JP3217861B2 - Materials for treating periodontal disease - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a material for treating periodontal disease, and more particularly to providing a material useful for bone augmentation performed during surgical treatment and implant treatment for periodontal disease. is there.

[0002]

2. Description of the Related Art Periodontal surgery methods for satisfactorily regenerating periodontal tissue destroyed by periodontal disease have conventionally promoted the proliferation of periodontal ligament-derived cells on the root surface,
It is known that it is effective to suppress the invasion of gingival or bone-derived cells (Milcher et al., J. Period.
ontol., 47 , 256 (1976)). From this, as a treatment and treatment method, there is a method of suppressing the invasion of epithelial cells and the like to the root surface by using a Millipore Filter (Millipore Filter, trade name) and forming a space necessary for the proliferation of periodontal ligament cells. Known as the GTR method (Guided Tissue Regeneration method) (Nyman et al., J. Clin. Periodontol., 9 , 290 (1
982)). As a clinical application example of this method, a porous polytetrafluoroethylene membrane (Coretex membrane, trade name of Gore) which is non-degradable in vivo is known. However, this GTR method requires operative skill, and after a certain period of time, it is necessary to perform a surgical operation on the surgical site again and to remove the membrane embedded in the surgical site, so that there is no damage to the affected area. Easy to occur. Therefore, a biodegradable membrane material that does not require reoperation after implantation into a living body is desired.

[0003] As for the membrane material which is degradable in vivo, a collagen film which is a natural polymer or a lactic acid-based polymer film which is an aliphatic polyester of a synthetic polymer is known. However, there is a problem that the degradation rate of the collagen membrane is not constant because the degradation proceeds by enzymatic degradation by an enzyme in the living body, and a tissue reaction occurs in the living body due to the telopeptide remaining in the collagen. From this fact, the main reaction is the hydrolysis of the ester bond, which has a constant biodegradability, and the application of lactic acid-based polymers, in which the degradation products are also generally present in the metabolic system, is important. Recently it has become mainstream.

As a material using such a lactic acid-based polymer, an L-lactic acid polymer film (Magnusson et al., J. Periodontol., 5
9 , 1 (1988)), a lactic acid-glycolic acid copolymer having 100 μm pores, Vicryl mesh, Polygl
actin 910, Ethicon company name) (Fleisher et al., Int. J. Per
io. Rest.Dent., 2 , 45 (1988)), L-lactic acid polymer film and lactic acid-glycolic acid copolymer film (Kubota et al., Nihon Gingaku, 31 , 870)
(1989)), and the use of these materials as a protective film has been reported. Furthermore, JP-A-2-
No. 63465 discloses a lactic acid-glycolic acid copolymer, lactic acid-
It is known to use a material made of ε-caprolactone copolymer. However, since these lactic acid-based polymer materials have a hard film, it is very difficult to fix the film to the tooth surface, and there is a problem in adhesion between the tooth surface and the film. Therefore, when such a membrane is attached,
The invasion of epithelial cells and the like and the compression of gingiva and the like caused detachment and detachment of the membrane.

As a method for improving the adhesion between the protective film material made of such a lactic acid polymer and the tooth surface, the present inventors have added alcohol to a (co) polymer of lactic acid and / or glycolic acid. The material was found to be excellent as a material for treating periodontal disease, and was filed earlier (Japanese Patent Application No. 3-237465).
However, the following problems became apparent in practical use. That is, the material is heated at the time of use in order to soften the material, but the user does not like to heat the alcohol-containing material. It is preferable that the material has more flexibility in operation. The storage stability of the material is not always sufficient due to evaporation of alcohol.

[0006]

Accordingly, the present inventors have further studied and found that the membrane is excellent in flexibility and storage stability, and the detachment and detachment of the membrane due to invasion of epithelial cells and the like and compression of gingiva and the like. As a result of intensive studies to obtain a material for treating periodontal disease with excellent adhesion that does not occur, it is found that those containing triethyl citrate in a lactic acid polymer or a copolymer of lactic acid and glycolic acid have excellent periodontal The present invention has been found to be a material for treating diseases and has reached the present invention.

[0007]

That is, the present invention relates to a material for treating periodontal disease comprising, as a main component, a component obtained by adding triethyl citrate to a lactic acid polymer or a copolymer of lactic acid and glycolic acid. .

[0008]

The material of the present invention is a material obtained by adding triethyl citrate to a lactic acid polymer or a copolymer of lactic acid and glycolic acid as a main component. The material of the present invention can be used in vivo by filling it between a tooth and a porous decomposable membrane made of a lactic acid-based polymer, that is, a membrane material made of a copolymer of lactic acid and / or glycolic acid. Detachment of degradable membrane,
An object of the present invention is to improve the adhesion without causing peeling and to regenerate the periodontal tissue favorably.

Regarding the lactic acid polymer or the copolymer of lactic acid and glycolic acid, which is a raw material used for producing this material, a polymer of DL-lactic acid, a copolymer of L-lactic acid-glycolic acid, A lactic acid-glycolic acid copolymer is used. Further, among these raw materials, the copolymer of lactic acid and glycolic acid has a composition of L-lactic acid-glycolic acid copolymer, and the L-lactic acid copolymer has an L-lactic acid content of 20 to 80 mol
%, In the case of a copolymer of DL-lactic acid-glycolic acid, use a DL-lactic acid content of 20 mol% or more.

[0010] These lactic acid polymers or copolymers of lactic acid and glycolic acid may be those produced by any known method. For example, lactic acid and glycolic acid can be obtained by obtaining a cyclic dimer from an oligomer in the presence of a catalyst such as zinc oxide and then performing ring-opening polymerization in the presence of a catalyst such as diethyl zinc and tin chloride. it can. Further, regarding the molecular weight of the lactic acid polymer or the copolymer of lactic acid and glycolic acid used in the present invention, the number average molecular weight is 10,0.
Use 00-90,000. That is, by using a copolymer having a molecular weight in this range, the best therapeutic material for periodontal disease of the present invention can be obtained when triethyl citrate described later is added thereto. Since the material for treating periodontal disease of the present invention is filled in the gap between the biodegradable membrane composed of the lactic acid-based polymer and the tooth as described above, it has moderate viscoelasticity and spinning as its characteristics. It is required to be rubbery or spinnable, and this property is related to the molecular weight of the copolymer.

Therefore, when its molecular weight is below 10,000,
The resulting periodontal disease treatment material becomes fluid at room temperature and flows out of the gap between the biodegradable membrane and the tooth, making its use difficult. In addition, it exhibited the property of swelling twice in volume when immersed in a pH 7.4 phosphate buffer at 37 ° C. for 24 hours, which means that the body fluid expands in vivo and the strength is reduced. Conversely, if the molecular weight of the copolymer exceeds 90,000, the resulting periodontal disease-treating material is hard, and is poor in biodegradability and adhesion, which is not preferable.

Using these raw materials, a therapeutic material for periodontal disease comprising a component obtained by adding triethyl citrate to a lactic acid polymer or a copolymer of lactic acid and glycolic acid as a main component of the present invention is produced. The method for doing this is as follows. First, a lactic acid polymer or a copolymer of lactic acid and glycolic acid is used.
Crush or cut to less than 150μm. Then, it is dissolved in a solvent in which the polymer dissolves, such as methylene chloride or chloroform or acetone. Next, triethyl citrate is added to this solution in an amount about 1/2 the amount of the lactic acid polymer or the copolymer of lactic acid and glycolic acid, and the mixture is stirred and dispersed at a temperature of about room temperature to about 70 ° C for about 1 hour. Some of the solvent evaporates,
When triethyl citrate is sufficiently homogenized to a lactic acid polymer or a copolymer of lactic acid and glycolic acid, vacuum drying is performed at room temperature to 70 ° C. Without using an organic solvent, a lactic acid polymer or a copolymer of lactic acid and glycolic acid is 100 to 1
After heating to 50 ° C. and softening, triethyl citrate can be dispersed by stirring. In this case, the content of triethyl citrate must be in the range of 10 to 40% by weight based on the lactic acid copolymer or the copolymer of lactic acid and glycolic acid. In terms of the content, it becomes difficult to obtain the excellent material for treating periodontal disease of the present invention. That is, when the content of triethyl citrate is less than 10% by weight, the material is not softened, the adhesion to the biodegradable membrane is reduced, and a gap is formed between the biodegradable membrane and the tooth. Conversely, when the content of triethyl citrate exceeds 40% by weight, the material is not preferable because it is dissolved by the water such as a body fluid.

The method of using the material of the present invention obtained as described above is as follows.
This may be uniformly rolled with a roller or the like and fixed to the tooth, or the material of the present invention may be previously adhered to the tooth to fix the biodegradable membrane. Alternatively, the biodegradable membrane and the tooth may be fixed, and the gap may be filled with this material. In carrying out these methods, it is also possible to previously mix an antibacterial agent, an oral preservative, an antibiotic, a local anesthetic or a physiologically active substance in the material of the present invention.

[0014]

The present invention will be further described below with reference to examples of the present invention, but the present invention is not limited to these examples. In the examples of the present invention, all percentages are by weight unless otherwise specified.

(Example 1) Methylene chloride (Kanto Chemical Co., Ltd.)
(Reagent made) 22 g of a pulverized D, L-lactic acid polymer (number average molecular weight 27000) was added to 400 ml and stirred and dissolved at room temperature. To this, 12 g of triethyl citrate (Kanto Chemical Co., Ltd. reagent) was added, and the mixture was heated to 40 ° C. and mixed. When the polymer concentration reached about 10% due to the change in weight due to the volatilization of methylene chloride, this was stretched on a Teflon film and dried at 70 ° C. under reduced pressure to obtain the material of the present invention. The content of triethyl citrate in the material of the present invention was determined to be 31%.

The material of the present invention is filled in a 1 ml syringe for tuberculin (manufactured by Terumo Corporation), and the mixture is dried with a drier for about 60 hours.
10mm × 15 porous biodegradable membrane made of L-lactic acid polymer (number average molecular weight 26000), which is softened by heating to ℃
The piston was pressed while pressing a syringe against one end of one side of mm × 150 μm, and attached with a width of 1.5 mm. Place the porous biodegradable membrane to which the material of the present invention is attached in a polyethylene bag
Soak in warm water at ℃. After heating for 5 minutes, it was softened and the thickness of the adhered portion was made uniform. Next, the part of the material protruding from the film was cut.

Using the porous biodegradable membrane to which the material of the present invention was adhered, the performance of the material was evaluated using a sample of a tooth of a hybrid dog. The evaluation method was such that the root of the tooth of a mongrel dog was covered with the above-mentioned film so as to cover the tooth root surface, and the periphery was tied with a suture. 100 ml of a 1% malachite green aqueous solution was dropped on this part with a dropper, and the membrane was removed after 3 hours. As a result, no coloration of malachite green was observed in the part covered with the porous biodegradable membrane. The fixation of the membrane with the above materials was well performed.

(Comparative Example 1) D, L-lactic acid polymer (number average molecular weight 27000) was filled in a 1 ml syringe for tuberculin (manufactured by Terumo Corporation), and this was heated and softened to about 80 ° C. with a drier, L-lactic acid polymer produced (number average molecular weight 26000)
Press the piston while pressing the syringe against one end of a porous biodegradable membrane consisting of 10 mm × 15 mm × 150 μm consisting of 1.
It was attached with a width of 5 mm. Put this in a polyethylene bag at 80 ° C
Immersed in warm water and heated for 5 minutes to soften it and make the thickness of the adhered portion uniform. Next, the part of the material protruding from the film was cut.

The performance of the material was evaluated using a porous biodegradable membrane to which the material was adhered and using a sample of a tooth of a hybrid adult dog. The evaluation method was that the tooth of the mongrel dog was covered with the above-mentioned film so as to cover the tooth root surface, but the adhesion to the tooth was poor, and 100 ml of a 1% malachite green aqueous solution was dropped on this part with a dropper, and after 3 hours As a result of removing the membrane, the portion covered with the porous biodegradable membrane was colored with malachite green. This confirmed that a gap was formed between the film and the teeth, which was clearly different from the case where the material of the present invention was used.

Example 2 Methylene chloride (Kanto Chemical Co., Ltd.)
(Reagent manufactured) 41 g of L-lactic acid-glycolic acid copolymer (number average molecular weight 90,000) pulverized to 400 ml and having an L-lactic acid content of 80 mol% was added and dissolved at room temperature with stirring. To this was added 28 g of triethyl citrate (a reagent manufactured by Kanto Chemical Co., Ltd.), and the mixture was heated to 40 ° C. and mixed. When the polymer concentration became about 20% due to weight change, it was stretched on a Teflon film and dried at 70 ° C. under reduced pressure to obtain the material of the present invention. The content of triethyl citrate in the material of the present invention was determined to be 40%.

This material was filled in a 1 ml syringe for tuberculin (manufactured by Terumo Corporation), which was heated and softened to about 60 ° C. with a drier, and then separately manufactured L-lactic acid-glycolic acid copolymer film (number average molecular weight) 131000, L-lactic acid content 78 mol%), porous biodegradable membrane 10 mm x 15 mm x 150 μm
The piston was pressed while pressing a syringe against one end of the, and attached with a width of 1.5 mm.

The performance of the material was evaluated using a porous biodegradable membrane to which the material was adhered and using a sample of a hybrid adult dog tooth. The evaluation method was such that the root of the tooth of a mongrel dog was covered with the above-mentioned film so as to cover the tooth root surface, and the periphery was tied with a suture. 100 ml of a 1% malachite green aqueous solution was dropped on this part with a dropper, and the membrane was removed after 3 hours. As a result, no coloration of malachite green was observed in the part covered with the porous biodegradable membrane. The fixation of the membrane with the above materials was well performed.

Example 3 Methylene chloride (Kanto Chemical Co., Ltd.)
Reagents) D, L- crushed to 50 ml D, L-lactic acid content of 50 mol%
Lactic acid-glycolic acid copolymer (number average molecular weight 45,000) 5.1
g was added and dissolved by stirring at room temperature. To this, 0.57 g of triethyl citrate (a reagent manufactured by Kanto Chemical Co., Ltd.) was added, and the mixture was heated to 40 ° C. and mixed. When the polymer concentration became about 10% by weight change, stretched this on a Teflon film,
The material of the present invention was obtained by drying under reduced pressure at 70 ° C. The content of triethyl citrate in the material of the present invention was determined to be 10%.

This material was filled in a 1 ml syringe for tuberculin (manufactured by Terumo Co.), which was heated and softened to about 60 ° C. with a drier, and a porous material made of a separately prepared D, L-lactic acid-glycolic acid copolymer was prepared. Biodegradable membrane (number average molecular weight 2
51000, D, L-lactic acid content 59mol%) 10mm × 15mm × 150μm
Press the piston while pressing the syringe against one end of the
It was attached in a 1.5 mm width. Put the porous biodegradable membrane with this material attached in a polyethylene bag and soak in 50 ° C hot water,
After heating for 5 minutes, the thickness of the adhered portion was made uniform by temperature and water pressure. Next, the part of the material protruding from the film was cut.

Using the porous biodegradable membrane to which the material was attached, the performance of the material was evaluated using a sample of a hybrid adult dog tooth. The evaluation method was such that the root of the tooth of a mongrel dog was covered with the above-mentioned film so as to cover the tooth root surface, and the periphery was tied with a suture. 100 ml of a 1% malachite green aqueous solution was dropped on this part with a dropper, and the membrane was removed after 3 hours. As a result, no coloration of malachite green was observed in the part covered with the porous biodegradable membrane. The fixation of the membrane with the above materials was well performed. In addition, the biodegradable membrane to which the material of the present invention obtained in Example 3 was attached was attached to the lower jaw P.
3.Mounted on the tooth root surface of a hybrid adult dog with a 5 mmφ bone defect formed on the P4 tooth, and coated suture coated bicyclyl (coate
d Vicryl, a brand name of Ethicon Co.), 8 weeks after the suture, no epithelial invasion was observed, cementum formation and new adhesion to the crown side were observed, and the membrane was fixed well. .

[0026]

The material for treating periodontal disease according to the present invention has higher flexibility than conventional materials, has no influence on the membrane even when it is previously attached to a biodegradable membrane, and has high storage stability. Further, there is a feature that there is no biological tissue reaction and the burden on the patient can be reduced. In addition, it has excellent adhesion to the biodegradable membrane made of a lactic acid-based polymer used as the biodegradable membrane, and furthermore, has excellent affinity with the teeth, so that the adhesion between the biodegradable membrane and the tooth is excellent. It has excellent properties and does not form a gap between teeth and does not cause detachment or peeling of the membrane in vivo. Therefore, due to these characteristics, the material of the present invention forms a place where the regeneration of periodontal tissue destroyed by periodontal disease is improved, and is useful as a material for treating periodontal disease.

────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Yoichi Nagaoka 1406-1 Shinnobe, Beppu-cho, Kakogawa-shi, Hyogo Examiner Yumi Ogoshi (56) References JP-A-1-104635 (JP, A) JP-A-2-63465 (JP, A) JP-A-4-231061 (JP, A) JP-A-5-194189 (JP, A) JP-A 1-113056 (JP, A) (58) Fields investigated (Int .Cl. ⁷ , DB name) A61C 19/06 A61K 6/00 A61K 31/765 ACK

Claims (3)

(57) [Claims] 1. A material for treating periodontal disease, comprising, as a main component, a component obtained by adding triethyl citrate to a lactic acid polymer or a copolymer of lactic acid and glycolic acid. 2. The material for treating periodontal disease according to claim 1, wherein the number average molecular weight of the lactic acid polymer or the copolymer of lactic acid and glycolic acid is in the range of 10,000 to 90,000. 3. The material for treating periodontal disease according to claim 1, wherein the content of triethyl citrate relative to the lactic acid polymer or the copolymer of lactic acid and glycolic acid is in the range of 10 to 40% by weight.