MXPA01007651A - Lubricious medical devices. - Google Patents

Abstract

Lubricious medical devices having physiologically active ingredients imbibed therein disclosed. A variety of polymeric substrates such as, for example, catheters, stents, dilatation balloons, guide wires, endotracheal tubes, instruments, implants and other medical devices can provide lubricity and abrasion resistance as well as substantially constant release profiles of the physiologically active ingredients for extended periods, e.g., 3 to 30 days or more.

Description

HEALTHY MEDICAL DEVICES Field of the Invention The present invention relates to lubricious medical devices. More specifically, the present invention relates to lubricious medical devices having a physiologically active ingredient impregnated therein.

BACKGROUND OF THE INVENTION A variety of lubricious coatings have been proposed for use on medical devices such as, for example, catheters, guidewires, endotracheal tubes and implants. Common materials used in the art to provide lubricious coatings for medical devices include, for example, oil, silicone and polymeric materials, such as poly N-vinylpyrrolidone, hydrophilic polyurethanes, Teflon, polyethylene oxide and polyacrylic acid. Among the most common materials used to provide lubricious coatings are hydrophilic polymers which are covalently bonded to the substrate with a binder polymer having reactive functional groups, for example, isocyanate, aldehyde and epoxy groups. Other binder polymers comprise, for example, copolymers containing a vinyl element, such as vinyl chloride or vinyl acetate and a carboxylic acid element. The details of such coatings are set forth in, for example, the E Patents. U.S. Nos. 5,091, 205 issued February 25, 1992 and 5, 731, 087, issued March 24, 1998. It is often desirable to provide a physiologically active ingredient from the medical device to a patient while the patient is find in contact with the patient's body. As used herein, the term "physiologically active ingredient" means any compound or element that has a therapeutic, medicinal or diagnostic effect on a human or animal. Typical physiologically active ingredients include, for example, drugs and antimicrobial agents. Although the provision of physiologically active ingredients from medical devices such as catheters or micro-scaffolds has generated a great deal of interest in the medical and scientific community, the efficacy of such methods has been unsatisfactory so far. One reason for the unsatisfactory performance of such medical devices is that only a limited amount of the physiologically active ingredient can typically be incorporated into the coatings on the medical devices while retaining the desired lubricity characteristics. As a result, the delivery of the physiologically active ingredient is often insufficient to provide a therapeutic dose in the case of a drug or exceeds the minimum inhibitory concentration ("MIC") to kill the proposed microorganisms. Also, the incorporation of physiologically active ingredients in the coatings of such medical devices often fails at the rate of a sustained and useful rate of release profile that is sufficient to allow the medical device to remain in contact with the body for a length of prolonged time, for example, from 3 to 30 days or more. This problem is especially acute with physiologically active ingredients which have a low solubility in water. On the other hand, if attempts are made to incorporate large amounts of physiologically active ingredients in the coatings of lubricious medical devices, the high level of incorporation may adversely affect the lubricity of the coating or the physiologically active ingredient may be released from the coating after insertion. Patient's body at a rate of release that is greater than the safe dose for the patient. Accordingly, improved lubricious medical devices are desired which have an effective amount of a physiologically active ingredient incorporated therein and which can release the physiologically active ingredient at a substantially constant release rate over a prolonged period of time, example, from about 3 to 30 days or more and to provide a patient with a desired dose of the physiologically active ingredient.

BRIEF DESCRIPTION OF THE INVENTION In accordance with the present invention, improved lubricious medical devices are provided such as, for example, catheters, guidewires, endotracheal tubes, balloons and implants. The lubricious medical devices of the present invention comprise a polymeric substrate which has impregnated therein a physiologically active ingredient in an amount effective to provide a substantially constant release rate of the physiologically active ingredient at an effective dose in order to achieve the desired effect. By the present invention it is now possible to provide desired doses of physiologically active proteins, especially those having low solubility in water, in a controlled manner, without diminishing the lubricity characteristics of the medical device. The present invention also provides methods for the delivery of the physiologically active ingredients to patients using the lubricious medical devices of the present invention, as well as the processes for making lubricious medical devices.

DETAILED DESCRIPTION OF THE INVENTION Typical physiologically active ingredients, suitable for use according to the present invention, include, for example, drugs and antimicrobial agents. Examples of classes of drugs that may be used in accordance with the present invention include abortifacients, hypnotics, sedatives, tranquilizers, anti-inflammatory agents, antihistamines, anti-tones, anti-convulsants, muscle relaxants, anti-tumor agents; for example, those of the treatment of malignant neoplasm, local anesthetics, anti-Parkinson's agents, diuretics, for example, those containing potassium, such as potassium iodide preparations, for example, those of the treatment of mental illness, for example, preparations containing lithium for use in the treatment of manic depression, anti-spasmodics, anti-ulcer agents, cardiovascular agents, preparations containing hormones, for example, androgenic and progestational hormones, remarkable steroids such as estradiol, sympathomimetic agents, hypoglycemic agents , nutritional agents, preparations containing enzymes of various types of activity, for example, chymotrypsin, preparations containing analgesics, for example, aspirin, and agents with other types of actions including nematocides, veterinary application agents, contraceptives, for example, spermicides, virucides, vitamins, vasodilators, antacids, querolitic agents, antidiarrheal agents, anti-alopecia agents, wound healing agents, and the like. Specific examples of drugs that may be suitable for use in accordance with the present invention, depending on their solubility in water, include ibuprofen, acetoprofen, chlorthalidone, sulfadimadine, papaverine, sulfamethoxyazine, hydrochlorothiazide, bendrofluazide, acetohexamide, diazepam, glipizide, nifedipine , griseofulvin, paracetamol, indomethacin, chlorpropamide, phenoxybenzamine, sulfathiazole, nitrazepam, furosemide, phenytoin, hydroflumetazide, tolbutamide, tialkylperazine maleate, dizoxin, reserpine, acetazolamide, methazolamide, bendroflumethiazide, chlorpropamide, tolazamide, chlormadinone acetate, acetaminophen, salicylic acid, methotrexate, acetyl sulfisoxazole, erythromycin, progestins, estroginia, progestational, and the like. These drugs cover a wide range of solubilities in water. The present invention is particularly effective for those drugs that have a low degree of water solubility. The water solubility of drugs can be easily identified in medical references such as the Merck index. Frequently, physiologically active ingredients, e.g., drugs or antimicrobial agents, suitable for use in accordance with the present invention, will be substantially insoluble in water, i.e., have a solubility in water of less than about 2000 parts per million by weight ("ppmw"), preferably less than about 1000 ppmw and more preferably less than about 600 ppmw. As used herein, the term "water solubility" means the amount of material, for example, the physiologically active ingredient, which is soluble in distilled water (pH = 7.0) at 20 ° C and one atmosphere, unless be established otherwise. For example, 2,4,4'-trichloro-2'-hydroxydiphenyl ether has a solubility in water of 1.0 ppm at 20 ° C, 8-hydroxyquinoline has a solubility in water of 520 ppm at 18 ° C. , Erythromycin has a solubility in water of 21 00 ppm, Rifampin has a solubility in water of 2500 ppm and Minocycline has a water solubility of 52,000 ppm. All measured in neutral water. A typical antimicrobial agent, suitable for use in accordance with the present invention, is one derived from a 2-hydroxy-diphenyl ether or a halogenated 2-acyloxy-diphenyl ether such as, for example, 2,4,4'- trichloro-2'-hydroxy diphenyl ether.

Typical microorganisms include bacteria such as staphylococcus epidermis, staphylococcus aureus, Escherichia coli, and Protens mirabilis, fungi and ferment such as Aspergillus fumigatus and Candia albicaus. Antimicrobial agents that may be useful in the treatment of microorganisms according to this invention, depending on their solubility in water, include, for example, the biaguanids, especially chlorhexidine and its salts, including chlorhexidine acetate, chlorhexidine gluconate, hydrochloride chlorhexidine and chlorhexidine sulfate, silver and its salts, including silver acetate, silver benzoate, silver carbonate, silver iodate, silver iodide, piala lactate, silver laurate, silver nitrate, silver oxide, palmitate silver, silver protein, and silver sulfadiazine, polymyxin, tetracycline, aminoglycosides, such as tobramycin and gentamicin, rifampicin, bacitracin, neomycin, chloramphenicol, miconazole, quinolones such as oxolinic acid, norfloxaci, nalidixic acid, pefloxacin, enoxacin and ciprofloxacin, penicillins such as oxacillin and piperacil, nonoxynol 9, fusidic acid, cephalosporins and combinations thereof. Suitable lubricious polymers for use in accordance with the present invention comprise any polymer that is substantially more lubricious when wetted with an aqueous liquid than when dried, for example, as evidenced by a reduction in the coefficient of friction. Typically, lubricious polymers have a solubility in water of at least about 1.0% by weight and preferably at least about 20% by weight or are expandable in water. As used herein, the term "water expandable" means a substantially hydrophilic polymer which, although not soluble in water, can absorb enough water to become lubricious in the hydrated state. In addition, the term "hydrophilic", as used herein, means that water droplets do not easily form beads on the surface of such a hydrophilic material, but rather, water droplets tend to assume a contact angle of less. 45 ° and spread quickly on its surface. Preferred hydrophilic polymers include, but are not limited to, those selected from the group consisting of polyvinyl compounds, polysaccharides, polyurethanes, polyacrylates, polyacrylamides, polyalkylene oxides, and copolymers, complexes, mixtures and derivatives thereof. Poly-vinyl lactams are preferred polyvinyl compounds for use in accordance with the present invention. As used herein, the term "polyN-vinyl lactam" means homopolymers and copolymers of such N-vinyl lactams such as N-vinyl pyrrolidone, N-vinyl butyrolactam, N-vinyl caprolactam, and the like, as well as also the above prepared with minor amounts, for example, up to about 20 weight percent, of one or a mixture of other copolymerizable vinyl monomers with the N-vinyl lactams. Of the polyN-vinyl lactams, homopolymers of polyN-vinyl pyrrolidones are preferred. A variety of polyN-vinyl pyrrolidones are commercially available and of these a polyN-vinyl pyrrolidone having a K-value of at least about 30 is especially preferred. The K value is a measure of molecular weight, details of the which are known to those skilled in the art. Other preferred hydrophilic polymers for use in accordance with the present invention include, but are not limited to, those selected from the group consisting of N-vinyl pyrrolidone-hydroxyethyl acrylate copolymers, carboxymethyl cellulose, hydroxyethyl cellulose, polyacrylamide, polyhydroxyethyl acrylate. , cationically modified hydroxyethyl cellulose, polyacrylic acid, polyethylene oxides, and complexes, mixtures and derivatives thereof. PolyN-vinylpyrrolidone is especially preferred, polyethylene oxide of polyacrylic acid and cellulosics such as, for example, carboxymethyl cellulose and cationically modified cellulose. Suitable lubricious polymers for use according to the present invention can be nonionic, cationic, anionic or amphoteric. Typically, the molecular weight of the lubricious polymers is from about 100,000 to 2,000,000,000 grams per mole of gram, preferably from about 200,000 to 5,000,000 grams per mole of gram and, more preferably from about 300,000 to 2,000,000 grams per mole of grams. gram. As used herein, the term "molecular weight" means weight average molecular weight. Methods for determining the weight average molecular weight, for example, light scattering, are known to those skilled in the art. Additional details concerning the preparation and selection of lubricious polymers suitable for use in accordance with the present invention are known to those skilled in the art. Such hydrophilic polymers are commercially available from a variety of sources such as, for example, Union Carbide Corporation, Danbury, CT. Preferably, a binder polymer having the functionality to promote binding of the lubricious polymer to the medical device substrate is used in accordance with the present invention. Typical binder polymers comprise elements that form a covalent bond between the binder polymer and lubricious polymer, for example, isocyanate, aldehyde or epoxy elements, or those that basically form a hydrogen or ionic bond, for example, polymers comprising an element of vinyl, such as vinyl chloride or vinyl acetate and a carboxylic acid element. Additional details of such binder polymers are known in the art and are described for example in U.S. Patent Nos. 5,091,205 issued February 25, 1992 and 5,731,087 issued March 24, 1998. In addition to the polymers binders, lubricious polymers and physiologically active ingredients, the lubricious coatings of the present invention may comprise one or more additives normally used in coating formulations such as, for example, surfactants, preservatives, viscosity modifiers, pigments, dyes and other additives known to those skilled in the art. Additionally, other functional additives that ionically bind to the hydrophilic polymer can also be used. These additives include physiologically active ingredients such as, for example, therapeutic agents, antithrombogenic agents, antimicrobial agents and antibiotic agents. When ionic additives are used in the coating, for example, heparin, which is anionic, it is preferred to use a cationic lubricious polymer, for example, a cationically modified hydroxyethyl cellulose. Similarly, when an additive is cationic, it is preferred to use an anionic lubricious polymer, for example, a polyacrylic acid-acrylamide polymer. The combination of an additive and a lubricious polymer can vary as necessary to provide the desired performance. The polymeric substrates to which the lubricious coatings of the present invention can be applied are not limited. Substances which are useful for substrates include, but are not limited to, various organic polymeric compounds such as, for example, polyamides, polyesters, for example, polyethylene terephthalate and polystyrene terephthalate, polyvinyl chloride, polyvinylidene chloride, polystyrene, esters of polyacrylic, polymethylmethacrylate and other esters of polymethacrylic, polyacrylonitrile, polyethylene, polypropylene, polyurethane, polyvinyl acetate, silicone resins, polycarbonate, polysulfone, polybutadiene-styrene copolymers, polyisoprene, nylon, polyethylene, polypropylene, polybutylene, halogenated polyolefins, various latexes, various copolymers, various derivatives and mixtures thereof. The polymer substrates may also comprise, in addition to the substrate polymer, various inorganic and metallic substances such as, for example, glass, ceramics, stainless steel and a super elastic metal or past alloys of the configuration such as Ni-Ti alloy. , for example. Typical medical devices to which the lubricious coatings of the present invention can be applied include, but are not limited to catheters, ball catheters, guidewires, endotracheal tubes, implants and other medical devices. The lubricious coatings of the present invention can be applied either by a two-stage coating process or by a one-stage coating process. In a preferred two-stage coating process, the portion of the substrate to be covered is first covered with the binder polymer and subsequently covered with the lubricious polymer. In a preferred stage coating process, the binder polymer and the lubricious polymer are applied to the substrate in a single step. In accordance with the present invention, any conventional liquid coating process can be used. Such processes include, for example, dip coating, spray coating, knife coating and roller coating. Dip coating is a preferred coating method, in accordance with the present invention. In a preferred coating process of the present invention, the binding polymers and lubricious polymers can be supplied from liquids contained in either a solution, a dispersion or an emulsion of the polymers. In the one-stage coating methods, the binder polymers and the lubricious polymers are contained in the same liquid medium. In the two-stage methods, the binding polymers and the lubricious polymers are separately contained in liquid media. Additional coating steps may also be employed to introduce different polymers or additives, for example, the physiologically active ingredient, as described below. The liquid media used for the supply of the binder polymers and the lubricious polymers can be organic, aqueous or an organic-aqueous mixture. The liquid medium used to supply the binder polymer can be selected so as to have some solvency for the substrate, that is, when the substrate is polymeric. This can improve the adhesion between the binder polymer and the substrate and aid in the film formation of the coating material. Preferred liquid media for the delivery of the binder polymers and lubricious polymers include, but are not limited to, esters, for example, ethyl acetate, isopropyl acetate, ethyl lactate; alcohols, for example, isopropyl alcohol, ethanol, butanol; ketones, for example, acetone, methyl ethyl ketone, diacetone alcohol, methyl isobutyl acetone; amides such as dimethyl formamide; toluene; glycol esters such as butyl glycol ether; chlorinated solvents such as dichloroethane, water and mixtures thereof. Preferably, the liquid media is selected so that the binder polymers and the lubricious polymer optionally wet the surface of the substrate to the surface. Preferably, the concentration of the binder polymer and the lubricious polymers in the liquid media is sufficient to provide the desired amounts of the respective polymers in the lubricious coatings. Typically, the concentration of the binder polymers in the liquid medium will vary from about 0.05 to 10 weight percent, and preferably from about 0.2 to 2 weight percent based on the total weight of the liquid medium. Typically, the concentration of the lubricious polymers will vary from about 0.1 to 20 weight percent, and preferably from about 0.5 to 5 weight percent, based on the total weight of the liquid medium. Additional details regarding the selection of liquid media for the supply of the binder polymers and lubricious polymers of the present invention are known to those skilled in the art. The coating processes of the present invention are preferably conducted in a liquid phase at atmospheric pressure and at a temperature of from about 20 to 90 ° C. Residence times for contacting the surface of the substrate to be covered with the liquid media containing the binder polymer or lubricious polymer, or both, vary from about 1 second to 30 minutes, preferably from about 5 seconds to 10 minutes. It is generally desirable to dry the coatings after application of the coating at a temperature of from about 30 to 150 ° C, preferably in a pressurized air oven. If desired, microwave ovens, vacuum ovens and infrared heaters can also be used. Typical drying times vary from about 1 minute to 24 hours and preferably range from about 10 minutes to 10 hours. When a two-stage coating process is employed, it is preferred to dry the binder polymer before application of the lubricious polymer. The lubricious coatings resulting from the coating processes of the present invention typically have a thickness of from about 0.05 to 10 microns and preferably from about 0.1 to about 5 microns. When a two-stage coating process is employed, the resulting coating preferably comprises an inner layer that is rich, ie, more than 50% of the binder polymer contacts the surface of the substrate, and an outer layer that is rich, i.e. , more than 50% in the lubricious polymer contacts the inner layer. The outer layer, which is rich in lubricious polymer, has an external surface that becomes lubricious when exposed to an aqueous or organic liquid. When a one-stage coating process is employed, the resulting coating comprises a single layer which is preferably a substantially homogeneous mixture of the binder polymer and the lubricious polymer. However, since the binder polymer often has more affinity with the substrate than the lubricious polymer, it is believed that there may be a higher concentration of the binder polymer in or near the surface of the substrate. In order to impregnate the physiologically active ingredient in the medical device according to the processes of the present invention, a polymer substrate having a base with (i) an internal region comprising a substrate polymer (as described above) and ( ii) an external surface is contacted with a liquid medium (as described above) having solvency for the substrate polymer. As used in this, the term "solvency" means that the liquid medium is a solvent for the substrate polymer (at the coating temperature) or is effective in promoting the expansion of the substrate polymer. The contact can be conducted before, simultaneously or after application of the lubric polymer to the polymeric substrate. Preferably, contact with the liquid medium comprising the physiologically active ingredient is conducted prior to the application of the lubricious polymer. As used herein, the term "impregnation" means that it causes the transport of the physiologically active ingredient from the liquid medium to the internal region of the matrix of the substrate polymer. The liquid medium comprises an effective concentration of the physiologically active ingredient to promote the impregnation of the physiologically active ingredient in the matrix of the substrate polymer. The impregnation process is typically carried out at atmospheric pressure and at a temperature of from about 20 to 90 ° C by dipping, spraying, winding or otherwise contacting the polymer substrate in the liquid medium for a relati short duration, in such a manner that there is no change of more than 10%, more preferably no more than 7% in any of the longitudinal or horizontal dimensions or shapes after the drying of the polymeric substrate. Preferably, the transverse dimension, for example, the diameter of the catheter, evidences a change no greater than 10% in the transverse dimension after contact with the liquid medium compared to the transverse dimension before said contact. The resulting impregnated substrate can be dried as described above either before or after the application of the lubricious coating.

In accordance with the present invention, quite surprisingly, it has been found that relatively short contact times, coupled with relatively high concentrations of the physiologically active ingredient, can result in substantially less dimensional changes than longer contact times with lower concentrations of the physiologically active ingredient. Typically, according to the present invention, the contact time lasts from about 5 sec. up to 60 minutes, preferably from about 30 sec. up to 30 minutes and more preferably from about 1 to 20 minutes. Typically the liquid medium will contain from about 5 to 50% by weight, preferably from about 7.5 to 40% by weight, more preferably from about 8 to 25% by weight and more preferably from about 10 to 20% by weight of the physiologically active ingredient in based on the total weight of the liquid medium. Furthermore, according to the present invention, more than one liquid medium can be used to effect impregnation. For example, a liquid medium can be a solvent for the physiologically active ingredient and a solvent or dilation agent for the polymeric substrate. Another liquid medium can be a solvent for the physiologically active ingredient and a non-solvent for the polymeric substrate. The various liquid media can be combined in such a way that the resulting mixture, while capable of impregnating the physiologically active ingredient in the polymeric substrate, causes minimal dimensional changes to the polymeric substrate. Quite surprisingly, according to the present invention, it has been found that the release rates of the physiologically active ingredients described in this invention can be predicted by using the following equation: dm / dt = K CL (Equation 1) where dm / dt is the rate of release of the physiologically active ingredient, K is a constant to be measured experimentally and CL is the loading of the physiologically active ingredient in the device. For example, when the medical device is a polymeric micro-scaffold made of (ethylene-vinyl acetate) copolymer covered with a lubricious coating and the physiologically active ingredient is Irgasan DP 300, 2, 4,4'-trichloro-2, -hydroxyphenyl ether, K has been measured experimentally as 4.47 x 10"5 hr" 1. Once this constant has been experimentally determined, Equation 1 becomes useful for the designation of any desired release rate of Irgasan DP 300 in such a way that the release dose is both therapeutically effective for the patient or animal and safe. Table 1 illustrates the correlation between the release rate of Irgasan DP 300 and the load of Irgasan DP 300 for this particular polymeric medical device.

TABLE 1 Load of Iraiasan (milligrams Irgasan Release Rate per 100 milligrams of (micrograms per 100 milligrams of Micro-scaffold) Micro-scaffold) 0 0 0.2 0.2 1 .8 1 .7 5.3 6.6 The total amount of the physiologically active ingredient impregnated in the matrix is effective in the proportion of a substantially constant release rate of the physiologically active ingredient when the lubricious medical device is contacted with a physiologically saline solution, ie, 9 grams of sodium chloride per liter. liter of water, for at least 3 days, preferably at least 7 days. As used herein, the term "substantially constant release rate" means that the release rate of the physiologically active ingredient for 3 days is at least 50%, preferably at least 60% of the rate of release after 1 day. In cases where the physiologically active ingredient is an antimicrobial, it is preferred that the rate of release after 3 days is greater than the MIC for the microorganism. Preferably, the zone of inhibition ("ZOI") will be at least 5 millimeters, preferably at least 10 millimeters, after 3 days. Typically, the matrix comprises at least 5% by weight, preferably at least 10% by weight of the physiologically active ingredient. In one aspect of the present invention, a portion of the physiologically active ingredient is comprised in the lubricious coating layer. In this aspect of the invention, typically less than about 50%, preferably less than about 20% of the total amount of the physiologically active ingredient comprised in the lubricious medical device is comprised in the lubricious polymer layer. The following examples are presented for illustrative purposes and are not intended to limit the scope of the claims that follow. Examples The following test was used in driving the examples. Friction Coefficient Test: A physiologically active catheter ingredient lies parallel to each other on a horizontal stainless steel platform at a distance of approximately 3.81 centimeters apart. The platform and catheters are subsequently carefully moistened with approximately 1 000 milliliters ("ml") of distilled water. An aluminum block of rectangular shape (5.08 x 5.08 x 7.62 centimeters) weighing 100 grams ("g") wrapped in a wet cellulose acetate membrane is placed on top of the catheters at the free-motion end of the tube. the platform. After this, the platform rises gradually and steadily from the freely moving end until an angle of inclination "0" is reached where the block begins to slide on the surfaces of the wet catheter. The coefficient of friction ("COF") is calculated as tangent 0. The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims that follow. EXAMPLE 1 This example illustrates the incorporation of a physiologically active ingredient (also referred to herein as "physiologically active ingredient"), i.e., an antimicrobial, Irgasan DP 300, in a polymeric device prior to the coating process. French 8-size micro-scaffolds extruded from (ethylene-vinyl acetate) copolymer were cut into 24.5-centimeter-long pieces. The micro-scaffolds were cleaned with isopropyl alcohol (IPA) and air dried. The micro-scaffolds were then immersed in a solution of toluene containing 1 5% by weight of Irgasan DP 300 for a period of 10 minutes and followed by drying in a pressurized air oven at 65 ° C for 3 hours. After this, the micro-scaffolds were removed from the furnace and immersed in another coating bath containing 3.3% by weight of poly (vinyl pyrrolidone) (PVP; Kollidon® 90F produced by BASF of Germany), 3.3% Vinyl Resin of UCAR® VMCA Solution (a copolymer of (vinyl chloride-vinyl acetate-maieic anhydride) produced by Union Carbide of Danbury, CT) and 46.7% both of acetone as ethyl lactate over a period of 30 seconds and followed by drying for another 3 hours under the same condition described above. The finished coating had a contact angle with water of less than 5o. The measurement of lubricity in the presence of distilled water with a Slipper-Block Examiner showed a coefficient of friction (COF) of 0.13 compared to that of 1.73 for the uncovered micro-scaffold. EXAMPLE 2 This example illustrates the loading of Irgasan DP 300 during the coating process according to the method of this invention. The same micro-scaffolds used in Example 1 were cleaned and air dried. The micro-scaffolds were immersed in a POLYSLIP® P-106 COATING solution (an aromatic polyisocyanate in toluene produced by Union Carbide of Danbury, CT) containing 15% by weight of Irgasan DP 300 for 1 minute and followed by drying in a Pressurized air oven at 65 ° C for 20 minutes. The micro-scaffolds were then ved from the furnace and immersed in another coating bath containing POLYSLIP T-503M COATING (a dispersion of poly (acrylic acid) in a solvent mixture of dimethyl formamide, t-butyl alcohol, and methyl ethyl acetone produced by Union Carbide of Danbury, CT) for 1 second and followed by drying at 65 ° C for 1 hour. The covered micro-scaffolds were further immersed in an aqueous sodium phosphate bath for 1 second and followed by drying at 65 ° C for 1 2 hours. The finished coating is smooth and uniform. The water lubricity measunt showed a COF of 0.1 3 compared to that of 1.73 for the uncovered micro-scaffold.

EXAMPLE 3 The control of this example illustrates the loading of Irgasan DP 300 during the coating process, but without following the method of this invention. The same micro-scaffolds used in Example 1 were cleaned with IPA and air dried. The micro-scaffolds were immersed in a bath containing POLYSLIP P-106 COATING for 30 seconds and followed by drying in a pressurized air oven at 65 ° C for 30 minutes. The micro-scaffolds were then ved from the furnace and immersed in another coating bath containing POLYSLIP T-503M COAT and 3.5% by weight of Irgasan DP 300 for a period of 1 second and followed by drying at 65 ° C for 1 hour. . The micro-scaffolds were then immersed in an aqueous sodium phosphate solution for 1 second and followed by drying for 1 2 hours at 65 ° C. The finished coating was smooth and uniform and showed a contact angle with water of 32 °. The water lubricity measunt showed a COF of 0.1 1 compared to that of 1.73 for the uncovered micro-scaffold. EXAMPLE 4 The release rates of Irgasan DP 300 from the micro-scaffolds prepared according to Examples 1 -3 in phosphate buffered saline ("PBS") at body temperature were measured for a duration of seven days by the use of a high pressure liquid chromatography ("HPLC") methodology set forth in "Broad Antimicrobial Spectrum of Irgasan DP 300" published by Ciba Geigy Corporation, Greensboro, North Carolina (1988). For each series of experiments, 4 pieces of micro-scaffolding of 8 cm in length were used. Two were used to measure the initial total load of Irgasan DP 300 and the others to measure the rate of Irgasan release in PBS for a duration of seven consecutive days. Each 8 cm micro-scaffold was cut into 4 pieces and placed in a sealed glass vial containing 5 ml of PBS. The glass bottle was placed in a culture chamber at 37 ° C for a duration of 24 hr. At the end of the 24 hr period, the aqueous extract in the flask was ved for the determination of Irgasan DP 300. The extracted micro-scaffolds were transferred to a new flask with 5 ml of fresh PBS solution and placed in a chamber of cultivation for another 24 hrs. This procedure was repeated for a total of seven times. In this way, the release rate of the Irgasan DP 300 from the same 8 cm micro-scaffold was measured for 7 consecutive days. At the end of the seventh day, the residual Irgasan DP 300, total, was measured in the micro-scaffold. For the measunt of the total Irgasan DP 300, the extraction was made by the use of 1.5 ml ethyl methyl acetone and the HPLC methodology was somewhat similar to that used for the PBS extract. The HPLC results are compiled in Table 2.

Table 2 Irgasan DP 300 Release Speeds of Different Micro-scaffolds Micro-scaffold Example Example Example Example Example 1 A ** 1 B 2A 2B 3A 3B Irgasan DP300 2.49 2.60 0.77 0.82 0.05 0.04 initial total (milligram per centimeter of length ) mg / cm. Release rate 3.62 2.75 0.73 0.87 0.05 0.03 Irgasan DP300 1st day (microgram per centimeter in length per 24 hours) ug / cm micro-scaffold * n 2? 0 day 5.1 9 2.99 0.62 0.70 0.07 0.05 3rd day 4.53 3.60 0.65 0.67 0.05 0.02 4t0 day 3.38 3.31 0.51 0.52 0.03 0.03 5t0 day 3.41 2.56 0.51 0.67 0.04 0.07 day 3.61 2.36 0.70 0.51 0.02 0.03 7th day 2.42 3.21 0.77 0.63 0.03 0.03 Irg asan DP300 2.33 2.57 0.76 0.75 0.06 0.05 tot ai residual mg / cm "1 ug / cm micro-scaffold = 1.6 ug / ml or 1.6 ppm in this series of experiments ** A and B denote duplicate samples The release rates of Irgasan DP 300 of the Samples 1 A, 1 B, 2 A, 2 B, 3 A and 3 B were maintained at substantially constant rates. During the seven days of duration that followed the release rates, none fell below 50% of their initial release rate. According to the methodology of Ciba Specialty Chemicals, the minimum inhibitory concentration (MIC) of Irgasan DP 300 against two common infectious bacteria, Staphylococcus aureus and Escherichia coli, is 0.01 to 0.1 ppm and 0.03 to 0.3 ppm, respectively. On the basis of the release rate data for Irgasan DP 300 listed in Table 1, it could be expected that the micro-scaffolds prepared in Examples 1 and 2 should be effective in controlling the growth of both of the two infectious bacteria. On the other hand, the marginal release rate of Irgasan DP 300 from Samples 3A and 3B prepared in Example 3 may show only marginal bioefficacy against S. aureus and very little against E. coli. This will be demonstrated by the bioefficacy results shown in the following series of experiments. EXAMPLE 5 The bioefficacy of the micro-scaffolds prepared in the Examples 1 -3 were determined by the measurement of the zone of inhibition (ZOI). All ZOI tests were done in triplicates. The sterilized micro scaffolds were cut 2 cm in length and placed horizontally on an inoculated Petri dish containing Tripticase and 106 CFU of either E. coli (ATCC 8739) or S. Aureus (ATCC 6538). The Petri dish was placed in a culture chamber at 37 ° C for 24 hrs. At the end of 24 hrs, the petri dish was removed from the culture chamber and the size of the zone in mm was measured with a ruler. Then, the micro-scaffold sections were transferred to a freshly prepared inoculated Petri dish containing Tripticase and 106 CFU of the same bacteria and placed in the culture chamber for another 24 hrs. This procedure was repeated for a total of seven times to generate seven consecutive days of ZOI data for each of the tested micro-scaffolds. The results of ZOI are summarized in Tables 3 and 4.

Table 3 ZOI Data from Various Micro-scaffolds against E. coli (ATCC 8739) Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Example 1 20.3 17.7 17 17 18 18.3 17.7 Example 2 13.3 13.3 12 12.7 12.3 12.3 12.7 Example 3 3.5 1.0 0 Control without 0 0 0 0 0 0 0 cover r oo Table 4 ZOI Data from Various Micro-scaffolds against S. aureus (ATCC 6538) Micro- Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 scaffold Example 1 40.0 38.0 37.7 38.3 39.7 41.0 37.3 Example 2 31.7 31.7 33.0 27.7 32.0 31.7 31.7 Example 3 11.0 11.5 12.5 12.0 11.5 11.5 11.5 Micro- 0 0 0 0 0 0 0 scaffolding without r or cover The bioefficacy shown in Table 4 has confirmed the prediction based on the release rate of Irgasan DP 300 generated in Example 4. The micro-scaffolds prepared according to the methods of this invention of Example 1 and 2 showed a rate of release of Irgasan DP 300 higher than MIC for either of the two infectious bacteria and sustained at a substantially constant rate during the seven days of testing. Also, both showed good and sustained bioefficacy against both of the infectious bacteria. On the other hand, the micro-scaffolds prepared according to Example 3 showed inadequate release of Irgasan DP 300 at a concentration below the MIC required to control E. coli. This was reflected in their deficient ZOI data against this bacterium. EXAMPLE 6 The measurement of ZOI against E. coli from micro-scaffolds prepared in Examples 1-3 was extended for a period of thirty days, and the results are plotted in Figure 1. These results convincingly show that when a micro-scaffold was loaded according to the method of the present invention, as demonstrated by the micro-scaffolds prepared according to Example 1 and 2, it shows a good bioefficacy against E. coli for a period of time. of sustained time. On the other hand, when a micro-scaffold was not loaded according to the method of this invention, as demonstrated by the micro-scaffolds prepared according to Example 3, its bioefficacy was inferior. EXAMPLE 7 This example illustrates a key advantage of the present invention when comparing the release velocity profiles of devices prepared according to the present invention to those teachings described by Darouiche et al., (US Patent 5,902,283, May 1 1999) and by Solomon et al., (J. Controlled Reléase, 6, 343-352, 1987; US Patent 4,442, 1 33); Pre-coated tridodecymethyl ammonium chloride (TDMAC) catheters are commercially available from Cook Critical Care, Bloomington, Ind.). Table 5 lists the release rate profiles of minocycline and rifampin from catheters prepared according to the impregnation process described by Darouiche et al., (Example 2 and Table 5 in U.S. Patent 5,902,283). Release rates for minocycline ranged from an increase of 354 on the first day to a decrease of 2.3 ug / cm micro-scaffold / 24 hrs. on the 30th day. Even on the second day, the release rate was only 1 5.5% of that of the first day. The release rates for Rifampin were just as radiant and range from an increase of 287 to a decrease of 4.5 ug / cm micro-scaffold / 24 hrs. The initial loading of the two antibiotics and the hundreds that remain after given days of release are shown in the lower portion of Table 5. The data shows that the teachings provided by Darouiche et al. Do not provide a medical device that produces a sustained release of a physiologically active ingredient at a substantially constant rate for a prolonged period of time. Table 6 lists the release rate profiles of minocycline and rifampin from catheters prepared according to the TDMAC method but reported by Darouiche ef al (Example 2 and Table 5 in U.S. Patent 5,902,283). The release rates of minocycline ranged from an increase of 23 to a decrease of 0.82 ug / cm micro-scaffold / 24 hrs, corresponding to 16.5 and 0.59% / cm micro-scaffolding / 24hrs release of the initial drug load, respectively . Consequently none of the antibiotics produced a substantially constant release rate, which is a serious disadvantage from the point of view of both safety and therapeutic effectiveness for the patients. Table 7 illustrates the efficacy of the present invention when a water-insoluble physiologically active agent, such as Irgasan DP 300 was loaded according to the method of this invention. The release rates of Irgasan 300 varied from an increase of 4.09 to a decrease of 2.85 ug / cm micro-scaffold / 24 hrs corresponding to 0.16 to 0.1 1% / c? M micro-scaffold / 24 hrs, respectively. At the end of a seven-day release, there was only a 5% reduction of the Irgasan DP 300 that is loaded into the micro-scaffold at its initial value. In comparison, the Darouiche catheter ef al., Lost approximately 70-85% of its assets after only 3 days. The catheter prepared through the TDMAC method lost approximately 45% of its activities after only 3 days. Accordingly, this example clearly demonstrates the advantage of the present invention for providing a medical device that is capable of delivering a sparingly water-soluble drug at a substantially constant rate for a prolonged period of time. . TABLE 5 MINOCICLINE RELEASE SPEED PROFILES AND RIFAMPUNA REPORTED BY DAROUICHE ET AL * Ingredient Velocity of% Speed of physiologicme liberation release release of nte active minocycline minocycline / rifampin rifampin / ug / cm / 24 hr cm / 24 hr ug / cm / 24 hr cm / 24 hr DO-DT 354 52.4 287 38.6 D2-D3 1 03 1 5.3 213 28.6 D1 E.-D30 2.3 0.34 5.5 0.74 Initial load 675 ug / cm 744 ug / cm After 3 15.3% 29.6% release days After 7.6% 22.3% 1 5 days of release After 2.5% 1 1 .2% 30 days of release TABLE 6 PERFILES OF SPEED OF MINOCICLINE RELEASE AND RIFAMPUNA USING CATHETERS TREATED BY THE METHOD TDMAC (derivatives of Example 2 v Table 5 in U.S. Patent 5,902,283) Ingredient Rate% Speed of physiological release release of active nte release minocycline minocycline / rifampin rifampin / ug / cm / 24 hr cm / 24 hr ug / cm / 24 hr cm / 24 hr Days 16 1 1 .5 1 .0 7.1 D ^ Da 24 24 2.5 18.0 D15-D30 0.82 0.82 0.2 1 .4 Initial loading 1 39 ug / cm 14 ug / cm After 3 55.4% 57.1% remaining days * remaining release After 1 5.5% 23.6% 15 days remaining remaining release After 6.6% 6.6 remaining 2.1% 30 days ug / cm release TABLE 7 IRGASAN DP 300 RELEASE SPEED PROFILES ACCORDING TO THE METHOD OF THE PRESENT INVENTION Oias% Release rate Rate% release release from the micro-release of the micro-scaffold scaffolding A1 / micro- scaffolding scaffolding B2 / ua / cm / 24 hr a / cm / 24 hr Do-Di 3.19 0.10 0.80 0. 10 D1-D2 4.09 0.16 0.66 0.08 D2-D3 4.07 0.16 0.66 0.08 D3-D4 3.35 0. 13 0.52 0.07 D4-D5 2.99 0.12 0.59 0.07 D5-D6 2.99 0.12 0.61 0.08 D6-D7 2.82 0. 1 1 0.70 0.09 Loading 2,545 ug / cm 795 ug / cm initial After 2450 ug / cm 755 ug / cm 7 (96%) remaining (95%) remaining days of release 1 Micro-and amio A prepared according to Example 1 2 Micro-scaffolding B prepared according to Example 2 EXAMPLE 8 This example illustrates a preferred process for producing a luric coating in a polymeric medical device containing a high charge of the physiologically active agent. Example 2 was repeated with the exception that the immersion time in the POLYSLIP T-503M COATINGS varied from 1 to 60 sec. As shown in Table 8, the finished micro-scaffolds showed equivalent initial lubricity as measured using a Chatillon Force Calibrator in the presence of distilled water. However, the abrasion resistance of the micro-andarnium increases with longer immersion time in the top coating bath. TABLE 8 LUBRICATION OF BIOSTATIC MICRO-SCAFFOLDS CONTAINING HIGH IRGASAN DP LOAD 300 T deep in frictional force bath Frictional force after upper coating, sec As g is 10 g abrasions Control 35.5 35.5 1 3.2 27.1 30 4.3 1 2.3 60 2.3 2.3 EXAMPLE 9 This example demonstrates that the lubricity produced by the process of this invention for polymeric micro-scaffolds containing a high load of physiologically active agent was not affected by the process of ethylene-oxide sterilization commonly used by the medical device industry. Six french-sized micro-scaffolds extruded from the copolymer (ethylene-vinyl acetate) were cut into 12-inch-long pieces. The micro-scaffolds were cleaned with IPA and dried with air. The micro-scaffolds were immersed in a POLYSLIP P-106 COATING solution containing 20% by weight of Irgasan DP 300 for 15 min and then dried in a forced air oven at 65 ° C for 20 min. The micro-scaffolds were then immersed in another coating bath containing POLYSLIP T-503M COVERAGE for 10 sec. And then by drying at 65 ° C for 2 hrs. The micro-scaffolds were then cooled in a bath of sodium phosphate bulking for 10 min, and then by drying at 65 ° C for 1 1 hrs. The finished coating was uniform and flat. The lubricity of the micro-scaffolds either before or after the ethylene-oxide sterilization was tested with a Chatillon Force Calibrator and the results are shown in Table 9. Both sterilized and non-sterilized micro-scaffolds showed excellent lubricity that the uncoated controls. TABLE 9 LUBRICIDE DIE MICRO-SCAFFOLDS CONTAINING HIGH LOAD FROM IRGASAN DP 300 BEFORE & AFTER STERILIZATION MEASURED WITH A CHATILLON FORCE CALIBRATOR Sample Frictional force Frictional force after 10 g As a result of abrasions Control 35.5 35.5 Not sterile 5.8 2.5 Sterilized 0.8 0.8 EXAMPLE 10 This example illustrates the load of Irgasan DP 300 on micro-scaffolds that were already coated with a hydrophilic coating. The same micro-scaffolds used in Example 1 were cleaned with IPA and air dried. The micro-scaffolds were immersed in a coating solution identical to the VMCA solution of Vinyl Resin Solvent PVP / UCAR described in Example 1 for 30 seconds and followed by drying in a forced air oven at 65 ° C for 3 hrs. . The micro-scaffolds were removed from the furnace and immersed in a toluene solution containing 3.5% by weight of Irgasan DP 300 for 30 min, and followed by drying at 65 ° C for 3 hrs. The finished coating was flat and uniform. The coated micro-scaffold showed a contact angle with water of 51 °. The bioefficacy of this micro-scaffold was determined using the ZOI method described in Example 5, and the results are compiled in Table 10.

Table 10 ZOI Against E. coliÍATCC 8739) (average triplicate measurements) Micro-scaffold Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Zone 17.3 16.3 15.7 14.7 16.7 16.0 15.7 (mm) ? co EXAMPLE 11 This example illustrates the effects of the impregnation time and the concentration of the physiologically active ingredient in the solution of impregnation of the charge of the physiologically active ingredient, which in turn, affects its performance of bioefficacy. The same micro-scaffolds used in Example 1 were cleaned with IPA and air dried. The micro-scaffolds were either immersed in a toluene solution containing 3.5 wt% of Irgasan DP 300 for a specified duration, or in a toluene solution containing a specified concentration of Irgasan DP 300 for a duration of 30 min, and followed by drying in a forced air oven at 65 ° C for 3hrs. The finished micro-scaffolds were uniform and flat. The rate of release of Irgasan DP 300 from these micro-scaffolds and their bioefficacy as measured by ZOI are listed in Table 1 TABLE 11 Release Speed of Iraasan DP 300 v ZOI Against E. coli (ATCC 8739) Sample T Tiieemmppoo of C Coonncc dde IIrrggaassaann D DOO V Veelloocciiddaadd of ZOI impregnation, 300,% by weight Release of Mm min Iroasan DP 300, ug / ml 1 1 00 3 3..55 0 0..5522 1 7 2 5 3.5 0.27 13.5 3 1 3.5 0.07 8.5 4 30 1 .7 27 5 30 0.97 21 6 30 Not determined 1 7 EXAMPLE 12 This example illustrates the utility of this invention for predicting the correct release rate of a physiologically active ingredient from a polymeric device using the kinetic model represented by Equation 1. The physiologically active ingredient used in this example is Irgasan DP 300, and the polymeric devices used in this example included a variety of copolymer (ethylene-vinyl acetate) micro-scaffolds coated with hydrogel. The total physiologically active ingredient loads and the experimental release rates of the physiologically active ingredient in PBS were measured using the HPLC method described above. The predicted release rates were calculated from Equation 1. In this way, there is a good agreement between the predicted release rates of Irgasan DP 300 calculated according to the kinetic model of this invention (Equation 1) and the experimental values. The results of this experiment demonstrate that a desired release rate of a physiologically active ingredient from a given polymeric device, which reflects both therapeutic effectiveness and patient safety, can be conveniently calculated from the kinetic model constructed according to the method of this invention.

Table 12 Comparison of Release Rates of Irgasan DP 300 Experimental and Predicted Type of Coating Irgasan DP 300 Load Release Rate Release Rate mg / 100 mg micro-predicted experimental scaffold ug / 24 hrs-100 mg micro-ug / 24 hrs-100 mg scaffold scaffold Example 3 cooled in 0.18 0.1 9 0.13 PVP solution ? I Duplicate 0.19 0.20 0.13 Example 2 cooled in 1.60 1.71 1 .46 0.01 N sodium phosphate solution Duplicate 1 .63 1.75 1 .76 Table 12 (continued) A Comparison of Release Rates of irgasan DP 300 Experimental and Predicted Coating Type Irgasan DP 300 Load Release Rate Release Rate mg / 100 mg micro-predicted experimental scaffold ug / 24 hrs-1 00 mg micro - ug / 24 hrs-1 00 mg scaffold scaffold microscopy Example 2, cooled in 1 .64 1 .75 1 .42 0.1 N sodium phosphate solution Duplicate 1 .65 1 .75 1 .42 i- Example 1 except 4. 12 4.41 3.91 PVP / VMCA = 3/1 Example 1, except 4.86 5.21 4.66 PVP / VMCA = 2/1 Example 1 5.48 5.88 6.29 EXAMPLE 13 This experiment illustrates the effect of the time of impregnation in a solvent aggressive to the dimensional integrity of the polymeric device. The same micro-scaffolds used in Example 1 were immersed in toluene, which is both a solvent for the Irgasan DP 300 and a swelling agent for the polymeric device, for different durations and followed by drying in a forced air oven at 65 ° C. ° C for 30 min. The dimensional changes before and after the impregnation process were measured and compiled in Table 13. Up to 30 minutes of impregnation time were used for the toluene solvent without causing more than 10% change in any diameter or length of the micro -scaffold. The micro-scaffolds impregnated for 60 minutes or more showed more than 12% shrinkage in diameter which is undesirable for the preferred aspects of this invention. When a 50/50 isopropyl lactate / acetone mixture solvent is used to impregnate Irgasan DP 300, the emotional stability of the ethylene-vinyl acetate polymeric scaffold was sufficiently good that the main consideration for the impregnation time was referred to to the effectiveness of the process to charge the correct level of the physiologically active ingredient in the polymeric device.

Table 13 Dimensional Changes of Copolymer Micro-scaffolds (Ethylene-vinyl acetate) in the Exposure to Toluene or Mixture of Isopropyl Lactate / Acetone 50/50 Solvent Impregnation time, min Retention of diameter. % Length retention. % Toluene 1 95.5 100 5 94.2 105 1 0 95.1 105.6 20 92.2 105.0 30 92.2 105.3 1 1 60 87.3 105.9 50/50 IL / A 1 99.7 100 5 99.4 100 10 99.0 100 20 98.1 100 30 98.1 100 60 97.6 100 EXAMPLE 14 This example illustrates WHEN when the micro-scaffolds were impregnated with physiologically active ingredient according to the method of this invention, they showed good bioefficacy against E. coli. The same micro-scaffolds used in Example 1 were cleaned with IPA and air dried. The micro-scaffolds were immersed in an IPA solution containing a given concentration of Irgasan DP 300 for a given duration, and followed by drying in a forced air oven for 30 min. The micro-scaffolds treated with Irgasan DP 300 were then coated with a lubricious coating according to the procedure described in Example 2 with the exception that nothing of Irgasan DP 300 was added to the POLYSIP P-106 COATING solution. The finished coating was uniform and flat. The bioefficacy of these micro-scaffolds was determined using the ZOI method described in Example 5, and the results were compiled in Table 14. The micro-scaffolds prepared according to the process of the present invention, to impregnate Irgasan DP 300 of an initial charge containing 1 5% by weight of the physiologically active ingredient for a period of one minute showed a consistent area against E. coli for the entire test period. On the other hand, those prepared on impregnation of an initial charge containing 1% by weight of the physiologically active ingredient did not show a detectable area against E. coli. EXAMPLES 15-17 Examples 15-1 7 compare the performance of the bioefficacy of F: oley catheters impregnated with Irgasan DP using any method of this invention. In each case, three units of 16 French Foley catheters were cleaned with IPA and air dried. The Foley catheters were immersed in a solution consisting of 1% by weight of VMCA Vinyl Resin UCAR Solution, and 49.5% each of acetone and isopropyl lactate for 30 seconds, and followed by drying in a forced air oven at 85 ° C for 1 hr. The catheters were subsequently submerged in another coating bath containing a solution prepared of 1-10% by weight of Irgasan DP 300, 2.98% of poly (vinylpyrrolidone) and 48.01% of each of acetone and isopropyl lactate per 1 -10. min, and followed by drying at 85 ° C for 3 more hours. The finished coating was uniform and clear. The bioefficacy of these Foley catheters against E. coli was determined by the ZOI method described in Example 5. The results of the ZOI tests are shown in Table 1 5.

Table 14 ZOI data against E. coli (ATCC 8739) Concentration method Time of ZOI, ZOI, ZOI, impregnation of Irgasan DP impregnation mm mm mm 300% by weight Min Day 1 Day 2 Day 3 According to 15 1 12 10 10 method of this invention • t. co I Comparative 1 30 0 0 0 Micro-scaffolding - - 0 0 0 as it is Table 15 ZOI Data of Folev Catheters Impregnated with Irgasan DP 300 against E. coii (ATCC) Sample C Coonncc .. of IIrrgoaassaann DDPP Tiieemmppoo of Z ZOOII, ZOI, 300 in sol lution Impregnation, mm mm min. Day 1 Day 4 Example 15 1% 1 16 6 Example 16 1 100 1 1 2 222 20 Example 17 1100 1 100 2 244 20 Micro-scaffolding without 00 00 0 0 0 n or cover Foley catheters treated according to the methods of this invention exemplified by Examples 18-19 showed good efficacy on both day 1 and day 4. On the other hand, Foley catheters treated by the comparative method, exemplified by Example 1 5, showed only marginal performance as evidenced by a marked decrease in ZOI by day 4. EXAMPLE 18-21 Examples 18-21 demonstrate the utility of this invention for application to another physiologically active ingredient sparingly soluble in water , 8-hydroquinoline. This physiologically active ingredient is useful as a fungistate or a disinfectant according to the Merck index. Additionally, these examples further demonstrate the benefit of the impregnation process as described in this invention. The copolymer (ethylene-vinyl acetate) micro-scaffolds described in Example 1 were immersed in an IPA or toluene solution containing either 1% or 20% by weight of 8-hydroxyquinoline for a duration of 10 sec. min, and followed by drying in a forced air oven at 65 ° C for 30 min. The micro-scaffolds were then immersed in POLYSLIP P-106 COATING for 30 sec, and followed by drying in a forced air oven at 65 ° C for 30 min. The micro-scaffolds were then immersed in POLYSLIP T-503M COATING solution for 1 sec, followed by drying at 65 ° C for 1 hr. The micro-scaffolds were subsequently submd in an aqueous sodium phosphate bath for 1 sec, and followed by drying at 65 ° C for 1 2 hrs. The finished coating is clear and flat.

The micro-scaffolds treated in Examples 1 8-21 were tested for bioefficacy against E. coli using the method described in Example 5. The results are shown in Table 16.

TABLE 16 Data of ZOI with tra E. coli (ATCC 8739) Sample Conc-8-HQ Time of Following the I ZOI. ZO% in immersion method of this mm mm weight / solvent invention Day 1 Day 2 Example 18 20 / toluene 10 min Yes 21 16 Example 19 1 / toluene 10 sec No 0 0 Example 20 20 / IPA 10 min No 4 0 Example 21 1 / IPA 10 sec No 0 0 cn? Micro-scaffolding - - - 0 0 uncovered The micro-scaffolds impregnated in Example 18 used a solution containing sufficiently high concentration of the physiologically active ingredient in a solvent which is both a good solvent for the physiologically active ingredient and a good swelling agent for the polymeric matrix for a sufficiently long duration so that the physiologically active ingredient is loaded into the device according to the criteria of this invention. The result was an effective device to control the growth of E. coli bacteria. On the other hand, the micro-scaffolds prepared according to Example 19 were not effective because the concentration of the physiologically active ingredient in the solution does not allow a sufficient loading of the physiologically active ingredient to achieve bioefficacy. Examples 20 and 21 clearly show the importance of selecting a suitable solvent for the impregnation process. Since IPA is not a very effective swelling solvent for the polymer matrix, even though it is a good solvent for the physiologically active ingredient, the impregnation process became ineffective regardless of the concentration of the physiologically active ingredient or the impregnation time employed. Although the invention has been described above with respect to specific aspects, those skilled in the art will recognize that other aspects are proposed to be included within the scope of the claims that follow. For example, polymers other than specific binding polymers and lubricious polymers and physiologically active ingredients may be employed in accordance with the present invention.

Claims (9)

1. CLAIMS 1. A lubricious medical device comprising: (a) a polymeric substrate having a matrix with; (i) an internal region comprising a substrate polymer, and (ii) an outer surface; t (b) a layer of lubricious polymer fixed to the outer surface, said lubricious polymer showing a reduction in its coefficient of friction when contacted with organic or aqueous fluids; characterized in that the matrix is impregnated in at least 5% by weight of a physiologically active ingredient having a solubility in water of less than about 2000 ppmw, which is effective to provide a rate of release of the physiologically active ingredient after 3 days of minus 50 ent of the release rate after 1 day.
2. 2. The lubricious medical device according to claim 1, characterized in that the physiologically active ingredient is a therapeutic agent.
3. 3. The lubricious medical device according to claim 2, characterized in that the physiologically active ingredient is an antimicrobial agent for an infectious microorganism.
4. The lubricious medical device according to claim 3, characterized in that the rate of release of the physiologically active ingredient after 3 days is higher than the minimum inhibitory concentration for the microorganism.
5. 5. The lubricious medical device according to claim 4, characterized in that it has a zone of inhibition of at least 10 millimeters after 3 days. The lubricious medical device according to claim 1, characterized in that less than about 50 weight ent of the total amount of the physiologically active ingredient comprised in the lubricious medical device is comprised in the lubricious polymer layer. The lubricious medical device according to claim 1, characterized in that it further comprises a binding polymer having functionality to promote the binding of the lubricious polymer to the external surface of the substrate. A method for introducing a physiologically active ingredient to an animal or human, which comprises contacting a lubricious medical device according to claim 1 with an internal area of the human or animal for an effective time to promote the transfer of the physiologically active ingredient to the animal. human or animal The method according to claim 8, characterized in that said contacting is conducted for a time from about 1 to 30 days. 1 0. A process for making a lubricious medical device impregnated with a physiologically active ingredient, said process comprising: (a) contacting a polymeric substrate having a matrix with; (i) an internal region comprising a substrate polymer, and (ii) an external surface, with a liquid medium having solvency for the substrate polymer, said liquid medium comprising a concentration of the physiologically active ingredient of from about 5-50. % in that and effective to promote the impregnation of the physiologically active ingredient in the matrix to provide a concentration of at least 5% by weight of the physiologically active ingredient in the matrix, and said contact being conducted over a short duration to provide less than 10% by weight. one hundred change in the transverse dimension of the medical device after said contact with the liquid medium compared to the transverse dimension before said contact; (b) applying a layer of lubricious polymer to the external surface; and (c) removing at least a portion of the liquid medium from the polymeric substrate. eleven . The process according to claim 1, characterized in that the concentration of the physiologically active ingredient in the liquid medium is effective to provide a substantially constant release rate of the physiologically active ingredient when the lubricious medical device is contacted with a physiological saline solution for at least 3 minutes. days. The process according to claim 1, characterized in that the concentration of the physiologically active ingredient in the liquid medium is proportional to the amount of physiologically active ingredient impregnated in the matrix. The process according to claim 10, characterized in that the lubricious polymer is applied to the polymeric substrate before, simultaneously with or after said contact with the liquid medium.