagnetically by means of a programmed controller arranged with the housing and therefore implanted, and / or by a programmed controller located outside the patient and in proximity to the implanted housing. In any configuration, the energy can be applied intermittently to replicate the peristaltic movement of tissue fluid through the pumping tubes and therefore in contact of movement with the living secretory cells located within the housing. The tissue fluid may reflect whether the need for the particular secretion provided by the secretory cells (eg, glucose level for insulin secreting cells) is present, so the secretory cells will naturally respond to the transmitted need. and will automatically produce a specific amount of secretion for this need as it is detected by the secretory cells. The tissue fluid collects this secretion as it makes contact with the secretory cells, and is subsequently delivered into the host. Finally, when the tissue fluid indicates less need for secretion (eg, the required secretion activity has been completed for time), the secretory cells sense that reduced need as the tissue fluid continues to contact. with them and the secretory activity naturally ceases. As is evident, the implantable bioartificial active secretion system defined here can significantly replicate the natural metabolic function by using living secretory cells both as a detector and as a provider of physiological equilibrium. Such use of living cells can eliminate the work of external divination with respect to the amount and time of injection of secretion product or other type of introduction since the real cells make a natural determination of need followed by a natural production and natural release of an exactly necessary quantity of the secretory product. In an illustrative embodiment, the present invention can provide the supply on physiologically beneficial insulin demand for glucose metabolism within a patient suffering from type I diabetes. Particularly, the system can function in the capacity of an artificial pancreas and can be implanted in a site within the peritoneal cavity in such a way that the peritoneal fluid can enter the device. The device can be placed inside the peritoneal cavity. This placement allows a relatively easy recovery, fast and complete in case of any failure or malfunction of the supply device. The implantation can usually be carried out under local anesthesia. It should be noted that the peritoneal fluid is chosen to determine the need for insulin because a change in the glucose concentration in the peritoneal fluid is in the same direction, same amount and relatively the same time factor as in the blood. The insulin secreting cells may be present with beta cells or as tissue as described above. In the preferred embodiment, groups of cells, with a total count of at least about 1,000,000 cells, are contained within the delivery device 10. Generally, the movement of the peritoneal fluid can continue through the delivery device 10 for contact with insulin secreting cells. These secretory cells naturally react to the glucose level of the peritoneal fluid and naturally secrete insulin into the peritoneal fluid as determined by the secretory cells as necessary for proper glucose metabolism. In addition, oxygen and nutrients can be passed to the secretory cells while the waste of metabolites from the secretory cells passes into the peritoneal fluid. The lifetimes of the secretory cells, of course, depend on the number of factors including nutrition and proper oxygen supply, removal of waste product and the degree of secretion required by the host. When the effectiveness of the cell decreases or ceases, however, the devices can be retrieved relatively easily and replaced by fresh units, with the device then returning to its implanted site. As is clear from the foregoing description, the secretory system defined herein can bioartificially emulate a secretory system that occurs naturally by providing living secretory producing cells to detect and produce secretions at naturally determined levels due to such living authenticity. In addition to the implantation of secretion producing cells, other means, including drugs, medicines and / or enzymes for treatment or prevention of diseases in accordance with physiological demands, can also be administered by using the system described herein and within which the chosen medium is placed. Therefore, although herein illustrative and currently preferred embodiments of the invention have been described in detail, it is to be understood that the inventive concepts may otherwise be modalized in varied and utilized form and that the appended claims are designed to be considered to include said variations except to where limited by the prior art. In summary, numerous benefits resulting from using the concepts of the invention have been described. The above descriptions of one or more embodiments of the invention have been presented for purposes of illustration and description. It is not intended to be exhaustive and to limit the invention to the precise form described. Modifications or obvious variations are possible in light of the previous teachings. One or more modalities were chosen and described to better illustrate the principles of the invention and their practical application to enable one skilled in the art to make better use of the invention in various modalities and with various modifications as appropriate for the particular use contemplated. It is intended that the scope of the invention be defined by the claims appended thereto.

Claims (60)

1. NOVELTY OF THE INVENTION CLAIMS 1. - An implantable active agent delivery device for providing an active agent to a subject, the delivery device comprising a biomaterial comprising a volume of active agent having a front surface and a back surface, wherein the front surface of the biomaterial is adapted to be maintained substantially adjacent to vascular tissue within the subject; and wherein the biomaterial is capable of administering a biologically active agent or of providing a metabolic or immunological function to the subject. 2. The device according to claim 1, further characterized in that the delivery device further comprises a strap for anchoring at an implantation or recovery site after implantation. 3. The device according to claim 2, further characterized in that the belt is adapted to maintain the biomaterial substantially adjacent to the vascular tissue. 4. The device according to claim 3, further characterized in that the material of the belt is bioabsorbable. 5. The device according to claim 3, further characterized in that the belt is capable of serving as a means for filling the device with active agent. 6. The device according to claim 3, further characterized in that the device further comprises a radiopaque material. 7. The device according to claim 3, further characterized in that the device is adapted to deliver active agent to the peritoneum. 8. The device according to claim 3, further characterized in that the device is adapted to deliver active agent to the omentum. 9. The device according to claim 7 or 8, further characterized in that the delivery device is adapted to supply through a cannula. 10. The device according to claim 7 or 8, further characterized in that the delivery device is a substantially flat sheet. 11. The device according to claim 3, further characterized in that the active agent is stable in the presence of elevated temperature or organic solvents. 12. The device according to claim 1, 7 or 8, further characterized in that the active agent is selected from the group consisting of antibodies, enzymes, trophic factors, growth factors, hormones and biological response modifiers. 13. - The device according to claim 1, 7 or 8, further characterized in that the active agent is an analgesic or pain reducing substance. 14. The device according to claim 12, further characterized in that the active agent is a peptide or protein. 15. The device according to claim 14, further characterized in that the active agent is a cytokine or iinfocin. 16. The device according to claim 3, further characterized in that the active agent is an immunogen. 17. The device according to claim 3, further characterized in that the active agent is prophylactic to be used as a vaccine. 18. The device according to claim 3, further characterized in that the active agent comprises an antigen and an adjuvant. 19. The device according to claim 3, further characterized in that the biomaterial further comprises one or more supply enhancing agents selected from the group consisting of polyethylene oxide (PEO), heparin, albumin, tissue growth factors, of angiogenic growth, surfactants, antioxidants, anti-inflammatory agents and anti-rejection drugs. 20. The device according to claim 3, further characterized in that the angiogenic growth factor is selected from the group consisting of fibroblast growth factor., acid fibroblast growth factor, vascular endothelial growth factor, platelet-derived endothelial growth factor bb, angiopoietin-1, transforming growth factor beta, transforming growth factor alpha, hepatocyte growth factor, tumor necrosis factor alpha , angiogenin, interleukin-8, hypoxia-inducible factor 1, angiotensin-converting enzyme inhibitor quiaprilat, angiotropin, thrombospondin, lactic acid, insulin and growth hormone. 21. The device according to claim 3, further characterized in that the anti-inflammatory agent is selected from the group consisting of cortisone and ACTH, dexamethasone, cortisol, interleukin-1 and its receptor antagonists, and antibodies to TGA-beta, for interleukin-1 (IL-1) and for interferon-gamma. 22. The device according to claim 3, further characterized in that the device is adapted to deliver active agent at a dose rate of about 0.001 to about 200 micrograms / hr. 23. The device according to claim 3, further characterized in that the device is adapted to deliver active agent at a volume rate of about 0.01 microliters / day to about 2 ml / day. 24. The device according to claim 3, further characterized in that the rear surface of the biomaterial further comprises a substantially elastic substrate material capable of substantially maintaining the shape of the biomaterial. 25. The device according to claim 3, further characterized in that the biomaterial comprises a patch suitable for adhering to tissues. 26. The device according to claim 25, further characterized in that the patch further comprises (a) a waterproof backing layer; (b) an active agent layer element; and (c) a layer of adhesive on the upper surface to adhere to the tissues. 27. The device according to claim 25, further characterized in that the delivery device further comprises an active agent layer element having a hollow space and a hollow surface and an upper surface having a microporous or semipermeable membrane. 28. The device according to claim 25, further characterized in that it comprises a reservoir, wherein the reservoir contains active agent and is adapted to deliver the active agent to the front surface to be delivered to the tissue. 29. The device according to claim 25, further characterized in that the device further comprises a penetration enhancer. 30. The device according to claim 29, further characterized in that the penetration enhancer is selected from the group consisting of disturbing compounds of the cell cover, solvents and mixtures thereof. 31. The device according to claim 3, further characterized in that the delivery device further comprises a selectively permeable outer jacket surrounding the core, the jacket comprises a biocompatible membrane that has a molecular weight cut that allows the passage of molecules of active agent to and from the core through the shirt to provide the biological product or function. 32. The device according to claim 31, further characterized in that the molecular weight cutoff of the membrane is between about 50-2000 kD. 33. The device according to claim 31, further characterized in that the molecular weight cut-off of the membrane is above about 100 kD. 34. The device according to claim 31, further characterized in that the core comprises a biocompatible matrix formed of a hydrogel. 35.- The device according to claim 34, further characterized in that the hydrogel is impregnated with pharmaceutical compounds. 36. The device according to claim 31, further characterized in that the jacket is selected from the group consisting of polyacrylonitrile-polyvinyl chloride, polyacrylonitrile, polymethyl methacrylate, polyvinyl difluoride, polyolefins, polysulfones and celluloses. 37.- The device according to claim 36, further characterized in that the sleeve further comprises a hydrophilic and hydrophobic additive. 38.- The device according to claim 3, further characterized in that the biomaterial is a structure of tissue matrix. 39.- The device according to claim 38, further characterized in that the tissue matrix structure includes mammalian cells. 40. The device according to claim 39, further characterized in that the cells are allogeneic or syngeneic when implanted. 41. The device according to claim 39, further characterized in that the cells are selected from the group consisting of enzyme-producing cells, adrenal chromaffin cells, antibody-secreting cells, fibroblasts, astrocytes, cell lines Beta and Chinese hamster ovary cells. 42. The device according to claim 39, further characterized in that the cells are insulin-producing cells. 43.- The device according to claim 39, further characterized in that the cells secrete antibodies. 44. The device according to claim 39, further characterized in that all the cells are arranged at a distance no greater than about 800 μ from the front face of the device. 45.- The device according to claim 39, further characterized in that the delivery device further comprises a core comprising a volume in excess of 1 μl and at least about 104 living cells dispersed in a biocompatible hydrogel array, the cells being able to secrete an active agent or to provide a metabolic or immunological function. 46. The device according to claim 39, further characterized in that it comprises a reservoir, wherein the reservoir contains material rich in nutrients and is adapted to supply the nutrient-rich material to the cells. 47. The device according to claim 39, further characterized in that the cells are aggregated in a dysfunctional aggregate form adapted for increased packaging per unit volume. 48. A method for implanting the material in a subject, comprising the steps of (a) inserting an implant of an active agent delivery device moored in the body of a subject; (b) releasing the delivery device to the body near the vascular tissue; (c) pulling the strap until the delivery device becomes substantially adjacent to the vascular tissue; and (d) generally securing the proximal end of the strap to substantially maintain the delivery device substantially in contact with the vascular tissue; wherein the delivery device comprises a biomaterial comprising a volume of active agent and wherein the biomaterial is capable of administering a biologically active agent or of providing a metabolic or immunological function to the subject. 49. The method according to claim 48, further characterized in that the administration is the delivery of a therapeutically effective amount. 50. The method according to claim 49, further characterized in that the therapeutically effective daily dose is from about OJ to about 100 mg / kg of body weight per day of active agent. 51. The method according to claim 49, further characterized in that the supply of active agent is substantially continuous. 52. The method according to claim 48, further characterized by the step of maintaining the contact cells and composition under conditions and for a sufficient time to cause the cells to grow. 53. The method according to claim 48, further characterized in that the step of bringing into contact with the tissues comprises administering the composition to a patient in need of said treatment of a therapeutically effective amount of the active agent. 54. The method according to claim 48, further characterized in that the active agent is administered by implantation of the composition and wherein the substrate is configured to match a desired tissue shape. 55. The method according to claim 48, further characterized in that the biomaterial is biodegradable. 56. The method according to claim 48, further characterized in that the biomaterial comprises an amount of the active agent sufficient for the treatment of a subject during a period of at least about 3 days to about 10 days. 57. The method according to claim 48, further characterized in that the biomaterial comprises an amount of the active agent sufficient for the treatment of a subject during a period of more than 20 days. 58.- The method according to claim 48, further characterized in that the biomaterial rises an amount of the active agent sufficient for the treatment of a subject during a period of more than 30 days. 59. The method according to claim 48, further characterized in that the device is adapted to deliver the active agent at a volume rate of about 0.01 microliters per day to 3 microliters per day. The method according to claim 48, further characterized in that the device delivers the active agent at a rate of about 0.01 micrograms of the active agent per hour to 300 micrograms of the active agent per hour.