JPH0798058B2 - Method for stabilizing TDMAC heparin coating - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for stabilizing heparin coatings on medical devices, and more particularly to stabilizing TDMAC heparin coatings on medical devices made of polyvinyl chloride (PVC). The method for making it happen.

[0002]

Heparin is used to prevent the formation of blood clots.
An anticoagulant substance that is often applied to the surface of medical devices used in the bloodstream. Many medical devices are made of polyvinyl chloride (PVC). Heparin is PVC
It may be bonded directly to the surface of the device. However, it is known that heparin has better antithrombogenic properties when the heparin molecule is separated from the PVC surface.
Especially tridodecylmethyl ammonium chloride (TDMA
Molecules such as C) and PEO-polyethylene oxide are used to separate the heparin molecule from the PVC surface and to attach the heparin molecule to the PVC.

The standard practice for applying TDMAC heparin to medical devices is to first assemble a medical device made of PVC. Next, medical equipment is TDM
A toluene / petroleum ether one-to-one mixture containing, for example, 1.25-2% by weight of AC heparin complex,
It is typically immersed for about 30 seconds. The coated medical device is then air dried at room temperature.

The method of binding heparin to TDMAC is believed to be a weak ionic bond. Furthermore, T
The DMAC material is believed to bond in contact with the PVC material by weak van der Waals bonds.
Therefore, it is relatively easy to break the van der Waals bond and remove heparin bound to it by TDMAC and weak ionic bonds from the medical device.

The PEO-polyethylene oxide molecule binds to both heparin and PVC by relatively strong covalent bonds. As a result, heparin is more strongly PV by PEO-polyethylene oxide than by TDMAC.
Bound to C. However, the method of binding heparin to PVC by PEO-polyethylene oxide is much more complicated than the one-step dipping process described above, which binds heparin to PVC by TDMAC.

Heparin may be separated from and bound to PVC medical devices by TDMAC, but when used in the body, heparin can still be dissolved from medical devices over time. It is desirable to maintain heparin on the medical device as long as possible to minimize the formation of blood clots, especially when the medical device is left in the patient's body for an extended period of time.
Further, it is desirable that the material that binds heparin to the medical device, in this case TDMAC, is not released into the patient's body.

The medical device may also be made of polyurethane or silicone. Heparin, like PVC, may be attached directly to polyurethane or silicone polymer materials or via spacer molecules. Again, as with medical devices made of PVC, it is known that heparin has better antithrombogenic properties when the heparin molecule is separated from the polyurethane or silicone surface.

A disadvantage of using polyurethane or silicone to make medical devices is that polyurethane and silicone are more expensive and difficult to process than PVC. Moreover, PVC has additional advantages over polyurethane or silicone. Unlike polyurethane or silicone, PVC is very heat sensitive. In particular, PVC is relatively stiff at room temperature for wearing on a patient and can become dramatically softer when the medical device is warmed to body temperature, increasing patient comfort and reducing injury. Further, by varying the resin to plasticizer percentage, PVC can be made to various stiffnesses,
It is possible to provide the desired balance of physical properties.

An additional advantage of using PVC is that P
The VC is that it can be easily compounded with high levels of radiopaque agents, making it possible for the resulting medical device to be easily identified in X-ray or fluoroscopy. Furthermore, unlike silicon, P
The tip of a VC catheter can be melt formed into a smooth, rounded shape, and tapered tubing, including those with integral connectors, can be easily formed.

[0010]

In view of the above, PV is used so that medical devices used in the blood stream, especially those that are left in the blood stream for extended periods of time, can be made of PVC.
It is desirable to bind heparin strongly to PVC via a spacer molecule that is easily applied to C.

Therefore, an object of the present invention is to provide a medical device having a T-type.
It is to provide a method for strongly binding DMAC heparin.

Another object of the present invention is to provide a TDM for medical devices.
It is to provide a method of sterilizing a medical device while binding AC heparin.

Another object of the invention is to attach heparin to PVC via a spacer molecule by a simple and easy method to carry out.

A further object of the present invention is to provide a method for coupling TDMAC heparin to a relatively inexpensive medical device.

A further object of the present invention is to provide a medical device with a TD.
It is to provide a method for binding MAC heparin that does not significantly affect the structural integrity of the medical device.

[0016]

A medical device made of PVC is coated with a solution of TDMAC heparin and then air dried. The coated medical device is then exposed to gamma rays. Gamma rays enhance the binding of TDMAC heparin to the materials of medical devices.

[0017]

In a modification of this method, the gamma-irradiated TDMAC heparin-coated medical device is heated for an extended period of time. It has been found that this heating further enhances the binding of TDMAC heparin to medical devices.

An additional advantage of gamma irradiating a TDMAC heparin coated medical device is that the medical device uses ethylene oxide (ETO) gas and is sterilized without the attendant problems. .

These and other objects of the invention will be apparent from the description herein, and more particularly with reference to the following detailed description.

[0020]

DETAILED DESCRIPTION OF THE INVENTION The present invention comprises a method for firmly attaching TDMAC heparin to the surface of a medical device. The medical device is preferably made of polyvinyl chloride (PVC) material. However, it is contemplated that the methods described herein may be applied to polyurethane or silicone medical devices.

In order to apply the method of the present invention, the medical device must first be assembled. Representative medical devices include, but are not limited to, catheters, shunts, cannulas, tubes and other devices used in contact with blood. The medical device is then immersed for about 30 seconds in a toluene / petroleum ether one-to-one (weight ratio) mixture containing a 1.25-2% by weight solution of TDMAC heparin. This coats the surface of the medical device with the TDMAC heparin solution.

After immersing the medical device in the TDMAC heparin solution, the medical device is removed and allowed to air dry at room temperature.

The next step is to expose the TDMAC heparin coated, naturally dried medical device to gamma radiation. The amount of gamma radiation is the amount commonly used to sterilize medical devices. The general range of gamma rays used to sterilize medical devices is
It is about 0.5 to 3.5 megarads. However, the preferred range of exposure is from about 1.5 to about 2.5 megarads.
The preferred gamma exposure range is about 1.5 to about 2.5 megarads, although low exposures of about 0.5 megarads and exposures up to about 3.5 megarads are also believed to be effective. A common source of gamma radiation is cobalt-60, although other sources of gamma radiation may be used if desired.

As a result of exposing the medical device to this particular amount of radiation, the medical device was sterilized as a result of exposure. Sterilization is an alternative to ethylene oxide (ETO) gas sterilization. By avoiding the use of ethylene oxide, there is no risk of residual toxic ethylene oxide or its by-products remaining in the packaging. In addition, ETO, which is commonly used to remove residual ETO gas or its by-products,
The weeks of aeration of the packaging containing the sterilized equipment are eliminated. By using gamma radiation according to the invention, aeration is not necessary.

Furthermore, ETO gas is used for sterilization.
It is often mixed with fluorocarbons such as freon to deliver gas, reducing the risk of explosion that is likely to occur with highly flammable ETO gas. Freon gas emissions are a problem with current systems. Eliminating ETO eliminates suspected freon emissions that are a source of ozone layer depletion under these circumstances.

A TDMAC heparin coated device exposed to gamma radiation in accordance with the teachings of the present invention in a saline or whole blood test to determine the amount of TDMAC heparin retained on a medical device; TDMAC not exposed to gamma radiation
Compared to heparin-coated devices, a significantly higher amount of TD is seen on gamma-irradiated medical devices.
The MAC heparin coating was retained.

As mentioned above, the medical device is equipped with a TDMAC.
It is believed that in the process of soaking in heparin, TDMAC binds to the surface of the medical device by weak van der Waals bonds and heparin binds TDMAC by ionic bonds. Gamma irradiation causes some cross-linking or covalent bonding between the heparin molecule and the TDMAC and surface molecules of the medical device, which results in TDMA.
It is believed to increase the bond strength between C-heparin and the medical device.

Furthermore, studies have shown that, after exposure to gamma radiation, heparin molecules appear to maintain their anticoagulant properties.

An additional step after exposing the medical device to gamma radiation provides a TDM for the medical device.
This results in a tighter binding of the AC heparin molecule. In this step, after removing the medical device from exposure to gamma rays, the coated, irradiated medical device is heated for an extended period of time. The preferred temperature is about 150 ° F. (65.5 ° C.) and the preferred time is about 3 days. The preferred heating method is forced air heating, although other heating methods may be used.

If the medical device is made of PVC, P
Due to the heat sensitivity of VC materials, the physical properties of PVC are TDMAC while exposed to higher temperatures.
It changes in a way that the heparin molecule binds more tightly to PVC. Even when the PVC is cooled, the bond between the PVC formed at elevated temperature and the TDMAC heparin molecule remains strong. By combining this heating with gamma radiation in accordance with the teachings of the present disclosure,
The TDMAC heparin molecule has been found to be more reliably bound to medical devices than it is with gamma radiation alone. Similar steps are followed when the gamma-irradiated medical device is then heated in accordance with the teachings of the present invention to more firmly bind the TDMAC heparin molecule to the surface of the polyurethane and silicone medical device. Thought to be usable.

In a saline test made to determine the bond strength that binds TDMAC heparin to a medical device in the method of irradiation and heating, the device is simply T
It was found that 4-5 times less heparin was removed within the same time compared to the method of soaking in the DMAC solution and allowing it to air dry.

Any composition of PVC material is considered to be in accordance with the method of the invention described herein. Especially 1
PVC material with 00 parts resin and about 60 parts plasticizer, as well as PVC with 100 parts resin and about 47 parts plasticizer were tested according to the disclosure provided herein. It was found that there was no significant difference in the binding strength of TDMAC heparin to PVC material.

[0033]

As mentioned above, one step of the methods disclosed herein is to coat a medical device with a coating of TDMAC heparin. The preferred method of coating the medical device is by dipping the medical device in a TDMAC heparin solution. However, other methods for coating medical devices with TDMAC heparin, as those skilled in the art can envision, are within the scope of the present invention. Examples of such means include, but are not limited to, spraying, wiping, and applying TDMAC heparin to medical devices.

Further, the preferred method of creating the TDMAC heparin solution is to mix TDMAC heparin with toluene / petroleum ester, although other solvents may be used in place of toluene / petroleum ester. In particular, other organic solvents, more particularly hydrocarbon solvents, can be used instead of toluene / petroleum ester.

Further, the step of drying the TDMAC heparin coated device is preferably accomplished by allowing the device to air dry at room temperature, although other methods of drying medical devices are within the scope of the invention. For example, TDMAC is just a few of the ways one skilled in the art can conceive.
The medical device coated with heparin may be dried by forced air heating or oven drying. Obviously, the temperature for drying the medical device may be raised above normal room temperature.

The invention has been described with respect to particular methods.
It should be understood that the description contained herein is for purposes of illustration and not limitation. Changes and modifications may be made to the description contained herein and still be within the scope of the invention. Furthermore, obvious changes and modifications will occur to those skilled in the art.

Claims (4)

[Claims] 1. A method for stabilizing a tridodecylmethyl ammonium chloride (TDMAC) heparin coating on a medical device, the method comprising: coating the medical device with a TDMAC heparin solution; Drying the TDMAC heparin solution on the medical device, irradiating the coated medical device with gamma rays, and heating the pre-gamma irradiated medical device. , A method for stabilizing a TDMAC heparin coating on a medical device. 2. A method of stabilizing a tridodecylmethyl ammonium chloride (TDMAC) heparin coating on a medical device, the method comprising coating a medical device with a TDMAC heparin solution comprising TDMAC heparin mixed with a solvent. A step of naturally drying the coated medical device at about room temperature, a step of irradiating the coated medical device with gamma rays, and a step of heating the medical device pre-gamma irradiated. A method of stabilizing a TDMAC heparin coating on a medical device, the method comprising: 3. A method for stabilizing a tridodecylmethylammonium chloride (TDMAC) heparin coating on a medical device, the method comprising: toluene / petroleum containing about 1.25-2 wt% TDMAC heparin solution. Immersing the medical device in a TDMAC heparin solution containing a 1: 1 mixture by weight of ester for about 30 seconds, allowing the coated medical device to air dry at about room temperature, and the coated medical device Exposing the device to gamma rays with an intensity of about 0.5 to about 3.5 megarads and pre-gamma-irradiating the medical device at about 150 ° F.
Heating at (65.5 ° C.) for about 3 days, for stabilizing the TDMAC heparin coating on the medical device. 4. A method of stabilizing a TDMAC heparin coating on a polyvinyl chloride (PVC) medical device, the method comprising: coating the medical device with a TDMAC heparin solution; Drying the TDMAC heparin solution on the medical device, irradiating the coated medical device with gamma rays, and heating the pre-gamma irradiated medical device. A method of stabilizing a TDMAC heparin coating on a vinyl chloride (PVC) medical device.