JP2901708B2 - Mucoadhesive - Google Patents

Description

Description: FIELD OF THE INVENTION 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. That is, it is harmless to the human body, has good adhesion to mucous membranes, has moderate cushioning properties (elasticity), easily peels off from the denture base after use, has good use stability, It is easy to apply to the surface.

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.

The first mucoadhesive according to the present invention is derived from [A] at least one compound selected from the group consisting of lower alkyl vinyl ethers, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives. It is characterized by comprising a copolymer [I] comprising 70 to 99 mol% of repeating units and [B] 1 to 30 mol% of repeating units derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms. And

The second mucoadhesive according to the present invention comprises: [A] a repeating unit derived from at least one compound selected from the group consisting of lower alkyl vinyl ethers, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives. 20 to 98 mol%, [B] 1 to 30 mol% of a repeating unit derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms, and [C] a vinyl compound having a side chain having 4 or less carbon atoms. [II] having 1 to 78 mol% of repeating units derived from
It is characterized by consisting of.

The third mucoadhesive according to the present invention comprises: [A] at least one compound selected from the group consisting of lower alkyl vinyl ethers, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives; It is characterized by comprising a copolymer [III] obtained by polymerizing a macromonomer having an average molecular weight of 500 to 20,000 and having a vinyl group at a terminal at a weight ratio of 70:30 to 99: 1. .

The fourth mucoadhesive according to the present invention further comprises: [A] at least one compound selected from the group consisting of lower alkyl vinyl ethers, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives; A macromonomer having an 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 are in a weight ratio of 98: 1: 1 to 20:30:78. Characterized by comprising a copolymer [IV] obtained by polymerization in

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] at least one compound selected from the group consisting of lower alkyl vinyl ethers, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives; [B] carbon number It consists of a copolymer [I] with a vinyl compound having 5 or more alkyl side chains.

Such a lower alkyl vinyl ether has 4 carbon atoms.
Vinyl ethers having the following alkyl groups, specifically, methyl vinyl ether, ethyl vinyl ether, butyl vinyl ether, isobutyl vinyl ether, and hydroxybutyl vinyl ether are preferably used.

As the acrylamide derivative, specifically, methacrylamide, N, N-dimethylacrylamide, diacetone acrylamide, N-isopropylacrylamide,
2-acrylamido-2-methylpropanesulfonic acid,
N-hydroxy-N-methylacrylamide, N, N'-
Methylenebisacrylamide, N, N'-dimethylaminopropylacrylamide and the like can be mentioned.

Examples of the vinyl compound used in the present invention include a vinyl carboxylic acid compound, an acrylic acid compound, and a methacrylic acid compound.

Specific examples of such a vinyl carboxylic acid compound having an alkyl side chain having 5 or more carbon atoms include, for example,
Vinyl caproate, vinyl 2-ethylhexanoate, vinyl caprylate, vinyl caprate, vinyl laurate,
Examples include vinyl dodecenoate, vinyl myristate, vinyl palmitate, vinyl stearate and the like.

Examples of the acrylate compound having an alkyl side chain having 5 or more carbon atoms include n-pentyl acrylate, isopentyl acrylate,
Examples thereof include n-hexyl acrylate, 2-ethylhexyl acrylate, n-octyl acrylate, isooctyl acrylate, isononyl acrylate, n-decyl acrylate, isodecyl acrylate, lauryl acrylate, and stearyl acrylate.

Examples of the methacrylic acid compound having an alkyl side chain having 5 or more carbon atoms include 2-ethylhexyl methacrylate, octyl methacrylate, isooctyl methacrylate, isodecyl methacrylate, lauryl methacrylate, tridecyl methacrylate, stearyl methacrylate and the like. .

In the present invention, as the vinyl compound having an alkyl side chain having 5 or more carbon atoms, vinyl laurate and vinyl dodecenoate are preferable, and vinyl laurate is particularly preferable.

Copolymer [I] used as a mucoadhesive in the present invention
Is a combination of at least one compound selected from the group consisting of lower alkyl vinyl ether, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives as described above, and a compound having an alkyl side chain having 5 or more carbon atoms. It is obtained by polymerizing.

In order to obtain such a copolymer [I], a conventional addition polymerization method may be used, and there is no particular limitation. For example, peroxides such as benzoyl peroxide and hydrogen peroxide, azobisisobutyronitrile, 4,4'-azobis-
Azobiss such as 4-cyanovaleric acid, benzoins such as benzoin and benzoin methyl ether, phenyl ketones such as dimethoxyphenylacetophenone and diethoxyphenylacetophenone;
Radical polymerization may be performed by heat and light using a polymerization initiator such as benzophenones such as benzophenone and benzoylbenzoic acid. Specifically, for example, it can be obtained by radical polymerization of ethyl vinyl ether and vinyl laurate using a polymerization initiator azobisisobutyronitrile.

In this case, the polymerization may be performed by any method such as bulk polymerization, solution polymerization, suspension polymerization, and emulsion polymerization.

The copolymer [I] thus obtained comprises: [A] a repeating unit derived from at least one compound selected from the group consisting of lower alkyl vinyl ethers, methacrylic acid acrylate, itaconic acid, acrylamide and acrylamide derivatives. And 70 to 99 mol%, preferably 85 to 95 mol%, and [B] 1 to 30 mol%, preferably 5 to 15 mol% of a repeating unit derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms. %.

The average molecular weight of such a copolymer [I] is from 20,000 to 1
500000 is preferred.

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

The polymer [V] used in the present invention is composed of at least one 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 include vinyl acetate and vinyl siloxane.

Further, methyl acrylate, ethyl acrylate, n-butyl acrylate, isobutyl acrylate, acrylic acid 2
An acrylic acid compound having a side chain having 4 or less carbon atoms, such as -hydroxyethyl, may also be used.

Further, methyl methacrylate, ethyl methacrylate,
Methacrylic acid compounds having a side chain having 4 or less carbon atoms, such as n-butyl methacrylate, isobutyl methacrylate, and 2-hydroxyethyl methacrylate, can also be mentioned. Of these, vinyl acetate is preferably used.

Polymer [V] used as a mucoadhesive in the present invention
Is obtained by polymerizing such a vinyl compound [C], but the polymerization method may be in accordance with a conventional method and is not particularly limited.

The average molecular weight of such a polymer [V] is 1000 to 7000
00 is particularly preferred.

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

The second mucoadhesive according to the present invention comprises: [A] at least one compound selected from the group consisting of lower alkyl vinyl ethers, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives, [B] 5 carbon atoms It comprises a vinyl compound having an alkyl side chain as described above and a copolymer [II] obtained by polymerizing [C] at least one vinyl compound having a side chain having 4 or less carbon atoms.

Examples of such a compound [A], [B] a compound having an alkyl side chain having 5 or more carbon atoms, and [C] a vinyl compound having a side chain having 4 or less carbon atoms include the above-mentioned copolymer [ The same [A] compound and [B] compound as in [I],
[C] compounds.

To obtain the copolymer [II], the above-mentioned copolymer [I]
The addition polymerization may be performed in the same manner as described above.

The copolymer [II] thus obtained comprises: [A] a repeating unit derived from at least one compound selected from the group consisting of lower alkyl vinyl ethers, methacrylic acid acrylate, itaconic acid, acrylamide and acrylamide derivatives And 20 to 98 mol%, preferably 40 to 80 mol%, and [B] 1 to 30 mol%, preferably 5 to 15 mol% of a repeating unit derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms. And [C] a repeating unit derived from a vinyl compound having a side chain having 4 or less carbon atoms is 1 to 30 mol%, preferably 5 to 15 mol%.
Mol%.

The average molecular weight of such a copolymer [II] is from 20,000 to 1
500000 is preferred.

The second mucoadhesive according to the present invention may contain the aforementioned polymer [V]. When the polymer [V] is added, the amount of the copolymer [II] is 20 to 99% by weight, preferably 50 to 99% by weight.
To 90% by weight, and the polymer [V] is 1 to 80% by weight, preferably 10% by weight.
Used in an amount of 5050% by weight.

The third mucoadhesive according to the present invention comprises: [A] at least one compound selected from the group consisting of lower alkyl vinyl ethers, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives; [D] weight average It is characterized by comprising a copolymer [III] obtained by polymerizing a macromonomer having a molecular weight of 500 to 20,000 and having a vinyl group at a terminal at a weight ratio of 70:30 to 99: 1.

As the compound [A], the same compound [A] as that of the copolymers [I] and [II] described above is used.

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 , 255-260.198)
2) 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, the initiator 4,4'-azobis - (4-cyanovaleric acid), as a chain transfer agent, styrene by radical polymerization using an acid such as HS-CH ₂ -COOH, a carboxylic acid-terminated ( Prepare low molecular weight polystyrene (telomerized). Next, the terminal of this semi-telekey 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 include a vinyl group, an acroyl 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 having a methacryloyl group at a terminal, and silicone having a methacryloyl group at a terminal.

Among them, polymethyl methacrylate having a methacrylolyl 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 used as mucoadhesive in the present invention [II
I] is obtained by copolymerizing the compound [A] with at least one of the above macromonomers.

In order to obtain such a copolymer [III], the compound [A] and the macromonomer may be addition-polymerized, and there is no particular limitation. For example, peroxides such as benzoyl peroxide and hydrogen peroxide, azobis such as azobisisobutyronitrile, 4-4'-azobis-4-cyanovaleric acid, benzoin, benzoin methyl ether, etc. Radical polymerization by heat and light using a polymerization initiator such as benzoin such as it can. At this time, the polymerization may be performed by any of bulk polymerization, solution polymerization, suspension polymerization, and emulsion polymerization.

At the time of polymerization, the compound [A] and the macromonomer as described above are in a weight ratio of 70:30 to 99: 1, preferably 85:15 to
Used in 98: 2 amount.

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

The third mucoadhesive according to the present invention may contain the polymer [V] described above.

When the polymer [V] is added to the third mucoadhesive, the content of the copolymer [III] is 20 to 99% by weight, preferably 50 to 90%.
% By weight, and the polymer [V] is 1 to 80% by weight, preferably 10 to 50% by weight.
It is used in amounts by weight.

The fourth mucoadhesive according to the present invention comprises: [A] at least one compound selected from the group consisting of lower alkyl vinyl ethers, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives; [D] weight average A macromonomer having a 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 are polymerized in a weight ratio of 98: 1 to 20:30:78. Of the copolymer [IV] obtained by the above method.

Such [A] compound, [D] macromonomer,
[C] Specific examples of the vinyl compound include [A] similar to the copolymers [I], [II], and [III] described above;
[D] macromonomer and [C] vinyl compound.

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

At this time, the compound [A], the macromonomer [D] and the vinyl compound [C] are in a weight ratio of 98: 1: 1 to 20:30:78, preferably 80: 2: 10 to 40:15:45. Used in

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

The fourth mucoadhesive according to the present invention may contain the aforementioned polymer [V]. When the polymer [V] is added, the copolymer [IV] is contained in an amount of 20 to 99% by weight, preferably 50 to 99% by weight.
To 90% by weight, and the polymer [V] is 1 to 80% by weight, preferably 10% by weight.
Used in an amount of 5050% by weight.

In the copolymers [I], [II], [III] and [IV] used as mucoadhesives in the present invention, the above [A] lower alkyl vinyl ether, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide The repeating unit derived from the derivative shows hydrophilicity. Further, in the repeating unit derived from the compound [B] or the macromonomer [D], the side chain alkyl group or the polymer segment is bonded in a graft form, and thus has hydrophobicity. Therefore, such a mucoadhesive consisting of the copolymer [I] or [II] or [III] or [IV], for example, when used as a denture stabilizer, is a cyclic derivative derived from a hydrophilic [A] compound. The unit is moderately swollen by water and adheres to the oral mucosa, and the repeating unit derived from the hydrophobic [B] compound or [D] macromonomer 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): ethanol, 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; (4) fillers: calcium carbonate, calcium phosphate, talc, etc. (5) adhesive aids: cellulose derivatives such as CMC, polyacrylic acid or its metal salts, etc. (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] or [III] or [IV] having both a hydrophobic unit and a hydrophilic unit, it adheres well to mucous membranes, It is water-resistant and has good use stability without being eluted with water. 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] 100 g of ethyl vinyl ether, 100 g of acrylic acid and 70 g of [B] vinyl laurate were copolymerized using a polymerization initiator azobisisobutyronitrile in a nitrogen stream at 60 ° C. for 8 hours. As a result, a copolymer [I] was obtained.

 Table 1 shows the composition of the obtained copolymer.

60% by weight of this copolymer [I], 25% by weight of ethanol,
5% by weight of purified water 10% and polyethylene glycol 400
A mucoadhesive 1 consisting of 1% by weight was prepared. With respect to the obtained mucoadhesive 1, the wet tack was measured with a probe tack tester in accordance with ASTM D2979-71, and the amount of dissolution in hot water at 37 ± 2 ° C. after 24 hours was measured. It is shown in FIG.

Example 2 [A] 100 g of ethyl vinyl ether, 100 g of acrylic acid
[D] 10 g of methyl methacrylate macromonomer AA-6 (methacryloyl-terminated polymethyl methacrylate, manufactured by Toa Gosei Chemical Industry Co., Ltd.) is copolymerized in a nitrogen stream at 60 ° C. for 8 hours to obtain a copolymer [ III].

60% by weight of this copolymer [III], 25% by weight of ethanol, 10% by weight of purified water and polyethylene glycol 400
Was prepared in an amount of 5% by weight. Table 1 shows the tack, the amount of dissolution and the overall evaluation of the obtained mucoadhesive 2 when wet.

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 (56) References JP-A-63-115805 (JP, A) JP-A-62-129210 (JP, A) International publication 90/3809 (WO, A1) (58) Fields investigated (Int.Cl. ⁶ , DB name) A61K 6/00 A61K ⁶ /08-6/083

Claims (8)

(57) [Claims] (A) a repeating unit derived from at least one compound selected from the group consisting of lower alkyl vinyl ethers, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives, in an amount of 70 to 99 mol%; [B] A mucoadhesive comprising a copolymer [I] having 1 to 30 mol% of repeating units derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms. 2. A copolymer comprising [I] according to claim 1 and [C] a polymer [V] comprising a repeating unit derived from a vinyl compound having a side chain having 4 or less carbon atoms. The mucoadhesive according to claim 1, characterized in that: (A) a repeating unit derived from at least one compound selected from the group consisting of lower alkyl vinyl ethers, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives, in an amount of 20 to 98 mol%; [B] 1 to 30 mol% of a repeating unit derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms, and [C] a repeating unit derived from a vinyl compound having a side chain having 4 or less carbon atoms. Copolymer with 1 to 78 mol% [II]
A mucoadhesive consisting of 4. A copolymer comprising the copolymer [II] according to claim 3 and [C] a polymer [V] 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. 5. [A] at least one compound selected from the group consisting of lower alkyl vinyl ethers, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives, and [D] a weight average molecular weight of 500 to 20,000. A mucoadhesive comprising a copolymer [III] obtained by polymerizing a macromonomer having a terminal vinyl group with a weight ratio of 70:30 to 99: 1. 6. The copolymer [III] according to claim 5,
The mucoadhesive according to claim 5, comprising: [C] a polymer [V] comprising a repeating unit derived from a vinyl compound having a side chain having 4 or less carbon atoms. 7. [A] at least one compound selected from the group consisting of lower alkyl vinyl ethers, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives, and [D] a weight average molecular weight of 500 to 20,000. A polymer obtained by polymerizing a macromonomer having a vinyl group at a terminal and a vinyl compound having a side chain having 4 or less carbon atoms at a weight ratio of 98: 1: 1 to 20:30:78. A mucoadhesive comprising a polymer [IV]. 8. The copolymer [IV] according to claim 7, and [C] a polymer [V] comprising a repeating unit derived from a vinyl compound having a side chain having 4 or less carbon atoms. The mucoadhesive according to claim 7, wherein