WO1993023012A1 - Liquid-containing drug delivery system - Google Patents

Abstract

An implantable device capable of administering at least one liquifiable dosage form is provided. The device includes a housing with at least one liquifiable dosage form sealed within the housing by a tissue-replaceable matrix. The matrix is a substantially solid barrier that is gradually converted into an in vivo barrier by proliferation and infiltration of tissue formed by an inflammatory tissue response induced by implanting the housing or exacerbated by other compounds in the tissue-replaceable matrix. A method for making the implantable device is also provided.

Description

LIQUID-CONTAINING DRUG DELIVERY SYSTEM

Field of the Invention This invention relates generally to implantable, drug-release systems and in particular to a liquid-drug release system.

Background of the Invention Over the course of many years, numerous systems have been developed for delivery of both solid and liquid drugs. Previous efforts to develop implants for delivering solid drugs have included polymeric and nonpolymeric systems. Polymeric systems are typically combined with a drug to create:

1. a matrix bioerosional system in which the drug is evenly distributed in a polymer matrix and is released as the polymer contacts biological fluid and abrades, erodes or otherwise disintegrates in the biological fluids;

2. a matrix diffusion system in which the drug is released by diffusion through pores or channels in the polymer matrix; or

3. a matrix diffusion/bioerosion system in which the drug is released by diffusion through pores or channels in the polymer matrix, as well as by erosion as the surface of the polymer breaks down.

The nonpolymeric systems include compressed or fused mixtures of a drug and an excipient. For example, such systems include a fused implant comprising a drug uniformly dispersed in a matrix of suitable lipid carrier (Gupta, U.S. Patent 4,244,949); or a cholesterol matrix comprising cholesterol powder and a homogeneously dispersed bioactive agent (Kent, U.S. Patent 4,452,775).

Previous efforts at sustained release of liquid medicaments have, however, been less clinically useful than solid dosage forms. One method for controlled release of liquids has been the implantable, osmotic infusion pump exemplified by U.S. Patent Number 4,096,238 (Alza Corporation Palo Alto, California). The pump is loaded typically with a drug in an aqueous solution which often includes additional absorption aids such as dimethylsulfoxide (DMSO) . Because of their bulkiness, these osmotic pump systems are useful primarily for establishing dose-response curves in pre-clinical investigations.

Certain drugs, complex compounds, or pharmaceutical preparations may exist as highly viscous liquids at body temperature and can have a syrupy consistency. These materials are believed unsuitable for any known drug delivery devices because of their viscous nature.

Clinical therapies require that a continuous dosage of a liquid be administered, or that multiple liquids be administered in sequence at regular intervals in continuous dosages over extended periods of time. Nevertheless, if such drugs are not orally active, other modes of administration are required. There is a need for a reliable, controlled release drug delivery system in which a viscous liquid drug or a drug suspended in a viscous liquid can be delivered to a subject over a prolonged period without repeated administration.

Summary of the Invention An implantable device for dispensing at least one Iiquifiable dosage form is described. The device includes a Iiquifiable dosage form disposed within a housing defining a chamber. At least some portion of the housing includes a tissue replaceable matrix which acts in part as a barrier to seal the Iiquifiable dosage form within the chamber prior to implantation. When the housing is implanted, tissue proliferation will normally result from an inflammatory response induced by the presence of the implant. As the inflammatory response proceeds, fibrous and vascular tissue will penetrate into the interior spaces of the housing through the tissue replaceable matrix. The tissue replaceable matrix thus is replaced by an in vivo barrier of the infiltrated tissue. The Iiquifiable dosage form then is absorbed by the barrier and released from the chamber by way of this barrier.

The housing defines a chamber and also can define an opening. A tissue replaceable matrix seals the opening to form a sealed chamber, ana the Iiquifiable dosage form is contained in the chamber.

The housing of the invention can be bioerodible so that it will eventually completely degrade, leaving only the fibrous capsule of tissue formed as a result of the inflammatory response. Erosion of the housing also provides a means for releasing an additional dosage form, particularly if that dosage form is captured within the housing material and is released as the housing erodes.

The tissue replaceable matrix can include one or more cell response modifiers or can consist entirely of one or more cell response modifiers. The cell response modifiers actively influence the local inflammatory response, for example to encourage proliferation of tissue into the chamber or to inhibit enzymes which may lyse the active compound.

According to an another aspect of the invention, a method is provided for making an implantable device for dispensing at least one Iiquifiable dosage form when implanted. A housing is formed defining a chamber and an opening. The opening is sealed with a tissue replaceable matrix to form a sealed chamber. A Iiquifiable dosage form preferably is introduced into the chamber. In a preferred embodiment, the housing is formed from a tube having closed first and second ends, the ends being sealed with the tissue replaceable matrix.

The present invention thus provides a sustained release device that is simple in design and also that can provide sustained release of highly viscous, Iiquifiable dosage forms . Other features of the present invention will become apparent from the following detailed description when taken in connection with the accompanying drawings which disclose multiple embodiments of the invention. It is to be understood that the drawings are designed for the purpose of illustration only, and are not intended as a definition of the limits of the invention.

Detailed Description of the Drawings

Fig. 1 is a schematic cross-sectional illustration of a first embodiment of the invention;

Fig. 2 is a schematic illustration of a second embodiment of the invention;

Fig. 3 is a schematic cross-sectional illustration showing conversion of a tissue replaceable matrix into an in vivo active processing barrier according to the invention;

Fig. 4 is a schematic illustration of a modular embodiment of the invention;

Fig. 5 is a schematic cross-sectional illustration of a method for forming the device of the invention.

Detailed Description of the Invention This invention pertains to devices and methods for releasing one or more Iiquifiable dosage forms into an environment of use. The devices and methods are adapted to deliver materials that have not heretofore been amenable to conventional delivery techniques.

The present invention relies, in part, on the discovery that a local inflammatory response can normally develop during the subcutaneous implantation of bioerodible, solid drug-release pellets. See R.J. Leonard, "Engineering the Local Inflammatory Response as a Means of Control Release Drug Delivery", PCT/US92/04059, published November 26, 1992 under number WO92/20325. Briefly, the term "local inflammatory response" pertains to chronic, nonpathogenic tissue responses characterized by:

1. macrophage stimulation and chemotaxis;

2. fibroblast stimulation and collagen deposition;

3. development and infiltration of neovasculature and lymphatics; and

4. lipophage formation and subsequent uptake of foreign material by the peripheral blood supply.

Therefore, a complex, functional biological system called a "paraglandular compartment" normally develops in response to the subcutaneous introduction of a foreign body (e.g. drug delivery system) .

This invention contemplates a device and method for controlled release of any Iiquifiable dosage form using features of this local inflammatory response. The device includes a barrier portion, called a "tissue replaceable matrix", that is replaced by tissue of the subject upon implantation as a result of the local inflammatory response. The tissue infiltrates the device and actively engages in absorption of the Iiquifiable dosage form and in release of the Iiquifiable dosage form from the device.

The term "Iiquifiable dosage form" can refer to states of matter that conform to the shape of a confining vessel, possess a free surface, and do not expand without limit. These well-known physical properties of the liquid state encompass aqueous solutions of low viscosity such as physiological saline, distilled water or similar liquids that can be used as solvents for one or more liquid-soluble drugs.

The term "Iiquifiable dosage form" is also meant to describe materials that are not commonly thought of as being aqueous; including compositions such as oily suspensions, oil-water or oil-oil emulsions and the like. Liquid phase suspensions or emulsions are well-known and are meant to have their art-recognized meanings. For example, an oily suspension may be formulated by suspending the Iiquifiable dosage form in a vegetable oil; such as arachis oil, olive oil. sesame oil or coconut oil, or in a mineral oil.

The term "Iiquifiable dosage form" is further meant to encompass substantially pure drugs that have a syrupy or viscous consistency at body temperature. It also refers to those materials that, while not liquid outside the body, become liquid at body temperature. This term also refers to those materials that become liquid upon contact with biological fluids such as blood or lymph.

The Iiquifiable dosage form either is a drug or contains at least one drug. The term "drug" means any substance used on, or administered to a subject (i.e. humans or other animals) as an aid in diagnosis, treatment or prevention of disease or other abnormal condition, for relief of pain or suffering or to control, affect, maintain or improve a physiological or pathological condition.

The housing can be of a shape or size that encloses the liquid dosage form. For example, the housing can have a single, continuous outer surface in the shape of a sphere or capsule defining a chamber within which the Iiquifiable dosage form is completely enclosed. More preferably, the housing can have a shape such as a tube, cone, cylinder and the like. The housing has at least one opening defining a passageway in communication with the environment of use, i.e. a passageway from the interior of the housing to the exterior of the housing. The tissue replaceable matrix preferably is disposed within the passageway to seal the passageway and contain the liquid dosage form within the interior of the housing.

The housing may be made of a variety of materials. In one embodiment of the invention, the housing is made of a polymeric material. If the housing is bioerodible, i.e. capable of being gradually worn away by the presence of bodily fluids, the rate of bioerosion of the housing must be slower than the rate of tissue growth into the tissue replaceable matrix to achieve all of the advantages of the invention. Optimally, the housing will completely erode only once all the Iiquifiable dosage form has been processed by the infiltrating tissue.

Bioerodible polymers include hydroxycarboxylic acids, especially lactic acid and glycolic acid, polycaprolactone and copolymers thereof. For instance, various proportions of lactide and glycolide can be employed, such as 50/50, 65/35, 75/25, and 85/15 percent weight ratios of poly (DL-lactide-co-glycolide) . In addition, substantially 100% weight percent poly (DL-lactide) , poly (L-lactide), and polyglycolide can be used. Bioerodible polymers of this type are obtained from Birmingham Polymers, Inc., Birmingham, Alabama 35222. Copolymers of gluconic acid and ethyl-L-glutamic acid and other polypeptides can be used, as well as poly(orthoesters) (Choi et a ., U.S. Patent No. 4,093,709) and poly(orthocarbonate) (Schmitt, U.S. Patent No. 4,346,709). Also, poly(acrylate) materials can be employed, such as copolymers of acrylic and methacrylic acid esters or copolymers of methacrylic acid and methyl methacrylate (Sothmann et al. , U.S. Patent No. 4,351,825). Cholesterol and ethylene vinyl acetate copolymers can also be used. See for example, U.S. Patents 4,452,775 (J.S. Kent) and 4,591,496 (J.M. Cohen et aX. ) , respectively.

Portions of certain housings described herein can be impregnated with a separate drug in solid form. In these particular embodiments, therefore, a plurality of drugs can be released into the environment of use, at least one drug of which is the Iiquifiable dosage form (contained within the interior of the housing and released by replacement of a portion of the housing with tissue) and the other of which is a solid dosage form (which is part of the polymeric housing itself and is released by diffusion, erosion or the like) .

Preferred drugs formed as part of the housing itself are those capable of acting in concert with the Iiquifiable dosage form in order to augment the efficacy of the Iiquifiable dosage form. Such drugs also can be capable of protecting against an unwanted tissue response to the Iiquifiable dosage. For example, a polymeric housing may include anti—inflammatory factors, antipeptidases or proteolytic enzyme inhibitors that protect the Iiquifiable dosage form from being enzymatically degraded.

Other housings are made of inert materials. The term "inert" refers to housings that are not eroded or otherwise structurally compromised when implanted. Exemplary materials include glass, polytetrafluoroethylene (Teflon®), plastic, silicone or ceramic materials. In embodiments where all, or part of, the inert housing can comprise a porous material, the pores of which are impregnated with a tissue replaceable matrix, the housing may also be formed of a porous fabric by knitting, weaving, braiding, etc. fibers into the shape or form desired. Examples of materials suitable for this type of porous, inert housing include vinyl chloride and acrylonitrile co-polymers, vinyl chloride polymers, (Saran®), polyamides (e.g. nylon), polyacrylonitriles, (e.g. Orion®) and ethylene glycol (e.g. Dacron®) .

Surfaces of the housings may provide sites where the growing tissue can easily attach. Thus, inert housings can include one or more portions that are roughened, scored or porous. These areas are preferably adjacent to the tissue replaceable matrix.

Whether polymeric or inert, a unique characteristic of the housing important to the controlled release of Iiquifiable dosage forms is that the housing includes at least a portion that is a tissue replaceable matrix. The matrix is substantially nonpermeable to the dosage form, and at least some portion of the matrix is adapted to allow for its own replacement by tissue of the inflammatory response.

The tissue replaceable matrix can be arranged as a seal or plug to constrain the Iiquifiable dosage form within the housing. Proliferation of fibers and vascular tissue into this plug will gradually transform the plug from a purely physical, artificial barrier against leakage, into an ji vivo barrier that will permit uptake of and may even actively process the Iiquifiable dosage form.

Referring to Fig. l, one example of a special housing 12 is illustrated in cross-section. The housing 12 has a wall 13 defining a single chamber 14 containing at least one Iiquifiable dosage form 16. The housing 12 has a plurality of openings 18 extending through the wall 13 from a housing surface 20 that is in contact with the environment of use (when implanted) to another housing surface 22 defining the chamber 14. The openings 18 can be of any configuration, e.g. either straight tubes or interconnected channels similar in cross section to microporous polymeric filtration membranes. The number, shape and design of the openings are not intended to limit the scope of the invention in any way.

The openings 18 are filled with a tissue replaceable matrix 24 which acts to seal the openings and constrain the Iiquifiable dosage form in the chamber. The surfaces defining the openings act as a physical support for the infiltrating external tissue and guide growth of individual tissue fibers into the interior of the housing when implanted. In the particular embodiment illustrated, the openings 24 are filled with material that will eventually be replaced by tissue.

A wide variety of materials can form the tissue replaceable matrix. For example, certain biologically compatible materials can be used to fill the opening(s) in the housing, these materials include cholesterol, cholesterol esters, proteinaceous gels, gelatin, agar, collagen, albumin, glycerol and the like. Specifically, a cross-linking agent such as glutaraldehyde can be combined with a protein such as albumin (Sawyer, U.S. Patent No. 4,167,045) to provide a tissue replaceable matrix suitable for sealing the Iiquifiable dosage form within the housing of the invention. Similarly, a gelatin mixture, later cross-linked with diisocyanateε, is also suitable (Fleckenstein et §_1. , U.S. Patent No. 4,902,290). Cross-linked collagen fibrils (Hoffman Jr. et al. , U.S. Patent No. 4,842,575), and gel/glycerol mixtures, where the gel is alginate gel, polyacrylamide, agar, xanthan gum, bean gum or carrageenan can also be used. Bioerodible polymers such as those described above also are useful as tissue replaceable matrix. Virtually any material can be used as the tissue replaceable matrix provided that it permits its own replacement upon implantation by tissue formed as a result of the local inflammatory response generated.

The tissue replaceable matrix can also include excipients, including a variety of wetting agents and emulsifiers. Such excipients may include but are not limited to: (1) suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; and (2) dispersing or wetting agents which may be (a) a naturally-occurring phosphatide such as lecithin, (b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, (c) a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol, (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

Another housing (Fig. 2) is an open-ended tube or hollow cylinder 30 loaded with a Iiquifiable dosage form 32 and plugged at each end 34 with a tissue replaceable matrix 36. The same, or different matrices 36 may be employed to seal the ends. The hollow cylinder 30 preferably is formed of Teflon® or εilicone.

The Iiquifiable dosage form 32 is sealed within the cylinder 30 by the tissue replaceable matrix 36 prior to implantion. Roughened areas 38 may provide attachment sites for external tissue. In one embodiment, the ends of the cylinder may be plugged with a porous material (e.g. expanded polytetrafluoroethylene, porous ceramic, silicone with preformed openings and the like), the pores being filled with the tissue replaceable matrix.

In other embodiments, a tissue replaceable matrix can also be associated with a drug that, for example, exacerbates the local inflammatory response, which inflammatory response is initiated by implanting the housing. The term "associated with" refers to a drug attached to, contained within, or placed on the surface of, the tissue replaceable matrix. This drug is called a "cell response modifier".

In certain embodiments of the invention, the cell response modifier can be homogeneously dispersed throughout the tissue replaceable matrix. In particular, a bioerodible tissue replaceable matrix can be made by compressing mixtures of a cell response modifier and a nonactive, compatible excipient into a solid pellet. The rate of release and the uniformity of release of cell response modifier depends on the relative amounts of the modifier and excipient and the homogeneity of the mixture prior to compression.

Solid forms of a bioerodible tissue replacement matrix can also include totally fused systems in which the cell response modifier is homogeneously distributed in, and melted together with, a nonpolymeric carrier and then recrystallized by cooling to form a solid tissue replaceable matrix. See for example, U.S. Patent No. 4,748,024 to R.J. Leonard.

In addition, a partially-fused, solid matrix can be fabricated by mixing a cell response modifier and a nonpolymeric carrier having a lower melting temperature than the cell response modifier, then heating, compressing, and cooling the mixture, such that only carrier melts and recrystallizes, capturing the unmelted cell response modifier (i.e. a partially-fused matrix). See U.S. patent No. 5,039,660 to R.J. Leonard. Both totally and partially-fused tissue replaceable matrices are characterized by nondiffusional, erosion-based release of cell response modifier.

Moreover, the tissue replaceable matrix may itself entirely consist of a drug that, for example, exacerbates the local inflammatory response. That is, the tissue replaceable matrix can be a substantially pure preparation of a cell response modifier, compressed, fused or the like.

The tissue that replaces the matrix forms an in vivo barrier that may actively process the Iiquifiable dosage form. The tissue that replaces the matrix thus prevents bulk flow and leakage of the Iiquifiable dosage form from the housing, while simultaneously controlling absorption and release of the Iiquifiable dosage form into the environment of use due to ordinary biological processing mechanisms such as capillary flow, transport across biological membranes and the like.

The device of the invention can be made in a wide variety of sizes and shapes, depending on the dose of liquid and/or drug. Preferred cylindrical devices have an internal volume in the microliter range. A preferred tube (to be used practically for most human clinical applications but need not be so limited) can range in length fro about 4-5 mm to about 8-10 mm and in width from about 2.5 mm to about 5.0 mm. For example, an inert Teflon® tube 10 mm long with an internal diameter of 2.5 mm can have disposed at either end a barrier about 2.5 mm long. The remaining internal volume available for a liquid dosage form is therefore about 24.5 μl.

Fig. 3 is a cross-sectional schematic representation of an implanted device of the invention contained in a tissue-capsule or paraglandular compartment formed as a result of the implantation of the device. The device is a hollow cylinder 40 closed at one end 41 by the material of the cylinder. The opposite end 42 of the cylinder is sealed by a tissue replaceable matrix 43. The device is surrounded by a paraglandular compartment 44 which also has replaced the tissue-replaceable matrix 43 and has processes 45 extending into the interior of the hollow cylinder 40. The infiltration of the tissue of the paraglandular compartment 44 into the interior of the housing by replacing the tissue-replaceable matrix 43 prevents bulk release of the liquid dosage form 46 from the hollow cylinder 40. Instead, release of the liquid dosage form is permitted only by way of the in vivo barrier, that is, uptake of drug by, into and across the _in vivo barrier.

It is believed that tissue proliferation begins within several hours of implantation. A dense, fibrous capsule surrounding the implant may form within 1-3 weeks of implantation.

The kinetics of release of the Iiquifiable dosage form are believed to be dependent upon the amount of surface area of tissue defining the _in vivo barrier and the nature of that tissue. Thus, if the openings are large and if highly vascularized tissue is encouraged to enter the interior of the housing, then Iiquifiable dosage form will penetrate the barrier more rapidly than if there are small openings and vascularization is not encouraged.

The invention also includes modular configurations that contain a plurality of chambers. In one embodiment, a single, tubular housing can include a plurality of compartments, each separated by a tissue-replaceable matrix. Each chamber can include a different liquid dosage form. Proliferation of a fibrous tissue matrix successively into the tissue-replaceable matrices, as described previously, will result in release of a multiplicity of different Iiquifiable dosage forms. Many such configurations will be readily constructed by those of ordinary skill in the art according to the methods described herein.

A device of the invention for sustained release of a plurality of Iiquifiable dosage forms can be a housing subsrantially in the shape of a disk (Fig. 4) having an upper surface 52 and a lower surface 54, these respective surfaces being joined by an integral wall 56. The housing includes a plurality of chambers 58 each defining a discrete opening in the wall 56. Each chamber 58 is substantially conical in shape, the apex or narrowest portion of the cone lying at the center of the disk. Each chamber 58 can be filled with the same, or a different, Iiquifiable dosage form. The Iiquifiable dosage forms are sealed into their respective chambers with a tissue-replaceable matrix 60. The identical matrix may seal all chambers 58, or different matrices may seal different chambers. The housing can conveniently be made of an inert polymeric material such as polytetrafluoroethylene (Teflon®, or plastic, silicone or ceramics.

The cell response modifier is generally any substance that affects the local inflammatory response, which inflammatory response is induced by the act of implanting the housing. By "affecting the local tissue response", it is meant that the cell response modifier is present in sufficient amount to accelerate, decelerate, increase, or decrease the inflammatory response to the implant (relative to that response resulting when no modifier is present) . This effect may result, for example, from the cell response modifier stimulating or retarding:

1. macrophage production;

2. proliferation of fibrous tissue penetrating the implant;

3. infiltration of the fibrous capsule by new blood vessels and lymphatics;

4. chemotaxis of cells and other biological material. Particularly preferred cell response modifiers exacerbate and accelerate the local inflammatory response and allow it to proceed more swiftly and aggressively into the tissue-replaceable matrix than it would in the absence of the cell response modifier. For example, certain fatty acids (e.g. palmitic, arachidic acids) may be pro-inflammatory since they mimic precursors of prostaglandins. Other ceil response modifiers are more specific for certain effects. For example, stimulation of angiogenesis can be accomplished by cholesteral palmitate or epidermal growth factor. Proteolytic enzyme inhibitors are useful cell response modifiers particularly if the Iiquifiable dosage is a glycosylated polypeptide that will come under attack by proteolytic enzymes once the dosage is released from the housing.

The cell response modifier is present in sufficient concentration to affect the local tissue response, but is not present in sufficient concentration to achieve a therapeutic effect for the particular condition or disease being treated.

Other preferred cell response modifiers include, but are not limited to, cytokines or oncogene products homologous to cytokines, or any compound which may inhibit or otherwise affect such regulators, such as a steroidal or non-steroidal anti-inflammatories. See, e.g. , K. Arai et al■ , "Cytokines: Coordinators of Immune and Inflammatory Responses," Ann■ Rev. Biochem. , 59:783-836 (1990); F.R. Balkwill and F. Burke, "The cytokine network," Immunology Today, 16:299-304, (September, 1989). Cytokines are involved in controlling the proliferation and differentation of mammalian cells and cellular interactions in the immune and inflammatory responses.

Preferred cell response modifiers are chemotactic factors. The term "chemotactic" refers to chemicals that signal other chemicals and/or cells to perform certain functions. For example, eosinophil chemotactic factor is a small peptide that is an attractant for eosinophilic leukocytes. Other chemotactic factors include platelet-derived growth factor (pDGF) neutrophii-activating protein, monocyte chemoattractant protein, macrophage-inflammatory protein, SIS (small inducible secreted), platelet factor, platelet basic protein, and melanoma growth stimulating activity; epidermal growth factor, transforming growth factor (alpha), fibroblast growrh factor, platelet-derived endothelial cell growth factor, insulin-like growth factor, nerve growth factor and bone growth/cartilage-inducing factor (alpha and beta) .

Other cell response modifiers include interleukins, interleukin inhibitors or interleukin receptors, including interleukin 1 through interleukin 12; interferons, including alpha, beta and gamma; hematopoietic factors, including erythropoietin, granulocyte colony stimulating factor, macrophage colony stimulating factor and granulocyte-macrophage colony stimulating factor (GM-CSF) ; tumor necrosis factors, including alpha and beta; transforming growth factors (beta), including beta-1, beta-2, beta-3, inhibin, and activin.

The invention also embodies a system in which more than one cell response modifier is introduced. Various combinations of these, as well as various times of introduction of different cell response modifiers, can be devised to either stimulate or inhibit various aspects of the local inflammatory response, so as to finely tune the rate of release of the liquid dosage form and maximize the therapeutic efficacy of the particular liquid dosage form involved in the patient's treatment.

The Iiquifiable dosage form may be any substance having biological activity, including proteins, polypeptides, polynucleotideε, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, and synthetic and biologically engineered analogs thereof.

Examples of compounds that can be released from the sustained release device of the invention include literally any bioactive compound if it is in a Iiquifiable dosage form, as the term is defined above. Furthermore, drugs that are not themselves liquid at body temperature can be incorporated into liquids such as oil/water emulsions with common fatty acids, sterile or neutral fats. Moreover, peptides and proteins which may normally be lysed by tissue-activated enzymes such as peptidases, can be passively protected in oily suspensions or oil/water emulsions as well. Use of oil/water emulsions is particularly advantageous since lipophages (i.e. "foam cells") will ingest the oil globule along with the aqueous phase containing a water-soluble drug.

Classes of Iiquifiable dosage forms which are intended to be included within this invention include anti-AIDS substances, anti-cancer substances, antibiotics, anti-viral substances, enzyme inhibitors, neurotoxins, opioids, hypnotics, tranquilizers, anti-convulsants, muscle relaxants and anti-Parkinson substances, anti-spasmodics and muscle contractants, anti-hypertensives, analgesics, anti-pyretics and anti-inflammatory agents, local anesthetics, prostaglandinε, anti-depresεantε, anti-pεychotic substances, anti-emetics, imaging agents, specific targeting agents, neurotransmitters and proteins.

Anti-AIDS substances are subεtances used to treat or prevent Autoimmune Deficiency Syndrome (AIDS) . Examples of such substanceε include CD4 (large quantitieε of which can be supplied this way for competitive binding) , 3 '-azido-3 '-deoxythymidine (AZT),

9-(2-hydroxyethoxymethyl)-guanine acyclovir (acyclovir), phoεphonoformic acid, 1-adamantanamine, peptide T, and 2',3' dideoxycytidine.

Anti-cancer εubstances are subεtanceε used to treat or prevent cancer. Examples of such εubεtances include methotrexate, ciεplatin, prednisone, hydroxyprogeεterone caproate, medroxyprogesterone acetate, megeεtrol acetate, diethylstilbestrol, ethinyl estradiol, tamoxifen, testosterone propionate, fluoxymesterone, vinblaεtine, vincristine, vindesine, etopoεide, tenipoεide, dactinomycin (actinomycin D) , daunorubicin (daunomycin; rubidomycin) , doxorubicin, bieomycin, plicamycin (mithramycin) , mitomycin (mitomycin C) , -asparaginase, hydroxyurea, procarbazine (N-methylhydrazine, MIH), mitotane, aminoglutethimide, mechlorethamine, cvcloohosphamide, melphalan ( -sarcolvεin) , uracil mustard, chlorambucil, busulfan, carmustine (BCNϋ) , lo usline (CCNU) , semuεtine (methyl-CCNϋ) , streptuzocin (steptozotocin) , dacarbazine (DTIC: dimethyltriazenomidazolecarboxamide) , methotrexate (amethopterin) , fluorouracil (5-fluorouracil: 5-FU) , cytarabine (cytosine arabinoxide), mercaptopurine (6-mercaptopurine: 6-MP) , thioguanine (6-thioguanine: TG) . Antibiotics are art recognized and are substances which inhibit the growth of or kill microorganisms. Antibiotics can be produced synthetically or by microorganisms. Examples of antibiotics include penicillin, tetracycline, minocycline, doxycycline, vanomycin, bacitracin, kanamycin, neomycin, erythromicin and cephalosporins. Examples of cephalosporins include cephalothin (keflin, "Seffin", a product of Glaxo, Inc., Research Triangle Park, NC), cephapirin, cefazolin ("Ancef", a product of Smithkline Consumer Products, Philadelphia, PA, "Kefzol", a product of Eli Lilly and Co., Indianapolis, IN), cephalexin ("Keflex", a product of Dista Products, Co., Indianapolis, IN), cephradine ("Anspor", a product of Smithkline and French Labs, Philadelphia, PA; "Velosef", a product of E.R. Squibb & Sons, Inc., Princeton, NJ) , cefadroxil ("Duricef", a product of Mead Johnson Pharmaceuticals, Evansville, IN; "Ultracef", a product of Bristol Laboratories, Evansville, IN), cefamandole ("Mandol", a product of Eli Lilly and Co., Indianapolis, IN), cefoxitin ("Mefoxin", a product of Merck, Sharpe & Dohme, West Point, PA), cefaclor ("Ceclor", a product of Eli Lilly and Co., Indianapolis, IN), cefuroxime ("Zinacef", a product of Glaxo Inc., Research Triangle Park, NC) , cefonicid ("Monocid", a product of Smith Kline & French Labs, Philadelphia, PA), ceforanide, cefotaxime ("Claforan", a product of Hoescht-Rousεel Pharmaceuticalε, Somerville, NJ) , moxalactam, ceftizoxime ("Cefizox", a product of Smith Kline and French Labs, Philadelphia, PA), ceftriaxone ("Rocephin", a product of Roche Laboratories, Nutley, NJ) , and cefoperazone ("Cefobid", a product of Roerig Co., New York, NY). Anti-viral agents are subεtanceε capable of deεtroying or suppressing the replication of viruses. Examples of anti-viral agents include -methyl-ϋ-adamantane methylamine, l-β-D-ribofuranosyl-l,2,4-triazole-3 carboxamide (ribavirin) , 9-[2-hydroxy-ethoxy]methylguanine, adamantanamine, 5-iodo-2 '-deoxyuridine and adenine arabinoside.

Enzyme inhibitors are substances which inhibit an enzymatic reaction. Examples of enzyme inhibitors include edrophonium chloride, N-methylphysostigmine, (-)-, neoεtigmine bromide, physostig ine sulfate, tacrine HCL (THA), tacrine,l-hydroxy maleate, iodotubercidin, p-bromotetramisole, (-)-, lθ-(α-diethylaminopropionyl)- phenothiazine hydrochloride (Aε-1397), calmidazolium chloride, hemicholinium-3, 3,5-dinitrocatechol (OR-486), diacylglycerol kinase inhibitor I (R59022), diacylglycerol kinase inhibitor II (R59949), 3-phenylpropargylamine, N -monomethyl-L-arginine acetate, carbidopa, 3-hydroxybenzylhydrazine HCI (NSD-1015), hydralazine HCI (apresoline) , clorgyline HCI, deprenyl HC1,L(-)-, deprenyl HC1,D(+)-, hydroxylamine HCI, iproniazid phosphate, 6-MeO-tetrahydro-9H-pyrido-indole, nialamide, pargyline HCI, quinacrine HCI, semicarbazide HCI, tranylcypromine HCI, N,N-diethylaminoethyl-2,2-diphenylvalerate hydrochloride, 3-isobutyl-l-methylxanthne, papaverine HCI, indomethacind, 2-cyclooctyl-2-hydroxyethylamine hydrochloride (CONH), (±)-2,3-dichloro-α-methylbenzylamine (DCMB) , (LY-78335) , 8,9-dichloro-2,3,4,5-tetrahydro-lH-2- benzazepine hydrochloride, p-aminoglutethimide, (±)-, p-aminoglutethimide tartrate,R(+)-, p-aminoglutethimide tartrate,S(-)-, 3-iodotyrosine,L-, α-methyltyrosine,L-, α-methyltyroεine,D L-, and allopurinol.

Neuroroxins are εubstances which have a toxic effect on the nervous system, e.g. nerve cells. Neurotoxins include adrenergic neurotoxins, cholinergic neurotoxins, dopaminergic neurotoxins, and other neurotoxins. Examples of adrenergic neurotoxinε include

N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride. Exampleε of cholinergic neurotoxins include acetylethylcholine mustard hydrochloride acetyl AF-64. Exampleε of dopaminergic neurotoxinε include 6-hydroxydopamine HBr, l-methyl-4-(2-methylphenyl)-l,2,3,6- tetrahydro-pyridine hydrochloride, l-methyl-4-phenyl-2,3- dihydropyridinium perchlorate, N-methyl-4-phenyl-l,2,5,6- tetrahydropyridine HCI, l-methyl-4-phenylpyridinium iodide. Other neurotoxins include L-β-methyl-α,β-diaminopropionic acid hydrochloride, (±)-β-methyl-α,β-diaminopropionic acid hydrochloride, L-β-oxalyl-α,β-diaminopropionic acid, and quinolinic acid.

Opioids are substances having opiate like effects that are not derived from opium. Opioids include opioid agonistε and opioid antagoniεts. Opioid agonists include codeine sulfate, fentanyl citrate, hydrocodone bitartrate, loperamide HCI, morphine sulfate, noscapine, norcodeine, normorphine, thebaine. Opioid antagonists include nor-binaltorphimine HCI, buprenorphine, β-chlomaltrexamine 2HC1, β-funaltrexamione HCI, nalbuphine HCI, nalorphine HCI, naloxone HCI, naloxonazine, naltrexone HCI, and naltrindole HCI(NTI) .

Hypnotics are substanceε which produce a hypnotic effect. Hypnoticε include pentobarbital sodium, phenobarbital, secobarbital, thiopental and mixtures, thereof, heterocyclic hypnoticε, dioxopiperidineε, glutarimideε, diethyl isovaleramide, α-bromoisovaleryl urea, urethaneε and disulfanes.

Tranquilizerε are substanceε which provide a tranquilizing effect. Exampleε of tranquilizerε include chloropromazine, pro azine, fluphenzaine, reserpine, deserpidine, and meprobamate.

Anti-convulsantε are εubεtances which have an effect of preventing, reducing, or eliminating convulsionε. Exampleε of such agents include primidone, phenytoin, valproate, Chk and ethosuximide.

Muscle relaxants and anti-Parkinson agentε are agents which relax muscles or reduce or eliminate symptoms associated with Parkinson's disease. Examples of such agentε include mephenesin, methocarbomal, cyclobenzaprine hydrochloride, trihexylphenidyl hydrochloride, levodopa/carbidopa, and biperiden.

Anti-spasmodics and muscle contractants are εubεtanceε capable of preventing or relieving muscle spasmε or contractionε. Exampleε of such agents include atropine, scopolamine, oxyphenonium, and papaverine.

Anti-hypertensives are substanceε capable of counteracting high blood preεsure. Examples of such substanceε include α-methyldapa and the pivaloyloxyethyl ester of α-methyldapa.

Analgesicε are substances capable of preventing, reducing, or relieving pain. Examples of analgesics include morphine sulfate, codeine sulfate, meperidine, and nalorphine,

Anti-pyretics are substances capable of relieving or reducing fever and anti-~_ιflammatory agentε are εubεtanceε capable of counteracting or suppresεing inflammation. Examples of such agents include aspirin (salicylic acid) , indomethacin, sodium indomethacin trihydrate, salicylamide, naproxen, colchicine, fenoprofen, sulindac, difluniεal, diclofenac, indoprofen and εodium εalicylamide.

Local anesthetics are substances which have an anesthetic effect in a localized region. Examples of such anesthetics include procaine, lidocain, tetracaine and dibucaine.

Prostaglandins are art recognized and are a class of naturally occurring chemically related, long-chain hydroxy fatty acids that have a variety of biological effects. Examples of εuch agentε include E2 and El.

Anti-depreεεants are εubεtanceε capable of preventing or relieving depreεεion. Exampleε of anti-depreεsants include imipramine, amitriptyline, nortriptyline, protriptyline, desipramine, amoxapine, doxepin, maprotiline, tranylcypromine, phenelzine, and isocarboxazide.

Anti-psychotic subεtances are subεtanceε which modify pεychotic behavior. Exampleε of εuch agentε include phenothiazineε, butyrophenoneε and thioxanthenes.

Anti-emetics are substanceε which prevent or alleviate nausea or vomiting. An example of such a subεtance includes dramamine.

Imaging agents are agents capable of imaging a desired site, e.g. tumor, in vivo. Examples of imaging agents include substances having a label which is detectable in vivo, e.g. antibodies attached to fluorescent labels. The term antibody includes whole antibodies or fragments thereof.

Specific targeting agents include agents capable of delivering a therapeutic agent to a desired site, e.g. tumor, and providing a therapeutic effect. Examples of targeting agentε include agents which can carry toxins or other agents which provide beneficial effects. The targeting agent can be an antibody linked to a toxin, e.g. ricin A or an antibody linked to a drug.

Neurotransmitters are εubεtanceε which are released from a neuron on excitation and travel to either inhibit or excite a target cell. Examples of neurotransmitterε include dopamine, serotonin, γ-aminobutyric acid, norepinephrine, histamine, acetylcholine, and epinephrine.

The term "protein" is art-recognized and for purposes of this invention also encompaεεeε peptideε. The proteins or peptides may be any bioactive protein or peptide, naturally occurring or synthetic. Examples of proteins include antibodies, enzymes, steroids, growth hormone and growth hormone-releasing hormone, gonadotropin-releasing hormone, and its agonist and antagonist analogueε, εomatostatin and its analogues, gonadotropinε such as luteinizing hormone and follicle-stimulating hormone, peptide-T, thyrocalcitonin, parathyroid hormone, glucagon, vasopreεεin, oxytocin, angiotenεin I and II, bradykinin, kallidin. adrenocorticotropic hormone, thyroid stimulating hormone, insulin, glucagon and the numerous analogues and congeners of the foregoing molecules.

The examples discussed above may be in their salt or non-salt form but for purposeε of thiε invention both forms are intended to be encompassed. Further, if a particular salt-form of a Iiquifiable dosage form is listed, other art recognized biologically accepted saltε can be used in place of the listed salt-form. Examples of acceptable saltε include hydrochloride, hydrobromide, sulfate, laurelate, palmatate, phosphate, nitrate, borate, acetate, maleate, tartrate, oleate, salisilate, salts of metals, or organic cations, e.g. quarternary ammonium.

This invention is also intended to encompasε derivativeε or equivalentε of the above discuεsed substances. A "derivative" is a substance which is structurally εimilar to the foregoing list of substances and is capable of achieving the εame or εubεtantially the same function or activity.

The biologically active substance is present in sufficient amount to achieve a therapeutic effect, preferably, for at least three months of delivery. A "therapeutically effective doεe" is that amount necesεary to prevent, treat, or reduce the symptoms asεociated with the particular condition or diseaεe being treated.

The device of the invention can be implanted into a εubject (i.e. an animal, preferably a mammal) in a variety of wayε. The moεt preferable means for implantation is subcutaneouεly, uεing one or more injector devices well known in the art. See, for example, U.S. Patent No. 4,846,793 to Leonard and Harman, incorporated herein by reference. Other modes of administration include intraperitoneally or intravascularly.

The tiεεue-replaceable matrix can be introduced into the housing by a number of techniques. For inert housings where substantially all of the material is porous, the housing can be sprayed with, or immersed in, a εolution of tissue-replaceable matrix for a suitable period of time, and the housing can then be removed and the matrix allowed to harden into a gelatinous or solid structure. For example, a porous housing can be soaked in a solution of glutaraldehyde and albumin. Croεε-linking initiated by the glutaraldehyde reεultε in gelation of the albumin and the gelled albumin fills the interstices of the housing. The gelation time can be easily controlled by varying the concentration of cross-linking agent. Thus, gelation can be initiated, aε above, and the Iiquifiable doεage form injected into the housing when the gelation is almost complete, ensuring little or no leakage of the dosage form from the housing.

Alternatively, a porous housing can be perfused with a solution of tissue-replaceable matrix, the solution driven by compressed air or a peristaltic pump. For example, a housing can be perfused with a solution of cross-linking agent and protein (e.g. albumin). Alternately, the housing can be perfused with a first solution of crosε-1inking agent, and a subsequent solution of protein.

If the tissue-replaceable matrix is intended to occupy a small portion of the housing, as in Fig. 2 where the matrix sealε only the endε of a tube, an end of the houεing can be immersed to a certain depth in a εolution of tissue-replaceable matrix, the depth of the solution defining the extent of the matrix within the housing. As before, if gelatinized protein is uεed aε the matrix, then the houεing iε immerεed for a εuitable period, removed and allowed to drain and dry. Many other methodε will be applicable to emplacement of gelatinouε (i.e. εemi-solid) types of tiεsue-replaceable matrix.

A method of manufacturing a preferred embodiment of the device is illustrated in Fig. 5. The method includeε forming a houεing 70 εubεtantially in the shape of a hollow tube having opposed first 72 and second 74 open ends. Aε diεcuεεed above, thiε houεing can be an inert material εuch as Teflon® or it can be a polymeric material. A polymeric housing or an inert housing is dispoεed within a solid retaining element 76 such as a steel or lucite retaining element. This retaining element 76 defines a straight cylindrical bore 78 shaped and sized to closely fit the outer periphery of the housing 70. The houεing 70 is inserted into the retaining element 76 and a first end 72 of the housing iε plugged with a tiεsue-replaceable matrix 80 (e.g. collagen, cross-linked albumin, a compressed pellet of platelet-derived growth factor, etc.). The tube then is loaded via the second end 74 with a Iiquifiable dosage form 82.

Loading of the dosage form can be accomplished by a variety of techniques including simple injection by a syringe 84, decantation from a larger reservoir, or other similar methods well known to those of ordinary skill in the art. Once the dosage form 82 is loaded into the housing 70, the remaining open end of the housing is similarly sealed or plugged with the tissue-replaceable matrix. The device then is ejected from the retaining element 76 and is ready for implantation.

Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentations, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompasεed in the εcope of the following claims.

Claims

1. A device for implantation into a mammal and for dispensing at least one Iiquifiable dosage form when implanted, comprising: a houεing defining a chamber containing a Iiquifiable dosage form, at leaεt a portion of the housing being a tissue-replaceable matrix sealing the dosage form within the chamber, whereby when the device is implanted, at leaεt a portion of the tissue-replaceable matrix is replaced with tissue, thereby permitting release of the dosage form from within the chamber by way of the tissue.

2. The device of claim 1, wherein said housing comprises a substantially hollow tube having opposed ends, at least one of said ends comprising the tisεue-replaceable matrix.

3. The device of claim 1, further comprising at least one cell responεe modifier aεεociated with said tisεue-replaceable matrix.

4. The device of claim 1, wherein the housing comprises a hollow tube having opposed ends, both of said ends sealed by the tisεue-replaceable matrix.

5. The device of claim 4, further comprising at least one cell response modifier associated with the tissue-replaceable matrix.

6. The device of claim 3, wherein said cell response modifier is platelet derived growth factor.

7. The device of claim 1, wherein the housing is polymeric.

8. The device of claim 7, wherein said housing includes a solid drug.

9. The device of claim 1, wherein said housing is bioerodible.

10. An implantable device for controlled release of a Iiquifiable dosage form comprising: a housing defining a chamber and an opening, a tissue-replaceable matrix sealing the opening to form a sealed chamber, and a Iiquifiable dosage form contained in said sealed chamber.

11. An implantable device as claimed in claim 10 wherein the houεing is formed at least in part of a polymeric material.

12. An implantable device as claimed in claim 10 wherein the housing is formed from a bioerodible material.

13. An implantable device as claimed in claim 10 wherein the housing is formed of a material containing a drug.

14. An implantable device as claimed in claimε 10, 11, 12 or 13 further compriεing at leaεt one cell response modifier associated with the tisεue-replaceable matrix.

15. An implantable device aε claimed in claim 11 wherein the cell response modifier is a chemotactant.

16. The device of claim 15 wherein the cell response modifier is platelet derived growth factor.

17. The device of claims 10, 11, 12 or 13 wherein the tisεue-replaceable matrix is a melted and recrystallized material .

18. The device of claim 17 wherein the tiεεue-replaceable matrix is selected from the group consisting of totally fused pellets and partially fused pellets.

19. The device of claim 10 wherein said housing defineε a εecond εealed chamber, and further compriεing a second opening asεociated with the εecond chamber, a tiεεue-replaceable matrix sealing the second opening to form said second sealed chamber, and a second Iiquifiable dosage form contained in said second sealed chamber.

20. A method for making an implantable device for dispensing at least one Iiquifiable dosage form when implanted into a subject, comprising forming a housing defining a chamber and an opening, and sealing the opening with a tissue-replaceable matrix to form a sealed chamber.

21. A method as claimed in claim 20 further comprising introducing a Iiquifiable dosage form into the chamber.

22. A method as claimed in claim 21 wherein the opening is sealed with a melted and recrystallized material.

23. A method as claimed in claim 21 wherein the housing is in the shape of a tube, wherein the opening is defined by an end of the tube, and wherein the end of the tube iε εealed by εaid t-issue-replaceable matrix.

24. A method as claimed in claims 20, 21, 22 or 23 wherein the opening iε εealed with a tissue-replaceable matrix that contains at least one cell reεponεe modifier.

25. A method for making an implantable device for diεpensing at least one Iiquifiable dosage form into an environment of use, comprising forming a hollow houεing having oppoεed firεt and εecond ends; sealing the firεt end of the houεing with a solid form of tissue-replaceable matrix; loading an amount of Iiquifiable dosage form into the housing from the second end; and sealing the εecond end of the houεing with a εolid form of tiεεue-replaceable matrix.

26. The method of claim 25, wherein the εtep of forming a housing comprises forming a polymeric housing.

27. The method of claim 25, wherein the step of forming a housing comprises forming an inert housing.

28. The method of claim 26, wherein the polymeric housing is bioerodible.

29. The method of claim 25, wherein the tisεue-replaceable matrix comprises at leaεt one cell response modifier.