FR2635685A1 - PERIODONTE REGENERATION MATERIALS - Google Patents

Abstract

Periodontal regeneration materials for periodontal regeneration treatment, which consist of bio-degradable / absorbable lactide / epsilon-caprolactone or lactide / glycolide copolymers, having a weight average molecular weight in the range of 40,000 to 500 000, as well as a dynamic elastic modulus of 5 X 10 ** 2 to 5 X 10 ** 4 N / cm ** 2 and an elongation rate of 100 to 2000%, both measured at temperature ambient (25 degree (s) C). These copolymers can be used in the form of a sheet or a film which can be porous (porous) or not.

Description

MATERIALS FOR REGENERATION OF PERIODONTE.

  The present invention relates to a biodegradable / absorbable dental material, which is required for the regeneration of tissues of a living body suffering from periodontitis. In common periodontal treatment of healthy cementum and periodontal ligament with periodontal disease, hydroxyapatite and calcium phosphate are used as fillers of the alveolar bone to be introduced into the tissues

lost periodontics.

  However, such treatments are considered to be only effective in preventing periodontal disease from reaching an advanced stage or from reappearing to a certain degree. In recent years, the Directed Tissue Regeneration Technique, developed by Professor S. Nyman et al. (University of Gothenburg) has, from a biological point of view, attracted attention in the dental fields. For such a landmark Directed Tissue Regeneration Technique, it has been reported that certain results can be obtained with what is called a Goretex membrane which is neither degradable nor absorbable in a living body. See S. Nyman et al., "The regenerative potential of the periodontal ligament - An experimental study in the monkey",

J. Clin. Periodontol, 9: 257, 1982.

  Since the Goretex membrane is neither degradable nor absorbable in a living body, it constitutes a substance foreign to the living body and it reacts with tissues. Consequently, the Goretex membrane must be removed after a first treatment and a second operation is therefore again necessary. From this point of view, a review of studies concerning the use of biodegradable / absorbable membranes for the Directed Tissue Regeneration Technique was presented. See I. Magnusson et al., "New Attachment Formation Following Controlled Tissue Regeneration Using Biodegradable

  Membrane ", J. Periodontol, 59, 1-6, January 1988.

  However, since a homopolymer consisting of 100% polylactic acid is used as a biodegradable / absorbable membrane, it is impossible to simultaneously control both the dynamic properties

  (or mechanical) and the rate of hydrolysis.

  Due to its glass transition temperature

  higher than the temperature of a living body, homo-

  polymer consisting of 100% polylactic acid gives a physical stimulus to the soft tissues of a living body, which gives rise to inflammation. With the homopolymer, it is difficult to freely vary the rate of hydrolysis. The present inventors have carried out intense and in-depth research to eliminate the weak points of the above polylactic acid homopolymer, in other words, to improve in particular its dynamic (or mechanical) properties, its thermal properties and the speed of hydrolysis. Consequently, it has been discovered that a film or sheet of a lactide / Ecaprolactone or - lactide / glycolide copolymer is most suitable for the Directed Tissue Regeneration Technique. The present invention has

  was accomplished on the basis of this discovery.

  The novelty of the present invention resides in the use of a lactide / -caprolactone copolymer or of a lactide / glycolide copolymer as bio-degradable / absorbable materials of high molecular mass applied to the Directed Tissue Regeneration Technique, effective in preventing periodontal disease. These bio-degradable / absorbable materials can be formed into films or sheets by dissolving the lactide / e-caprolactone or lactide / glycolide copolymers in a solvent such as an organic solvent, for example, methylene chloride, chloroform, dioxane, toluene, benzene, dimethylformamide or acetone, and subjecting the resulting solutions to hot casting or compression. To allow these films or sheets to be traversed by body fluids such as nutritive substances or to give them flexibility, they can be made porous by a stretching or lyophilization treatment in a benzene or dioxane solution. The high molecular weight bio-degradable / absorbable materials according to the present invention have not only excellent flexibility, but also excellent biocompatibility. Thus, they tend to disappear immediately after the healing of damaged sites without any risk of interference with bone ankylosis of the connective tissue separated from the surface of a root by a discission or an injury. The reason why this excellent biocompatibility is obtained is that it is possible to use materials whose dynamic and thermal properties, as well as the rate of hydrolysis, can be varied by the copolymerization of

  lactide which is an aliphatic polyester with the capro-

  lactone or glycolide, used in appropriate ratios, and that materials can be selected for application depending on the level of healing to be achieved for

damaged sites.

  The present invention will now be explained in more detail with reference to the accompanying drawing, which is given by way of illustration only and in which: - Figure 1 is a graphical representation showing the relationship between the molar fraction of e-caprolactone in the L-lactide / E-caprolactone copolymer and the glass transition temperature of this copolymer; - Figure 2 is a graphical representation illustrating the relationship between the molar fraction of e-caprolactone in the L-lactide / i-caprolactone copolymer and the dynamic elastic modulus of the latter at room temperature; FIG. 3 is a graphical representation showing the relationship between the duration of the hydrolysis and the weight and the rate of residual molecular mass of the L-lactide / E-caprolactone copolymer; and - Figure 4 is a graphical representation showing the relationship between the duration of hydrolysis and the resistance

  tensile strength of the L-lactide / a-capro- copolymer

  lactone. The high molecular weight bio-degradable / absorbable materials used in the present invention are widely distributed in the natural world and are copolymers. lactide / E-caprolactone or lactide / glycolide found in animal bodies. The composition and molecular mass of such a copolymer can be chosen according to the mechanical properties and the rate of biodegradation / absorption of the material which are suitable for a periodontal disease state. The lactide / 6-caprolactone copolymers used in the present invention are synthesized according to the following reaction scheme: L-lactide monomer Pf.96 C D, L-lactide, L-lactide Llactide monomer Pf-.128 C

3HC O

CH, C H \ 2 / \ C = O

I H OC =

OH - C - C00H - + O - C- IlI

00 CH3

H E-caprolactone

HC (CH,) 4

  Ic = I E-caprolactone monomer Pf .. -5 C Polymerization by opening of the cycle Lactide / caprolactone copolymer

HC \ O \ CH. O

  HC C-0 2HC- (CHa). I Il O-C CH O-C = O 1900C C O Il

  HIC IC- +, I I - (C, 4 0-CH O - CHC-8-C - \ 0 (C H,), - O

  O0 CH3 5 hours The lactide / glycolide copolymers used in the present invention are synthesized according to the following reaction scheme:

HC 0 O CHO O

HC C = O H.C C = O -s H -O-C-CH2- C

O = C CH O = C CH2 Q O

  \ 0 \ CH \ & CH, O n Lactide Glycolide Lactide / glycolide copolymer The high molecular weight bio-degradable / absorbable materials used in the present invention come into contact with the soft tissue of a living body, and therefore it is necessary that they have a certain flexibility, since inflammatory reactions are provoked by physical stimuli at the moment when there is an important difference between the dynamic properties of these materials and those of the soft tissues of a living body, in particular, when their hardness is excessive. To achieve this goal, it is preferable that their glass transition temperature is around body temperature. To satisfy this requirement, it is necessary to choose the composition of the lactide / E-caprolactone copolymer or of the lactide / glycolide copolymer with appropriate composition ratios. Figure 1 illustrates the variation of the transition temperature

  glassy as a function of the molar fraction of E-capro-

  lactone in the lactide / 6-caprolactone copolymer. It is understood that the measurement of the glass transition temperature was carried out using a differential scanning calorimeter (DCS) - marks by i and a

  dynamic module measurement device - benchmarks.

  It is necessary that bio-

  degradable / absorbable high molecular weight used in the present invention have some dynamic strength. In other words, when there is a need to fix the biodegradable / absorbable films or sheets in a given region using a suture, a serious problem will arise if the fixed part tears. Furthermore, in the absence of a certain resistance or modulus of elasticity, there is a problem linked to the preservation of the shape which tends to change due to hydrolysis, so that the objective desired cannot be achieved. Therefore, the materials used in the present invention should preferably have a dynamic modulus in the range of 5 x 102 to x 104 N / cm2 (5 x 107 to 5 x 109 dynes / cm2), than the one can obtain by the choice of the composition of the copolymers. Figure 2 illustrates the variation at room temperature of the dynamic elastic modulus as a function of the molar fraction of 6caprolactone in the L-lactide / E-caprolactone copolymer. It is understood that the dynamic elastic modulus has been measured using an available RheoVibron

with Toyo Balldwin.

  Furthermore, the high molecular weight bio-degradable / absorbable materials used in the present invention should be maintained in the form of a film or sheet during the period of time during which the regeneration of the alveolar bone and the Recombination of the root surface with the connective tissue are performed. Furthermore, it is not desirable that they remain as a foreign substance in a living body after healing. Thus, it is necessary that they are quickly broken down and absorbed and disappear. The rate of degradation / absorption can also be controlled by varying the composition and

  the molecular weight of the copolymers.

Variations in hydroylse in-

  in vitro as a function of the molar fraction of e-caprolactone in the L-lactide / E-caprolactone copolymer are illustrated in FIGS. 3 and 4, in which Odesigne

  a piar molecular mass 100% of L-lactide, D a molar mass

  circular by 88% of L-lactide, t a molecular mass for 65% of Lactide, Oune molecular mass pr 15% of L-lactide, Xune molecular mass pr 100% of 6-caprolactone, a weight for 100 X of L- lactide, i a weight per 88% of L-lactide, and Aun weight for% of L-lactide. The rate of hydrolysis of the in vitro samples was estimated in a solution having a certain volume (3 mm long x 5 mm wide x 1 mm thick) in a phosphate buffer solution at 37 C (pH: 7 , 4), with an elution control device in accordance with the JAPANESE PHARMACOPEE. The weight, molecular mass and rate of reduction of the tensile strength of the hydrolysed products were measured before and after

  hydrolysis and expressed in terms of percentage.

  Then, the rates of bio-degradation / absorption and the reactivity towards a tissue were studied by tests in vivo. The dorsal muscles of domestic rabbits, each weighing approximately 3 kg, were cut in the direction of the fibers, samples were introduced into them, and then the fascia was sutured. Before introduction, the samples were sterilized with gaseous ethylene oxide. After introduction, the rabbits were sacrificed over time to examine variations in the physical properties of the samples and the reactivity of the peripheral tissues. As a result, the homopolymer consisting of 100% polylactic acid remained substantially whole even after six months and the soft tissue in contact with the periphery of the material had undergone some inflammation. However, the lactide / E-caprolactone (in a molar ratio of 70:30 mol%) and lactide / glycolide (in a molar ratio of 75: 25 mol%) copolymers were completely decomposed and absorbed without any sign of any tissue reaction. From the above results, it is understood that the lactide / ú-caprolactone and lactide / glycolide copolymers are superior to the homopolymer consisting of% polylactic acid as regards the properties.

  dynamics and rate of hydrolysis, as well as bio-

  compatibility. Laid / caprolactone and lactide / glycolide copolymers are interesting materials since, as with the homopolymer consisting of 100% polylactic acid, they cause non-enzymatic hydrolysis in a living body to give hydrolysates which are broken down and absorbed and ultimately removed from the living body in the form of water and carbon dioxide. Thus, the high molecular weight biodegradable / absorbable materials according to the present invention are not only materials useful for the Directed Tissue Regeneration Technique, but are also

  clinically useful in other dental areas.

  The high molecular weight bio-degradable / absorbable materials of the present invention will now be explained in a specific but not exclusive manner

  with reference to the following examples.

Example 1:

  We periodically caused periodontal disease in a fully developed mongrel dog,

  inducing gingival retraction. Bio porous film

  degradable / absorbable was used in the form of a sheet of approximately 200 μm in thickness constituted by an L-lactide / E-caprolactone copolymer (in a molar ratio of 70:30 mol%), having a molecular mass weight average of around 220,000, as well as a dynamic elastic modulus of 9.5 x 102N / cm2 (9.5 x 107 dynes / cm2) and an elongation rate of 150%, both at room temperature (25 C). Once the root surface was covered with this leaf in the form of a patchwork tent, a flap of gum tissue was resutured to prevent the connective tissue from contacting the root surface and take part in the healing process. After a period of three months, the healing process was observed. As a result, it has been found that the L-lactide / E-caprolactone copolymer loses a substantial part of its dynamic strength and undergoes very significant hydrolysis, although its shape is maintained. However, a new attachment including the formation of the new alveolar bone indicated that the periodontal disease was cured.

Example 2

  As a biodegradable / absorbable film, use was made of a film-like material with a thickness of approximately Fm, consisting of a copolymer D, Llactide / glycolide (in a molar ratio of 80:20 mol%). , having a weight average molecular weight of 000, as well as a dynamic elastic modulus of

  9.8 x 102 N / cm2 (9.8 x 107 dynes / cm2) and an extension rate-

  200%, both at room temperature (25 C).

  In accordance with the procedures of Example 1, the healing process was estimated after a period of three months. As a result, it was found that the film constituted by the copolymer D, L-lactide / glycolide was substantially decomposed and absorbed, and that fibers of the periodontic ligament had formed simultaneously with the formation of a new bone, a sign of healing. periodontal disease.

Example 3

  A 10% solution in dioxane of an L-lactide / glycolide copolymer (in a molar ratio of 90:10% by moles), having a weight-average molecular mass of approximately 260,000, as well as a module d dynamic elasticity of 1.8 x 103 N / cm2 (1.8 x 108 dynes / cm2) and an elongation rate of 1000%, both at room temperature (25 C), was lyophilized to prepare a film porous bio-degradable / absorbable in the form of a sheet of about 220 µm. With this film, an animal experiment was carried out in a manner analogous to that described in Example 1. After a period of three months, it was found that the porous sheet-type film, constituted by the copolymer L-lactide / glycolide was completely broken down and absorbed, with healing of periodontal disease. he

Example 4

  A 10% solution in dioxane of a D, L-lactide / glycolide copolymer (in a molar ratio of 75:25 mol%), having a weight average molecular weight of approximately 190,000, as well as a dynamic elastic modulus of 3.2 x 103 N / cm2 (3.2 x 108 dynes / cm2) and an elongation rate of 1500%, both at room temperature

  (25 C) was lyophilized to prepare a porous bio-film

  degradable / absorbable in the form of a sheet of about 160 pu. With this film, an animal experiment was carried out in a manner analogous to that described in Example 1. After a period of three months, it was found that the porous sheet-type film, constituted by the copolymer D, L-lactide / glycolide was completely broken down and absorbed, with healing of periodontal disease. Comparative Example 1 An experiment was carried out in accordance with Example 1, except that a material with a thickness of approximately 200 μm, consisting of polylactic acid having a molecular base of approximately 220,000, was used in as a bio-degradable / absorbable film, to observe the degree of healing after a period of three months. As a result, it was found that the polylactic acid was practically not broken down, and that this resulted in partial inflammation of the gingival tissue in contact with the

  edges of the film consisting of 100% polylactic acid.

  The high molecular weight bio-degradable / absorbable materials of the present invention have the following advantages compared to the high molecular materials which are neither degradable nor

absorbable in a living body.

  In accordance with the Directed Tissue Regeneration Technique proposed by Professor S. Nyman et al. (University of Gothenburg), it is essentially required to remove the material implanted in the periodontium immediately after the periodontium is estimated to be cured by such an implant. For this removal, it is again necessary to perform an operation. However, with the high molecular weight bio-degradable / absorbable materials of the present invention, there is no need to perform a new operation, thereby relieving the patient of pain and reducing the load

  economic to a considerable degree.

  It is necessary that the material implanted in the periodontium present a resistance at the beginning, but it is rather requested that it loses this resistance after the cure of the periodontic disease. Failure to change resistance would tend to cause inflammation. However, the high molecular weight bio-degradable / absorbable materials of the present invention have an initial strength, which can be decreased gradually or suddenly over time, so that there is no possibility of causing

periodontitis inflammation.

  In addition, bio-degradable / absorbable materials -

  high molecular weight of the present invention have the following advantages in comparison with those

  consisting of homopolymers with 100% poly-

  lactic. The dynamic / mechanical properties suitable for the periodontal state can be given to the high molecular weight bio-degradable / absorbable materials of the present invention, because these materials consist of lactide / e-caprolactone or lactide / glycolide copolymers. It is necessary to vary the rates of biodegradation and bioabsorption of the material implanted in the periodontium according to the degree of the periodontic disease. In particular, when the aim is to abruptly decrease the dynamic / mechanical properties of bio-degradable / absorbable materials of high molecular mass at the time when a certain period of time has elapsed after its implantation in the period, there is a difficulty in freely varying the rate of hydrolysis of the bio-degradable / absorbable material of high molecular weight consisting of the homopolymer containing% polylactic acid. However, with the high molecular weight bio-degradable / absorbable materials of the present invention, it is possible to control them.

  freely degradation and absorption rates.

  In addition, the high molecular weight bio-degradable / absorbable materials of the present invention give little or no physical stimuli to the soft tissues of a living body because their glass transition temperature is around body heat, if we compare with bio-degradable / absorbable materials consisting of

  100% polylactic acid homopolymer.

Claims (6)

  1 - Periodontic regeneration material for the periodontic regeneration treatment, characterized in that it consists of a bio-degradable / absorbable material, of high molecular mass. 2 Periodontal regeneration material according to claim 1, characterized in that a lactide / E-caprolactone or lactide / glycolide copolymer is used as said bio-degradable material /   absorbable, high molecular weight.   3 - Periodontal regeneration material according to claim 2, characterized in that said lactide / e-caprolactone or lactide / glycolide copolymer has a weight-average molecular mass lying in the range of 40,000 to 500,000.   4 - Periodontal regeneration material according to claim 2, characterized in that the said lactide / E-caprolactone or lactide / glycolide copolymer has a molar ratio lying in the range of 95: 5 at 5:95.   - Periodontal regeneration material according to claim 2, characterized in that said lactide / E-caprolactone or lactide / glycolide copolymer is in the form of a film or a sheet having   a thickness in the range of 10 to 500, dm.   6 - Periodontal regeneration material according to claim 5, characterized in that said film or said sheet of said lactide / E-caprolactone copolymer or   lactide / glycolide is porous (porous).   7 - Periodontal regeneration material according to claim 2, characterized in that said lactide / E-caprolactone or lactide / glycolide copolymer has a dynamic elasticity modulus ranging from 5 x 102 to 5 x 104 N / cm2 (5 x 107 to 5 x 109 dynes / cm2) and an elongation rate of 100 to 2,000%, all   two being measured at room temperature (25 C).   8 - Periodontal regeneration material according to claim 2, characterized in that the said lactide / j-caprolactone or lactide / glycolide copolymer sees its retention rate of the tensile strength reduced to zero after a at six months due to the in vitro hydrolysis action (in a solution   phosphate buffer at 37 C and pH 7.4).