RU2620161C1 - Method for manufacture of bypass system catheter with antimicrobial properties for hydrocephalia treatment - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: for manufacture of a bypass system catheter for hydrocephalia treatment, rifampicin is included into the catheter wall material. A silicone composition is preliminarily mixed with rifampicin to the rifampicin content of 1 to 3 parts by weight, followed by catheterization. At that, moulding is combined with the first vulcanisation stage carried out at a temperature of 170-190°C. Subsequently, immediately after moulding, the second vulcanisation stage is carried out. The temperature limits of the second vulcanisation stage are 150-190°C.

EFFECT: retained antimicrobial effect for at least two months after the implantation of catheter used for hydrocephalia treatment.

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Description

The invention relates to medicine, namely to neurosurgery, and can be used in the manufacture of a silicone catheter of the shunt system (SCS) used to treat hydrocephalus.

Hydrocephalus is a lifelong disease, which is one of the most common pathologies observed at birth and the most common cause of brain surgery in children. This disease affects about one in five hundred children.

In addition, head injuries and intracranial hemorrhages, which, according to the World Health Organization, occur on average every fifteen seconds, can lead to the development of hydrocephalus.

To date, the most effective way to treat hydrocephalus is a surgical procedure (liquor-assisting surgery), in which a shunt device (flexible tubule-catheter with valve) is installed in the cerebrospinal fluid circulation system to remove cerebrospinal fluid from the ventricles of the brain into the abdominal cavity (abdominal or peritoneal catheter) or into the right atrium (cardiac catheter). In this case, the shunt device should be completely implanted under the skin without causing cosmetic defects, without causing patients discomfort and deterioration in their quality of life.

For this reason, among shunt systems widely used in clinics and hospitals, systems made of silicone have long been preferred [Bayston R. et al. Prevention of hydrocephalus shunt catheter colonization in vitro by impregnation with antimicrobials // Journal of Neurology, Neurosurgery & Psychiatry. - 1989. - T. 52. - No. 5. - C. 605-609].

The latter circumstance is explained by a number of valuable properties of silicone: non-toxicity, low surface charge, resistance to temperature and chemical influences. In addition, silicones are atraumatic and bioinert with respect to body tissues.

Meanwhile, despite a number of obvious advantages that occur when using shunt systems made of silicone for the treatment of hydrocephalus, there are a number of problems, among which, first of all, it is necessary to name the development of various inflammatory diseases associated with the occurrence of a bacterial infection in the tissues of the body during finding in them a foreign body (bypass device).

These inflammatory processes, most often caused by several pathogenic factors - viruses, bacteria, fungi, protozoa, in some cases can even lead to death.

Among the effective methods to achieve reduction in bacteremia associated with shunting is the creation of an antimicrobial coating on both the external and internal surfaces of the catheters used. Studies by a number of scientists have found that for successful protection against infection of shunt devices in young children, the action of an antimicrobial preparation should last at least two months from the moment of implantation of the device.

The need for such a long-term action of antimicrobial agents is explained by the high susceptibility (low immunity) of the child's body to various infectious pathogens, their toxins, as well as foreign bodies [Aryan N.E. et al. Initial experience with antibiotic-impregnated silicone catheters for shunting of cerebrospinal fluid in children // Child's Nervous System. - 2005. - T. 21. - No. 1. - C. 56-61].

These circumstances put forward special requirements for the technology of introducing a bactericidal preparation into the composition of the material from which the catheter of the shunt device is made.

In analogs known from the prior art, which describe methods for imparting the antimicrobial properties of SCSS, it is proposed to include in its surface various methods, mainly impregnation, known antiseptics or antibiotics: rifampicin, trimethoprim, spiramycin, clindamycin hydrochloride, diethanolamine fusidate, vancomycin, gentamicin, ceftri ciproflooxoacin and other drugs or combinations thereof, for example, rifampicin and clindamycin, rifampicin and diethanolamine fusidate, diethanolamine fusidate and trimethoprim [Raffa G. et al. Antibiotic-impregnated catheters reduce ventriculoperitoneal shunt infection rate in high-risk newborns and infants // Child's Nervous System. - 2015. - T. 31. - No. 7. - S. 1129-1138].

Among these drugs, preference is given to rifampicin, as a drug well tolerated by children at an early age, including newborns.

This drug is universal, effective against a wide range of bacteria and has high antibacterial activity in very low doses.

In addition, a number of researchers have noted that rifampicin is well compatible with silicone [Hampl J.A. et al. Rifampin-impregnated silicone catheters: a potential tool for prevention and treatment of CSF shunt infections // Infection. - 2003. - T. 31. - No. 2. - C. 109-111].

In relation to the rifampicin-silicone system, the essence of impregnation is that the catheters are treated with rifampicin solutions in non-polar or low-polar solvents (for example, chloroform or methylene chloride) for a certain time, usually several hours, in which organosilicon rubbers swell strongly. After removal of the solvents, carried out over several days (usually 2-3) by drying the products under reduced pressure and elevated temperature, up to about 60 ° C, rifampicin remains in the catheters, which, after implantation, can be released into the body, providing an antibacterial effect.

Of the well-known publications related to the production of antimicrobial CFS, impregnated with rifampicin, the intake of which occurs during the time interval necessary for the manifestation of a certain therapeutic effect, in our opinion, the work performed in Russia is of interest [Shirshov A.V. Supratentorial hypertensive intracerebral hemorrhage complicated by acute obstructive hydrocephalus and a breakthrough of blood into the ventricular system: dis.- M .: AV Shirshov, 2006], as well as American researchers [Kohnen W. et al. Development of a long-lasting ventricular catheter impregnated with a combination of antibiotics // Biomaterials. - 2003. - T. 24. - No. 26. - C. 4865-4869].

In these works, it was shown that the amount of rifampicin injected to a certain limit depends on its concentration in solutions taken for the treatment of catheters. The concentrations of solutions taken for swelling are given, at which the maximum saturation of the catheter with an antibiotic is achieved.

For rifampicin solutions in chloroform, this concentration was 25 g / l; for solutions in methylene chloride, 29.2 g / l. The content of the antibiotic in the wall of the catheter, respectively, reached 1.5% and 1.4% of the weight of the catheters, respectively.

According to the data cited in the work of A. Shirshov, with such a saturation of the catheter with rifampicin, the period of manifestation of antibacterial activity is from 7 to 14 days.

Meanwhile, as already mentioned above, the antimicrobial (antibacterial) effect on the surface of the catheter should last at least two months from the moment of their implantation.

The solution to this problem by further increasing the concentration of rifampicin in solutions [Darouiche R. O., Raad I. Implantable medical device: US Pat. 5902283 United States. - 1999], used for impregnation, proved to be inappropriate, since no effect on the duration of antibacterial action was noted.

It should also be noted that when imparting antimicrobial properties to the catheter by the method of impregnation after removal of solvents and restoration of the size of the catheter, their shape can be distorted, as well as the appearance of roughness on the surface of the latter [Liang X. et al. Effect of cast molded rifampicin / silicone on Staphylococcus epidermidis biofilm formation // Journal of Biomedical Materials Research Part A. - 2006. - T. 76. - No. 3. - C. 580-588], can help maintain bacterial colonization and cause clogging of catheters.

In order to avoid this dangerous phenomenon, individual catheters are subject to rejection, which in turn causes their significant appreciation. This also contributes to the additional costs associated with the removal, capture and subsequent disposal of solvents used in the impregnation of catheters. This also contributes to the additional costs associated with the removal, capture and subsequent disposal of solvents used in the impregnation of catheters.

The problem solved by the claimed invention is the creation of low-cost antimicrobial SCHS with controlled release of the active substance (rifampicin), which, while maintaining the required surface quality and, accordingly, the necessary throughput of the catheter, ensures the continuous flow of the active drug into the body tissue for the time necessary to provide the desired therapeutic effect .

The problem is solved by introducing rifampicin into rubber compositions based on siloxane rubber, used for the manufacture of medical devices.

An example of the formulation of one of these compositions is presented below.

On the rollers prepare a rubber mixture of the following composition, mass. hours:

Rubber SKTV one hundred Aerosil A-300 45 Mixture stabilizer ND-8 10 Silicone fluid GKZH-94 2 Platinum catalyst (H2PtCl6-6HCl, 0.02 M p-in THF) 0.02 Rifampicin 1-3

At the same time, the determination of the main factors affecting the process of rifampicin release from the catheter wall remains important.

The studies showed that such factors are the amount of rifampicin introduced into the initial composition based on silicone rubber, as well as the temperature regime of the second stage of vulcanization, which is carried out immediately after the first stage, combined with the process of forming the catheter.

It was found that when using the mixture used to obtain SCSS filled with rifampicin in the range of 1-3 parts by weight, followed by its molding, combined with the first stage of vulcanization, carried out at a temperature of 170-190 ° C, and the second stage of vulcanization, carried out immediately after molding within the temperature range of 150-190 ° С, a catheter is obtained which, when implanted into the body, is capable of releasing the antibiotic in the amounts necessary to maintain the antimicrobial effect of at least two due to the diffusion factor x months from the moment of implantation.

The temperature regime of molding, combined with the first stage of vulcanization, is justified, on the one hand, by the need to obtain a catheter with a set of required technical properties, and, on the other hand, by the requirement to protect the antibiotic (rifampicin) from decomposition taking place at higher temperatures (starting from 200 ° FROM).

At the same time, the temperature regime of the second stage of vulcanization is a decisive factor determining the gradual release of rifampicin from catheters after their implantation for at least two months.

Thus, by changing the nature of the diffusion introduced in an amount of 1-3 parts by weight rifampicin through the wall of the catheter as a result of changes in the temperature regime of the second stage of vulcanization, an increase in the yield of rifampicin to amounts that guarantee protection of patients from bacterial infection in a period of two or more months is achieved.

The latter circumstance, namely the increase in the duration of the antibacterial action of the catheter to two months or more due to the diffusion of rifampicin, introduced in the specified amount, is the main technical result of the claimed invention. The achievement of the technical result - giving the silicone catheter the shunt system used to treat hydrocephalus, prolonged antimicrobial properties due to the creation of conditions for a gradual, uniform and, due to this, longer release of rifampicin, evenly distributed over the entire thickness of the catheter wall, i.e. a fundamental change in the nature of the diffusion of rifampicin and its practically constant concentration upon exit, which lasts for a long time.

It should be noted that the selected limits for the administration of rifampicin are dictated by the following reasons. With a rifampicin content of more than 3 parts by weight it is possible to isolate it in quantities so large (more than 4.5 mg / (s⋅cm ² ) that it can have a negative effect on the children's body, as well as adversely affect the quality of the surface of the catheter.

On the contrary, with a lower content, less than 1 mass.h, the release of rifampicin may be insufficient (less than 1 mg / (s⋅cm ² )) to organize the required level of treatment.

To illustrate the invention, the antibacterial activity of catheters with different rifampicin content and manufactured at different temperature conditions of the second vulcanization stage was compared.

To study the antibacterial activity of the samples, the modified Kirby-Bauer method was used. S. aureus (Staphylococcus aureus), S. Eepidermidis (Staphylococcus epidermis) were selected as test strains.

Evaluation of antibacterial activity was carried out in Petri dishes on a solid nutrient medium Agar Mueller-Hinton (pH 7.4 ± 0.2). The inoculum dose of bacteria was 10 ⁶ CFU / ml (colony forming units). 3-4 samples from each test product group were placed on the surface of the seeded plates. All samples were incubated at 37 ° C for 24 hours, after which the diameters of the zones of growth inhibition of bacteria around the product samples were measured.

To determine the duration of the antibacterial activity of the product, samples around which there were growth inhibition zones (even minimal ones) were transferred daily to freshly seeded plates until there were no zones of inhibition of microorganism growth.

Experimental data illustrating the patent application submitted are given in table. one.

As can be seen from the data presented, with a decrease in the temperature of the second stage of vulcanization of the catheter, the duration of the antimicrobial action changes markedly. From this, the optimal temperature parameters of the second stage of vulcanization of the catheter were revealed in combination with the necessary rifampicin content, which ensure the required regimen for rifampicin release on the surface of the catheters. These are temperature limits from 150-190 ° C with a rifampicin content of 1-3 wt.h.

At temperatures above 190 ° C, the process of melting and subsequent destruction of rifampicin begins, while lowering the temperature below 150 ° C does not seem appropriate, since the catalytic activity of the platinum catalyst is minimal.

Claims (1)

A method of manufacturing a shunt system catheter for treating hydrocephalus, comprising rifampicin in the wall material of a catheter molded from a silicone composition, characterized in that the silicone composition is pre-mixed with rifampicin to a rifampicin content of 1 to 3 parts by mass and the catheter is subsequently molded, combining the molding with the first stage of vulcanization, carried out at a temperature of 170-190 ° C, then immediately after the molding, the second stage of vulcanization is carried out, p and this temperature limits the second curing step is 150-190 ° C.