Method of obtaining porous polymer biodegradable products for osteanagenesis

FIELD: chemistry.

SUBSTANCE: effect is achieved by using compositions based on different stereoregular amorphous biodegradable polymers - polylactides and copolymers of lactides with glycolides (18-72 mass ratio) as the second component of biocompatible mineral filler - hydroxyapatite with particle size of the main fraction of 1-12 mcm (8-41 mass ratio), as well as an organic solvent with boiling temperature equal to or higher than softening temperature by 3-20°C (20-41 mass ratio). After preparation of a homogenous mixture, the composition is undergoes thermal treatment at 80-130°C in a vacuum in a shaping vessel with the required shape. A porous product is obtained due to removal of solvent. Density of the obtained porous product is about 0.4-0.8 g/cm³.

EFFECT: design of a method of obtaining porous biodegradable composite polymer products based on polylactides or copolymers of lactides and gylcolides.

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The objective of the invention is to provide a method of producing a porous biodegradable polymer materials based on polylactide or copolymers of lactide and glycolide for use in medicine, preferably in oral and maxillofacial surgery for bone tissue regeneration.

This issue of global importance and is solved in current use (see Patent EPO 795336. A-4) monolithic products of biodegradable polymers, mainly from the class of polylactide or polyglycolides, or their copolymers with a molecular mass of from 100 to 600 thousand daltons. As fillers such polymers generally used are phosphates of various chemical structures: dicalcium phosphate, hydroxyapatite, tricalcium phosphate, tetracalcium phosphate, biostable, bioceramics.

From such filled compositions of the various communities in which the processing methods through the translation of the polymers in the melt receive high-strength biodegradable blanks, of which by means of additional mechanical processing products can be made of simple shapes (disks, cylinders).

Preparation and properties of similar, related composition, composites described in the leading domestic collection this direction "Biomedical technologies" (issue 21, p.105-117, 2003, proceedings of the Interagency H.-I. and academic-met. center biome is izinski technologies).

In contrast to the above patent, to obtain homogeneous mixtures of biodegradable polymer and hydroxyapatite in this case was used the technique of chrismessina in the atmosphere of liquid nitrogen, which helps avoid undesirable oxidation processes.

There is also a patent ("the Material for osteosynthesis" C1 2059405 from 1996.05.10)stating the material for osteosynthesis, comprising biodegradable polymers (polylactide, polyglycolide, copolymer glycolide with lactide, polyetherimide, polydioxanone and others), filled with the purpose of reinforcement, the fibers of the same polymer. This provides increased strength and elasticity of the composites. Obtaining such composites also passes through the stage of melting bioresorbable polymers.

All obtained in this way driven counterparts of the product aim at increasing the source strength of implants for osteosynthesis and longer durability by biodegradation.

But such methods are filled with biodegradable composites have a number of shortcomings that hinder their use as biodegradable implants for osteosynthesis in oral and maxillofacial surgery for the regeneration of bone tissue.

Thus, to obtain similar products used methods of polymer processing is via the melt (injection moulding, press-molding, injection molding, compression extrusion). All of these methods require translation of polymer in the melt and excerpts in this state. Chemical structure of biodegradable polymers does not provide a high thermal stability of such compositions. Our review of songs of polylactide filled with 30% hydroxyapatite showed that in the processing method compression or injection molding is the decrease srednevekovoi molecular mass (M_wwith a 5.5·10³to 4.7·10³Dalton (determination of molecular weight by light scattering). Such thermal destruction processes occur through the formation of free radicals, oxidative processes, which are not desirable for materials used for osteosynthesis.

Another drawback of these materials is their high density (˜ 1,25-1.7 g/cm³). Because in the process of biodegradation is the decomposition of the used polymers to monomers, each representing a different type of hydroxy acid such as lactic, glycolic, thus, the high density of the implants with their degradation leads to a significant concentration of these products, such as lactic acid, in the area of the implant that is not conducive to intensive course osteointegration processes and leads to an increase in the time b is degradatio implants, and hinders regeneration of bone tissue.

The disadvantage is also the practical impossibility of obtaining such compounds in the complex-shaped products, technology investment model, which is necessary, for example, implants for maxillofacial surgery.

This complexity has led to the fact that, despite a long period of research, until now there is no industrial production filled with biodegradable polymers and are produced only products of simple shapes (bars, cylinders) of the unfilled polymers (polylactide and a copolymer of lactide with glycolide).

To solve this problem is proposed a method of obtaining porous biodegradable products for the regeneration of bone tissue.

The technical result is to obtain a porous biodegradable polymer implants with a density of 0.4-0.8 g/cm³i.e. in 1,5-2,5 times lower than monolithic mouldings of the same composition, with high physical-mechanical properties (bending strength 35-55 MPa (20-35 MPa)), due to orientational effects occurring in the material when it is foaming. The resulting products is significant (approximately 1.5-2 times) acceleration of the process of hydrolysis, due to the rapid growth of the area and the degradation due to the pores and reducing the wall thickness hydrolyzable sample, what is achieved by reducing the number formed by the hydrolysis of lactic and glycolic acids, while maintaining sufficient strength implantable products in the initial period, which allows a wide variation to vary the duration of the degradation of the used porous implant to ensure the regeneration of bone tissue that occurs in this case, as shown by recent research from the bone bed.

One of the most important technical results of the proposed method is to obtain a porous biodegradable polymer implants required size and configuration (shape) of different methods, up to the use of the method according to "investment model". This will allow to refuse additional machining, after the operation of steam formation, and creates the basis for the use of the proposed method in everyday surgical practice.

An important technical result, which provides the possibility of applying this method in surgery, is the lack of derived products even trace amounts of solvents used in the foaming process, as proven by us using the most sensitive instrumental methods - mass spectrometry. A similar result can be realized only because, as had the camping, in the process of steam formation in the samples, along with macroporosity (pores 30-700 μm), is formed and microporous structure with pores close to 0.01 to 0.1 ám. It is similar to the structure of the samples provides the required technical effect in the framework of this method.

The technical result is achieved by the use of the method of manufacture of porous biodegradable polymer composite articles of desired shape, comprising preparing a mixture of amorphous polylactide or copolymers of lactides with glycolide molecular weight 50-800 thousand, with a softening temperature (the softening temperature was determined by thermomechanical method at a load of 1 kg/cm and a heating rate of 5°C/min) 35° to 55°with an inorganic filler - hydroxyapatite with particle sizes of the main fraction from 1 to 12 μm and an organic solvent selected from the range fluorine-containing aliphatic ethers, chlorinated aliphatic compounds, aliphatic ketones with boiling points above the glass transition temperature of the polymer components 2-20°when the ratio of the components (moschata) with the subsequent operation of the heat treatment of the mass in the desired form at a temperature of 80-130°in vacuum at a residual pressure of 1-20 mm Hg for 0.5-1 hour to obtain a porous product with a density of 0.4-0.8 g/sup> 3and a Flexural strength of 35-55 MPa (20-35 MPa).

After receiving the product the desired shape, it is subjected to heat treatment at temperatures of 50-75°within 3-28 hours in vacuum at a residual pressure of 1-20 mm Hg.

Among the essential features characterizing the method of manufacture of porous biodegradable polymer composite products (implants), the required form for the regeneration of bone tissue, distinctive are the following:

- use as a biodegradable polymer component amorphous polylactide or copolymers of lactide and glycolide with molecular masses 50-700·10³Dalton and temperature softening 35-55°C;

- research as a biocompatible filler - hydroxyapatite with particle size of the main fraction from 1 to 12 microns;

- use as a pore-forming organic solvent selected from the range fluorine-containing aliphatic ethers, chlorinated aliphatic compounds, aliphatic ketones having a boiling point either equal to, or higher than the glass transition temperature of the polymer component 3-20°C;

- stage heat treatment of the mixture of the above components at a temperature of from 80° to 130°in vacuum at a residual pressure of 1-20 mm Hg to obtain Paris the CSOs products with a density of 0.4-0.8 g/cm ³;

- carrying out heat treatment of the mixture in a forming vessel corresponding to the desired shape of the porous product;

- additional heat treatment of the obtained porous product at a temperature of 50-75°within 3-28 hours in vacuum at a residual pressure of 1-20 mm Hg.

Used stereoregular the polylactide and copolymers of lactides and glycolide include all such polymers having an amorphous structure. This is accomplished, generally, by using as monomers of two different stereoisomers, because the polymer on the basis of a single stereoisomer, such as polylactic L, has a crystalline structure and unsatisfactory properties biodegradation (over 5 years).

Therefore, the most popular currently received polylactic on the basis of two stereoisomers - polylactid DL, with relatively short biodegradation (1-1 .5 years).

Also used a more complex structure, such as polylactic L/DL, as well as copolymers of lactide and glycolide.

The process of biodegradation depends largely on the molecular weight of the polymer, and therefore in the claims indicate the border of the used polymers.

The proposed method is performed by the following operations. The source then is the loud or granules of amorphous polylactide or copolymers of lactides and glycolide mixed for 1 hour in a laboratory mixer type "drunken barrel" with a molecular mass of 5-70·10⁴Dalton and temperature softening 35-55°With biocompatible inorganic filler - hydroxyapatite. Hydroxyapatite is biocompatible, well-studied us filled with valuable biomedical properties. This is because in vivo hydroxyapatite is the main component of bones. Therefore, the main work in this application were conducted on different types of hydroxyapatite. Then the mixture is injected organic solvent selected from the range fluorine-containing aliphatic compounds, aliphatic ketones having a boiling point equal to or higher than the glass transition temperature of the polymer components 3-20°C. Specific representatives of such solvents are chloroform - with a boiling point 61,15°With characteristic mass spectral peaks, m/z 83 and m/z 85, m/z 87, methylene chloride - 40°C, m/z 35 and m/z 47, acetone - 56,24°With, m/z 58 and m/z 43, tetrafluorethylene ether - 35°C, m/z 51 and m/z 81.

The mixing ratio in the mass parts the following:

polymer - 18-72 parts by weight of

hydroxyapatite - 8-41 parts by weight of

solvent - 20-41 parts by weight of

The mixture is stirred until the formation of homogeneous mass. Then made a mass composed of a mixture of components, is placed in a forming vessel having fo the mu corresponding in size to the configuration of the desired implant.

The form with it a mixture of components subjected to heat treatment at a temperature of 80-130°in vacuum at a residual pressure of 1-20 mm Hg for 0.5-1 hour for the implementation of steam formation in the course of which the morphology of the porous product with a density of 0.4-0.8 g/cm³, a Flexural strength of 20-35 MPa.

Then the obtained porous implant is extracted from the mold and subjected to heat treatment at a temperature of 50-75°within 3-28 hours in vacuum at a residual pressure of 1-20 mm Hg.

Experimental tests of the proposed method of manufacture of the implants showed their high efficiency. The obtained porous implants do not contain even trace amounts of solvents used in the manufacture of implants. This has been proven using the most sensitive instrumental mass-spectral method. So, for example, methylene chloride in the mass spectrum was no characteristic peaks with m/z 35 and m/z 47.

An obvious advantage of the method, indicating its high efficiency, is the manufacture of implants not only simple shapes (rods, plates), but a complex configuration corresponding to the shape of individual sections of bone.

Pic is b allows you to change the porosity of the resulting implants, that provides the ability to control the timing of their biodegradation. The same capability can be created by using the method of biodegradable polymers with different molecular weight and structure. The way for its implementation does not require sophisticated equipment and can be implemented both in laboratory and in clinical settings at minimum cost.

Despite the porous structure, in this way the obtained product with sufficient strength in bending, which allows their use as implants in the loaded parts of the skeleton to provide initial strength in the postoperative period.

Implementation of the proposed method of manufacture of porous biodegradable polymer implants required form is illustrated by the following examples.

Example 1. Granules of amorphous polylactide (DL) with a ratio of D and L stereoisomers (50:50), with a softening temperature 41°and With a molecular mass of 50·10³Dalton in the amount of 70 wt. parts are mixed in the mixer "drunken barrel for 1 hour with synthetic hydroxyapatite with particle size of main fractions 1-12 μm in the amount of 8 parts by weight, then the resulting mixture was added 20 parts by weight of solvent - tetrafluorethylene ether with a boiling point of 35°C. the resulting mixture was stirred for p and room temperature for 0.5 hours before the formation of a homogeneous mass. Then the mass is loaded into a vacuum form a given configuration of the implant and thermoablative at a temperature of 80°With water bath, in vacuum at a residual pressure of 20 mm Hg for 0.5 hours.

The obtained porous implant is removed from the form and additionally thermoablative at a temperature of 50°C for 3 hours in vacuum at a residual pressure of 1 mm Hg. Mass spectrometric analysis shows that the obtained porous implant does not contain solvent of the characteristic bands of m/z 51 and m/z 81.

The tensile strength in bending of the samples 35 MPa. The density of the obtained sample of 0.4 g/cm³.

Example 2. Powder amorphous polylactide representing a copolymer of stereoisomers with a ratio of L and DL monomers 70:30, with a softening temperature of 50°and molecular weight of 400·10³Dalton, in the amount of 18 wt. parts are mixed as in example 1 with hydroxyapatite with particle size of the main fraction from 1 to 12 microns in the amount of 41 wt. part and an organic solvent is chloroform with a boiling point 61°C. the resulting mixture was stirred for 1 hour to set configuration of the implant and thermoablative at a temperature of 130°With silicone bath for 1.5 hours in vacuum at a residual pressure of 1 mm Hg. Mass spectrometries the th analysis shows the resulting porous implant does not contain solvent of the characteristic bands of m/z 83 and m/z 85, m/z 87.

The tensile strength in bending of the samples 20 MPa. The density of the obtained sample 0.8 g/cm³.

Example 3. The amorphous powder polielektrolita representing a copolymer of lactide DL and glycolide in a molar ratio of 75:25, with a molecular mass of 100·10³Dalton and the softening temperature of 37°With, in the amount of 46 wt. parts are mixed as in example 1 with powdered synthetic hydroxyapatite with particle size of the main fraction from 1 to 12 μm in an amount of 20 wt. parts and organic solvent - methylene chloride, having a boiling point of 40°With, in the amount of 37 wt. parts.

The resulting mixture was stirred at room temperature for 1 hour before the formation of a homogeneous mass.

Then the mass is loaded into a vacuum form a given configuration of the implant and thermoablative in a boiling water bath at 100°C for 40 minutes in vacuum at a residual pressure of 10 mm Hg. The obtained porous implant is removed from the form and additionally thermoablative at a temperature of 60°C for 10 hours in vacuum at a residual pressure of 10 mm Hg.

The tensile strength in bending of the samples 25 MPa. The density of the obtained sample of 0.54 g/cm^{3 .}

^{Mass spectrometric analysis shows that the product contains no solvent in the absence of the characteristic bands of m/z 35 and m/z 47.}

^{Example 4. The amorphous powder polielektrolita representing a copolymer of lactide L, DL and glycolide in a molar ratio of 96:4, with a molecular mass of 350·103daltons and a melting point 42°With, in the amount of 50 wt. parts are mixed as in example 1 with powdered synthetic hydroxyapatite with particle size of the main fraction from 1 to 12 μm in an amount of 12.5 parts by weight and the organic solvent is acetone, having a boiling point of 56°With, in the amount of 37.5 wt. parts. The resulting mixture was stirred at room temperature for 1 hour before the formation of a homogeneous mass.}

Then the resulting mass is loaded into a vacuum form a given configuration of the implant and thermoablative silicone bath at a temperature of 110°C for 1 hour in vacuum at a residual pressure of 1 mm Hg.

The obtained porous implant is removed from the form and additionally thermoablative at a temperature of 55°C for 10 hours in vacuum at a residual pressure of 1 mm Hg.

The tensile strength in bending of the samples 32 MPa. The density of the obtained sample of 0.48 g/cm³.

Mass spectrometric analysis shows that the product of n which contains the solvent in the absence of the characteristic bands of m/z 58 and m/z 43.

1. The method of manufacture of porous biodegradable polymer composite articles of the desired shape based on polylactide or copolymers of lactide and glycolide, characterized in that a composition comprising a stereoisomeric amorphous polylactide and copolymers of lactides and glycolide [PL(DL), PLP(DL), PLP(L+DL)] molecular weight of 5-70·10⁴Dalton with a softening temperature from 35 to 55°with the addition of biocompatible inorganic filler - hydroxyapatite with particle size of the main fraction from 1 to 12 μm, impose additional organic solvent with boiling points equal to or above the softening temperature of the polymer components 3-20°With the following ratio of components, parts by weight:

with a subsequent heat treatment of the mass in a forming vessel corresponding to the desired shape of the product at a temperature of 80-130°in vacuum, to obtain a porous product with a density of 0.4-0.8 g/cm³and tensile strength in bending 20-35 MPa.

2. The method according to claim 1, characterized in that after the manufacture of the product, it is subjected to heat treatment at temperatures of 50-75#x000B0; With over 3-28 h in vacuum at a residual pressure of 1-20 mm Hg.

3. The method according to claim 1 or 2, characterized in that the polymer product is intended for use as implants in medicine, preferably in oral and maxillofacial surgery to ensure the regeneration of bone tissue.