LV14256B - Device and method for impregnation and/or coating of porous implants with substancies - Google Patents

Abstract

There is offered a new implant impregnation and /or coating device and method referable to the medical field, mainly in orthopedics, traumatology, dentistry, face, jaw and other hard porous bone tissue surgery. It improves quality of the implant impregnation and/or coating process, creates economic opportunities of pharmaceutical drug use (consumption). It is multifunctional and is based on controlled impregnation of the implant open pores and/or implant coating with one or more of the necessary substances (pharmaceuticals, polymers, suspensions, etc. applicable to agents) under depression conditions. Impregnation parameters are set according to the choice of implant and substance (impregnation and / or coating substances), physical-chemical properties (porosity, capillary forces, viscosity, etc.). Optimum impregnation parameters are determined by varying the implant holding time under depression conditions before and after impregnating solution is added, as well as changing the impregnation and/or coating pressure. The device is characterized by the fact that it is compact, simple and economical in operation, equipped with a graduated dropping funnel and vacuum pump, includes interrelated functional parts what form hermetically sealed system, which allows to maintain sterility throughout whole process.

Description

The invention relates to the medical field and is applicable to impregnation and / or coating of porous implants with the necessary pharmaceutical substances or biocompatible and biodegradable polymers in thinning. The device and process can be implemented sequentially in three technological steps: sterilization, vacuuming, impregnation and / or coating. It provides process multifunctionality, an economical and efficient impregnation and / or coating process, and maintains sterility throughout the process.

The results of research by Japanese scientists to impregnate chemotherapeutic agents in porous hydroxylapatite ceramic blocks (2x2x2 cm) are known [lj. The results of the studies confirm the general applicability of thinning to the impregnation of a particular material, but do not employ a controlled delivery of the impregnating pharmaceutical agent, nor are the device designs applicable to impregnation sequentially with one or more impregnating agents while maintaining process sterility. In addition, the sample is completely coated with an impregnating pharmaceutical solution prior to vacuuming, making it difficult to expel air from the open pores.

The method of fixation of antibiotics in porous implants is also known [2]. According to this method, the implant's pores are impregnated with antibiotics under the influence of the capillary forces of the implant. The impregnation control of implants made mainly of titanium nickel is carried out by weighing. In this technique, the air is expelled from the open pores gradually before impregnation, so that the impregnated implant is only partially submerged in the gel so that it covers a% of the implant height. The disadvantages of this technique are that it does not provide an adjustable degree of impregnation, nor can it be impregnated sequentially and / or coated with several substances while maintaining the sterility of the process. The process is time consuming and is mainly applicable to antibiotic impregnation of titanium nickelide only, with the preparation of a sterile antibiotic and a gel of a soluble macromolecular compound such as gelatin.

A device and technique for vacuum infusion of porous implants are also known [3]. This device and method cannot provide sequential impregnation and / or coating. Constructively, it is not applicable to the controlled delivery of the impregnating agent. In addition, it is a single use device and is not economical in operation.

None of the known devices and techniques [1-3] can accomplish the impregnation and / or coating of sequential and adjustable implants with the required substrates (polymers and other agents) because they are not constructively capable of providing such functions while maintaining the sterility of the process. They are technically difficult to operate and not economical.

The device and method for impregnation of porous bone material, patented in Switzerland, have been chosen as the prototype [4]. With this device and technique, the vacuuming and impregnation of bone material is accomplished in a specialized device with the aid of a medical syringe. This does not allow the adjustment of thinning, which in turn does not provide optimal and effective implant impregnation and / or coating and effective control of the process. The drawback of the device is the need to make a special design - a flexible spring, which fixes the implant to be impregnated. This makes it difficult to operate the device in practice because the implant can be impregnated by moving the spring. The technique does not provide the multifunctionality of the impregnation process, including impregnation of granular samples.

The object of the invention is to develop a simplified technological construction of the impregnation device, to expand its applicability, to provide multifunctionality by sequentially impregnating and / or coating the implant with the necessary pharmaceutical and other substances and maintaining the sterility of the process, and to provide economical medication.

The object of the present invention is achieved by developing and assembling a device (Fig. 1) for impregnating and / or covering porous implants with pharmaceutical and other necessary substances, the embodiment of which comprises a vacuum vessel 1 impregnated and / or covered with a lid 2, through which a graduated cylindrical dropping funnel 3 is provided with a stopcock 4 for adjustable delivery of impregnating and / or coating agents 5. The impregnation vacuum vessel 1 has an opening 6 on its side, through which a vacuum pump 7 is connected via a sealed shutter (eg KNF vacuum pump manufactured in Germany) with a pressure gauge 8. The vacuum pump is connected to the impregnation vacuum vessel via Teflon or silicone tube 9. with regulating valve 10.

The size of the impregnation vacuum vessel depends on the size of the implant required. If it is necessary to impregnate and / or cover small implants of less than 5 cm in length, 5 cm in height and 5 cm in width, or granular implants, a suitable smaller container 12 is selected which is sized according to the size of the implant to be impregnated and / or coated. . This facilitates the economical and useful use of impregnating and / or coating agents.

The device is made with prefabricated components made of chemically and thermally resistant material, such as glass, which allows the impregnation process to be observed visually. Compared to the prototype, the device incorporates technologically-related functional components, is easy to assemble, and has a graduated drip funnel capable of delivering an adjustable amount of impregnating and / or coating fluid required, depending on the purpose of implant impregnation and / or coating to ensure process efficiency and economic use of reagents.

The purpose of impregnation is to eliminate the risk of infection, promote biocompatibility of bone tissue and implant, and prevent toxic or allergic reactions.

In order to technologically implement a multifunctional variant using the device described above, the proposed method of impregnating porous implants with porosity of 1-95% (recommended porosity of 3070%) with pharmaceutical substances can be implemented in three steps:

- during the first stage, sterilization of the component parts of the device (except for the vacuum pump) and the implant according to the surgical requirements (high temperature, chemical reagents, steam, pressure, etc.);

- in a second step, vacuuming the implant inserted into the vacuum vessel impregnating the complete device for the purpose of evacuating the air from the open, interconnected micropores;

- in the third step, upon returning the tap of the dropping funnel, the implant is gradually coated with the required amount of solution to be impregnated and / or coated, depending on the desired degree of impregnation and / or coating and the physico-chemical properties of the implant and pharmaceutical impregnating agent.

Implant impregnation may be performed sequentially with multiple substances, thereby providing a multifunctional technique. By varying the thinning, the holding time with and without the impregnating agent experimentally determines the amount of solution to be impregnated and the efficiency of the process.

Implants can be used for impregnation, for example, on the basis of calcium phosphate ceramic and glass ceramic with porosity of l-95%>. Solutions for injection and sterilized solutions, i.e. solutions in ampoules, are used for impregnation. As impregnating agents, medicaments, suspensions, emulsions, etc. may be used. biological fluids or solutions. Their necessity is determined by the specifics and requirements of the surgical process.

In order to determine the optimal parameters of the vacuum process and to evaluate its efficiency, experimental studies were carried out using 44% calcium phosphate-based ceramics for porous implants and 2% lidocaine hydrochloride solution for injection as impregnating agents (manufactured by GRINDEX, LATVIA). ) and gentamicin solution for injection (manufactured by KRKA, SLOVENIA). For characterization of the degree of impregnation, the weight of impregnated material in the open pores of the implant was compared with the porosity of the implants. The amount of impregnated substance in the implant was calculated as the ratio of the impregnated implant mass to the initial implant mass relative to the implant initial mass:

100%, zn ₀ where m _impr . is the weight of the impregnated substance and Am is the difference between the weight of the impregnated implant and the initial mass m ₀ .

The effect of the vacuum time of the implants (before and after the impregnation and / or coating) on the impregnation process was also experimentally tested, as well as the efficiency of the vacuum process during the impregnation and / or coating process.

At implant porosity 44%, without pre-vacuuming the implant, the amount of impregnated substance (distilled water) in the implant after 10 min. holding solution reached 32%. By contrast, using 600 mbar thinning prior to impregnation, it is possible to achieve 41 to 42% impregnation and 35 m impregnation at 500 mbar. By varying the depression, it is possible to achieve the desired venting of open pores and adjustable amount of impregnating agent in the implant.

Studies have shown that, depending on the porosity of the implant and the technological parameters of the impregnation (pressure, vacuum time), it is possible to provide an adjustable amount of impregnated substance in the implant and complete or partial filling of open pores. The amount of impregnated substance in the implant also depends on the physico-chemical properties of the impregnating substance (surface tension, viscosity, density, etc.).

If lidocaine hydrochloride and gentamicin solutions are used as impregnating agents but 44% porosity hydroxylapatite ceramics is used as implants, then the optimum amount of impregnating agent in the implant can be achieved by vacuuming the implant at 600 mbar with a holding time of 15 min. without impregnating substance, after which the implant was held for 5 min. in thinning mode with an impregnating substance and then for an additional 20 minutes without thinning. With such impregnation process parameters it is possible to achieve complete impregnation of the open pores of the implant.

It has been experimentally demonstrated that changing the impregnation process parameters (pressure, vacuum time before and after the impregnating agent is added) can provide a controlled and controlled delivery of the required pharmaceutical agent to the implant.

The device and method of the present invention differs from the known devices and methods which are applicable only to impregnation of implants with pharmaceutical substances, in that not only impregnation of the implants but also their coating, for example with biocompatible and biodegradable polymers, is realized. The purpose of bioceramic backing is to provide a gradual, controlled release of the drug from the impregnated implants. The following coatings were used:

- polyvinyl alcohol having the following characteristics: 1) Mw = 6 kDa, 80 mol% hydrolyzed, Lot. No.558575, Cat. No.22225, Polyscience; 2) Mw = 25 kDa, 98 mol% hydrolyzed, Lot. No.560524, Cat. No. 4397, Polyscience;

- Polylactate, characterized by: Biomer L9000 PLLA Biodegradable Polymer, Mw 200 kDa, Polyscience and

- polycaprolactone with the characterization: Mw = 43-50 kDa, Lot. No.541261, Cat no. 19561, Polyscience.

Implant coating using the apparatus according to the present invention is accomplished as follows: inserting a container containing a polymer solution and a bioceramic implant pre-impregnated with a lidocaine or gentamicin solution; in the case of an aqueous solution, vacuum for 10 min. at 600 mbar, but vacuum for 10 min for methylene chloride solutions. at a depression of 400 mbar.

Comparison of polymer coatings on bioceramic substrates using optical microscopy showed that the thickness of the polymer coating layer depends on the type of polymer and its concentration. Polyvinyl alcohol has a maximum coating layer thickness (24 pm) of 40% concentration. As the concentration decreases, the thickness of the coating layer also decreases. When polylactate or polycaprolactone is used as a coating agent for bioceramic substrates, surface coatings are formed at a 10% solution concentration. By increasing the concentration of polymer solutions, the amount of polymer coating on the bioceramic substrates increases.

Evaluating the results of experimental studies on the effect of biodegradable coatings on the retention time of the impregnating pharmaceuticals, it is reasonable to conclude that they provide a gradual, sustained and controlled release of the drug. If implants without surface-coated biocompatible and biodegradable polymers are used in the studies, for example, the samples impregnated with lidocaine hydrochloride intense drug release within the first three hours and the amount of lidocaine released reaches 90%. If the surface of the ceramic substrate is covered with 15% polyvinyl alcohol solution (25 kDz), the amount of lidocaine hydrochloride released after three hours shall not exceed 60%. Of all investigated formulations, polylactate coating is the most effective in slowing lidocaine release. The maximum amount of lidocaine (0.8 mg) is excreted after 4 hours. When the other polymers - polyvinyl alcohol and polycaprolactone - are applied to the coating, the maximum amount of lidocaine released from the implant can be observed as early as 30 minutes.

Studies have shown the efficacy of bioceramic backing coatings to provide controlled and slower drug release from the impregnated implant. The efficacy of drug release depends on the type of polymer used and its concentration.

The bioceramic implants prepared in accordance with the present invention by impregnation and coating with a 30% aqueous solution of polyvinyl alcohol, a 20% solution of polylactate in methylene chloride and a solution of 20% in polycaprolactone in methylene chloride are transferred for in vivo experimental animals (rabbits).

Used information sources:

1. Itokazy M., Esaki M., Jamamoto K., Tanemori T., Kasai T. Local drug delivery system using ceramies: vacuum method for impregnating a chemotherapeutic agent into a porous hydroxyapatite block.:// Journal of Materials Science: Materials in medicine, 10,1999, pp.249-252.

2. Ea3apoB A.IO., OcuHņeB B. Μ., ΕεκετοΒ E.H., IīaTeHT Pocchh No.2330685, Int.cl. A61L 27/06; A61L27 / 52; A61L 27/54 (01.01.2006)

3. William F., Mc Kay Device and method for vacuum infusion of a porous medical implant. United States Pat. US 2006 / 0135938A1, Int.cl. A561M 31/00, 01.01.2006.

4. Horger Flavio, Stoll Thierry. Device for impregnating a porous hone replacement material. Pat. Zurich (CH), no. WO 2005 / 118017A1, Int.cl. A61L 27/56, 12/15/2005.

Claims (2)

1. A device for impregnating and / or covering porous implants with the necessary substances (medicaments, suspensions, emulsions, polymers, etc.) in a thinner, comprising a hermetically sealed impregnation and / or coating vacuum vessel, characterized in that the device is equipped with a graduated dropping funnel and vacuum pump. , which are hermetically sealed to said vacuum vessel and provide a variable and controllable thinning process. 2. A method of impregnating and / or coating porous implants that technologically facilitates the expulsion of air from the open pores of the implant and its impregnation with the required materials, such as to provide controlled and controlled venting of open micropores in the implant and economical and effective impregnating and / or the use of a coating agent, sequentially performing the device defined in paragraph 1 (except vacuum pump) and sterilizing the implant with subsequent implant vacuum and impregnation of the implant and / or coating it with the necessary substances while maintaining the sterility of the process.