DE10025803A1 - Polymer surface with biologically active properties and process for their production - Google Patents

Abstract

The invention relates to polymer surfaces with biological properties and processes for their production. Small particles, e.g. B. nanocapsules, microcapsules or liposomes that contain biologically active substances, chemically fixed to the polymer surface. Depending on the field of application, the biologically active substances are released from these fixed particles in a controllable manner after the medical devices equipped with them are introduced into the body. Mixtures of these particles, which release the biologically active substances over different times, can also be used, so that it is possible to achieve the required almost uniform active concentrations on the surface of the medical devices over a long period of time. Mixtures of these particles, each containing different biologically active substances with different chemical and physical properties and, as a result, different release kinetics, can be used, so that it is possible for the different biologically active substances to also have different active concentrations on the surface of the medical technology Devices.

Description

The introduction is often associated with the use of polymers in vivo of biologically active substances, such as chemotherapy drugs, Disinfectant, substances that prevent the deposition of the body's own substances counteract that affect blood clotting or immunoregulatory u. a. Substances, required. Infections occur in 1 to 50% depending on the type of catheter of cases. You put through the elaborate treatment and prolonged Hospitalization is a major financial burden for the affected patients. Approx. 10% of cases lead to death. The necessary additional medical alone Treatment costs are currently estimated at a few billion dollars worldwide. The pathogenesis of catheter infection is not fully understood. It seems certain that the local weakening of the immune system caused by mechanical stress of the tissue at the entry point of the catheter, and the coating of the catheter with a settlement of microorganisms is facilitated for the patient's biomolecules. Various coating methods are used to try to reduce the risk of settlement and thus reducing the risk of infection with permanent catheters.  

By chemical pretreatment of the catheter surface or coating with Silver compounds have only limited success in the adhesion and colonization of bacteria Reduce.

Prevent antimicrobial substances that are placed on the catheter Infections over a period of time. Such catheters are made by the following technological processes manufactured:

A. Incorporation of the active substance into the polymer

• 1. WO 86-02 561 (Brohult, 1984)
• 2. US 4,581,028 (Columbia Univ. N.Y., 1984)
• 3. EP 229 862 (Terumo, 1986)
• 4. US 4 925 668 (Becton-Dickinson, 1989)
• 5. WO 93-11 821 (Rochester Med. Corp., 1990)
• 6. EP 379 269 (Becton Dickinson, 1990)
• 7. WO 97-47 696 (Merlin, Frankr., 1996)
• 8. JP 10 081 717 (Roray Ind. Inc., 1996)

B. Application of a layer containing the active substance

• 1. US 3,695,921 (Shepherd and Gould, 1970, cont-in-part 1966)
• 2. EP 65 884 (Unitika, Japan, 1981)
• 3. WO 84-1102 (Hydromer, 1982)
• 4. USP 4,769,013 (Hydromer Inc., 1986)
• 5. USP 4 950 256 (Luther Medical Products, 1990)
• 6. USP 5,013,306 (Becton Dickinson, 1990)
• 7. EP 470 443 (Becton Dickinson, 1990)
• 8. EP 596 615 (Medtronics, 1992)
• 9. DE 43 34 272 (Sternberger, 1993)
• 10. WO 96-22 114 (Vitaphore Corp., 1995)
• 11. WO 96-39215 (Univ. Texas, Raad et al., 1995)
• 12. W 95-21 636 (Lepetiti, 1995)
• 13. WO 97-46 268 (Cook Incorp., USA, 1996)
• 14. JP 10 015 042 (Tokyo Kogyo KK, 1996)
• 15. WO 98-04 296 (Institute Curie, Fra, 1996)
• 16. JP 10 211 272 (Unitika, 1997)
• 17. JP 10 248 919 (Unitika, 1997)
• 18. EP 882 461 (Unitika, 1997)

C. Pretreatment of the layer with surfactant, biguanamide, ammonium compounds and the like. Ä. before the application of the active substance

• 1. EP 338 418 (Becton-Dickinson, 1988)
• 2. USP 4,895,566 (C.R. Bard, Inc., 1988)
• 3. EP 520 160 (BOC Health Care)
• 4. WO 93-01 842 (Dellamonica, 1991)
• 5. USP 5 217 493 (Univ. Texas System, 1992, Raad and Darouiche)
• 6. WO 94-29 325 (Kimberly-Clark Corp., 1993)
• 7. WO 95-32 977 (Kimberly-Clark Corp., 1994)
• 8. EP 761 243 (Unio Carbide Chemicals, 1995)
• 9. EP 799 623 (BOC, 1996)
• 10. WO 97-42200 (Bioshield Technologies, 1996)
• 11. DE 196 19 327 (Dunzendorfer, 1996)  
• 12. EP 818 207 (BOC, 1996)
• 13. JP 08 117 326 (Unitika, 1996)

D. Introducing the active substance into the polymer by swelling, dipping and the like. Ä.

• 1. USP 4,612,337 (Columbia University, N.Y., 1985)
• 2. WO 87-03 495 (Denver Surg. Developm. Inc., 1985)
• 3. WO 89-04 682 (Coloradeo Biomedical Inc., 1987)
• 4. EP 405 284 (Hercules Inc., 1989)
• 5. DE 41 43 239 and EP 550 875 (Schierholz, 1991)
• 6. WO 94-10 838 (Univ. Of Texas, 1992, Raad and Sherertz)
• 7. DE 43 37 492 (Schierholz, 1993)
• 8. WO 96-33 670 (Univ. Of Texas System, 1995)

The state of the art and its disadvantages are also described in the following reviews:

• 1. Catheter-Related Infections, Editors H. Seifert, B. Jansen, B. M. Farr, Marcel Dekker Inc., New York / Basel / Hong Kong 1997,
• 2. High Performance Biomaterials, Editor M. Szycher, Technomic Publishing Co. Inc., Lancaster / Basel 1991,
• 3. Bach A. and Motsch J., infusion therapist. Transfusion Med. 21, 104-114 (1994),
• 4. Jansen B. and Peters G., J. Hospital Infections 19, 83-88 (1991),
• 5. Raad I. et al, Annals of Internal Medicine 127 (4), 267-274 (1997),
• 6. Schierholz J.M. et al, cent. Bl. Bacteriol. 289: 165-177 (1999).

The disadvantages of the known methods and technical solutions are:
The active ingredients are not released evenly.
The timing of the drug release is not controllable.
The release of active substances from a mixture cannot be controlled.
The drug release cannot be influenced from the outside.

The invention was therefore based on the object of such a modification of an in vivo polymer surface to be used, the disadvantages described avoids.

According to the invention, small particles, e.g. B. nanocapsules, microcapsules or liposomes containing biologically active substances, chemically fixed to the polymer surface. These fixed particles become depending on Application area controllable the biologically active substances after the introduction of the equipped medical technology materials released into the body. It can too Mixtures of these particles that contain the biologically active substances over different times release, are used, so that it becomes possible for a long period of time required almost uniform active concentrations on the surface of the to achieve implanted or imported biomaterials. Mixtures can also be used  of these particles, each with different biologically active substances with different chemical and physical properties and resulting different Release kinetics are included, so that it is possible for the different biologically active substances also different active concentrations at the Adjust surface of medical technology materials.

Depending on the application, nano- or Microcapsules or liposomes with defined release behavior. The so particles containing active substance are attached to the by means of bifunctional spacer groups Polymer surface bound. The selection of these spacer groups depends on the chemical properties on the one hand of the polymer to be modified and on the other hand the particles to be fixed and the medium in which the coupling takes place. Especially suitable spacers are the isocyanate, isothiocyanate, epoxy and amino groups as well as carboxylic acid derivatives. For the selection of the spacers can both chemical structures with predominantly hydrophobic or extremely hydrophilic Properties to be considered. For a number of applications Spacer groups consisting of polyalkylene glycol derivatives, in particular of Polyethylene glycol derivatives or their block polymers with polypropylene glycol units proven.

In this way, surfaces of polymers, from which usually medical devices such. B. catheters, drainages, prostheses, skin replacement materials or other implants, for a time required by medical considerations to be implanted or introduced into the body.

The biologically active substances selected for medical use that are used in the particles bound to the polymer surface are introduced, e.g. B. antimicrobial substances, hormonally active substances, immunologically active Substances that e.g. B. counteract the rejection of implants, substances that Tumor growth affect substances that are deposited by the body's own Prevent or prevent molecules, substances that influence blood clotting, or Mixtures of the listed substances.

When using nano or micro capsules or liposomes, which in addition to the biologically active substances or substance mixtures to be released, including magnetic ones Containing domains, the particles can be generated by an external electromagnetic Alternating field can be heated specifically. Due to the higher permeability achieved Capsule wall of the particles can have a defined release of the biologically active Substances are achieved.

The advantages of the invention are that by the choice of encapsulation materials and modification of its chemical properties over time  Drug release can be made controllable, and that when using Particle mixtures with different, predefined defined Release behavior of the individual particle types Periods, preferably in weeks, at the desired location of the catheter position in the Patients can be reached. Another advantage is that depending on the medical need the individual particle types one at the Polymer surface fixed particle mixtures different biologically active Contain substances and can be released with the appropriate time characteristics. The advantage of the invention is also that by using particles that contain magnetic domains, the possibility is given to release the encapsulated biologically active substance or mixture thereof to a freely selectable Time after insertion or implantation of the medical device in the To induce patients. This advantage can e.g. B. in the case of suddenly occurring infections or Defense reactions or when a staggered release of active ingredient is required be exploited.

Embodiments example 1 A. Production of the active ingredient-containing PVP-co-AS microcapsules

300 mg rifampicin (Fluka) and 2.7 g poly (1-vinylpyrrolidone-co-acrylic acid) (PVP-co-AS) (Aldrich) are dissolved in 120 ml of water and spray dried (Büchi Mini Spray Dryer B-191) transferred into capsules with a size of 1-5 microns.

For crosslinking, 500 mg of these capsules are resuspended in 70 ml of petroleum ether. To Adding 227 mg (1.1 mmol) of dicyclohexylcarbodiimide (DCC) to the suspension Stirred for one hour at room temperature. Then 65 mg (0.5 mmol) of 1,7-diaminoheptane admitted. The suspension is stirred for a further 2 h at room temperature. After that the capsules separated by filtration, washed with petroleum ether and again in 70 ml Petroleum ether resuspended.

For amino functionalization, 227 mg (1.1 mmol) DCC again become the capsule suspension given and stirred for one hour at room temperature. After adding 240 µl (2.2 mmol) Diethylenetriamine, the suspension is stirred for a further 2 hours at room temperature Capsule material filtered, washed with petroleum ether and dried. There will be 475 mg cross-linked and functionalized rifampizine poly (1-vinylpyrrolidone-co-acrylic acid) - Get microcapsules.  

B. Isocyanate modification of the polyurethane surface

A 4 cm length of polyurethane (PUR) tube is filled with 4 ml of Hexa methylene diisocyanate / petroleum ether (1: 4) for three days at room temperature and washed once with 4 ml of n-hexane.

C. Immobilization of the active ingredient-containing microcapsules on the Polyurethane surface

100 mg of rifampizine-PVP-co-AS microcapsules are in 4 ml of petroleum ether for 2 h at 40 ° C in Shake incubator reacted with the pretreated tube section, once washed with 4 ml of n-hexane and dried in vacuo at room temperature for 3 h.

Example 2 A. Preparation of the PMMA-co-MAS Microcapsules Containing Active Ingredients

0.9 g poly (methyl methacrylate-co-methacrylic acid) (PMMA-co-MAS) (Aldrich) and 100 mg Rifampizin are dissolved in 4 ml of chloroform and stirred at 1500 rpm (IKA, Eurostar) into a 1% polyvinyl alcohol solution (MW: 100,000 Da). The suspension is stirred for 2 hours at room temperature. Then the particles are filtered and with Washed water.

For amino functionalization, 500 mg of the particles in 10 ml 0.1 M MES (2-Mor pholinoethanesulfonic acid) and after adding 192 mg (1 mmol) EDC (1- (3- Dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride) for one hour at room temperature shaken. After adding 240 ul (2.2 mmol) of diethylenetriamine the suspension shaken for a further 2 hours at room temperature. Then the particles with Washed water and freeze-dried. 485 mg of amino functionalized Rifampizin poly (methyl methacrylate-co-methacrylic acid) microcapsules obtained.

B. Modification of the polyurethane surface

The polyurethane surface is modified analogously to Example 1.

C. Immobilization of the active ingredient-containing microcapsules on the Polyurethane surface

100 mg of rifampizine-PMMA-co-MAS microcapsules are placed in 4 ml of petroleum ether for 2 h at 40 ° C reacted with the pretreated tube section in the shaking incubator, washed once with 4 ml of n-hexane and dried in vacuo at room temperature for 3 h.  

Example 3 A. Production of the PLA Microcapsules Containing Active Ingredients

0.9 g of polylactic acid (MW: 2000 Da, Boehringer Ingelheim) and 100 mg of rifampicin dissolved in 5 ml of ethyl acetate (solution A). To 54 ml 1% polyvinyl alcohol solution (MW: 100,000 Da) 6 ml of ethyl acetate are added with stirring at 800 rpm (solution B). Solution A will added to solution B with stirring at 800 rpm. 200 ml of water are at 500 rpm (IKA, Eurostar) stirred. The ethyl acetate emulsion is dropped into the water with stirring and stirred overnight. The particles are filtered, washed with water and freeze-dried.

For amino functionalization, the particles are coated with polymethacrylic acid. To 600 mg of the particles obtained are resuspended in 25 ml of water. After adding 50 mg Sodium dodecyl sulfate, the suspension is rotated in a rotary evaporator for 1 hour. Then 120 ul methacrylic acid, 12 ul ethylene glycol dimethacrylate and 24 mg Potassium peroxydisulfate added. The surface coating takes place while rotating at 65 ° C over night. After washing the particles with ethanol and water, the particles in 10 ml Water resuspended.

For amino functionalization, 100 mg EDC and 54 mg are added to the aqueous particle suspension Sodium carbonate and. Given 66 mg of N-hydroxysuccinimide and at 2 hours Shaken at room temperature. After adding 60 µl of diethylenetriamine, the suspension shaken for a further 2 hours at room temperature. After that, the particles with water washed and freeze-dried. 560 mg of amino-functionalized rifampicin Get polylactic acid microcapsules.

B. Epoxy modification of the polyurethane surface

A 4 cm length of PUR tubing is filled with 4 ml of hexamethylene diisocyanate / petroleum ether (1: 4) swirled at room temperature for three days, once with 4 ml Washed n-hexane and dried in vacuo at room temperature for 3 h. Then will swirled the PUR hose section with 4 ml of water overnight at room temperature (Gas evolution) and washed once with 10 ml of water. The incubation with water will Repeated two more times and the PUR hose section then in a vacuum Room temperature dried for 3 hours. Then the tube section with 4 ml Polyethylene glycol diglycidyl ether / petroleum ether (1: 4) with swirling overnight Reacted and washed once with 4 ml of n-hexane.

C. Immobilization of the active ingredient-containing microcapsules on the polyurethane surface

The functionalized tube section is in 4 ml of petroleum ether, the 100 mg of rifampizine-PLA Contains microcapsules, swirled at room temperature overnight. The hose section is washed once with 4 ml of n-hexane and in vacuo at room temperature for 3 h dried.

Example 4 A. Production of the PLA Microcapsules Containing Active Ingredients

0.9 g amino-modified polylactic acid (MW: 2000 Da, micromod GmbH) and 100 mg Rifampizin are dissolved in 5 ml of ethyl acetate (solution A). To 54 ml of 1% polyvinyl alcohol solution (MW: 100,000 Da) 6 ml of ethyl acetate are added with stirring at 800 rpm (solution B). Solution A is added to solution B with stirring at 800 rpm. 200 ml of water stirred at 500 rpm (IKA, Eurostar). The ethyl acetate emulsion is stirred into the Water dripped and stirred overnight. The particles are filtered, washed with water and freeze-dried.

820 mg of amino-functionalized rifampizine-polylactic acid microcapsules are obtained.

B. Modification of the polyurethane surface

The polyurethane surface is modified analogously to Example 1.

C. Immobilization of the active ingredient-containing PLA microcapsules on the Polyurethane surface

The functionalized tube section is in 4 ml of petroleum ether, the 100 mg of rifampizine-PLA Contains microcapsules, swirled at room temperature overnight. The hose section is washed once with 4 ml of n-hexane and in vacuo at room temperature for 3 h dried.

D. Release behavior of the immobilized amino-modified PLA microcapsules

The immobilized PLA microcapsules show in the observed period of 49 hours a continuous release of active ingredient when incubated in plasma of approx. 130 µg active ingredient from 50 mg capsule material.  

Applicant

Research & Development Center of Bioengineering GmbH Charles Darwin Ring 1 D-18059 Rostock

inventor

Dieter Lohmann, 01445 Radebeul
Joachim Teller, 18276 Mistorf
Horst Klinkmann, 18059 Rostock
Wolfgang Schütt, 18146 Rostock

Representative

Patent attorney Dr.-Ing. Bernhard Rother Parkstrasse 27 18059 Rostock

description

Polymer surfaces with biologically active properties and processes for your Manufacturing.

Claims (19)

1. Polymer surface with biologically active properties, characterized in that uniform particles or particles with different chemical and physical properties and / or different biodegradability, which control the release over a longer or to be determined periods of time encapsulated in one or more biologically active substances enables to be coupled on the surface of the polymer via chemical processes. 2. Polymer surface with biologically active properties according to claim 1, characterized characterized in that the particles structured as nano and or microencapsulations are. 3. Polymer surface with biologically active properties according to claim 2, characterized characterized in that the particles are constructed according to the core-shell principle, the outer shell is permeable or biodegradable.   4. Polymer surface with biologically active properties according to claim 2, characterized characterized in that the particles consist of different layers that successively through their biodegradation the intermediate ones release active substances. 5. Polymer surface with biologically active properties according to claim 2, characterized characterized in that the particles are liposomes. 6. polymer surface with biologically active properties according to claim 1, 2, 3, 4 and 5, characterized in that mixtures of particles with different Ingredients and / or different biodegradation behavior or different release kinetics can be coupled. 7. polymer surface with biologically active properties according to claim 1, 2, 3, 4 and 5, characterized in that the particles contain magnetic domains through an external electromagnetic field can be specifically heated and thus a have higher permeability for the enclosed biologically active substances, whereby a defined release of the pharmaceuticals can be achieved. 8. polymer surface with biologically active properties according to claim 1, 2, 3, 4, 5, 6 and 7, characterized in that they are applied to medical devices. 9. polymer surface with biologically active properties according to claim 8, characterized characterized in that the medical devices are central or peripheral vascular catheters, Dialysis catheters, peritoneal dialysis catheters, arterial and pulmonary catheters, urological catheters, catheter ports, shunts such as hydrocephalus shunts, peritoneal tubes, Tracheotomy devices, wound drainage tubes, abdominal drainage, artificial Sphincters, penile prostheses, implantable prostheses, angioplasty devices, Pacemaker capsules, artificial heart valves, urological dilators, urological Long-term devices, tissue-binding medical devices, and devices are designed for short or implanted or inserted into the body for a long time. 10. Polymer surface with biologically active properties according to claim 1, characterized characterized in that the biologically active substances for the application of the medical device are suitable.   11. Polymer surface with biologically active properties according to claim 10, characterized characterized in that the biologically active substances have antimicrobial activity are. 12. Polymer surface with biologically active properties according to claim 10, characterized characterized in that the biologically active substances disinfectants, anti-infectives from the most diverse classes of active substances or immunologically active substances. 13. polymer surface with biologically active properties according to claim 10 and 11, characterized in that the biologically active substances rifampicin and Miconazole and their mixtures are. 14. Polymer surface with biologically active properties according to claim 10, characterized characterized in that the biologically active substances are those which the Counteract rejection of implants. 15. Polymer surface with biologically active properties according to claim 10, characterized characterized in that the biologically active substances are those which the Prevent or prevent deposits of blood substances on the implants. 16. Polymer surface with biologically active properties according to claim 10, characterized characterized in that the biologically active substances are those which the Counteract blood coagulation on the surface of the implants. 17. Polymer surface with biologically active properties according to claim 1, characterized characterized in that the chemical process for coupling the particles to the Polymer consists in the use of bifunctional spacer groups. 18. Polymer surface with biologically active properties according to claim 17, characterized characterized in that the bifunctional spacer groups first on the polymer surface and then react chemically on the surface of the particles. 19. Polymer surface with biologically active properties according to claim 18, characterized characterized in that the bifunctional spacer groups are polyalkylene glycol derivatives, in particular with polyethylene glycol derivatives or their block polymers Are polypropylene glycol units.