Bioabsorbable device having composite structure for accelerating degradation.

(54) Title: BIO ABSORBABLE DEVICE THAT HAS A MIXED STRUCTURE TO ACCELERATE DEGRADATION. (54) Title: BIOABSORBABLE DEVICE HAVING COMPOSITE STRUCTURE FOR ACCELERATING DEGRADATION.

(57) Summary

A medical device having a structure made of a first biodegradable and / or bioabsorbable material and a second biodegradable and / or bioabsorbable material; the first biodegradable and / or bioabsorbable material has a degradation rate that is faster than a degradation rate of the second biodegradable and / or bioabsorbable material; and the structure undergoes a period of accelerated degradation upon exposing the first biodegradable and / or bioabsorbable material.

(57) Abstract

A medical device has a structure made of a first biodegradable and / or bioabsorbable material and a second biodegradable and / or bioabsorbable material. The first biodegradable and / or bioabsorbable material has a degradation rafe that ¡s faster than a degradation rafe of the second biodegradable and / or bioabsorbable material. And, the structure experiences a period of accelerated degradation upon exposure of the first biodegradable and / or bioabsorbable material.

BIO ABSORBABLE DEVICE THAT HAS A MIXED STRUCTURE FOR

ACCELERATE DEGRADATION

FIELD AND BACKGROUND OF THE INVENTION

The present invention relates generally to implantable medical devices and in particular to new and useful bioabsorbable medical devices that are capable of achieving a desired loss of mass through accelerated degradation after the medical device has achieved its desired functional effect or has achieved the end of its functional purpose or useful life.

It is widely accepted that polymers have found very relevant and practical uses in the medical field. Therefore, the high instability of these polymers, which leads to biodegradation, has proven to be immensely important in medical applications for the last number of decades.

For example, polymers made from glycolic acid and lactic acid have found a multitude of uses in the medical industry, starting with blockable sutures first approved in the 1920s. Since that time, various products based on lactic and glycolic acid - and on other materials, including copolymers of poly (dioxanone), poly (trimethylene carbonate), and homopolymers and copolymers of poll (ecaprolactone) - have been accepted for use as devices. doctors.

In addition to these approved devices, a great deal of research continues on polyanhydrides, polyorthoesters, polyphosphazenes, and other biodegradable polymers.

There are a number of reasons why a doctor wants a medical device made of a material that degrades. And the most basic reasons are the simple desire of the doctor to have a device that can be used as an implant and does not require a second surgical intervention to be removed. In addition to eliminating the need for a second surgery, biodegradation may offer other advantages. For example, a fractured bone that has been fixed with a rigid, non-biodegradable stainless steel implant has a tendency to fracture again upon removal from the implant. Since stress is produced by rigid stainless steel, the bone has not been able to carry enough load during the healing process.

However, an implant prepared from biodegradable polymer can be designed to degrade at a rate that will more slowly transfer the load to the healing bone. Another exciting use for which biodegradable polymers offer tremendous potential is as the basis for drug delivery, either as a single drug delivery system or as a whole to function as a medical device.

Bioabsorbable implants that are typically made of polymeric materials such as lactone-based polyesters. These volumetric wear materials break down over time due to chemical hydrolysis to produce water soluble low molecular weight fragments. Those fragments are then attacked by enzymes to produce lower molecular weight metabolites.

To date, there are no known bioabsorbable medical devices that are capable of achieving a desired loss of mass through accelerated degradation after the medical device has achieved its desired functional effect or has achieved the end of its functional purpose or shelf life. .

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to medical devices that are placed or implanted in the body including medical devices that are placed in vessels such as an artery or vein, or ducts or organs such as the heart. Particularly, the present invention is a medical device that is made of either composite structures comprising biodegradable and / or bioabsorbable material including mixtures, coatings or layers of biodegradable and / or bioabsorbable material to achieve a desired loss of mass through accelerated degradation after the medical device has achieved its desired functional effect or has reached the end of its functional purpose or useful life.

Furthermore, the present invention is a medical device that is made of either biodegradable and / or bioabsorbable material including mixtures, coatings or layers of biodegradable and / or bioabsorbable material and having encapsulated degradation additives that lead to acceleration of degradation of the structures or components of the medical device to achieve a desired mass loss through accelerated degradation after the medical device has achieved its desired functional effect or has achieved the end of its functional purpose or life. In some embodiments, the medical device in accordance with the present invention includes a therapeutic agent released from a medical device as well as other additives such as radiopaque agents and pH regulating agents.

The present invention is directed to a medical device having a structure made of a first biodegradable and / or bioabsorbable material and a second biodegradable and / or bioabsorbable material. The first biodegradable and / or bioabsorbable material has a degradation rate that is faster than a degradation rate of the second biodegradable and / or bioabsorbable material. And the structure undergoes a period of accelerated degradation by exposing the first biodegradable and / or bioabsorbable material.

The present invention is also directed to a medical device having a structure made of a biodegradable and / or bioabsorbable material. A degradation additive is encapsulated by another biodegradable and / or bioabsorbable material that forms a nanoparticle or microparticle. The nanoparticle or microparticle is together with a biodegradable and / or bioabsorbable material of the structure. The other blodegradable and / or bloabsorbable material of the nanoparticle or microparticle has a degradation rate that is faster than a degradation rate of a blodegradable and / or bioabsorbable material. The structure undergoes a period of accelerated degradation when it is released from the degradation additive of the nanoparticle or microparticle.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity in the appended claims. The invention itself, however, in terms of organization as methods of operation, together with the additional objects and advantages thereof, can be understood by reference to the following description, taken together with the accompanying drawings, in which:

Figure 1 is a schematic illustration of a medical device having a mixed structure of a first blodegradable and / or bioabsorbable material that degrades at a first rate of degradation and a second blodegradable and / or bioabsorbable material laminated or coated on the first material blodegradable and / or bioabsorbable, wherein the first degradation rate of the first blodegradable and / or bioabsorbable material is faster than the second degradation rate of the blodegradable and / or bioabsorbable material in accordance with the present invention;

Figure 2 is a schematic illustration of a structure portion of the medical device of Figure 1 in accordance with the present invention;

Figure 3 is a schematic illustration of a structural portion of the medical device of Figure 1 where a drug is incorporated therein to be released in accordance with the present invention;

Fig. 4 is a schematic illustration of a structural portion of the medical device of Fig. 1 wherein an additive such as a degradation additive, pH regulating agent, radiopaque agent or the like is incorporated therein to be released in accordance with the present invention;

Fig. 5 is a schematic illustration of a structural portion of the medical device of Fig. 1 wherein an additive such as a degradation additive, pH regulating agent, radiopaque agent or the like, and a drug are incorporated therein to be released. in accordance with the present invention;

Figure 6 is a schematic illustration of a structure portion of the medical device having a mixed structure of a first biodegradable and / or bioabsorbable material and an encapsulated degradation additive, shown as a cross section slice taken from a sphere, in accordance with the present invention;

Figure 7 is a schematic illustration of a structure portion of the medical device of Figure 6 in accordance with the present invention;

Figure 8 is a schematic illustration of a structural portion of the medical device of Figure 6 where a drug is incorporated therein to be released in accordance with the present invention;

Figure 9 is a schematic illustration of a structure portion of the medical device of Figure 6 where a breakdown additive and a drug are encapsulated therein, shown as a cross-sectional slice taken from a sphere, to be released from in accordance with the present invention; and Figure 10 is a graph schematically illustrating the different phases of physical structure degradation as a function of time for biodegradable and / or bioabsorbable medical devices 15 including comparisons of the current mass loss curve associated with known bioabsorbable medical implants. versus the desired mass loss curve for an implantable biodegradable and / or bioabsorbable medical device associated with the present invention.

DESCRIPTION OF THE PREFERRED MODALITIES

The present invention relates to medical devices that are placed or implanted in the body including medical devices that are placed in vessels such as an artery or vein, or ducts or organs such as the heart. Particularly, the present invention is a medical device that is made of either composite structures comprising blodegradable and / or bioabsorbable material including mixtures, coatings or layers of blodegradable and / or bioabsorbable material to achieve a desired mass loss through accelerated degradation after the medical device has achieved its desired functional effect or has reached the end of its functional purpose or useful life.

Furthermore, the present invention is a medical device that is made of either blodegradable and / or bioabsorbable material including mixtures, coatings or layers of blodegradable and / or bioabsorbable material and having encapsulated degradation additives that lead to acceleration of degradation of the structures or components of the medical device to achieve a desired loss of mass through accelerated degradation after the medical device has achieved its desired functional effect or has achieved the end of its functional purpose or useful life. In some embodiments, the medical device in accordance with the present invention includes a therapeutic agent released from a medical device as well as other additives such as radiopaque agents and pH regulating agents.

As used herein, the terms "blodegradable", "blodegradable", "degradable", "degradation," degraded "," bio-wearable "," wearable or wear "are used interchangeably and are defined as the decomposition and susceptibility of a material or component to decompose or break down into products, by-products, components or sub-components over time such as days, weeks, months or years.

As used herein, the terms "bioabsorbable", "absorbable", "reabsorbable" and bioresorbable "are used interchangeably and are defined as the biological elimination of any of the degradation products by metabolism and / or excretion.

As used herein, the terms "degradation additive," selected enzyme, "high pH material," are used interchangeably and are defined as any material, compound agent, or substance that accelerates the degradation of the structure, components, or material of the device. doctor.

As used herein, the terms pH regulating agent, "pH regulating compound," "pH regulating agent," neutralizing agent, neutralizing compound, neutralizing agent, or neutralizing compound are used interchangeably and are defined as any material, compounding agent. or substance that limits or moderates the rate of change of pH of a medical device or the local or close environment of medical devices when exposed to acid or base.

As used herein, the term "biodegradable material," biodegradable polymer ", bioabsorbable material", "bioabsorbable polymer", "blomaterial", "biodegradable and / or bioabsorbable material", or "biodegradable and / or bioabsorbable polymer are used interchangeably and they are defined as any polymer material that is biodegijadable or bioabsorbable in the body.

As used herein, the term mixed, mixed biodegradable material, "mixed biodegradable polymer", "mixed bioabsorbable material", "mixed bioabsorbable polymer," mixed blomaterlal ", biodegradable and / or bioabsorbable mixed material" or biodegradable and / or bioabsorbable polymer Mixed ”are used interchangeably and are defined as two or more polymer materials that are used in combination and are blodegradable or bioabsorbable in the body.

As used herein, the term "agent," therapeutic agent, "" active agent, "" drug, "" active drug, "and" pharmaceutical agent "are used interchangeably herein and define an agent, drug, compound, material composition, or mixture of the same that provides some therapeutic or beneficial effect. These include pesticides, herbicides, germicides, biocides, algicides, rodenticides, fungicides, insecticides, antioxidants, plant growth promoters, plant growth inhibitors, preservatives, anti-preservatives, disinfectants, sterilizing agents, catalysts, chemical reagents, agents fermentation, food, food supplements, nutrients, cosmetics, drugs, vitamins, sexual sterilants, fertility inhibitors, fertility promoters, microorganism attenuators and other agents that benefit the environment of use. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect or effects in animals, including warm-blooded mammals, humans and primates, birds; domestic or farm animals such as cats, dogs, sheep, goats, cattle, horses, and pigs; animals such as mice, rats, and guinea pigs; fish, reptiles; zoo and wild animals; and the like. The active drug that can be supplied includes Inorganic and organic compounds Including without limitation drugs that act on peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synaptic sites, sites of neuroeffective junction, endocrine and hormonal systems, the immune system, the reproductive system, the skeletal system, autacoid systems, the food and excretory systems, the histamine system and the central nervous system. Suitable agents can be selected, for example, from proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, antiparklnson agents, analgesics, anti-pain medications, , local anesthetics, muscle contractors, blood pressure medications and cholesterol lowering agents including statins, ntlmicrobial, antimalarial, hormonal agents including contraceptives, sympathomimetics, polypeptides and proteins capable of inducing physiological effects, diuretics, lipid regulating agents, antiandrogenic, antiparasitic, neoplastic, antineoplastic, hypoglycemic agents, nutritional supplements and supplements, fats, , antienteritis agents, electrolytes and diagnostic agents.

Examples of the therapeutic agents or drugs 99 useful in this invention include prochlorperazine edysylate, ferrous sulfate, aminocaproic acid, mecaxylamine hydrochloride, procainamide hydrochloride, methamphetamine hydrochloride, benzphetamine hydrochloride, isoproteronol hydrochloride , betanecol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, scopolamine bromide, isopropamide iodide, tridihexetil chloride, fenformin hydrochloride, methylphenidate hydrochloride, theophylline choline, cephalexin hydrochloride, diphenidol, meclizine hydrochloride, prochlorperazine maleate, phenoxybenzamide, thiethylperazine maleate, anisindione, diphenanedione, diphenanedin methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, fenaglycodol, allopurinol, aluminoaspirin, methotrexata, acetyl sulfisoxazole, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, dexamethasone and its derivatives such as betamethasone, triamcinolone, methyltestosterone, 17-.beta.-estradiol, ethinyl estradiol, ethynyl estradiol 3-methyl ether, prednisolone, 17-, 20-hydroxyproxy acetate, -nor-progesterone, norgestrel, norethindrone, norethisterone, norethiederone, progesterone, norgesterone, noretinodrel, indomethacin, naproxen, fenoprofen, sulindac, ndoprofen, nitroglycerin, isosorbide dinitrate, propranolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, methyldopa, dihydroxyphenylalanine, theophylline, calcium gluconate, ketoprofen, ibuprofen, atorvastatin, haloperidol, zomepirac, ferrous lactate, vincamine, phenoxybenzamine, diltiazem, milrinone, captropril, mandol, quanbenz, hydrochlorothiazide, ranitidine, flurbiprofen, fenbufen, fluprofen, tolmetin, alclofenac, mefenamic, flufenamic, difuninal, nimodipine, nitrendipine, nisoldipine, nicardipine, felodipine, lidoflazine, tiapamil, galopamil, amlodipine, mioflazin, lisinopril, enalapril, captopril, ramipriplatin minoxidil, chlordiazepoxide, diazepam, amitriptyline, and imipramine. Additional examples are proteins and peptides that include, but are not limited to insulin, colcycin, glucagon, thyroid-stimulating hormone, parathyroid and pituitary hormones, calcitonin, renin, prolactin, corticotrofin, thyrotropic hormone, follicle-stimulating hormone, gonadotropin chorionic, gonadotropin-releasing hormone, bovine somatotropin, porcine somatropin, oxytocin, vasopressin, prolactin, somatostatin, lipresin, pancreozimine, luteinizing hormone, LHRH, interferons, interleukins, growth hormones such as human growth hormone, bovine growth hormone and porcine growth hormone, fertility inhibitors such as prostaglandins, fertility promoters, growth factors and release factor human pancreas hormone.

Furthermore, the drugs or pharmaceutical agents 99 useful for the medical device 50 include: antiproliferativ / antimitotic agents including natural products such as vinca alkaloids (i.e. vinblastine, vincristine, and vinorelbine), paclitaxel, epidipodophyllinins (i.e. etoposide, teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin, doxorubicin) anthracyclines, mitoxantrone, bleomycins, plicamycin (mitramycin) and mitomycin, enzymes (L-asparaginase that systematically metabolizes L-asparagine and kills cells that do not have the ability to synthesize their own asparagine); antiplatelet agents such as G (GP) llblll inhibitors_to and vitronectin receptor antagonists;

antiproliferative / antithymotropic alkylating agents such as nitrogenous mustards (mechlorethamine, cyclophosphamide and melphalan analogs, chlorambucil), ethyleneimines and methylamines (hexamethylmelamine and thiotepa), alkylsulfonates-busulpins, carcinogens (carmustines) DTIC); antiproliferative / antimitotic antimetabolites such as folic acid analogs (methotrexate), pyrimidine analogs (fluorouracil, floxuridine, and cytarabine), purine analogs, and related inhibitors (mercaptopurine, thioguanine, pentostatin, and 2-chlorodeoxyadenosine {cladribine}; coordination complexes of platinum (cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones (i.e. estrogen); anticoagulants (heparin, synthetic heparin salts, and other thrombin inhibitors); fibrinolytic agents (such as tissue plasminogen activator, streptokinase, and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab;

antimigratory; antisecretory (breveldin); anti-inflammatories: such as adrenocortcal spheroids (cortisol, cortisone, fludrocortlsona, prednisone, prednisolone, 6a-metllpredn¡solone, triamclnolone, betamethasone, and dexamethasone), non-steroidal agents (salicylic acid derivatives, that is, aspirin derivatives, ie , that is, acetominophen; Indole-inden-acetic acids (indomethacin, sulindac, and etodalac), heteroarllacetic acids (tolmetin, diclofenac, and ketorolac), arylproplonic acids (ibuprofen and derivatives), anthranilic acids (mefenamic acid and meclophenamic acid), enolic acids ( piroxicam, tenoxicam, phenylbutazone and oxyentatrazone), nabumetone, gold compounds (auranofin, aurotloglucose, gold-sodium thiomalate), immunosuppressants: (cyclosporine, tacrolimus (FK-506), sirolimus analogs (rapamicline), azathioprine, mycophenolate mofetil); Angiogenic agents: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet derived growth factor (PDGF), erythropoietin; angglotensin receptor blocker; nitric oxide donors; antisense oligonucleotides and combinations thereof; cell cycle inhibitors; mTOR inhibitors, growth factor signal transduction kinase inhibitors, chemical compound, biological molecule, nucleic acids such as DNA and RNA, amino acids, peptides, proteins, or combinations thereof.

It is understood that the use of the term "agent", "therapeutic agent", "active agent", "drug", "active drug" and "pharmaceutical agent includes all derivatives, analogs and salts thereof and in no way excludes the use of two or more of those agents, therapeutic agents, active agents, drugs, active drugs or pharmaceutical agents.

The present invention, as best illustrated in Figures 1-9, is a medical device 50 such as a medical implant constructed of blodegradable and / or bloabsorbable polymers that are either natural or synthetic. In general, synthetic polymers offer greater advantages than natural materials in that they can be adjusted to give a wider range of properties and more predictable batch-to-batch uniformity than materials from natural sources. Synthetic polymers also represent a more reliable source of starting materials, one free from immunogenicity concerns.

The general criteria for selecting a polymer to be used as a blomaterlal (a blodegradable and / or bioabsorbable material) is to match the mechanical properties and degradation time with the needs of the application. The Ideal polymer for a particular application is configured in such a way that: (I) has mechanical properties that match the application, remaining strong enough until the surrounding tissue has healed, (¡I) does not Induce an inflammatory or toxic response, (ili) is metabolized in the body after fulfilling its purpose, without leave traces, (v) is easily processable in the final product form, (v) demonstrates acceptable shelf life, and (vi) is easily sterilized.

Factors that affect the mechanical performance of biodegradable polymers are those that are well known to the polymer scientist, and include monomer selection, initiator selection, processing conditions, and the presence of additives. These factors influence the hydrophilic character of the polymer, crystallinity, glass melting and transition temperatures, molecular weight, molecular weight distribution, extreme groups, sequence distribution (random versus block), and presence of residual monomer or additives.

In addition, the polymer scientist working with biodegradable materials must evaluate each of these variables for their effect on biodegradation. Biodebradaclón has been achieved by synthesizing polymers that have hydrolytically unstable bonds in the base structure. The most common chemical functional groups with this characteristic are esters, anhydrides, orthoesters and amides.

Preferably, medical device 50 has a structure, components, or characteristics, at least one blodegradable and / or bioabsorbable polymer that have crystalline, semi-crystalline, and amorphous characteristics. The degradation mechanism of semi-crystalline bioabsorbable polymers is primarily by hydrolysis of ester bonds or other labile bonds or hydrolytically unstable base structure. This is the most prevalent mechanism for polymer degradation. In general, degradation occurs in two phases. In the first phase, hydrolysis of an amorphous phase occurs and forms low molecular weight water soluble fragments, eg, lactic acid. This reduction in molecular weight in the amorphous phase does not result in reduction in mechanical properties since the crystalline regions provide the required strength to the structure. Then, crystalline phase hydrolysis occurs which results in loss in molecular weight and mechanical properties. This is followed by enzymatic attack that leads to fragment metabolisms and results in accelerated polymer mass loss. These fragments then enter the Kreb cycle and are excreted as carbon dioxide and water. This degradation process can vary from days to months to years and depends on the type of polymer. Factors that accelerate polymer degradation include hydrophilic base structure and end groups, less crystallinity, more porosity, and higher surface area, no orientation, no physical aging, low density, presence of additives such as plasticizers, and water soluble materials or leaching.

Furthermore, it is well established that the degradation of polymers such as polylactic acid (PLA) and polyglycolic acid (PGA) are catalyzed by carboxylic end groups formed by chain digestion and the amorphous regions are preferably degraded. See Suming Li, Hydrolitic Degradation Charcteristics of Aliphatic Polyesters Derived from Lactic and Glycolic Acids, J Biomed Mater Res (Appl Biomattter) 48: 342-353 (1999). In general, digestion of an ester bond produces a carboxyl end group and a hydroxyl end group where the carboxyl end groups formed are capable of catalyzing the hydrolysis of other ester bonds. This process is commonly known as autocatalysis.

An example of rapid degradation of PLA polymers is degradation of PLA in a phosphate pH regulator where in approximately a 5 week degradation period, the PLA material becomes heterogeneous with the interior of the material being composed of various oligomers slimy. The degradation process is known as heterogeneous degradation "or faster Internal degradation".

Therefore, in an aqueous medium, water penetrates into the polymer material resulting in hydrolytic digestion at the ester linkages where digestion of the ester linkages forms a new carboxyl end group thereby accelerating the reaction of the other ester bonds through autocatalysis. As part of this process, initially, degradation occurs in volume and is macroscopically homogeneous. However, when soluble oligomers are generated, those oligomers near the surface of the matrix escape from the matrix before being completely degraded while those oligomers trapped within the matrix result in the higher acidity within the polymer matrix than on the surface of the matrix. Therefore, autocatalysis is greater in volume (within the matrix) than at the matrix surface, and as polymer degradation continues more carboxyl end groups form within the matrix leading to accelerated internal degradation. Finally, hollow structures are formed in the material by this degradation phenomenon.

The degradation process outlined above has been identified for those polymers containing PLA and PGA, for example, PLA75GA25; PLA85GA15; PLA₈7.5 PLA96; and PLA100 ·

Biodegradable and / or bioabsorbable polymers consist of volume and surface wear materials. Surface erosion polymers are typically hydrophobic with water labile bonds. Hydrolysis tends to occur rapidly on the surface of such surface erosion polymers without penetration of water into the volume. The initial strength of such surface erosion polymers tends to be low however, and often such surface erosion polymers are not readily available commercially. However, examples of surface erosion polymers include polyanhydrides such as poly (carboxyphenoxy hexane-sebacic acid), poly (fumaric acid-sebacic acid), poly (carboxyphenoxy hexane-sebacic acid), poly (imide-sebacic acid) (50 -50), poly (imide-carboxyphenoxy hexane (33-67) and polyorthoesters (dikethenacetal based polymers).

Bulk erosion polymers, on the other hand, are typically hydrophilic with water labile bonds. Hydrolysis of bulk erosion polymers tend to occur at more uniform rates through the polymer matrix of the device. Bulk erosion polymers exhibit superior initial strength and are readily available commercially.

Examples of volume erosion polymers include poly (ahydroxy esters) such as poly (lactic acid), poll (glycolic acid), poly (caprolactone), poly (p-dioxanone), poly (trimethylene carbonate), poly (oxaesters) , poly (oxaamides), and their copolymers and mixtures. Some readily available commercially available volume erosion polymers and their commonly associated medical applications include poly (dioxanone) [PDS® suture available from Ethicon, Inc., Somerville, NJ], poly (glycolide) [Dexon® sutures available from United States Surgical Corporation, North Haven,

CT], poly (lactide) -PLLA [bone repair], poly (lactide / glycolide) [saturated with Vicryl® (10/90) and Panacryl® (95/5) available from Ethicon, Inc.,

Somerville, NJ], poly (glycolide / caprolactone (75/25) [Monocryl® 10 sutures available from Ethicon, Inc., Somerville, NJ] and poly (glycolide / trimethylene carbonate) [Maxon® sutures available from United States Surgical

Corporation, North Haven, CT]

Other bulk erosion polymers are tyrosine-derived polyamino acid [examples: poly (DTH carbonates), poly (arylates), and poly (iminocarbonates)], phosphorous-containing polymers [examples: poly (phosphoesters) and poly (phosphazenes )], block copolymers based on poly (ethylene glycol) [PEG]; [PEG-PLA, PEG-poly (propylene glycol), PEGpoli (butylene terephthalate)], poly (a-methyl acid), poly (ester amide), and polyalkanoates] examples: copolymers of poly (hydroxybutyrate (HB) and poly ( hydroxyvalerate) (HV)].

Of course, the devices can be made from combinations of surface and volume erosion polymers in order to achieve desired physical properties and control the degradation mechanism. For example, two or more polymers can be mixed to achieve the desired physical properties and degradation rate of the device. Alternatively, the device can be made from a volume erosion polymer that is coated with a surface erosion polymer. The drug delivery device can be made from a volume erosion polymer that is coated with a drug that contains a surface erosion polymer. For example, the drug coating can be thick enough such that high drug loads can be achieved, and the volume erosion polymer can be made thick enough such that the mechanical properties of the device are maintained even after all the drug has been dispensed and the surface worn. Alternatively, the device can also be formed from layers of different polymer and drug combinations to provide programmable drug release during polymer absorption. Accordingly, in these embodiments in accordance with the present invention, drug 99 (which may include only one or combinations of different drugs, i.e. more than one type of drug 99) is programmatically released from one or both of the first blodegradable material and / or bioabsorbable 75 and the second blodegradable and / or bioabsorbable material 80 as different polymer layers.

Referring now to Figure 1, the present invention is a blodegradable and / or bioabsorbable medical device, generally designated 50, for placement or implantation in the body of a patient. Medical device 50 is any type of medical device, such as a medical implant, and in this example, medical device 50 is a stent for deployment within a vessel. Medical device 50 has a mixed structure of a first blodegradable and / or bioabsorbable material 75 that degrades at a first rate of degradation and a second blodegradable and / or bioabsorbable material 80 laminated or coated on or combined with the first blodegradable and / or or bioabsorbable 75, wherein the first degradation rate of the first biodegradable and / or bioabsorbable material 75 is faster than the second degradation rate of the second biodegradable and / or bioabsorbable material 80 in accordance with the present invention.

Particularly, the medical device 50 is made of mixed structures comprising different biodegradable and / or bioabsorbable materials 75 and 80 respectively including coatings or layers or mixtures of different biodegradable and / or bioabsorbable 75 and 80 respectively. Each of the biodegradable and / or bioabsorbable materials 75 and 80 respectively has a different degradation rate. And, medical device 50 is designed such that second blodegradable and / or bioabsorbable material 80 has a degradation rate that is slower than the degradation rate of first blodegradable and / or bioabsorbable material 75. And as described in more detail later in this description, the second blodegradable and / or bioabsorbable material 80 is coated or laminated on the first biodegradable and / or bioabsorbable material 75 and both the first biodegradable and / or bioabsorbable material 75 and the second biodegradable and / or bioabsorbable material 80 are selected and configured or arranged in such a way that a desired loss of mass is achieved to include accelerated degradation after the medical device has achieved its desired functional effect or has achieved the end of its functional purpose or useful life. This accelerated degradation period occurs after the coating or layer (s) of the second biodegradable and / or bioabsorbable material has degraded by exposing portions of the first biodegradable and / or bioabsorbable material 75. Therefore, the period of accelerated degradation occurs in time point after medical device 50 has achieved its functional purpose or useful life.

In an embodiment in accordance with the present invention, medical device 50 (Figures 1-5) is made of mixed structures where the first structure (first biodegradable and / or bioabsorbable material 75) follows as a polymer core or base structure polymer and has physical properties and characteristics that allow rapid degradation through hydrolysis on exposure. The coating or layer (s) of the second biodegradable and / or bioabsorbable material 80 on the first structure 75 has physical properties and characteristics that result from the degradation rate slower than the degradation rate of the first structure 75. An example is using poly-L- (lactic acid) (PLLA) on the surface (e.g., as a thick layer or coating) to serve as the second biodegradable and / or bioabsorbable material 80 of device 50 and poly (acid glycolic) (PGA) as the first biodegradable and / or bioabsorbable material 75 to serve as the core or base structure of device 50. These two materials 75 and 80 provide rigidity to device 50 (in this example, thus allowing stent 50 to keep a vessel properly open) until the functional effect of device 50 is achieved or device 50 has reached the end of its functional purpose. or shelf life. Accordingly, device 50 is degraded in such a way that the functional end of device 50 is being achieved as the PLLA 80 material degrades and exposes the core of the PGA 75 material which, in turn, degrades very rapidly, at a much higher degradation rate than the PLLA 80 material coating. PGA absorption will make the device porous and increase the surface area and accelerate the adsorption rate of any remaining PLLA. This allows the entire device 50 to be completely removed from the patient's system after the device 50 has completed its functional purpose or shelf life. Other derivatives of PLLA and PGA can be used in addition to other polymers to achieve the desired absorption profile. Examples of other materials for 80 include DLPLA; PLA / PGA copolymers (95/5;

85/15); PLA-PCL copolymers that have a lower absorption time than PLLA. Accordingly, suitable examples for the second biodegradable and / or bioabsorbable material 80 include polylactide based polymers, polyglycolide based polymers, poll (a-hydroxy esters) such as poly (lactic acid), poly (glycolic acid), poly (caprolactone ), poly (p-dioxanone), poll (trimethylene carbonate), poly (oxaesters), poll (oxaamides), poly (lactide) PLLA, poly (lactide / glycolide), poly (glycolide / caprolactone) (75/25) , poly (glycolide / trimethylene carbonate), Tyrosine-derived polyaminoacid, poly (DTH carbonates), poly (arylates), poly (iminocarbonates), phosphorous-containing polymers, poly (phosphoesters) and poly (phosphazenes), block copolymers based on poly (etllengylcol), PEG- PLA, PEG-poly (propylene glycol), PEGpoly (butylene terephthalate), poly (a-malic acid), poly (ester amide), pollalcanoates, poly (hydroxybutyrate (HB), poly (hydroxyvalerate) (HV) copolymers, DLPLA PLA / PGA copolymers (95/5; 85/15); PLAPCL copolymers that have a lower absorption time than PLLA and its copolymers and blends.

Examples of other materials for 75 include PGA / PLA (90/10); PGA / PCL (75/25; 50/50; 65/35; poly (p-dioxanone) and its derivatives that have a longer absorption time than PGA. Other examples for 75 include poly (ethylene glycol); citrate esters and Other water soluble materials that will dissolve and create a higher surface area for faster absorption than 80. Accordingly, suitable examples for the first biodegradable and / or bioabsorbable material 75 Include poly (glycolic acid) (PGA), poly (<x20 hydroxy esters), polyanhydrides such as poly (carboxyphenoxy hexane-sebacic acid) poly (fumaric acid-sebacic acid ), poly (carboxyphenoxy hexane-sebacic acid), poly (imide-sebacic acid (50/50), poly (imide-carboxyphenoxy hexane) (33-67), polyamino acid derived from tyrosine, polyorthoesters (dikethenacetal based polymers), phosphorous-containing polymers, poly (ethylene glycol); Citrate esters and other soluble materials that will dissolve and create a larger surface area for faster absorption and their copolymers and blends.

Although medical device 50 is not limited to any particular configuration, in certain embodiments in accordance with the present invention, medical device 50 has a substantially cylindrical configuration and is substantially hollow along its longitudinal axis and terminates at an open end in each end of its cylindrical configuration. Accordingly, the configuration of medical device 50 in accordance with the present invention and as described above is best suited as a stent for placement within a vessel for treatment of cardiovascular disease such as stenosis, atherosclerosis, vulnerable plaque, or Ischemic heart disease or like a valve such as a heart valve to regulate blood flow.

Medical device 50 has structure, features, and components 70 that optionally include hoops, loops, flexible links, or bridges or extensions (not shown) that are made of either a first blodegradable and / or bloabsorblble material 75 that may be in the form of or more layers or coatings or blends. Furthermore, the blodegradable and / or bloabsorbable material 75 is the core that is coated with a second blodegradable and / or bloabsorbable material 80, i.e., second material 80 serves as an initial protective coating for the first blodegradable and / or bioabsorbable material 80 ( based on gastric differences in degradation rates of materials 75 and 80 respectively).

The first blodegradable and / or bioabsorbable material 75 is used as the base material for structural aspects 70 of the device 50 such as rings, loops, flexible links or bridges or extensions of the stent 50 or the housing, flaps or other components 70 of the medical device desired 50. When applied as a liner 80, the second blodegradable and / or bioabsorbable material 80 is used as the liner material 80 to be applied as a liner and essentially protects the structural aspects 75 of the device or stent 50 such as rings, loops, flexible links or bridges or extensions of the stent 50 or the other components of the desired medical device 50.

By way of example, the first blodegradable and / or bioabsorbable material 75 is a volume-depletable polymer (either a homopolymer, copolymer, or polymer blend) such as any of the polyesters belonging to the group poll (alpha-hydroxy acids) . This includes allphatic polyesters such as poly (lactic acid); poly (gallic acid); poll (caprolactone); poly (p-dloxanone) and poll (trmethyl carbonate); and its copolymers and blends. Other polymers useful as the first bioabsorbable material 75 include polymers derived from amino acids [eg, pli (iminocarbonates)]; phosphorous-containing polymers [eg, poll (phosphazenes); poll (phosphoesters)] and poll (amide ester).

The rate of hydrolysis of the first blodegradable and / or bioabsorbable material 75 depends on the type of monomer used to prepare the volume depletable polymer. For example, absorption times (time to complete degradation or fully degrade) are estimated as follows: poll (caprolactone), pol (trimethylene carbonate), and poly (1-lactic acid) require approximately 2-4 years; poly (dioxanone) requires approximately 7 months; and poly (glycolic acid) requires approximately 3-6 months. Preferably, the degradation rate for the first biodegradable and / or bioabsorbable material 75 is between 1 day and 3 months.

Absorption rates for copolymers prepared from monomers such as poly (lactic acid-co-glycolic acid); poly (glycolic acid-co-caprolactone); and poly (glycolic acid-trimethylene co-carbonate) depend on the molar amounts of the monomers. The degradation of the polymers is by hydrolysis and the by-products are typically water soluble fragments such as monomers that are used to prepare the polymers [eg, lactic acid from poly (lactic acid); glycolic acid from poly (glycolic acid)] that are metabolized by enzymatic attack that enters the Krebs cycle and is excreted as carbon dioxide and water.

In accordance with the present invention, the second biodegradable and / or bioabsorbable material 80 has a much slower rate of hydrolysis (degradation rate) than biodegradable and / or bioabsorbable material 75. For example, based on the outlined hydrolysis rates above, PLLA is a suitable material for liner 80 and PGA as a suitable material for core 75 of device 50. For example, preferably, the degradation rate for the second biodegradable and / or bioabsorbable material 80 is between 3 months and 48 months.

FIG. 3 illustrates a further embodiment of the medical device illustrated in FIG. 1 wherein device 50 further includes a drug 99 that is incorporated into one or more portions of the device, for example, drug 99 incorporated into the layer (s) of outer coating of the second biodegradable and / or bioabsorbable material 80 or within the polymer core or base structure material 75 (first biodegradable and / or bioabsorbable material 75 which is the base of the structure, components or characteristics of the medical device 50) or drug 99 incorporated in materials 75 and 80 respectively.

Therefore, in this example where the medical device 50 is a stent, the device 50 illustrated in FIG. 3 is a drug eluting stent where the drug 99 is released from the stent 50 in accordance with a release profile default drug. Furthermore, the rate of degradation or hydrolysis of outer material 80 and inner core 75 are time-regulated to coincide with the desired drug release profile. Details of an illustrative drug 99 is used with stent 50 as a drug delivery system based on degradation parameters in accordance with a predetermined or desired mass loss curve for stent 50 itself that includes an accelerated degradation phase after achieve the desired drug release profile, i.e. After the stent 50 has achieved its functional purpose of delivering its drug 99 into the vessel wall into which it is deployed it will be described in greater detail in this disclosure. Furthermore, one or more drugs 99 can be used in medical device 50 in accordance with the present invention.

Fig. 4 is a further embodiment of medical device 50 of Fig. 1 wherein device 50 includes an additive 95 such as a degradation additive, pH regulating agent, radiopaque agent or the like to be released with degradation of material 80 and / or material 75 in accordance with the present invention. Furthermore, one or more additives 95 can be used in medical device 50 in accordance with the present invention. Highly reactive enzymes, for example such as proteinase K, are particularly useful as degradation additives 95 for use with medical device 50 in accordance with the present invention.

FIG. 5 is a further embodiment of medical device 50 of FIG. 1 wherein medical device 50 includes both drug 99 and additive 95 such as a degradation additive, pH regulating agent, radiopaque agent or the like to be released with degradation of material 80 and / or material 75 in accordance with the present invention.

Furthermore, one or more drugs 99 can be used in combination with one or more additives 95 in medical device 50 in accordance with the present invention.

Furthermore, as best illustrated in FIG. 6 and FIG. 7, the present invention is also directed to a new and useful medical device 50 that is made of biodegradable and / or bioabsorbable material 80 which may be either the main structure 70 of the device 50 and may also be in the form of one or more coatings or mixtures or layers of the biodegradable and / or bioabsorbable material 80. PLLA is an example polymer that has been identified to be particularly useful as the biodegradable and / or bioabsorbable material 80 for the main structure 70. In addition, the device 50 includes encapsulated degradation additives 95 that are encapsulated in biodegradable and / or bioabsorbable material. 75 which upon release (upon hydrolysis of the encapsulating material 75) will preferably digest the polymeric framework material 80. PGA is an exemplary polymer that has been identified as being particularly useful as the biodegradable and / or bioabsorbable material 75 for backbone 70. Examples of degradation additives 95 are selected enzymes, high pH materials, etc. An enzyme useful as a degradation additive 95 is proteinase K encapsulated in

PGA.

There are several enzymes that can be used for the degradation of bioabsorbable materials. The enzymatic degradation of polymers depends on the specificity of the enzymes. In vitro degradation studies using enzymes are generally conducted at 37 ° C at a pH of about 6 to 8.6 in pH regulator (phosphate or Tris / HCI) in the presence of sodium azide. Proteinase-K, Bromelain and Pronase are among the first enzymes to be used to demonstrate enzymatic degradation of PLLA. The enzyme hydrolyzes amide and ester linkages. Proteinase-K is very effective and has been used to study the degradation of PLLA and copolymers. It is a serine protease produced by Tritirachium album, a fungus that grows on native keratin with its only source of carbohydrate and nitrogen. It has been observed that this enzyme preferably degrades L-lactyl units as opposed to D-lactyl units, and poly (D-lactide) is not degrading. The enzyme breaks down LL, LD and DL bonds as opposed to DD bond. Degradation preferably occurs in the amorphous regions of semicrystalline PLLA. It cannot degrade PLLA and PCL crystal domains. This is due to the fact that the proteinase-K active site preferably hydrolyzes in the disordered chain packing regions of crystal edges rather than the individual crystal chain fold surfaces. The absorption of water will lead to swelling of the polymer and will facilitate the enzymatic attack.

The enzymatic degradation of PCL has been investigated in the presence of lipase-like enzymes. These enzymes are capable of digesting ester linkages on the hydrophobic surface. Three types of lipase significantly accelerate the degradation of PCL namely lipase from R.

delemer, Rhizopus arrhizus lipase and Pseudomonase lipase. Highly crystalline PCL is fully degraded in 4 days, therefore these enzymes can degrade amorphous and crystalline phases of the polymer. These enzymes cannot degrade PLLA.

An HT-32 strain of Amycolatopsis sp. it has been successfully isolated and used to demonstrate degradation of PLLA. The further isolation of PLLA-degrading microorganisms has led to the isolation of four actlnomycetes and four bacteria. An actinomycete has been identified as Amycolatopsis sp. (strain 41) based on morphological observations and analysis of 16s RNA. The isolation of PLLA-degrading actinomycete is taxonomically similar to the Amycolatopsis strain. The Amycolatopsis strain can degrade PLLA. 25 reference strains belonging to the genus Amycolatopsis, 15 are capable of forming light areas on a PLLA-emulsified agar plate. Therefore, Amycolatopsis plays an important role in the biodegradation of PLLA. Enzymes can be produced from Amycolatopsis sp (strain 41) with an estimated molecular weight of approximately 40 to 42 KDa with an optimal pH and temperature of 6.0 and 37-45 ° C, respectively, for higher activity. This enzyme will preferably degrade PLLA but not ροϋ (εcaprolactone) and poly (p-hydrobutlrate).

Poly (hydroxybutyrate) [PHB] and its copolymers can be enzymatically degraded by extracellular PHB depolymerases isolated from various environments of Pseudomonas lemoignei, Alcaligenes faecalis,

Comamonas testosterone, Pseudomonas stutzeri, Pseudomonas pickettii and Comamonas acidovorans. These enzymes preferably attack the disorganized chain packaging regions of the crystal edge rather than the chain fold surfaces of the crystal structure.

Therefore, the selection of the degradation enzyme or additive is based on the type of material that needs to be degraded in a short time.

Since the degradation rate of polymer material 75 is greater than the degradation rate of polymer core material 80, as soon as encapsulation material 75 is sufficiently degraded, degradation additive 95 is released and acts on the material of polymer core 80 thereby increasing the degradation rate of polymer core material 80 to achieve a desired mass loss for device 50.

Again, for this embodiment as well, an additive 95 can be either a degradation additive, pH regulating agent, radiopaque agent or the like to release under degradation the encapsulating material 75 in accordance with the present invention. Furthermore, one or more additives 95 can be used in medical device 50 in accordance with the present invention. Highly reactive enzymes, for example such as protein k, are particularly useful as degradation additives 95 for use with medical device 50 in accordance with the present invention.

Furthermore, as shown in Figures 8 and 9 respectively, drug 99 is incorporated into one or more portions of device 50, for example, drug 99 Directly incorporated into biodegradable and / or bioabsorbable material 80 (which is the basis of the structure, components or characteristics of the medical device 50 as shown in figure 8) or encapsulated together with the degradation additive 95 within the biodegradable and / or bioabsorbable material 75 as shown in figure 9. Furthermore, drug 99 can be incorporated into both materials 75 and 80 respectively.

Therefore, in the example where medical device 50 is a stent, device 50 illustrated in FIG. 8 and FIG. 9 is an eluting drug stent where drug 99 is released from stent 50 in accordance with a profile predetermined drug release. Furthermore, the rates of degradation or hydrolysis of the encapsulating polymer material 75 and finally the polymer material of the main structure 80 are time regulated to coincide with the desired drug release profile. Details of an illustrative drug 99 used with stent 50 as a drug delivery system based on degradation parameters in accordance with a predetermined or desired mass loss curve for stent 50 itself including an accelerated degradation phase after achieving the desired drug release profile, i.e. after the stent 50 has achieved its functional purpose of delivering its drug 99 into the vessel wall into which it is implanted it will be described in more detail later in this description.

Furthermore, one or more drugs 99 can be used in medical device 50 in accordance with the present invention.

Accordingly, for the medical device modalities of Figures 6-9, the biodegradable and / or bioabsorbable material 80 for the π

Stent structure has a much slower hydrolysis rate (degradation rate) than the biodegradable and / or bioabsorbable material 75 used in the encapsulating material. For example, based on the hydrolysis rates outlined above, PLLA is an appropriate material for main structure 80 of device 50 and PGA is an appropriate material for encapsulating material 75. Therefore, the

PGA of encapsulating material 75 will degrade at a much faster rate thereby releasing degradation additive 95, for example proteinase K, (as well as one or more drugs 99 and other desired additives 95, such as pH regulating agents or radiopaque agents , encapsulated therein) that will react enzymatically with the framework material of

PLLA 80 in order to accelerate the hydrolysis of device 50.

The encapsulation of the degradation additive 95 or other additives (such as pH regulating agent or radiopaque agent) can be in the form of microparticles or nanoparticles that do not adversely affect the physical properties of the device 50.

Different types of pH 95 regulating agents, such as inorganic basic fillers, can be used with all modalities of device 50 in accordance with the present invention. Some examples of these basic compounds for use as pH regulating agents include calcium hydroxyapatite; carbonated apatite; tricalcium phosphate;

calcium carbonate; sodium bicarbonate; calcium phosphates; carbonated calcium phosphates; and magnesium hydroxide. Also acid / base titration compounds (amine monomers); and lactate dehydrogenase (will convert lactate to pyruvate which is the end product of glycolysis and starting component of the citric acid cycle) can also be used as the pH 95 regulating agent.

The inorganic fillers 95 will react with the acid and neutralize the acid that is formed during the absorption of the polymers 75 and

80. In this way, they behave as pH regulating agents and prevent acid in the immediate environment from being maintained at a pH ranging from about 5 to about 7 and most preferably at a pH ranging from about 6 to about 7.4. The total amount of inorganic filler or pH 95 regulating agent will be enough to neutralize the total amount of acid that is generated during the absorption process. For example, 1 mole of calcium carbonate needs to be reacted with 2 moles of lactic acid (see the following):

Thief₃ (solid) + 2CH₃CH (OH) - COOH (aqueous) =>

AC²⁺ (ac.) + H₂O + CO₂ (ac.) + 2 CH₃CH (OH) - (ac.)

A method of forming the blomaterlal structure, materials or coatings or mixtures 75 and 80 of medical device 50 is described in greater detail below. This method is also applicable to be combined with degradation additives 95 (or other additives such as pH regulating agents or radiopaque agents), and therapeutic agent or drug 99 that can be mixed together with the polymer material of device 50 in some modalities or mixed with the biodegradable and / or bioabsorbable material 75 to encapsulate the degradation additive 95, and optionally together with the drug 99.

Appropriate types of degradation additives 95 include pH regulators such as bioactive glass, ceramics, and calcium phosphates that are used to stabilize the pH of the environment surrounding device 50 in order to control degradation of the biomaterial structure, materials, or coatings or mixtures 75 and 80 of the medical device 50. See, K. Rezwan et al. "Biodegradable and Bioactive Porous Polymer / lnorganic Composite Scaffolds for Bone Tissue Engineering", Biomaterials 27 (2006)

3413-3431. In general, the basic components of bioactive glasses useful for the medical device 50 according to the present invention are S¡C> 2, NA2O, CaO and P2O5. A particular type of bioactive glass useful as the 95 breakdown additive is 45S5 BIOGLASS® ((University of Florida) which is a bioactive glass containing 45% S1O2, 24.5% NA₂O, 24.4% CaO and 6% P₂OR₅ in percent by weight.

The use of bioactive glass as part of the scaffolding material of the medical device 50 in accordance with degradation of the device control 50 is to control a range of chemical properties as well as the rate of bio-absorption under degradation of the device 50. Therefore, the structure and chemistry of the bioactive glasses used in the present invention, such as glasses derived from sol and a gel, can be customized at the molecular level through the variation of compounds such as composition, thermal properties or history. of environmental processing.

Furthermore, degradation of the medical device 50 in accordance with the present invention is also accomplished through the addition of active bases to the biodegradable and / or bioabsorbable material 75 and 80. The addition of bioactive phases to polymers used in the material 75 and 80 alters the degradation behavior of the polymer, by allowing the rapid exchange of protons in water for alkali in glass or ceramics. It is suggested that this mechanism provides a pH regulating effect on the polymer surface, thus modifying the degradation of acidic polymer. The inclusion of bioactive glass in medical device 50 can modify the surface and volume properties of device 50 itself, including any mixed scaffolding, by increasing the hydrophilicity and water absorption of the hydrophobic polymer matrix, thereby altering the degradation kinetics of device 50. In particular, the inclusion of particles of

45S5 BIOGLASS® can increase water absorption compared to pure polymer foams such as PDLLA and PLGA. Polymer mixed materials filled with hyaluronic acid (HA) particles are also known to hydrolyze homogeneously due to water penetrating the interfacial regions of the scaffold.

As described in Rezwan et al., In vitro studies in pH-regulated saline with phosphate at 37 ° C that the addition of bioactive glass, such as BIOGLASS®, increased water absorption and weight loss compared to foams from pure polymer.

Other types of degradation additives 95 are also important to the medical device 50 in accordance with the present invention. For example, either acidic compounds or basic compounds can be incorporated into the polymer matrix of device 50. Incorporation of acidic compounds can accelerate the degradation of the polymers used in device 50. Meanwhile, the incorporation of basic compounds can achieve two effects simultaneously, that is, base catalysis and neutralization of carboxyl end groups. Whether the degradation of device 50 is accelerated or slower depends on the relative importance of these effects.

For example, a pH 95 regulator such as inorganic coral compound (containing calcium carbonate granules) was first used in medical implants made of PLA and coral mix matrix to slow down the regulation of the polymer implant. to facilitate the regeneration of bone tissue. And it has been proven that large amounts of coral granule create interfaces that facilitate bionic exchanges between the external environment and the interior of the polymer mixture where the carboxyl end groups were neutralized and the autocatalytic effect eliminated, resulting in a mixture that was homogeneously degraded.

Another compound known to slow polymer degradation, which is useful as a pH 95 regulator for the medical device 50 of the present invention, is caffeine. Highly caffeine-loaded polymer devices reduce degradation due to neutralization of carboxy-end groups while caffeine-free polymer implants exhibit accelerated degradation due to autocatalysis.

The degradation of polymers, such as PLA and PGA polymers, 5 in the presence of basic compounds such as those mentioned above depends on parameters such as base catalysis, neutralization of carboxyl end groups, porosity, device dimensions, charge and morphology of incorporated compounds .

Other influences on the degradation of Polymer Implant 10 include molecular weight (MW). Therefore, the higher the MW of a polymer, the lower the carboxyl end group concentration will be and therefore the slower the degradation (in the early stages). However, the presence of cyclic or acyclic monomers and oligomers in a polymer matrix can result in rapid degradation of the polymer implant.

Furthermore, the size and shape of the polymer implant 50 is also important. For example, small polymer devices consisting of microparticles, thin fibers, or thin films degrade more slowly than larger polymer implants because autocatalytic degradation is reduced due to easier diffusion of oligomers and neutralization of extreme groups. carboxyl.

Gamma-ray irradiation, such as through sterilization of medical devices, also has an effect on the degradation of a polymer medical device implant. For example, gamma-ray irradiation of Dexon® fibers, (Davls & Geck) and Vlcryl® (Ethlcon, Inc.) results in the early pH drop of the degradation medium and faster loss of tensile strength .

Those of skill in the art will appreciate that the relative amounts of the blodegradable and / or bioabsorbable material 75 to the blodegradable and / or bioabsorbable material 80 and relative amounts of the degradation additive 95 and / or drug 99 in the mixed materials of the present invention will depend on various parameters including but not limited to strength, stiffness and other physical and thermal properties, absorption and resorption rates, setting and hardening rates, supply capacity, etc., that will be required. The desired properties of the mixed materials of the embodiments of the present invention and their level of requirement will depend on the area or anatomies of the body structure where the medical device 50 and / or degradation additive 95 (and / or pH regulating agent and / or radlopaque agent and / or drug 99) is necessary.

Figure 10 is a graph schematically illustrating the different phases of physical structure degradation as a function of time for blodegradable and / or bioabsorbable medical devices Including comparisons of the current mass loss curve associated with known bioabsorbable medical implants versus the Desired mass loss curve for an implantable blodegradable and / or bioabsorbable medical device 50 associated with the present invention.

As shown in Figure 10, the different phases of a biodegradable and / or bioabsorbable device implanted during polymer degradation are physical states in which the polymer device has different properties and / or characteristics. Furthermore, the functional aspects for a given implantable bioabsorbable device (e.g., Stent as for example for figure 10) is limited to the transition of a device from being rigid ”or in a rigid state 100 (phase I) to being“ flexible ”or in a flexible state 200 (phase II) to transition to a form of "sponge" or a sponge state or a highly absorbent state 300 (phase III) where the device loses the retention of physical properties to include the transition to a fragmentation state 400 (phase IV) whereby the device hydrolyzes in fragments that are absorbed by the body. This process for known polymer medical device implants is schematically represented in the "current mass loss curve" designated by the letter A. Under these circumstances, prior art polymer devices remain in place in the body until complete absorption even when it is not required or desired in the body. This will avoid on-site pre-intervention, if necessary, and limit treatment options available to patients. This can also have an additional inflammatory effect on the tissues associated with the implant, something that is avoided with the accelerated degradation process or accelerated mass curve (identified as letter B) of the present invention (medical device 50).

Therefore, the degradation profile of medical device 50 in accordance with the present invention allows curve B for the desired mass loss curve. In this way, medical device 50 is excreted from the body earlier (in less time) than prior art polymer devices (as shown in curve B).

An example of the medical device 50 in use is for those modalities whereby the device 50 is a stent that uses a drug 99 for elusion from polymer material of the stent (Figures 3, 5, 8 and 9) in accordance with Desired mass loss curve B illustrated in Figure 10. In this example (for all modalities using a 99 drug), the 99 drug is rapamlcin. Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus, as described in US Patent No. 3,929,992. Rapamycin, among other things, has been found to inhibit the proliferation of vascular smooth muscle cells in vivo. Accordingly, rapamycin can be used in the treatment of intimal smooth muscle cell hyperplasia, restenosis, and vascular occlusion in a mammal, particularly after either biologically or mechanically mediated vascular injury, or under conditions that would predispose a mammal. to suffer said vascular injury. Rapamlcin works to inhibit the proliferation of smooth muscle cells and does not interfere with endothelialization of the vessel walls.

Rapamycin reduces vascular hyperplasia by antagonizing smooth muscle proliferation in response to mitogenic signals that are released during an angioplasty-induced injury. Inhibition of growth factor and cytosine-mediated smooth muscle proliferation in the late G1 phase of the cell cycle is believed to be the dominant mechanism of action of rapamycin. However, rapamycin is also known to prevent T cell proliferation and differentiation when administered systemically. This is the basis for its immunosuppressive activity and its ability to prevent graft rejection.

As described here, rapamycin includes rapamycin and all analogs, derivatives and conjugates that bind to FKBP12, and other immunophilins that possess the same pharmacological properties including inhibition of TOR.

Although the antiprollferative effects of rapamycin can be achieved through systemic use, superior results can be achieved through local delivery of the compound. Essentially, rapamycin works in the tissues, which are in close proximity to the compound, and has a decreased effect as the distance from the delivery device increases. To take advantage of this effect, it is desired that rapamycin be in direct contact with the walls of the lumen. Accordingly, in a preferred embodiment, rapamycin is incorporated onto the surface of the stent or portions thereof. Essentially, rapamycin is preferably incorporated into stent 50 as described above and as best illustrated in (Figures 3, 5, 8, and 9) where stent 50 contacts the lumen wall of the vessel to be treated. .

The rapamycin can be Incorporated on or attached to the stent 50 in a number of ways. In illustrative embodiments, rapamycin is directly incorporated into the polymer matrix of polymer materials 75 and / or 80 as described above. The rapamycin elutes from the polymeric material over time and enters the surrounding tissue. Rapamycin preferably remains on the stent for at least one (1) day up to approximately six (6) months, and most preferably between seven (7) days and sixty (60) days (i.e., a period ranging from 7 days 60 days). Therefore, these periods constitute the functional purpose of functional life or shelf life for stent 50 for these examples of the present invention.

Rapamycin works to inhibit smooth muscle cell proliferation through a number of mechanisms. Furthermore, rapamycin reduces the other effects caused by vascular injury, for example inflammation, the mechanisms of action and various functions of rapamycin are described in detail below. Rapamycin as used throughout this application will include rapamycin, rapamycin analogs, derivatives and congeners that bind to FKBP12 and possess the same pharmacological properties as rapamycin, as described below.

Rapamycin reduces vascular hyperplasia by antagonizing smooth muscle proliferation in response to mitogenic signals that are released during angioplasty. Cytosine-mediated smooth muscle growth and proliferation inhibition in the late G1 phase of the cell cycle is believed to be the dominant mechanism of action of rapamycin. However, rapamycin is also known to anticipate T cell proliferation and differentiation when administered systemically. This is the basis for its immunosuppressive activity and its ability to prevent graft rejection.

The molecular events that are responsible for the actions of rapamycin, an antiproliferative, which acts to reduce the magnitude and duration of neointimal hyperplasia, have yet to be elucidated. However, rapamycin is known to enter cells and bind to the high-affinity cytosolic protein called FKBP12. The rapamycin and FKPB12 complex in turn binds to and inhibits a phosphoinositide (PI) -3 kinase called the mammalian target of rapamycin, ”or TOR. TOR is a protein kinase that plays a key role in mediating signaling events towards the 3 'end associated with mitogenic growth factors and cytokines in smooth muscle cells and T lymphocytes. These events include p27 phosphorylation, p70 phosphorylation s6 kinase and phosphorylation of 4BP-1, an important regulator of protein translation.

Rapamycin is recognized to reduce restenosis by inhibiting neointimal hyperplasia. However, there is evidence that rapamycin can also inhibit the other important components of restenosis, namely negative remodeling. Remodeling is a process whose mechanism has not been clearly understood but which results in shrinkage of the external elastic lamina and reduction in the lumen area over time, generally a period of approximately three to six months in humans.

Negative or constrictive vascular remodeling can be quantified angiographically the percent diameter of stenosis at the site of injury where there is no stent obstructing the process. If the loss of late lumen is annulled in-lesion, it can be inferred that negative remodeling has been inhibited. Another method to determine the degree of remodeling involves measuring the area of ​​the external elastic lamina in-lesion using intravascular ultrasound (IVUS). Intravascular ultrasound is a technique that can image the external elastic lamina as well as the vascular lumen. Changes in the external elastic lamina proximal and distal to the stent from the post-procedure time point up to four months and four months of follow-up are reflective of change and remodeling.

Evidence that rapamycin has an effect on remodeling comes from human implant studies with rapamycin-coated stents showing very low restenosis inlesion as well as in-stent. Injury parameters are usually measured approximately five millimeters on each side of the stent ie proximal and distal. Since the stent is not present to control remodeling in these areas that are still affected by balloon expansion, it can be inferred that rapamycin is preventing vascular remodeling.

The data in Table 1 below illustrates that the percent diameter of injury stenosis remains low in the rapamycin-treated groups, even at twelve months. Therefore, these results support the hypothesis that rapamycin reduces remodeling.

TABLE 1

Percent diameter of angiographic stenosis-in- sion (%, mean ±

SD and “n =”) ​​in patients who received a cot rapamycin coated stent

<td>Coating group</td><td>Post-placement</td><td>Follow-up at 46 months</td><td>Follow-up at 12 months</td>

<td>Brazil</td><td> 10.6 ±5.7 (30)</td><td> 13.6 ±8.6 (30)</td><td> 22.3 ±72 (15)</td>

<td>Netherlands</td><td> 14.7 + 8.8</td><td> 22.4 ±6.4</td><td></td>

Additional evidence supporting a reduction in negative rapamycin remodeling comes from intravascular ultrasound data obtained from a first-man clinical program as illustrated in Table 2 below.

TABLE 2

IVUS data matched in patients who received a stent with tapamycin

<td>IVUS parameter</td><td>Post (n =)</td><td>Follow-up at 4-6 months (n =)</td><td>Follow-up at 12 months (n =)</td>

<td>Main proximal cup area (mm²)</td><td> 16.53 + 3.53 (27)</td><td> 16.31 ±4.36 (28)</td><td> 13.96 ±2.26 (13)</td>

<td>Average distal vessel area (mm²)</td><td> 13.12 ±3.68 (26)</td><td> 13.53 ±4.17 (26)</td><td> 12.49 ±3.25 (14)</td>

The data illustrated that there is minimal loss of vessel area proximally or laterally indicating that inhibition of negative remodeling has occurred in vessels treated with rapamlclin-coated stents.

In addition to the stent itself, there have been no effective solutions to the problem of vascular remodeling. Therefore, rapamycin may represent a biological approach to control the phenomenon of vascular remodeling.

The hypothesis that rapamlclna acts to reduce negative remodeling in several ways can be postulated. By specifically blocking fibroblast proliferation in the vascular wall in response to injury, rapamycin can reduce the formation of vascular scar tissue. Rapamycin can affect the translation of key proteins involved in collagen formation or metabolism.

Rapamycin used in this context Includes rapamycin and all analogs, derivatives and congeners that bind to FKBP12 and possess the same pharmacological properties as rapamycin.

In a preferred embodiment, rapamycin is delivered by a local delivery device to control negative remodeling of an arterial segment after balloon angioplasty as a means of reducing or preventing restenosis. Although any delivery device can be used, it is preferred that the delivery device comprises a biodegradable and / or bioabsorbable stent 50 that elutes or releases rapamycin such as those modalities illustrated in Figures 3, 5, 8 and 9 and as described previously.

Data generated in pig and rabbit models show that release of rapamycin into the vascular wall of drug eluting stents over a dose range (35-430 ug / 15-18 mm coronary stent) produces a peak reduction of fifty to fifty-five percent in hyperplasia of the neointima. This reduction, which is maximum at approximately twenty-eight to thirty days, is typically not sustained in the ninety to one hundred and eight day interval in the pig model.

Rapamycin produces an unexpected benefit in humans when delivered from a stent by causing a profound reduction in hyperplasia of the neointima in-stent that is sustained for at least one year. The magnitude and duration of this benefit in humans is not predicted from animal model data. Rapamycin used in this context includes rapamycin and all analogs, derivatives and congeners that bind to FKBP12 and possess the same pharmacological properties as rapamycin.

As noted above, rapamycin reduces vascular hyperplasia by antagonizing smooth muscle proliferation in response to mitogenic signals that are released during angloplasty injury. Also, rapamycin is known to prevent T cell proliferation and differentiation when administered systemically. Rapamycin has also been determined to exert a local inflammatory effect on the vessel wall when administered from a low-dose stent over a sustained period (approximately two to six weeks). The local anti-inflammatory benefit is profound and unexpected. In combination with the smooth muscle antiproliferative effect, this dual mode of action of rapamycin may be responsible for its exceptional efficacy.

Accordingly, rapamycin delivered from a local device platform reduces neointimal hyperplasia by a combination of smooth muscle anti-inflammatory and antiproliferative effects. Rapamycin used in this context means rapamycin and all analogs, derivatives and congeners that bind to FKBP12 and possess the same pharmacological properties as rapamycin.

Rapamycin has also been found to reduce cytosine levels in vascular tissue when delivered from a stent. Data has shown that rapamycin is highly effective in reducing levels of monocyte chemotactic protein (MCP-1) in the vascular wall. MCP-1 is an example of a proinflammatory / chemotactic cytosine that is made during vessel injury. The reduction in MCP-1 illustrates the beneficial effect of rapamycin in reducing the expression of proinflammatory mediators and contributing to the anti-inflammatory effect of rapamycin supplied locally from a stent. Vascular inflammation in response to injury is recognized as a major contributor to the development of neointimal hyperplasia.

Since rapamyline can be shown to inhibit events

Local inflammatories in the vessel, it is believed that this could explain the unexpected superiority of rapamycin in neointimal inhibition.

As discussed above, rapamycin works at a number of levels to produce desired effects such as preventing T-cell proliferation, inhibiting negative remodeling, reducing inflammation, and preventing smooth muscle cell proliferation. Although the exact mechanisms of these functions are not fully understood, the mechanisms that have been identified can be expanded.

Studies with rapamycin suggest that the prevention of smooth muscle cell proliferation by blocking the cell cycle is a valid strategy to reduce neointimal hlperplasia. Drastic and sustained reductions in late lumen loss and neointimal plaque volume have been observed in patients receiving rapamycin delivered locally from a stent. The present invention expands the mechanism of rapamycin to include additional approaches to inhibit the cell cycle and reduce hyperplasla of the neointimal without producing toxicity.

The cell cycle is a tightly controlled biochemical cascade of events that regulate the process of cell replication. When cells are stimulated by appropriate growth factors, they move from G_or (quiescence) to the G1 phase of the cell cycle. Selective inhibition of the cell cycle in the G1 phase, before DNA replication (phase

S), can offer therapeutic benefits for cell preservation and viability while retaining antiproliferative efficacy when compared to therapeutics that act late in the cell cycle, that is, in the S, G2 or M phase.

Accordingly, prevention of intimal hyperplasia in blood vessels and other duct vessels in the body can be accomplished using cell cycle inhibitors that selectively act on the G1 phase of the cell cycle. These inhibitors of the G1 phase of the cell cycle can be small molecules, peptides, proteins, oligonucleotides or DNA sequences. More specifically, these drugs or agents include cyclin-dependent kinase inhibitors (cdk's) involved with cell cycle progression through the G1 phase, in particular cdk2 and cdk4.

Examples of drugs 99 that act selectively on the phase

Cell cycle G1 includes small molecules such as flavopyridol and its structural analogues that have been found to inhibit the cell cycle in the late G1 phase by antagonism of cyclin-dependent kinases. Therapeutic agents that elevate an endogenous kinase inhibitor protein^kip called p27, sometimes referred to as P27^kip1, which selectively inhibits cyclin-dependent kinases can be used. This includes small molecules, peptides, and proteins that either block P27 degradation or increase cell production of P27, including gene vectors that can transfect the gene to produce P27. Staurosporin and related small molecules that block the cell cycle by inhibiting protein kinases can be used. Protein Clnase Inhibitors, Including the class of triphoslins that selectively inhibit kinase proteins to antagonize signal transduction in smooth muscle in response to a wide range of growth factors such as PDGF and FGF can also be used.

As discussed above, the rapamllin complex and 10 FKPB12 bind to and inhibit a phosphoinosyltid (PI) -3 kinase called the mammalian rapamlcin target or TOR. An antagonist of the catalytic activity of TOR, which functions either as an active site inhibitor or as an allosteric modulator, i.e. an indirect inhibitor that modulates allosterically, will simulate the actions of rapamlclna but will deviate the requirement for FKBP12. The potential benefits of a direct TOR inhibitor include better tissue penetration and better physical / chemical stability. Furthermore, other potential advantages include greater selectivity and specificity of action due to the specificity of an antagonist for one of multiple TOR isoforms that may exist in different tissues, and a potentially different spectrum of effects towards the 5 'end leading to a greater efficacy and / or safety of the drug.

Furthermore, the Inhibitor can be formulated for quick release or slow release of the medical device 50 of the present invention with the aim of keeping rapamycin or another drug, agent or compound in contact with target tissues for a period that varies from three days to eight weeks, i.e., the functional life or useful life for the medical device 50 in this example.

As noted earlier, coronary stent implantation along with balloon angioplasty is highly effective in treating acute vessel closure and may reduce the risk of restenosis. Intravascular ultrasound studies suggest that the coronary stent effectively prevents vessel constriction and that the majority of late luminal loss after stent implantation is due to plaque growth, probably related to neointimal hyperplasia. Late luminal loss after coronary stent is almost twice as high as that observed after conventional balloon angioplasty. Therefore, since stens prevent at least a portion of the restenosis process, the use of drugs, agents, or compounds that prevent inflammation and proliferation, or that prevent proliferation by multiple mechanisms, combined with a stent can provide treatment most effective for post-angioplasty restenosis.

The polymers selected from the first biodegradable and / or bioabsorbable material 75 and the second biodegradable and / or bioabsorbable material 80 for some preferred embodiments of the medical device 50 of the present invention have been selected based on generally delineated properties below. For example, polyglycolide (PGA), a rapidly degrading polymer, has been selected for the biodegradable and / or bioabsorbable material 75 for various embodiments of the present invention.

PGA is the simplest linear aliphatic polyester and was used to develop the first fully synthetic absorptive suture, marketed as Dexon in the 1960s by Davis and Geck, Inc. (Danbury, CT). The glycolide monomer is synthesized from the glycolic acid dimerization. Ring-opening polymerization yields high molecular weight materials with approximately 1-3% residual monomer present. PGA is highly crystalline (45-55%), with a high melting point (22010 225 ° C) and a glass transition temperature of 35-40 ° C. Due to its high degree of crystallinity, it is not soluble in most solvents; exceptions with highly fluorinated organic compounds such as hexafluoroisopropanol. PGA fibers have high strength and modulus and are too stiff to be used as sutures except in the form of pressed material. PGA sutures lose approximately 50% of their strength after 2 weeks and 100% after 4 weeks, and are fully absorbed in 4-6 months. The glycolide has been copolymerized with other monomers to reduce the stiffness of the resulting fibers.

Polylactic (PLA) and poly-L-lactide (PLLA), a slow degradation polymer (when compared to degradation rates associated with PGA), have been selected for the biodegradable and / or bioabsorbable material 80 for some modalities of the present invention.

As is known, lactide is the cyclic dimer of lactide that exists as two optical isomers, d- and I. L-lactide is the naturally occurring isomer, and dl-lactide is the synthetic mixture of d-lactide and l -lactide. The l-lactide homopolymer (LPLA or PLLA) is a semi-crystalline polymer. These types of materials have high tensile strength and low elongation, and consequently have a high modulus that makes them more suitable for load-bearing applications such as orthopedic fixation and sutures. Poly (dl-lactide) (DLPLA) is an amorphous polymer that exhibits a random distribution of both isomeric forms of lactic acid and is therefore unable to settle into an organized crystal structure. This material has lower tensile strength, higher elongation, and much faster degradation time, making it more attractive as a drug delivery system. Poly (l-lactide) (PLLA) is approximately 37% crystalline, with a melting point of 175-178 ° C and a glass transition temperature of 60-65 ° C. The degradation time of LPLA (PLLA) is much slower than that of DLPLA, requiring more than 2 years to be fully absorbed. The l-lactide and dl-lactide copolymers have been prepared to alter the crystallinity of l-lactide and accelerate the degradation process.

Poly (lactide-co-glycolide) copolymers [PLGA] can be formed to extend the range of homopolymer properties. The copolymers of glycolide with l-lactide and dl-glycolide have been developed for device delivery and drug applications. It is important to note that there is no linear relationship between the copolymer composition and the mechanical and degradation properties of the materials. For example, a copolymer of 50% glycolide and 50% dl-lactide degrades faster than any homopolymer. Copolymers of l-lactide with 25-70% glycolide are amorphous due to the alteration of the regularity of the polymer chain by the other monomer. A copolymer of 90% glycolide and 10% l-lactide was developed by Ethlcon as a absorbed suture material under the trade name Vicryl. Absorbed within 3-4 months but has a slightly longer endurance retention time.

Poly (dioxanone) can be prepared by p-dioxanone ring opening polymerization. This resulted in the first clinically proven monofilament synthetic suture known as PDS (manufactured by Ethicon). This material has approximately 55% crystallinity, with a glass transition temperature of -10 to 0 ° C. The polymer should be processed at the lowest possible temperature to avoid depolymerization back to monomer. Poly (dioxanone) has been shown to have no acute or toxic effects on implantation. The monofilament loses 50% of its initial breaking strength after 3 weeks and is absorbed within 6 months, providing an advantage over other slow healing wound products.

The poll (e-caprolactone) can be prepared by ring-opening polymerization of ε-caprolactone which gives a semi-crystalline polymer with a melting point of 59-64 ° C and a glass transition temperature of -60 ° C. The polymer has been considered tissue compatible and is used as a biodegradable suture in Europe. Because the homopolymer has a degradation time of the order of 2 years, copolymers have been synthesized to accelerate the rate of bioabsorption. For example, copolymers of ε-caprolactone with dl-lactide have produced materials with faster degradation rates. A glycolide ε-caprolactone block copolymer, which offers reduced stiffness compared to pure PGA, is sold as a monofilament suture by Ethico, Inc. (Somerville, NJ), under the tradename of

Monocryl.

The mixed materials of the present invention can be made in the following procedure as an example. The preformed polymers, i.e. the first biodegradable and / or bioabsorbable material 75 and the second biodegradable and / or bioabsorbable material 80 and the degradation additive 95 (or other additives) and optionally drug 99 and any of its required excipients are individually loaded into a conventional mixing container having a conventional mixing device mounted thereon such as an impeller, i.e. the polymer material 75 and the degradation additive 95 and drug 99 (if included) are first mixed to form encapsulated degradation additive 95 and drug 99 (if included). The polymer (s) of biodegradable and / or bioabsorbable material 75 and additive 95 and optionally drug 99 are mixed at a temperature suitable for the given polymers as known in this field until a uniform dispersion is obtained in order to ensure that the degradation additive 95 and drug 99 when optionally included as part of encapsulation by the biodegradable and / or bioabsorbable polymer 75 (Figure 6-9). The mixture can then be processed by removing it from the mixing device, cooling to room temperature, grinding and drying under below atmospheric pressures at elevated temperatures for a period. Typical encapsulation procedures that include spray drying, coacervation, etc. can be used. alternatively, the encapsulation can be prepared by extruding, tray drying, drum drying, or the like to form solids which are then milled to the desired particle size. Encapsulated degradation additive 95 and drug 99 (if included) are then mixed with the biodegradable and / or bioabsorbable material 80 using suitable temperatures and process steps such as mentioned above and below.

It is important to note that all of the processing techniques used in the present invention will be at sufficient temperatures that will not degrade drug 99, degradation additive 95, polymer material 75, and polymer material 80.

As mentioned above, items such as medical devices 50 themselves can be molded from the mixed materials of the present invention by using various conventional injection and extrusion procedures and molding equipment equipped with atmospheric dry nitrogen chambers at temperatures acceptable.

The mixed materials of this invention can be melt processed by numerous conventional methods to prepare a vast array of useful devices 50. These materials can be injection or compression molded to make implantable blodegradable and / or bloabsorbable medical and surgical devices, especially blodegradable and / or bloabsorbable vascular devices such as stents including drug eluting stents and blodegradable and / or bloabsorbable cardiovascular devices that are heart valves They include heart valves that are capable of elulr drugs 99.

Alternatively, the mixed materials can be extruded (melt or solution) to prepare fibers and films. The filaments thus produced can be spun as multifilament yarn, or meshes, knitted or woven, and formed by conventional molding technique in reinforcing devices 50 and used where it is desirable for the structure to have high tensile strength and levels desirable elasticity and / or ductility. Useful modalities include preformed valves or stents for areas where the vessels and cardiac tissue including heart valves have been or are easily damaged or surgically removed.

In accordance with the systems and methods of the present invention, a drug delivery device composed of polymeric bloabsorbable materials can be made by any of a variety of procedures. The procedure used to prepare the drug delivery devices are preferably low temperature procedures in order to minimize degradation of drugs or other bioactive agents which are unstable at high temperatures and incorporated into the matrix of bloabsorbable polymeric materials comprising the device. Processing methods may comprise forming the device from bioabsorbable polymeric materials by low-temperature solution-based procedures using solvents such as, for example, fiber spinning, including wet and dry spinning, electrostatic fiber spinning, fibers. co-matted, solvent extraction, coating, wire coating, hollow fiber and membrane spinning, spinning disc (thin films with uniform thickness), Inkjet printing (Three-dimensional printing and the like), freeze-drying, extrusion and co-extrusion, supercritical fluids, solvent cast films or solvent cast tubes. Alternatively, drug delivery devices can also be prepared by more conventional melt polymer processing methods for drugs or agents that are stable at high temperatures, such as fiber spinning, extrusion, co-extrusion, molding. By Injection, blow molding, pultrusion and compression molding. Alternatively, the drugs can also be incorporated into the drug delivery device by diffusion through the polymer matrix. This can be accomplished by various methods such as swelling of the device in a drug enriched solution followed by high pressure diffusion or by swelling and diffusion of the drug in the device using supercritical fluids. Alternatively, drugs or agents may be sprayed, dipped, or coated on the device after formation of the device from the bioabsorbable polymers. In any case, the polymer matrix and drug or mixed agent when provided, is then converted into a structure such as fibers, films, discs / rings or tubes, for example, which will subsequently be manipulated in various geometries or configurations as desired. .

Different procedures can provide different structures, geometries, or configurations to the bloabsorbable polymer being processed. For example, tubes processed from rigid polymers tend to be very rigid, but can be very flexible when processed by electrostatic processing or lyophilization. In the first case, the tubes are solid, while in the latter case the tubes are porous. Other procedures provide additional geometries and structures that may include fibers, microfibers, thin and thick films, discs, foams, microspheres, and even more intricate geometries or configurations. The fibers spun by melting or in solution, films and tubes can be further processed into different designs such as tubular, slip and lock, helical or otherwise braiding and / or laser cutting. Differences in structures, geometries, or configurations provided by different procedures are useful for preparing different drug delivery devices with desired dimensions, strengths, drug delivery, and display characteristics. Fibers, films, or tubes can be laser cut to a desired geometry or configuration such as in the form of a stent. Other machining techniques can also be used.

Different procedures can also alter the morphological characteristics of the bioabsorbable polymer that is being processed. For example, when dilute polymer solutions are rapidly stirred, polymers tend to have polymer chains that are generally parallel to the overall axis of the structure. On the other hand, when a polymer melt or solution is subjected to shear stress and cooled to a thermally stable condition, the polymer chains tend to elongate parallel to the direction of shear stress. Other morphological changes tend to occur in accordance with other processing techniques. Such changes may include, for example, transformation of spherulite to fibril, change of polymorphic crystal formation, reorientation of already formed crystalline lamellae, formation of oriented crystallites, orientation of amorphous polymer chains, crystallization and / or combinations thereof.

In the case of a stent composed of bioabsorbable polymeric materials formed by supercritical fluids, such as supercritical carbon dioxide, supercritical fluids are used to reduce processing temperatures during extrusion, molding or other conventional processing techniques. Different structures, such as fibers, tubes, films, or foams can be formed using supercritical fluids, so the lower temperature processing that accompanies supercritical fluids tends to minimize the degradation of drugs incorporated into the structures formed .

The bioabsorbable polymer materials comprising the drug delivery device according to the invention may include radiopaque additives added directly thereto during the processing of the matrix of the bioabsorbable polymer materials to increase the radiopacity of the device. Radiopaque additives can include inorganic fillers such as barium sulfate, bismuth subcarbonate, bismuth oxides, and / or iodine compounds. Radiopaque additives may rather include metal powders such as tantalum, tungsten, or gold, or metal alloys having gold, platinum, iridium, palladium, radius, a combination thereof, or other materials known in the art. The particle size of radiopaque materials can range from nanometers to microns, preferably from less than or equal to about 1 micron to about 5 microns, and the amount of radiopaque materials can range from 0-99 percent (weight percent) .

Since the density of radiopaque additives is typically very high where radiopaque materials are distributed throughout the matrix of bioabsorbable materials, dispersion techniques are preferably used to distribute radiopaque additives in all bioabsorbable materials as desired. Such techniques include high shear mixing, lubricant and surfactant additions, viscosity control, additive surface modification, and other particle size, shape, and distribution techniques. In this regard, it should be noted that the radlopaque materials can be uniformly distributed in all the bloabsorbable materials of the device, or can be concentrated in sections of the device to appear as markers similar to those previously described.

The amount of drugs or other agents incorporated within the drug delivery device in accordance with the systems and methods of the present invention can range from about 0 to 99 percent (weight percent of the device). Drugs or other agents can be incorporated into the device in different ways. For example, drugs or other agents may be applied as a coating on the device after the device has been formed, wherein the coating is composed of bioabsorbable polymers in which the drugs or other agents are Incorporated. Alternatively, drugs or other agents can be incorporated into the matrix of bloabsorbable materials that comprise the device. The drugs or agents incorporated in the bloabsorbable polymer matrix may be in an amount that is the same as or different from the amount of drugs or agents provided in the coating techniques originally described if desired. These various techniques of Incorporating drugs or other agents into or on the drug delivery device can also be combined to optimize the performance of the device and to help control the release of drugs or other agents from the device.

Wherein the drug or agent is incorporated into the matrix of bioabsorbable polymers comprising the device, for example, the drug or agent will be released by diffusion and during degradation of the device. The amount of drug or agent released by diffusion will tend to be released over a longer period that occurs using coating techniques, and can often more effectively treat local and diffuse injuries or conditions thereof. For regional drug or agent delivery, such diffusion release of the drugs or agents is also effective. The polymer compositions and their diffusion and absorption characteristics will control the drug elusion profile for these devices. Drug release kinetics will be controlled by drug diffusion and polymer absorption. Initially, most of the drug will be released by diffusion from the surfaces and volume of the device and will then gradually transition to drug release due to polymer absorption. There may be other factors that also control drug release. If the polymer composition is of the same monomer units (eg, lactide, glycolide), then the diffusion and absorption characteristics will be more uniform compared to polymers prepared from mixed monomers. Also, if there are layers of different polymers with different drug in each layer, there will be less controlled release of drug from each layer. There is the possibility of drug present in the device until the polymer is fully absorbed thereby providing drug release throughout the life cycle of the device.

The drug delivery device in accordance with the systems and methods of the present invention preferably retains its mechanical integrity during the active drug delivery phase of the device. After drug delivery is achieved, the structure of the device ideally disappears as a result of bioabsorption of the materials that comprise the device. The bioabsorbable materials comprising the drug delivery device are preferably biocompatible with the tissue in which the device is implanted such that the interaction of the tissue with the device is minimized even after the device is deployed within the patient. . Minimal inflammation of the tissue in which it unfolds is also preferred even as degradation of the bioabsorbable materials of the device occurs. In order to provide multiple drug therapy, encapsulated or enriched drug particles or capsules can be incorporated into the polymer matrix. Some of these active compounds can provide different therapeutic benefits such as anti-inflammatory, antithrombotic, etc.

As described above, polymer stents can contain therapeutic agents such as a coating, eg, a surface modification. Alternatively, the therapeutic agents can be incorporated into the stent structure, eg, a volume modification that may not require a coating. For stents prepared from biostable and / or bioresorbable polymers, the coating, if used, could be either biostable or bioresorbable. However, as noted above, the coating may not be necessary because the device itself is made from a supply material. This modality offers a number of advantages. For example, the highest concentrations of the therapeutic agent or agents can be achieved such as approximately&gt; 50 weight percent. Furthermore, with higher concentrations of therapeutic agent or agents, regional drug delivery (&gt; 5 mm) can be achieved for longer durations. This can treat different injuries such as diffuse injuries, bifurcated injuries, small sinuous vessels, and vulnerable plaque. Drug-loaded stents can be delivered by different delivery systems such as balloon expandable systems; self-expanding or self-expanding balloon-assisted.

As mentioned above, the mixed materials of the present invention can also be used to coat substrates, i.e. serve as a biodegradable and / or bioabsorbable polymer coating or a biodegradable and / or bioabsorbable drug elution polymer coating, such as biocompatible substrates such as meshes, the various components and structural elements of medical devices, for example, rings, loops, flexible links or stent bridges or extensions

fifty or the housing, flaps, or other components of the heart valve

50, etc. The coatings or mixtures 70 would be made using liquid mixed materials of the present invention which would then be applied to the substrate by conventional coating techniques such as dipping, spraying, brushing, roller coating, etc.

Furthermore, the mixed materials can be molded to form films that are particularly useful for those applications where the tissue drug delivery matrix (eg, growth factors) is desired, for example to achieve angiogenesis and / or myogenesis. in cardiovascular tissue including the vessels, myocardium, endocardium, and epicardium or pericardium of the heart.

Furthermore, the mixed materials of the present invention can be formed into open or closed cell foams, which are useful for applications where a high rate of internal tissue growth is required such as cardiac tissue remodeling to induce myogenesis or angiogenesis for treatment. of cardiovascular disease such as congestive heart failure (CHF) or ischemic heart disease.

In greater detail, the surgical and medical uses of the filaments, films, foams, molded articles, and injectable devices of the present invention include but are not necessarily limited to vessels or tissue of the heart. The medical device 50 in accordance with the present invention also can be used for devices such as clamps, screws and plates; clips; staples; hooks, buttons and snaps;

preformed tissue substitutes such as prostheses or grafts; injectable polymers; vertebral discs; anchoring devices such as suture anchoring; septum occlusion devices; injectable defect fillers;

preformed defect fillers; bone waxes; cartilage replacement; spinal fixation devices; drug delivery devices; foams with open or closed cells, and others.

All of the embodiments of the present invention allow all blodegradable and / or bioabsorbable material 75 and 80 respectively to be removed or removed from the body in a short period after the functional aspects of device 50 have been achieved. Accordingly, the present invention allows reintervention of the same treatment site by physicians to treat diseased tissue (or organ) in many cases the vessels (in cases where the medical device 50 is a stent). Therefore, the present invention also allows a programmable drug release of drug 99 from device 50 (Figures 3, 5, 8 and 9).

Since the above specification comprises preferred embodiments of the invention, it should be understood that variations and modifications may be made thereto, in accordance with the described inventive principles, without departing from the scope of the invention.

Although preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes and substitutions will occur to those skilled in the art without departing from the invention. Accordingly, the invention is intended to be limited only by the spirit and scope of the appended claims.