JP2862960B2 - Mucoadhesive - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a mucoadhesive, and more particularly to a mucoadhesive used as a denture stabilizer and the like.

TECHNICAL BACKGROUND OF THE INVENTION Mucoadhesives having an adhesive property to the oral mucosa of the human body are used as, for example, denture stabilizers, but there are various restrictions and demands on their use. In other words, it is harmless to the human body. It has good adhesion to the mucous membrane. It has moderate cushioning (elasticity). It can be easily peeled off from the denture base after use. It has good use stability. It can be easily applied to the denture base. And so on.

Conventionally, as a mucoadhesive such as a denture stabilizer, a cellulose derivative such as CMC (carboxymethylcellulose), a hydrophilic polymer such as polyethylene oxide, polyacrylic acid or a derivative thereof is used, or a polyvinyl acetate or the like is used. A hydrophobic polymer has been used.

For example, JP-A-55-38143, JP-A-61-87608 and JP-A-63-77806 disclose denture stabilizers using the above hydrophilic material. The denture stabilizer made of such a hydrophilic material has excellent adhesion to mucous membranes, but when it contains moisture, it becomes a viscous fluid, which not only reduces cushioning properties but also elutes into the mouth during use. Resulting in.

JP-A-53-148197, JP-A-53-76591, JP-A-60-253440, and JP-A-61-73648 disclose a hydrophobic material mainly containing polyvinyl acetate. A denture stabilizer is disclosed. Such denture stabilizers are
Although it has excellent cushioning properties and has water resistance, it has low affinity for wet mucous membranes and poor adhesion to mucous membranes.

Therefore, the appearance of a mucoadhesive agent that has good adhesion to mucous membranes, has excellent cushioning properties, and does not elute during use is desired.

Object of the Invention The present invention has been made in view of the prior art as described above, and provides a mucoadhesive which has excellent adhesion, can maintain excellent cushioning properties for a long time, and has good use stability. It is intended to be.

SUMMARY OF THE INVENTION The first mucoadhesive according to the present invention comprises: [A] vinylpyrrolidone; [B] a macromonomer having a weight average molecular weight of 500 to 20,000 and having a vinyl group at a terminal; It is characterized by comprising a copolymer [I] obtained by polymerizing at a weight ratio of 99: 1.

Further, the second mucoadhesive according to the present invention comprises: [A] vinylpyrrolidone; [B] a macromonomer having a weight average molecular weight of 500 to 20,000 and having a vinyl group at a terminal; It is characterized by comprising a copolymer [II] obtained by polymerizing a vinyl compound having the following side chain at a weight ratio of 20:30:78 to 98: 1: 1.

Such mucoadhesives not only have excellent adhesion, but also have excellent cushioning properties over a long period of time,
Excellent in use stability.

DETAILED DESCRIPTION OF THE INVENTION The mucoadhesive according to the present invention will be specifically described below.

The first mucoadhesive according to the present invention comprises: [A] vinylpyrrolidone; and [B] a macromonomer having a weight-average molecular weight of 500 to 20,000 and having a vinyl group at a terminal, from 70:30 to 99: It is characterized by comprising a copolymer [I] obtained by polymerization at a weight ratio of 1.

The macromonomer used in the present invention is a monomer having a polymerizable functional group at the terminal of the polymer segment, for example, U.S. Patent Nos. 3,786,116 and 3,842,0
No. 59, Yamashita et al .; Polymer Journal 14 , 255-260.1982
And the like.

Specifically, for example, there is a method in which a semi-telekey polymer is first polymerized, and then a terminal is vinylated by a condensation reaction, a ring opening reaction, or the like. That is, 4,4'-azobis - (4-cyanovaleric acid), using an acid such as HS-CH ₂ -COOH as a chain transfer agent of styrene by radical polymerization, having a carboxylic acid-terminated (terrorism A low molecular weight polystyrene (melted) is prepared. Next, the terminal of this semi-telekeyric polystyrene is vinylated using ring opening of glycidyl methacrylate. In this way, a macromonomer having a vinyl group at the terminal of the polymer segment such as polystyrene can be obtained, but the macromonomer used in the present invention is not limited to the above-mentioned production method. Further, such a macromonomer may be in a liquid state or a solid state.

The unit capable of forming the polymer segment of such a macromonomer is not particularly limited, but the polymer segment obtained in the present invention is preferably hydrophobic, and specifically, styrene, styrene / acrylonitrile, methyl methacrylate, Examples include butyl acrylate and silicone. Further, as the polymerizable functional group, a functional group capable of addition polymerization is preferable, and a terminal is preferably a vinyl group. Specific examples of the functional group having a terminal vinyl group include a vinyl group, an acryloyl group, a methacryloyl group, and a vinylcarbonyl group.

As such a macromonomer, specifically, polymethyl methacrylate having a methacryloyl group at a terminal,
Examples include polystyrene having a methacryloyl group at a terminal, polybutyl acrylate having a methacryloyl group at a terminal, styrene / acrylonitrile copolymer having a methacryloyl group at a terminal, and silicone having a methacryloyl group at a terminal.

Among them, polymethyl methacrylate having a methacryloyl group at a terminal is preferably used.

In the present invention, the weight average molecular weight is 500 to 20000, preferably 20.
From 100 to 10,000 macromonomers are used. In addition, such a macromonomer is used in water, toluene,
It may be used by dissolving, dispersing, or emulsifying in an organic solvent such as methyl ethyl ketone, ethyl acetate, lower alcohol, tetrahydrofuran, acetone, and a mixed solvent thereof.

Copolymer [I] used as a mucoadhesive in the present invention
Is obtained by copolymerizing vinylpyrrolidone and at least one of the above macromonomers.

At this time, a compound [D] selected from lower alkyl vinyl ether, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives may be copolymerized in addition to the above vinylpyrrolidone and macromonomer.

As such a lower alkyl vinyl ether, specifically, methyl vinyl ether, ethyl vinyl ether, butyl vinyl ether, isobutyl vinyl ether, and hydroxybutyl vinyl ether can be used.

Further, as the acrylamide derivative, specifically,
Methacrylamide, N, N-dimethylacrylamide, diacetone acrylamide, N-isopropylacrylamide, 2-acrylamide-2-methylpropanesulfonic acid, N-hydroxy-N-methylacrylamide, N,
N'-methylenebisacrylamide, N, N'-dimethylaminopropylacrylamide and the like can be mentioned.

In order to obtain the copolymer [I], vinylpyrrolidone, a macromonomer and, if necessary, a compound [D] may be added for addition polymerization, and the polymerization method is not particularly limited. For example, peroxides such as benzoyl peroxide and hydrogen peroxide, azobisisobutyronitrile, 4,4 '
-Azobis such as azobis-4-cyanovaleric acid, benzoin such as benzoin, benzoin methyl ether, dimethoxyphenylacetophenone,
Radical polymerization can be performed by heat and light using a polymerization initiator such as phenyl ketones such as diethoxyphenyl acetophenone and benzophenones such as benzophenone and benzoylbenzoic acid. At this time, the polymerization may be performed by any of bulk polymerization, solution polymerization, suspension polymerization, and emulsion polymerization.

In the polymerization, vinylpyrrolidone and the macromonomer as described above are in a weight ratio of 70:30 to 99: 1, preferably 85:
An amount of 15 to 98: 2 is preferably used.

When the compound [D] as described above is used, vinylpyrrolidone, the macromonomer and the compound [D] are in a weight ratio of 20:30:50 to 98: 1: 1, preferably 45: 1.
An amount of 5:40 to 90: 2: 5 is preferably used.

The average molecular weight of the copolymer [I] thus obtained is preferably from 20,000 to 150,000.

The first mucoadhesive according to the present invention may contain the following polymer [III].

The polymer [III] used in the present invention is composed of a repeating unit derived from a vinyl compound [C] having a side chain having 4 or less carbon atoms.

Specific examples of such a vinyl compound having a side chain having 4 or less carbon atoms [C] include, for example, vinyl acetate, vinyl siloxane; methyl acrylate, ethyl acrylate, n-butyl acrylate, and acrylic acid. Isobutyl, acrylic acid 2
An acrylic acid compound having a side chain having 4 or less carbon atoms such as -hydroxyethyl; further, methyl methacrylate, ethyl methacrylate, n-butyl methacrylate, t-butyl methacrylate, isobutyl methacrylate, 2-hydroxyethyl methacrylate, And a methacrylic acid compound having a side chain having 4 or less carbon atoms.

 Of these, vinyl acetate is preferably used.

Polymer [III] used as a mucoadhesive in the present invention
Is obtained by polymerizing such a vinyl compound [C], and the polymerization method may be according to a conventional addition polymerization method.
There is no particular limitation.

The average molecular weight of such a copolymer [III] is 1000 to 7
00000 is preferred.

When the polymer [III] is added to the first mucoadhesive, the copolymer [I] is 20 to 99% by weight, preferably 50 to 90% by weight, and the polymer [III] is 1 to 80% by weight. Preferably 10 to 50
It is used in amounts by weight.

The second mucoadhesive according to the present invention comprises: [A] vinylpyrrolidone; [B] a macromonomer having a weight average molecular weight of 500 to 20,000 and having a vinyl group at a terminal; [C] a side having 4 or less carbon atoms. A vinyl compound having a chain,
It consists of a copolymer [II] obtained by polymerization at a weight ratio of 20:30:78 to 98: 1: 1.

Specific examples of such a macromonomer [B] and vinyl compound [C] include the same macromonomer [B] and vinyl compound [C] as in the copolymer [I] described above.

Further, in addition to these, the aforementioned compound [D] can be used.

To obtain the copolymer [II], the above-mentioned copolymer [I]
In a manner similar to the method for obtaining the above, a conventional addition polymerization may be used.

At this time, vinylpyrrolidone [A], macromonomer [B] and vinyl compound [C] were mixed at a weight ratio of 20:30:78.
9898: 1: 1, preferably 40:15:45 to 80: 2: 10 are preferably used. When compound [D] as described above is used, vinylpyrrolidone [A], macromonomer [B], vinyl compound [C] and compound [D] are in a weight ratio of 20:30:78: 78-97: 1: 1: 1 preferably 40: 15: 45: 45
An amount of ~ 80: 2: 10: 10 is preferably used.

The copolymer [II] thus obtained preferably has an average molecular weight of 20,000 to 150,000.

The second mucoadhesive according to the present invention may contain the aforementioned polymer [III]. When the polymer [III] is added, the copolymer [II] is preferably 20 to 99% by weight, preferably
It is used in an amount of 50 to 90% by weight and the polymer [III] in an amount of 1 to 80% by weight, preferably 10 to 50% by weight.

Copolymer [I] used as a mucoadhesive in the present invention
In [II] and [II], the repeating unit derived from the above [A] vinylpyrrolidone shows hydrophilicity. [B]
In the repeating unit derived from the macromonomer, the polymer segments are bonded in a graft-like manner, and thus have a hydrophobic property. Therefore, when a mucoadhesive comprising such a copolymer [I] or a copolymer [II] is used as, for example, a denture stabilizer, the repeating unit derived from the hydrophilic [A] compound has an appropriate amount due to moisture. Swelling on the oral mucosa and the repeating unit derived from the hydrophobic [B] compound has an affinity for the denture palate (usually made of acrylic resin). Further, since it has water resistance, it does not elute into the mouth and has excellent cushioning properties (elasticity).

The mucoadhesive according to the present invention may appropriately contain the following additives in addition to the above copolymer.

(1) Solvent (softening agent): athanol, purified water, polyethylene glycol, glycerin, propylene glycol,
(2) plasticizers: non-toxic oil waxes such as beeswax, wood wax, candelilla wax, carnauba wax, white petrolatum, liquid paraffin, and (3) emulsifiers: glycerin fatty acid esters such as glycerin monostearate Sorbitan fatty acid esters such as sorbitan monostearate, etc. (4) Fillers: calcium carbonate, calcium phosphate, talc, etc. (5) Adhesive aids: cellulose derivatives such as CMC, polyacrylic acid or metal salts thereof (6) Flavoring Agents, fragrances, etc.

The mucoadhesive according to the present invention may be used by filling it into a tube or the like, or may be used after being formed into a film.

Effect of the Invention Since the mucoadhesive of the present invention comprises a copolymer [I] or [II] having both a hydrophobic unit and a hydrophilic unit, it adheres well to mucous membranes, is water-resistant, and has a high water content. Good use stability without elution. Furthermore, it has an affinity for non-mucous membranes such as acrylic resin, and has excellent cushioning properties over a long period of time.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited to these examples.

Example 1 [A] 50% by weight of vinylpyrrolidone, [B] 5% by weight of methyl methacrylate macromonomer AA-6 (manufactured by Toa Gosei Chemical Industry Co., Ltd., methacryloyl-terminated polymethyl methacrylate), and [C] vinyl acetate 45% by weight 100g,
In the presence of the polymerization initiator azobisisobutyronitrile, the copolymer was copolymerized in a nitrogen stream at 60 ° C. for 8 hours, and the copolymer [I
I].

60% by weight of this copolymer [II], 25% by weight of ethanol,
5% by weight of purified water 10 and polyethylene glycol 400
Was prepared.

For the obtained mucoadhesive, the tack when wet was determined by ASTM.
Measured with a probe tack tester according to D2979-71,
The amount of dissolution in warm water at 37 ± 2 ° C after 24 hours was measured and is shown in Table 1 together with the overall evaluation.

Comparative Example 1 A mucoadhesive consisting of 75% by weight of polyvinyl acetate and 25% by weight of ethanol was prepared. Table 1 shows the evaluation in the same manner as in Example.
Shown in

Comparative Example 2 Evaluation of a mucoadhesive comprising 100% by weight of polyethylene oxide is shown in Table 1 in the same manner as in Example.

Continuation of the front page (51) Int.Cl. ⁶ Identification symbol FI // (C08F 290/04 226: 10) (56) References JP-A-55-38143 (JP, A) JP-A-61-87608 (JP) JP-A-63-77806 (JP, A) JP-A-53-148197 (JP, A) JP-A-53-76591 (JP, A) JP-A-60-253440 (JP, A) 61-73648 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C08F 290/00-290/14 C08F 26/00-26/12 C08F 226/00-226/12 A61C 13 / 00-13/38 A61K 6/00-6/10 C08L 1/00-101/14

Claims (4)

(57) [Claims] 1. A method of polymerizing [A] vinylpyrrolidone and [B] a macromonomer having a weight average molecular weight of 500 to 20,000 and having a vinyl group at a terminal in a weight ratio of 70:30 to 99: 1. A mucoadhesive comprising the copolymer [I] obtained by the above method. 2. The copolymer [I] according to claim 1, and [C] a polymer [III] comprising a repeating unit derived from a vinyl compound having a side chain of 4 or less carbon atoms. The mucoadhesive according to claim 1, wherein 3. [A] vinylpyrrolidone, [B] a macromonomer having a weight average molecular weight of 500 to 20,000 and having a vinyl group at a terminal, and [C] a vinyl compound having a side chain having 4 or less carbon atoms. Is polymerized at a weight ratio of 20:30:78 to 98: 1: 1, thereby obtaining a mucoadhesive comprising a copolymer [II]. 4. The copolymer [II] according to claim 3, and [C] a polymer [III] comprising a repeating unit derived from a vinyl compound having a side chain having 4 or less carbon atoms. 4. The mucoadhesive according to claim 3, wherein the adhesive is used.