The method of preparation material lekarstvovedenija

 

The method of preparation lekarstvovedenija material is carried out by swelling polyurethane film in a solution of the drug. Before the introduction of drugs film made of polyurethane having a spatial-chemically cross-linked structure, is kept in a polar solvent for 1-30 hours, dried in vacuum to constant weight, and then subjected to swelling in the solution of the drug in an inert towards him the solvent to obtain the equilibrium degree of swelling with subsequent drying and surface treatment in a vacuum high-energy ion flux. The surface treatment in vacuum is carried out at a voltage pulse of 20 Kev, current density pulse 15 mA/cm2, pulse width of 5 microseconds with a repetition rate of 0.3 to 50 Hz at a dose of from 1013up to 1016ion/cm2. The invention allows to obtain a material with a uniform allocation of drugs and prolonged action. 1 C.p. f-crystals, 3 ill.

The invention relates to medicine, namely to the production of prosthetic products with polyurethane coating with biologically active substances enclosed within the gap of the polymer, as well as the production reoperated (steely) - based metal alloys [Van der Ven, G. J. P., Kaatee R., Beuter J. J., Beek J. A. F., Woittiez J. A., Buskens E., A. Koomans, H., Mali P. Th.-W. Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomised trial. Lancet. 1999. 353: 282-286].

The use of such implants is often accompanied by problems associated with insufficient biocompatibility and necessity of medications prolonged action. One of the possible solutions to these problems is the creation of a polymer layer on the surface of stanza, the introduction of the drug in the polymer matrix and the surface modification coating to improve its biocompatibility. This reduces the body's reaction to the introduction of stanza in a vessel.

As a polymer coating on stench often use polyurethane (hereinafter CP). Polyurethane coatings are characterized by high elasticity and high strength coatings, small residual deformation, high adhesion to metals, the ability to work in the aquatic environment and the active medium of the body. On stench coverage is usually obtained on the basis of a linear polyurethane, applied from a solvent.

There is a method of drug administration method of swelling in the finished polyurethane coating (linear polyurethane). In the process, special attention was paid to the process of swelling, so that the polyurethane does not Dor>

However, in the known method when the swelling is not up to the equilibrium state, we should expect significant uneven distribution of drugs in the polyurethane and therefore unequal kinetics of excretion of the drug over time. In addition, when using linear polyurethane there is a danger of dissolving polyurethane lipids, which are able to diffuse in a linear polyurethane, partially dissolving it with the release of the dissolved part of the polyurethane in the environment of the organism. Thus, the disadvantages of the prototype method is the uneven distribution of the drug in the film and, accordingly, the uneven allocation of medicines in time; the dissolution of the polymer; it is possible destruction of the polymer in the swelling of the Task of the invention is to develop a method of preparation lekarstvovedenija material, such as cross-linked polyurethane with a uniform allocation of drugs and prolonged action.

The problem is solved using the characteristics listed in the 1st paragraph of the claims, in common with the prototype, such as the method of preparation lekarstvovedenija material by swelling polyurethane film in a solution of the drug, and distinctive sushestvennee-chemically cross-linked structure, kept in a polar solvent for 1-30 hours, dried in vacuum to constant weight, and then subjected to swelling in the solution of the drug in an inert towards him the solvent to obtain the equilibrium degree of swelling with subsequent drying and surface treatment in a vacuum high-energy ion flux.

This allows you to create lekarstovedeniu material, such as cross-linked polyurethane with a uniform allocation of drugs in the body and prolonged action.

In paragraph 2 of the formula reflects the processing modes in vacuum high-energy ion flux to the surface of the polyurethane coating, namely, the treatment is carried out at a voltage pulse of 20 Kev, current density pulse 15 mA/cm2, pulse width of 5 microseconds with a repetition rate of 0.3 to 50 Hz at a dose of from 1013up to 1016ion/cm2.

This allows you to adjust the diffusion processes of isolation of drugs through the surface layer of polyurethane, because plasma immersion implantation (PINI) leads to destruction of the abundance of medicinal substances on the treated surface and the alignment of the mass distribution of drugs in the material.

The above distinctive take. The use of the proposed combination of essential distinctive features in the prior art was not found, therefore the proposed solution meets the patentability criteria of "novelty."

One set of new essential features with common, well-known provides a solution to the problem is obvious to experts in the field of technology and demonstrates compliance of the claimed technical solution to the patentability criterion of "inventive step".

Example 1 the Present invention is specifically illustrated by the following example of the invention, which illustrates but does not limit the scope of use of the invention.

Synthesis of PU coating.

For experiments was used poliuretanoviy (PU), obtained on the basis of simple polifonicos, aromatic diisocyanate and an aromatic diamine. The polyurethane synthesis was carried out in two stages. At the first stage, the synthesized prepolymer with an active terminal isocyanate groups. For the synthesis of the prepolymer used is a copolymer based on simple polifonicos poly(oxytetracyline-oxypropylene) glycol (LSM-BCP) (MM=1700). As dietrichson, 4,4'-diaminodiphenylmethane (DH) received linear polymer. For the synthesis was prepared by the reaction mixture of the prepolymer with a diamine in a molar ratio of reactive groups NCO:NH2as of 1: 0,7 (in the synthesis of crosslinked PU). If necessary, was added a solvent (e.g. ethyl acetate). After mixing, the reaction mixture was applied to stems or poured on steel, glass or Teflon substrate. The resulting film was placed in a heat chamber with a temperature of 120oWith to complete the polymerization reaction and the formation of chemical crosslinks. The presence of three-dimensional polymer network was determined by swelling in tributyl phosphate.

The introduction of drugs in the polyurethane coating.

Before the introduction of drugs to eliminate the influence of low molecular weight products that are not reacted in the synthesis of PU, the film was kept in pure ethanol for 24 hours and dried in vacuum to constant weight.

Swelling of polyurethanes in ethanol were analyzed for changes in the weight of the swollen samples produced in the form of discs with a diameter of 35 mm and a thickness of 0.4 mm To determine the weight used analytical balance Sartorius.

It is established that a linear polyurethane when approaching equilibrium, i.e., the marginal degree of swelling, carried slushaetsa due to internal stresses under the action of prodifferentiating ethanol. Such destruction was observed for all linear polyurethanes with the utmost degree of swelling in solvents. Therefore, for further experiments linear polyurethanes could not be used. For polyurethane-based polifonicos LSM-BCP having a density value of physical and chemical nets of 0.33 and 0,635 KMOL/m3accordingly, the maximum degree of swelling in ethanol is 40%, which undoubtedly leads to some increase in the size of the sample. The diameter of the sample in the form of a disk has increased from 35 mm for the original sample of 40 mm for extremely swollen sample. In further studies it is established that this value of the equilibrium swelling does not lead to the delamination of thin coatings from metal substrates.

As entered in PU cover medication was selected prednisolone. For the introduction of prednisolone in PU was selected method of swelling in a good solvent for prednisolone - ethanol. In addition to these requirements, consideration was given to the toxicity of ethanol. When using this method of drug administration prevent reactions prednisolone with active isocyanate groups of the prepolymer as possible with the introduction of drugs in BP is using neravnovesnogo swelling PU in the solvent.

Medication in PU produced by the method of swelling PU in 0.1% (wt.) the solution of the drug in ethanol. When calculating the concentration of the solution was taken into account: - the maximum degree of swelling PU, is obtained when the concentration of prednisolone in PU, optimal physiological limits of concentration of prednisolone in a patient's blood when selecting it from the PU coating on stems and placed into the channel of the blood vessel.

Swelling of the PU in the ethanol solution of prednisolone was carried out before the equilibrium degree of swelling, which reduced or eliminated the uneven distribution of drugs in PU thickness. When the limit swelling for PU films with a thickness of 0.3 mm for 10 minutes PU was kept in the solution for from 1 to 24 hours to achieve knowingly equilibrium distribution of drugs.

Surface modification of polyurethane using plasma immersion ion implantation (ion-beam processing).

Processing of polyurethane was carried out on the plasma-immersion ion implantation (BEEP). Nitrogen plasma generated by a plasma source based e-zikatanov resonance with a density of 1010cm-3and electron temperature of a few electron-on to the sample holder relative to the plasma. The current density per pulse was 15 mA/cm2the pulse duration of 5 μs, the pulse repetition rate of from 0.3 to 50 Hz. Dose of treatment ranged from 1013up to 1016ion/cm2.

After the BEEP treatment with doses above 1015ion/cm2the PU surface acquires a silvery hue due to carbonization of the surface layer. Formed wavy structure on the surface of the PU as a result of processes of stitching, carbonization and the appearance of internal stresses in the surface layer of polyurethane (Fig.1) the effect of the BEEP on the kinetics of excretion of prednisolone.

The kinetics of excretion of prednisolone modified PU is linear in time, as observed for unmodified polyurethane (Fig. 2). That is, the front selection mode prednisolone modified polyurethane is saved. During this initial part of the rate of release of prednisolone is more gently sloping, uneven distribution of prednisolone in the surface layer of polyurethane is reduced. This is caused by the destruction of prednisolone in the surface layer of polyurethane. The rate of excretion of prednisolone during this period decreases as compared with the unmodified polyurethane (Fig.3).

Analyticities dose BEEP growing. This is due to the increase of the diffusion coefficient of water and prednisolone over the surface layer of the polymer, in which, after the BEEP cavity formed due to degradation of the polyurethane to the gas components and the permeability of this layer increases. This reduction in the rate of excretion of prednisolone in the initial period of time and increase the rate of release of prednisolone with longer time reduces the range of change of the concentration of prednisolone eye-catching of polyurethane coatings in the blood of the patient, thus the concentration of prednisolone in polyurethane coating can be increased so that the effect of prednisolone maintained therapeutic effect at large times after the introduction of stanza in the body.

Example 2.

Synthesis of PU coating, as in example 1. Before the introduction of tetracycline polyurethane film with a thickness of 0.2 mm was kept in ethanol for 24 hours, then dried under vacuum until constant weight.

The introduction of tetracycline in the polyurethane matrix was performed by the method of soaking in 0.2% solution of tetracycline in ethanol for 2 hours, after which the alcohol was removed.

The surface modification was performed on the plasma-immersion ion implantation, where nitrogen is GTC pulse repetition from 0.3 to 57 Hz at the dose of treatment 1013-1016ion/cm2.

The speed of separation of tetracycline after the BEEP has a uniform character over time, similar to that shown for prednisolone in Fig.3.

Example 3.

Synthesis of PU coating, as in example 1. Before the introduction of novocaine polyurethane film with a thickness of 0.3 mm was kept in ethanol for 24 hours, then dried under vacuum until constant weight.

The introduction of novocaine in the polyurethane matrix was performed by the method of soaking in a 0.5% solution of novocaine in ethanol for 10 hours, after which the alcohol was removed.

The surface modification was performed as in example 2.

According to the invention the polyurethane synthesis method, the polymerization reaction on the surface can be used to obtain a polymer with a chemically cross-linked structure for subsequent introduction into it of the drug from the solution.

The proposed method of producing polyurethane coatings containing medicines and modified using BEEP, can be used for Stenson and provides a prolonged therapeutic effect is controlled by the selection of medication.

Claims

1. The method of preparation lekarstvovedenija material by swelling is built from polyurethane, spatially-chemically cross-linked structure, is kept in a polar solvent for 1-30 hours, dried in vacuum to constant weight, and then subjected to swelling in the solution of the drug in an inert towards him the solvent to obtain the equilibrium degree of swelling, followed by drying and surface treatment in a vacuum high-energy ion flux.

2. The method according to p. 1, characterized in that the surface treatment in vacuum is carried out at a voltage pulse of 20 Kev, current density pulse 15 mA/cm2, pulse width of 5 μs, repetition rate from 0.3 to 50 Hz, at a dose of from 1013up to 1016ion/cm2.

 

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