WO1995020381A1

WO1995020381A1 - Coating of biomedical objects with microspheres obtained with biocompatible polymers

Info

Publication number: WO1995020381A1
Application number: PCT/EP1995/000316
Authority: WO
Inventors: Franco Dorigatti; Lanfranco Callegaro
Original assignee: Fidia Advanced Biopolymers S.R.L.
Priority date: 1994-01-28
Filing date: 1995-01-27
Publication date: 1995-08-03
Also published as: AU1662895A; ITPD940011A1; ITPD940011A0

Abstract

Provided is a process for coating the surface of a medical object or device, comprising adhering microspheres comprising a biocompatible polymer, a bioabsorbable polymer, or a mixture of a biocompatible polymer and a bioabsorbable polymer to said surface, wherein the mechanical characteristics of said medical object or device are unaffected by said coating. Such microspheres can be produced from total or partial esters of hyaluronic acid, and can contain pharmacologically active substances. These microspheres can be adhered with or without the use of an adhesive. Also provided are medical objects or devices coated with such microspheres.

Description

COATING OF BIOMEDICAL OBJECTS WITH MICROSPHERES OBTAINED WITH BIOCOMPATIBLE POLYMERS

Background Of The Invention

Field Of The Invention The present invention relates to a process for preparing a coating for the outer surface of highly elastic biomedical objects or devices having complex chemical/physical characteristics, employing microspheres composed of biocompatible and/or bioabsorbable polymers, including, for example, esters of hyaluronic acid. Via this process, the elastic characteristics of the biomedical object or device remains unaffected. The microspheres can contain within them or upon them active principles such as antibiotics, antibacterials, antimycotics, antimicrobials, glycosphingolipids, peptide, polypeptide, and protein agents.

The present invention also relates to the coated biomedical objects and devices per se, which can be used in human or veterinary medicine.

Description Of Related Art

Studies to devise highly elastic biomedical objects comprising polymeric materials of synthetic origin, obtained by coating with polymers, have led. to the development of a variety of techniques. Coating techniques include those such as extrusion, by which threads are extruded, are widely used (Agassant et al . , Polymer Processing, Principles and Modeling. Hanser Publishers, New York, pp.116-117 and 125-127) . Other techniques include coating with films comprising two or more materials, or the technique known as "plasma coating, " which employs a plasma as a surface activation vehicle for the subsequent deposition of biopoϊymeric material (Ambrosio et al . <(1992) Fourth World Biomaterials Congress, "Surface Modification of Bioresorbable Fibers", p. 169) .

The most widely used techniques consist of spraying or spreading solutions or pastes to form a coating, which is then solidified by exacting/evaporating the solubilizing solvent, or by cooling in cases where the coating is made with polymers that harden when cool.

The quality of the coating produced by such techniques depends on factors such as the adherence of the two polymeric materials, the maintenance of their mechanical characteristics, and in particular, the elastic nature of the manufactured article.

The adherence of the two materials can be physical, chemical, or chemical-physical, and depends upon the forces acting on the interface between the two materials. When adherence is physical, these forces will necessarily be of a compressive nature, while in the case of chemical adherence, the type of forces will depend upon the bond(s) which form(s) in the interface between the two materials. Clearly, in the case of solely physical adherence, the coating will merely be a "cover" for the material, and there will be no forces influencing their close adherence.

Maintenance of the original elastic characteristics of the starting material depends on Ml (modulus of elasticity of the product to be coated) being greater than or equal to M2 (modulus of elasticity of the coating material) .

Trial coating on polymeric materials such as silicone, polyurethane, polyglycol, and polylactate, which possess low chemical affinity and lower modulae of elasticity than biopolymers that are soluble in aqueous solvents or solvents other than those which solubilize such polymeric materials, have shown that the quality of the coating, measured by the parameters of adherence and elasticity of the polymeric material, proves ^~ to be extremely low when spreading and spraying techniques are used. Coatings presently used on various different biomedical objects such as catheters, grafts, and tubes produced from synthetic polymers, wherein such coatings are produced from biopolymers such as polysaccharides and their derivatives, including esters of hyaluronic acid, as disclosed in U.S. Patents 4,851,521 and 4,965,353, are of a physical, compressive type. Furthermore, coatings obtained by spreading or spraying do not allow the elastic characteristics of the biomedical object to be maintained because of the different physical characteristics of the polymers used. Moreover, further cross-linking of the biopolymers adsorbed at the surface adversely affect the elastic characteristics of the biomedical objects.

Coatings comprising hyaluronic acid per se suffer from the disadvantage that hyaluronic acid is water- soluble, and therefore such coatings quickly dissolve in the body. Coatings comprising films of hyaluronic acid esters suffer from the disadvantage that such hyaluronic acid ester films are rigid, and therefore such coatings easily crack during use of the biomedical object or device.

Summary Of The Invention

It is therefore an object of the present invention to provide a process for preparing surface coatings for objects and devices having complex shapes, low modulae of elasticity, and poor affinity for biopolymers such as hyaluronic acid esters, while maintaining the mechanical characteristics of the objects and devices, enhancing their surface biocompatibility, and if necessary or desirable, incorporating pharmacologically active molecules therein. By this technique, it is possible to create biomedical objects using polymers having low modulae of elasticity and having biologically and pharmacologically active surfaces, while maintaining the physical characteristics of the synthetic polymer comprising the biomedical object. The use of microspheres rather than films, threads, etc., as a coating avoids the problem of cracking of the coating upon use of flexible objects or devices. Another advantage of this process is that the use of microspheres comprising hyaluronic acid esters facilitates the controlled release of substances having pharmacological and biological activity from the surface of the biomedical object as such esters are water- insoluble, degrade slowly within the body, and retard the release of active substances contained therein as the release of such substances is controlled by their rate of diffusion through the polymer network.

These and other objects and advantages are achieved by providing a process for coating the surface of a medical object or device, comprising adhering microspheres comprising a member selected from the group consisting of a biocompatible polymer, a bioabsorbable polymer, and a mixture of a biocompatible polymer and a bioabsorbable polymer to said surface, wherein the mechanical characteristics of said medical object or device are unaffected by said coating. The microspheres can comprise total or partial esters of hyaluronic acid, or mixtures thereof, and can be adhered to the surface of the biomedical object or device with or without the use of an adhesive. In addition, they can contain pharmacologically active substances.

Another object of the present invention is a medical object or device produced by the foregoing process. Another object of the present invention is a medical object or device having a coating comprising microspheres on the surface thereof. Such microspheres can comprise total or partial esters of hyaluronic acid, or mixtures thereof. In addition, these microspheres can contain a pharmacologically active substance^".

A further object of the present invention is the use of the foregoing medical objects or devices in surgery, or as temporary or permanent implants.

Yet another object of the present invention is the use of microspheres comprising a total hyaluronic acid ester, a partial hyaluronic acid ester, or a mixture of a total hyaluronic acid ester and a partial hyaluronic acid ester, to coat the surface of a medical object or device.

Further scope of the applicability of the present invention will become apparent from the detailed description and drawings provided below. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Brief Description Of The Drawings The above and other objects, features, and advantages of the present invention will be better understood from the following detailed descriptions taken in conjunction with the accompanying drawings, which are given by way of illustration only and are not limitative of the present invention, in which: Figure 1 is a schematic illustration of the surface of a biomedical object or device coated with microspheres according to the process of the present invention, showing that these microspheres are not affected by flexion of the object or device as these microspheres form a discontinuous system with a large number of points via which pressure can be discharged. The large hatched area is the surface of the biomedical object or device. The smaller circular objects on this surface are microspheres . The arrows show tension discharge points between the microspheres. When the biomedical object or device is flexed, the surface coating does not crack as the force is discharged between the microspheres.

Figure 2 is a schematic diagram showing the apparatus and accompanying steps employed in the present method for coating biomedical objects and devices. 1 is an adhesive container; 2 is a steel rod; 3 is a motor; 4 is a tail stock; 5 is a spraying mechanism; 6 is a slide; 7 is a motor; 8 is a container containing microspheres; 9 is a spraying mechanism; 10 is a slide; 11 is a motor; 12 is an aspirator.

Figure 3A shows the microsphere coating on the surface of the urological catheter of Example 5 before mechanical treatments and soaking.

Figure 3B shows the microsphere coating on the surface of the urological catheter of Example 5 after mechanical treatments and soaking.

Detailed Description Of The Invention

The following detailed description is provided to aid those skilled in the art in practicing the present invention, but should not be construed to unduly limit the present invention as modifications and variations thereof may be made by those of ordinary skill in the art without departing from the spirit or scope of the present inventive discovery. The contents of each of the references discussed herein are incorporated by reference in their entirety.

The objects and advantages of the present invention are attained by using microspheres comprising esters of hyaluronic acid as described in European Patent Application No. 0 517 565 and U.S. Patents Nos. 4,851,521 and 4,965,353 as a coating material made to adhere to the surface of medical objects and devices by means of an adhesive material . This adhesive material can be the same material as the object, but solubilized with a suitable solvent. Via the,present invention, the microspheres cover the surface of the object, and remain perfectly adhered thereto as they are unaffected by flexion of the object as they themselves constitute a discontinuous system with a large number of points through which pressure can be discharged (Figure 1) . Moreover, the microspheres aid in maintaining the pharmacological characteristics of the biomedical object or device as they remain in place, and controllably release the drug(s) or bioactive principle (s) incorporated therein or thereon.

Biomedical Objects And Devices

Biomedical objects and devices to which the coating technology described herein can be applied include, for example, catheters, including venous catheters, prostheses, including vascular protheses, cannulas, natural gums, and artificial bones, although not limited thereto.

The types of materials from which such biomedical objects and devices can be made and further subjected to the process described infra include synthetic materials such as silicone, polyurethane, polyethylene, polypropylene, polyacetals, polyglycolic acid, polylactic acid, other polymers and co-polymers routinely used in the art, semi-synthetic materials, and metals such as stainless steel and titanium.

Microspheres

The microspheres comprise partial or total hyaluronic acid esters as described in the patent documents listed supra, and can be used singly or in mixtures of varying percentages. The microspheres can have a diameter of between about 2 and about 120 microns, preferably between about 2 and about 10 microns, more preferably between about 7 and about 9 microns . Their density on the surface of the biomedical object or device can be in the range of from about 1 to about 10 mg/cm², preferably from about 1 to about 5 mg/cm², more preferably about 1.5 mg/cm².

Pharmaceutically Active Substances The microspheres can be loaded with bacteriostatic agents such as silver sulfadiazine and chlorhexidine (Medical Textiles. November, 1992, pages 1-2) , antimycotic agents such as clotrimazole, antibiotic agents such as rifamycin and novobiocin (Medical Textiles, December, 1993, pages 6-7) , glycosphingolipids such as naturally occurring gangliosides or their chemical derivatives, and biologically active peptides, polypeptides, and proteins such as calcitonin, insulin, immunoglobulins, and trophic factors like Nerve Growth Factor and Ciliary Neuronotrophic Factor.

Adhesives Adhesives that can be employed to "glue" the microspheres to the surface of the material to be coated can be of a biologically or medically acceptable type, preferably for internal use. A number of such adhesives are presently commercially available. These include silicone-based adhesives such as Dow Corning medical adhesive B, acrylic adhesives, alginic acid/acrylic acid adhesive mixtures, etc. The choice of adhesive with respect to the surface to be coated is not critical.

The technique for coating the biomedical object or device is shown in Figure 2, and comprises the steps of:

- Preparing the adhesive agent;

- Preparing the biomedical object or device;

- Coating the biomedical object or device; and

- Eliminating the solvent Preparation of Microspheres

Example 1 Method For The Preparation .of Microspheres From Esters of Hyaluronic Acid The microspheres employed in the present invention can be prepared from any of the total or partial hyaluronic acid ester (HYAFF) derivatives disclosed in U.S. Patents Nos. 4,851,521 and 4,965,353 and European Patent Application 0 517 565, the entire contents of which are herein incorporated by reference. The noted U.S. Patents disclose in detail the method of preparing these hyaluronic acid esters; the noted European Patent Application discloses in detail the method of preparing microspheres comprising these hyaluronic acid esters, including the method of incorporating pharmaceutically active substances therein and thereon.

Examples of such esters useful for preparing microspheres include, but are not limited to, the 100% ethyl ester of hyaluronic acid (HYAFF-7) ; the 100% benzyl ester (HYAFF-11) ; the 75% benzyl ester (HYAFF- llp75) , wherein 75% of the carboxyl groups of hyaluronic acid are esterified with benzyl alcohol, while the remaining 25% of the carboxyl groups are salified with sodium; and the 100% dodecyl ester (HYAFF-73) . HYAFF-11 and HYAFF-llp75 are preferred.

For example, the 100% benzyl ester of hyaluronic acid, HYAFF-11, is dissolved in an aprotic solvent such as dimethylsulfoxide at a concentration varying between 5 and 10% w/v, generally 7% w/v. This solution will be referred to hereinafter as the discontinuous phase.

At the same time, a mixture of high-viscosity mineral oil containing Arlacel^R, a non-ionic surface- active agent, at a concentration of 1% w/v is prepared in a suitable reactor. This mixture will be referred to hereinafter as the continuous phase.

The continuous phase is kept at 25°C while being stirred at a fixed speed of 1000 rpm. The discontinuous phase is then added to the continuous phase in a ratio of about 1:16, respectively. Under these conditions, emulsification of the two phases occurs instantaneously. After 15 minutes of stirring, ethyl acetate is added to the mixture. This solvent mixes perfectly with the two phases of the emulsion, but is not a solvent for the polymer. The volume of ethyl acetate required to obtain complete extraction is two and a half times the total volume of the emulsion. To facilitate extraction, the stirring speed is set at 1400-1500 rpm for 10 minutes, and is then lowered to 500 rpm. The suspension thus obtained continues to be stirred while being pumped with a screw pump through a filter press set at 1 atmosphere. Once this filtration is complete, the suspension is pumped through a filter of normal-hexane, this being a solvent with the double action of "drying" the preparation and solubilizing any residual surfactant which may be present on the surface of the microspheres. The product obtained is then placed in suitable containers and stored at 4°C.

Preparation Of Microspheres Containing Antibiotic, Antibacterial, Antimvcotic, And Antimicrobial Substances

Example 2 Microspheres for use in the present invention can contain a wide variety of different antibiotic, antibacterial, antimycotic, or antimicrobial substances. Such substances can be incorporated into or onto the surface of the microspheres by either of two different methods.

First Method

The 100% benzyl ester of hyaluronic acid, HYAFF-11, is dissolved in an aprotic solvent such as dimethyl- sulfoxide at a concentration varying between 5 and 10% w/v, generally 7% w/v. Once the polymer has solubilized, an antibiotic, antibacterial, antimycotic, or antimicrobial substance, -at a predetermined concentration, is added to the solubilized ester^". The mixture obtained will be referred to hereinafter as the discontinuous phase.

The continuous phase is kept at 25°C while being stirred at a fixed speed of 1000 rpm. The discontinuous phase is then added to the continuous phase in a ratio of about 1:16, respectively. Under these conditions, emulsification of the two phases occurs instantaneously.

After 15 minutes of stirring, ethyl acetate is added to the mixture. This solvent mixes perfectly with the two phases of the emulsion. The volume of ethyl acetate required to obtain complete extraction is two and a half times the total volume of the emulsion. To facilitate extraction, the stirring speed is set at

1400-1500 rpm for 10 minutes, and is then lowered to 500 rpm. The suspension thus obtained continues to be stirred while being pumped with a screw pump through a filter press set at 1 atmosphere. Once this filtration is complete, the suspension is pumped through a filter of normal-hexane, this being a solvent with the double action of "drying" the preparation and solubilizing any residual surfactant which may be present on the surface of the microspheres. The product obtained is then placed in suitable containers and stored at 4°C.

The quantity of active substance incorporated into or onto the microspheres depends upon the concentration thereof added to the solubilized ester in the • discontinuous phase.

SUBSTITUTE SHEET (RULE 26} Second Method

The 100% benzyl ester of hyaluronic acid, HYAFF-11, is dissolved in an aprotic solvent such as dimethyl- sulfoxide at a concentration varying from 5 to 10% w/v, generally 7% w/v. The solution obtained will be referred to hereinafter as the discontinuous phase. t the same time, a mixture of high-viscosity mineral oil containing Arlacel^R, a non-ionic surface-active agent, at a concentration of 1% w/v is prepared in a suitable reactor. This mixture will be referred to hereinafter as the continuous phase.

The continuous phase is kept at a temperature of 25°C and stirred at a rate of 1000 rpm, while the discontinuous phase is added to it. Under these conditions, emulsification of the two phases occurs instantaneously. The ratio between the discontinuous and continuous phases is about 1 to 16. After stirring the emulsion for 15 minutes, ethyl acetate is added. This solvent can be mixed perfectly with the two emulsion phases, but it is not a solvent for the polymer. The volume of extracting solvent needed to obtain complete extraction is two and a half times the total volume of the emulsion. To facilitate extraction, the stirring speed is set at 1400-1500 rpm for 10 minutes, then lowered to 500 rpm. The suspension thus obtained continues to be stirred, while being pumped by a screw pump through a filter press set at 1 atmosphere. Once this filtration is complete, the suspension is pumped through a filter of normal-hexane, this- being a solvent with the double action of "drying" the preparation and solubilizing any residue surfactant which may be present on the surface of the microspheres.

The microspheres thus prepared are suspended in a buffer solution containing a predetermined concentration of an antibiotic, antibacterial, antimycotic, or antimicrobial substance. After 15 minutes stirring with a semiautomatic system, the suspension is immersed in liquid nitrogen until it is completely frozen.

Once frozen, the suspension,is freeze-dried for 24 hrs and the product stored at 4°C.

The quantity of active substance incorporated into or onto the microspheres depends upon the concentration of this substance in the antibiotic, antibacterial, antimycotic, or antimicrobial substance-containing buffer solution.

Preparation Of Microspheres Containing Peptides, Polypeptides Or Proteins

Example 3

Microspheres for use in the present invention can also contain a wide variety of different peptides, polypeptides, or proteins, including hormones such as insulin and calcitonin; trophic factors such as Nerve Growth Factor and Ciliary Neuronotrophic Factor; and immunoactive molecules such as immunoglobulins. Such molecules can be incorporated into or onto the surface of the microspheres by either of two different methods .

First Method The 100% benzyl ester of hyaluronic acid, HYAFF-11, is dissolved in an aprotic solvent, such as dimethyl- sulfoxide at a concentration varying between 5 and 10% w/v, generally 7% w/v. Once the polymer has solubilized, a polypeptide such as insulin, at a predetermined concentration of, for example, 5 I.U. per mg of polymer, is added to the solubilized ester. The mixture obtained will be referred to hereinafter as the discontinuous phase.

The continuous phase is kept at 25°C while being stirred at a fixed speed of 1000.rpm. The discontinuous phase is then added to the continuous phase in a ratio of about 1:16, respectively. Under these conditions, emulsification of the two phases occurs instantaneously. After 15 minutes of stirring, ethyl acetate is added to the mixture. This solvent mixes perfectly with the two phases of the emulsion, but is not a solvent for either the ester polymer or the insulin polypeptide. The volume of ethyl acetate required to obtain complete extraction is two and a half times the total volume of the emulsion. To facilitate extraction, the stirring speed is set at 1400-1500 rpm for 10 minutes, and is then lowered to 500 rpm. The suspension thus obtained continues to be stirred while being pumped with a screw pump through a filter press set at 1 atmosphere. Once this filtration is complete, the suspension is pumped through a filter of normal-hexane, this being a solvent with the double action of "drying" the preparation and solubilizing any residual surfactant which may be present on the surface of the microspheres. The^' product obtained is then placed in suitable containers and stored at 4°C.

The quantity of insulin incorporated is 4 I.U. per mg of microspheres.

Second Method

The 100% benzyl ester of hyaluronic acid, HYAFF-11, is dissolved in an aprotic solvent such as dimethyl- sulfoxide at a concentration varying from 5 to 10% w/v, generally 7% w/v. The solution obtained will be referred to hereinafter as the discontinuous phase.

The continuous phase is kept at a temperature of 25°C and stirred at a rate of, 1000 rpm, while the discontinuous phase is added to it.

Under these conditions, emulsification of the two phases occurs instantaneously. The ratio between the discontinuous and continuous phases is about 1 to 16. After stirring the emulsion for 15 minutes, ethyl acetate is added.

This solvent mixes perfectly with the two emulsion phases, but is not a solvent for the ester polymer. The volume of extracting solvent needed to obtain complete extraction is two and a half times the total volume of the emulsion. To facilitate extraction, the stirring speed is set at 1400-1500 rpm for 10 minutes,- and is then lowered to 500 rpm. The suspension thus obtained continues to be stirred, while being pumped by a screw pump through a filter press set at 1 atmosphere. Once this filtration is complete, the suspension is pumped through a filter of normal-hexane, this being a solvent with the double action of "drying" the preparation and solubilizing any residual surfactant which may be present on the surface of the microspheres. The microspheres thus prepared are suspended in a 0.01M phosphate buffer solution (ionic strength 0.15M), containing a concentration of insulin such that a protein titer of 2 I.U. per mg of suspended microspheres is attained. After 15 minutes stirring with a semiautomatic system, the suspension is immersed in liquid nitrogen until it is completely frozen.

Once frozen, the suspension is freeze-dried for 24 hrs and the product stored at 4°C.

The quantity of insulin incorporated is 2 Ϊ.U. per mg of microspheres. Example 4

Preparation Of Microspheres

Containing Gangliosides

The 100% benzyl ester of hyaluronic acid, HYAFF-11, is dissolved in an aprotic solvent such as dimethyl- sulfoxide at a concentration varying from 5 to 10% w/v, generally 8% w/v. Once the polymer has solubilized, a solution of GMl ganglioside at a predetermined concentration of, for example, 20% of the weight of the polymer mass, is added thereto. The solution thus obtained will be referred to hereinafter as the discontinuous phase.

At the same time, a mixture of high-viscosity mineral oil containing Arlacel^R, a non-ionic surface- active agent, at a concentration of 1% w/v is prepared in a suitable reactor. This mixture will be referred to hereinafter as the continuous phase. It is kept at a temperature of 25°C and stirred at a rate of 700 rpm while the discontinuous phase is added to it. Under these conditions, emulsification of the two phases occurs instantaneously. The ratio between the discontinuous and continuous phases is about 1 to 16.

After stirring the emulsion for 15 minutes, ethyl acetate is added. This solvent mixes perfectly with the two emulsion phases, but is not a solvent for the polymer. The volume of extracting solvent needed to obtain complete extraction is two and a half times the total volume of the emulsion. To facilitate extraction, the stirring speed is set at 1400-1500 rpm for 10 minutes, and is then lowered to 500 rpm. The suspension thus obtained continues to be stirred, while being pumped by a screw pump through a filter press set at 1 atmosphere. Once this filtration is complete, the suspension is pumped through a filter of normal-hexane, this being a solvent with the double action of "drying" the preparation and solubilizing any residual surfactant which may be present on the surface of the microspheres . The product is then put in suitable containers and stored at 4°C.

The quantity of incorporated GM_! is 180 μg per mg of microspheres .

Coating Of Biomedical Objects With Microspheres

The general method for coating biomedical objects and devices with microspheres according to the present invention is shown schematically in Figure 2.

First, the adhesive in container 1 is appropriately diluted with a solvent at a ratio of between about 1:1 and about 1:5, preferably about 1:1.25. The nature of the solvent depends upon the type of adhesive used for the particular polymeric surface to be coated.

Next, the object to be coated is placed on a suitable support 2 that can be rotated by means of a suitable mechanism 3.

The object is then rotated at a speed of between about 30 and 250 rpm, preferably about 60 rpm, and at the same time, the adhesive is sprayed over it by a mechanism 5 moving backwards and forwards, driven by a worm screw 6 activated by the motor 7. The linear speed of the motor varies between about 0.25 m/minute to about

3 m/minute, preferably about 1 m/minute. Once the adhesive agent has been distributed, the microspheres, contained in a suitable container 8, are sprayed with the spraying mechanism. 9 which moves backwards and forwards, activated by a worm screw 10 driven by the motor 11. The linear speed varies between about 0.1 m/minute and about 1 m/minute, preferably about 0.5 m/minute. Any excess microspheres are gathered by an aspirator 12 and conveyed back to container 8.

The object is then removed from the support system and placed in a vacuum drying chamber to eliminate the solvent. The temperature of the chamber varies between about 25°C and about 45°C, and is preferably about 35°C.

The vacuum ratio is 10^"3 bar. Example 5

Preparation Of A Coating Based On Microspheres

Prepared From The Total Benzyl Ester of Hyaluronic Acid

(HYAFF 11), A urological catheter made of latex, FOLEYCAT WRP, was coated with microspheres prepared from hyaluronic acid benzyl ester, HYAFF 11, having a mean diameter of 9 microns, at a coating density of 1.5 mg/cm² adhered to the catheter surface with silicone glue (Dow Corning Medical Adhesive B) according to the following procedure.

With reference to Figure 2, 128 ml of the adhesive in container 1 are diluted with n-hexane at a ratio of 1:1. The catheter is fitted onto a steel rod 2 which is supported at one end by a tail stock 4, and the motor 3 rotates it at a speed of 60 rpm. The spray mechanism 5 is then activated and moves backwards and forwards by means of the motor 7 at a speed of 1 m/minute. Forty- five seconds later, the microspheres in container 8 are sprayed by the spraying mechanism 9 which moves backwards and forwards at a linear speed of 0.5 m/minute, driven by the motor 11. Any excess microspheres are gathered by an aspirator 12 and returned to container 8. The object is removed from the support system and placed in a vacuum drying chamber to eliminate the solvent. The temperature in the drying chamber is 35°C.

The quality of the coating .is assessed by the following operations: - Traction of the catheter with 50% elongation (operation repeated 10 times) ;

- Flexion of the catheter at an angle of 90°

(operation repeated 10 times) ;

- Soaking of the catheter in phosphate buffer for 96 hours

The results are shown in Figure 3A (microsphere coating before mechanical treatments and soaking) and Figure 3B (microsphere coating after mechanical treatments and soaking) . As shown by these figures, the microsphere coating showed no signs of cracking or detachment from the catheter after these treatments .

Example 6

Preparation Of A Coating Based On Microspheres

Prepared From The Partial 75% Benzyl Ester Of

Hyaluronic Acid (HYAFF 11P75)

A urological catheter made of silicone, SILKOMED, was coated with microspheres prepared from 75% partially esterified hyaluronic acid benzyl ester, HYAFF llp75, having a mean diameter of 8.8 microns, at a coating density of 1.5 mg/cm², adhered to the catheter surface with silicone glue (Dow Corning Medical Adhesive B) , according to the following procedure.

With reference to Figure 2, 98 ml of adhesive contained in container 1 are diluted with n-hexane at a ratio of 1:1.25. The catheter is fitted onto a steel rod 2, and the system is rotated by means of motor 3. The catheter is rotated at 60 rpm. The spray is then activated, and moves backwards and forwards, driven by motor 7 at a speed of 1 m/minute. Forty-five seconds later, the microspheres in container 8 are sprayed by spraying mechanism 9, which moves backward and forward at a linear speed of 0.5 m/minute, driven by motor 11.

Any excess microspheres are gathered by the aspirator

12, and returned to container 8. The catheter is removed from the support system and placed in a vacuum drying chamber to eliminate the solvent. The temperature in the drying chamber is 35°C.

The quality of the coating is assessed by the following operations:

- Traction of the catheter with 50% elongation (operation repeated 10 times) ; - Flexion of the catheter at an angle of 90° (operation repeated 10 times) ; - Soaking of the catheter in phosphate buffer for 96 hours Visual observation revealed that the microsphere coating showed no signs of cracking or detachment from the catheter after these treatments .

Example 7 Preparation Of A Coating Based On Microspheres Prepared From The Total Benzyl Ester Of Hyaluronic Acid (HYAFF 11) Plus Silver Sulfadiazine A urological catheter made of latex, FOLEYCAT WRP, medicated with silver sulfadiazine was prepared according to the procedure described in Example 5, using microspheres of hyaluronic acid benzyl ester, HYAFF 11, containing 1% by weight of silver sulfa-diazine.

After testing by traction and soaking in water according to the procedure described in Example 5, visual observation revealed no signs of cracking or detachment of the microsphere coating.

Example 8 Preparation Of A Coating Based On Microspheres

Prepared From the Total Benzyl Ester Of Hyaluronic Acid (HYAFF 11) Plus Clotrimazole A urological catheter made of latex, FOLEYCAT WRP, medicated with clotrimazole was prepared by the procedure described in Example 5, using microspheres of hyaluronic acid benzyl ester, HYAFF 11, containing 1% by weight of clotrimazole. After testing by traction and soaking in water according to the procedure described in Example 5, no signs of cracking or detachment of the microsphere coating were detected. Example 9 Preparation Of A Coating Based On Microspheres Prepared From The Total Benzyl Ester Of Hyaluronic Acid (HYAFF II) Plus Rifamycin A urological catheter made of latex, FOLEYCAT WRP, medicated with rifamycin was prepared according to the procedure described in Example 5, using microspheres of hyaluronic acid benzyl ester, HYAFF 11, containing 2% by weight of rifamycin. After testing by traction and immersion in water according to the procedure described in Example 5, no signs of cracking or detachment of the microsphere coating were detected.

Example 10 Preparation Of A Coating Based On

Adhering Microspheres To The Surface Of A Biomedical Object Or Device Without The Use Of An Adhesive The previous examples describe the use of an adhesive to adhere microspheres comprising total or partial esters of hyaluronic acid to the surface of a biomedical object or device. It is also possible to adhere such microspheres without the use of an adhesive. The surface of the biomedical object or device can be treated with a solvent that solubilizes this surface, creating a gel-like surface. For example, silicone surfaces can be treated with hexane to create this gel- like surface consistency.

Thereafter, microspheres can be applied to this gel-like surface. Upon drying and subsequent hardening of the surface, the microspheres adhere thereto,, without the need for use of an additional adhesive.

The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope" of the following claims.

Claims

What Is Claimed Is:

1. A process for coating the surface of a medical object or device, comprising adhering microspheres comprising a member selected from the group consisting of a biocompatible polymer, a bioabsorbable polymer, and a mixture of a biocompatible polymer and a bioabsorbable polymer to said surface, wherein the mechanical characteristics of said medical object or device are unaffected by said coating.

2. The process of claim 1, wherein said microspheres are adhered to said surface using an adhesive.

3. The process of claim 1, wherein said microspheres are adhered to said surface by solubilizing said surface with a solvent, and applying said microspheres to said surface.

4. The process of claim 1, wherein said microspheres comprise at least one derivative of hyaluronic acid.

5. The process of claim 4, wherein said at least one derivative of hyaluronic acid is a total or partial ester of hyaluronic acid.

6. The process of claim 5, wherein said total or partial ester of hyaluronic acid is selected from the group consisting of the 100% benzyl ester of hyaluronic acid and the 75% benzyl ester of hyaluronic acid.

7. The process of claim 1, wherein said microspheres contain at least one pharmacologically active agent.

8. The process of claim 7, wherein said at least one pharmacologically active agent is selected from the group consisting of an antibiotic, an antibacterial, an antimycotic, an antimicrobial, a glycosphingolipid, a peptide, a polypeptide, and a protein.

9. The process of claim 1, wherein said microspheres have a mean diameter between about 2 microns and about 120 microns.

10. The process of claim 9, wherein said microspheres have a mean diameter between about 7 microns and about

9 microns.

11. The process of claim 1, wherein said microspheres are present on said surface at a density between about 1 and about 10 mg/cm².

12. The process of claim 1, wherein said microspheres are present on said surface at a density of about 1.5 mg/cm².

13. The process of claim 1, wherein said medical object or device is flexible, and maintains its elastic characteristics after coating.

14. The process of claim 1, wherein said surface of said medical object or device is biocompatible.

15. A medical object or device produced by a process according to any one of claims 1-14.

16. A medical object or device having a coating comprising microspheres adhered to the surface thereof.

17. The medical object or device of claim 16, wherein said microspheres comprise at least one derivative of hyaluronic acid.

18. The medical object or device of claim 17, wherein said at least one derivative of hyaluronic acid is a total or partial ester of hyaluronic acid.

19. The medical object or device of claim 16, wherein said microspheres contain at least one pharmacologically active agent.

20. The medical object or device of claim 19, wherein said at least one pharmacologically active agent is selected from the group consisting of an antibiotic, an antibacterial, an antimycotic, an antimicrobial, a glycosphingolipid, a peptide, a polypeptide, and a protein.

21. Use of said medical object or device of claim 15 or 16 in surgery.

22. Use of said medical object or device of claim 15 or 16 as a temporary or permanent implant.

23. Use of said medical object or device of claim 22, wherein said medical object or device is implanted surgically or non-surgically.

24. Use of said medical object or device of claim 15 or 16 in urology, cardiovascular surgery, orthopaedics, or otorhinolaryngology.

25. Use of microspheres comprising a member selected from the group consisting of a total hyaluronic acid ester, a partial hyaluronic acid ester, and a mixture of a total hyaluronic acid ester and a partial hyaluronic acid ester, to coat the surface of a medical object or device.