JPH0449210A - Adhesive to mucosa - Google Patents

Abstract

PURPOSE:To obtain an adhesive for mucosa, useful as a stabilizer for denture, having excellent adhesivity to mucosa, maintaining excellent cushioning properties for many hours, not eluting with water, having excellent stability of use, comprising a copolymer having both a specific hydrophilic unit and a specific hydrophobic unit. CONSTITUTION:An adhesive to mucosa comprising copolymer I composed of specific amounts of (A) a repeating unit derived from a specific hydrophilic compound such as lower alkyl vinyl ether, acrylic acid or methacrylic acid and (B) a repeating unit derived from a hydrophobic vinyl compound containing >=5C alkyl side chain, copolymer II composed of specific amounts of the repeating unit A, the repeating unit B and (C) a repeating unit derived from a vinyl compound containing <=4C alkyl side chain, copolymer III prepared by polymerizing the repeating unit A with a hydrophobic micromonomer having 500-20,000 weight-average molecular weight and terminal vinyl group in a specific ratio, copolymer IV prepared by polymerizing the repeating unit A with the repeating units D and C in a specific ratio or the copolymer I, II, III or IV and polymer V composed of the repeating unit C and having the above- mentioned effects.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to mucoadhesives, and more particularly to mucoadhesives used as denture adhesives and the like.

Technical Background of the Invention Mucoadhesives that adhere to the oral mucosa of the human body are used, for example, as denture stabilizers, but there are certain restrictions and demands on their use. In other words, it must be harmless to the human body, have good adhesion to mucous membranes, and have cushioning properties (elasticity).
After use, it is easier to peel off than the denture base surface, it has good stability in use, and it is easy to apply to the denture base surface.

By the way, conventional mucoadhesive agents such as denture stabilizers include:
Hydrophilic polymers such as cellulose derivatives such as CMC (carboxymethylcellulose), polyethylene oxide, polyacrylic acid or derivatives thereof, or hydrophobic polymers such as polyvinyl acetate are used.

For example, JP-A-55-38143, JP-A-61-
No. 87608 and Japanese Unexamined Patent Publication No. 63-77806 disclose denture stabilizers using the above-mentioned hydrophilic materials. Denture adhesives made of such hydrophilic materials have excellent adhesion to mucous membranes, but when they contain water, they become viscous fluids that not only reduce their cushioning properties but also tend to elute into the mouth during use. Resulting in.

Also, JP-A-53-148197, JP-A-53-7
No. 6591, JP-A No. 60-253440, and JP-A No. 61-73648 disclose denture stabilizers made of hydrophobic materials mainly consisting of polyvinyl acetate. Although such denture stabilizers have excellent cushioning properties and water resistance, they have low affinity with moist mucous membranes and are poor in adhesion to mucous membranes.

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

Purpose of the Invention The present invention has been made in view of the prior art as described above, and provides a mucoadhesive agent that has excellent adhesive properties, maintains excellent cushioning properties for a long period of time, and has good stability in use. The purpose is to

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

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 ether, acrylic acid, methacrylic acid, itaconic acid, acrylamide, and acrylamide derivatives; 20 to 98 mol%, [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 [C] a vinyl compound having a side chain having 4 or less carbon atoms. A copolymer with 1 to 78 mol% of repeating units derived from [I
It is characterized by consisting of [ ].

Further, the third mucoadhesive according to the present invention comprises [A] at least one compound selected from the group consisting of lower alkyl vinyl ether, acrylic acid, methacrylic acid, itaconic acid, acrylamide, and acrylamide derivatives, and [D] weight A macromonomer having an average molecular weight of 500 to 20,000 and having a vinyl group at the end in a ratio of 70:3.
It is characterized by consisting of a copolymer [I[] obtained by polymerization at a weight ratio of 0 to 99:1.

Furthermore, the fourth mucoadhesive according to the present invention has [A] low m
Alkyl vinyl ether, acrylic acid, methacrylic acid,
at least one compound selected from the group consisting of itaconic acid, acrylamide, and acrylamide derivatives, [D] a macromonomer having a weight average molecular weight of 500 to 20,000 and having a vinyl group at the end, and [C] a carbon number of 4 or less. It is characterized by consisting of a copolymer [IV] obtained by polymerizing a vinyl compound having a side chain of 98:1:1 to 20:30 at a weight ratio of 8.

Such a mucoadhesive agent not only has excellent adhesive properties, but also maintains excellent cushioning properties over a long period of time, and has excellent stability in use.

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

Such lower alkyl vinyl ethers are vinyl ethers having an alkyl group having 4 or less carbon atoms, and specifically include methyl vinyl ether, ethyl vinyl ether,
butyl vinyl ether, isobutyl vinyl ether,
Hydroxybutyl vinyl ether is preferably used.

Specific examples of acrylamide derivatives include 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.

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

Specific examples of vinyl carboxylic acid compounds having an alkyl side chain having 5 or more carbon atoms include vinyl caproate, vinyl 2-ethylhexanoate, vinyl caprylate, vinyl caprate, and vinyl laurate. , vinyl dodecenoate, vinyl myristate, vinyl valmitate, vinyl stearate, and the like.

In addition, examples of acrylic acid compounds having an alkyl side chain having 5 or more carbon atoms include n-pentyl acrylate, isopentyl acrylate, n-hexyl acrylate, 2-ethylhexyl acrylate, n-octyl acrylate, isooctyl acrylate,
Examples include t-butyl alkyl, isononyl acrylate, n-decyl acrylate, isodecyl acrylate, lauryl acrylate, and stearyl acrylate.

Further, methacrylic acid compounds 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,
Examples include stearyl methacrylate.

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 preferred, and vinyl laurate is particularly preferred.

The copolymer [I] used as a mucoadhesive in the present invention contains 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.

To obtain such a copolymer [I], a conventional addition polymerization method may be used, and there are no particular limitations. Peroxides such as benzoyl peroxide, hydrogen peroxide, azobisisobutyronitrile, 4,4-azobis-4
- Azobis such as cyanovaleric acid, benzoin,
Benzoins, such as benzoin methyl ether,
Radical polymerization may be carried out using heat and light using a polymerization initiator such as phenyl ketones such as dimethoxyphenylacetophenone and jetoxyphenylacetophenone, and benzophenones such as benzophenone and benzoylbenzoic acid. Specifically, it is obtained, for example, by radical polymerizing ethyl vinyl ether and vinyl laurate using a polymerization initiator azobisisobutyronitrile.

At this time, the polymerization may be carried out by any method such as bulk polymerization, solution polymerization, suspension polymerization, or emulsion polymerization.

The copolymer [I] thus obtained is composed of [A] lower alkyl vinyl ether, acrylic acid, methacrylic acid,
Repeating units derived from at least one compound selected from the group consisting of itaconic acid, acrylamide and acrylamide derivatives, preferably 70 to 99 mol%, preferably 8
[B] A repeating unit derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms, or 1 to 30 mol%, preferably 5 to 15 mol%.

The average molecular weight of such copolymer [I] is 20,000
~1,500,000 is preferred.

The first mucoadhesive according to the present invention is made of the following polymer [
V].

The polymer [V] used in the present invention is composed of repeating units derived from a vinyl compound [C] having at least one type of 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, vinyl siloxane, and the like.

Mata, methyl acrylate, ethyl acrylate, n-butyl acrylate, isophthyl acrylate, 2-acrylate
Acrylic acid compounds having a side chain having 4 or less carbon atoms, such as hydroxyethyl, can also be mentioned.

Furthermore, methacrylic acid compounds having a side chain having 4 or less carbon atoms, such as methyl methacrylate, ethyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, and 2-hydroxyethyl methacrylate, can also be mentioned.

Among these, vinyl acetate is preferably used.

The polymer [V] used as a mucoadhesive in the present invention is
The vinyl compound [C] may be obtained by polymerizing the vinyl compound [C], and the polymerization method may be any conventional method and is not particularly limited.

The average molecular weight of such polymer [V] is 1000 to 7
00000 is preferred.

When polymer [V] is added to the first mucoadhesive,
20 to 99% by weight of copolymer [I], preferably 50 to 9% by weight
0% by weight, 1 to 80% by weight of polymer [V], preferably 1
It is used in amounts of 0 to 50% by weight.

The second mucoadhesive according to the present invention includes: [A] at least one compound selected from the group consisting of lower alkyl vinyl ether, acrylic acid, methacrylic acid, itaconic acid, acrylamide, and acrylamide derivatives; [B] carbon number 5 It consists of a copolymer [I[] obtained by polymerizing a vinyl compound having the above alkyl side chain and [C] a vinyl compound having at least one type of side chain having 4 or less carbon atoms.

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

To obtain copolymer [II], the above-mentioned copolymer [I]
Addition polymerization may be carried out in the same manner as in .

The thus obtained copolymer [II] is a repeating polymer derived from at least one compound selected from the group consisting of [A] lower alkyl vinyl ether, acrylic acid, methacrylic acid, itaconic acid, acrylamide, and acrylamide derivatives. 20 to 98 mol% of units, preferably 40 to 80 mol%, [B] 1 to 30 mol% of repeating units derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms, preferably 5 to 15 mol% and [C] repeating unit derived from a vinyl compound having a side chain having 4 or less carbon atoms is 1 to 3
0 mol%, preferably 5 to 15 mol%.

The average molecular weight of such copolymer [II] is 2000
0 to 1,500,000 is preferred.

The second mucoadhesive according to the present invention is composed of the above-mentioned polymer [V
] may be included. When polymer [V] is added, copolymer [II] is 20 to 99% by weight, preferably 50 to 90% by weight, and polymer [V] is 1 to 80% by weight, preferably 10 to 50% by weight. used in amounts of

The third mucoadhesive according to the present invention includes: [A] at least one compound selected from the group consisting of lower alkyl vinyl ether, acrylic acid, methacrylic acid, itaconic acid, acrylamide, and acrylamide derivatives, and [D] weight average A macromonomer having a molecular weight of 500 to 20,000 and having a vinyl group at the end in a ratio of 70:30.
It is characterized by consisting of a copolymer [I] obtained by polymerization at a weight ratio of ~99:1.

Such [A] compounds include the above-mentioned copolymer [I],
The same [A] compound as [n] can be used.

The macromonomer used in the present invention is a monomer having a polymerizable functional group at the end of a polymer segment,
For example, U.S. Patent No. 3,786.116;
．． Publication No. 842.059, Sanno et al.
urnal 14.255-260.1982) and others.

Specifically, for example, there is a method in which a semitelechelic polymer is first polymerized, and then the terminal is vinylized by a condensation reaction, a ring-opening reaction, or the like.

That is, 4,4°-azobis-(4-cyanovaleric acid) was used as an initiator, and H3-CH2- was used as a chain transfer agent.
Styrene is radically polymerized using an acid such as COOH to prepare carboxylic acid-terminated (telomerized) low molecular weight polystyrene. Next, the ends of this semitelechelic polystyrene are vinylized using ring opening of glycidyl methacrylate. In this way, a macromonomer having a vinyl group at the end of a polymer segment such as polystyrene is 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.

Units that can form polymer segments of such macromonomers are not particularly limited, but it is preferable that the polymer segments obtained in the present invention are hydrophobic. Specifically, styrene, styrene/acrylonitrile, methylmethacrylate, -butyl acrylate, silicone, etc. The polymerizable functional group is preferably a functional group that can undergo addition polymerization, and preferably has a vinyl group at the end. Specific examples of the functional group having a vinyl terminal include a vinyl group, an acroyl group, a methacryloyl group, and a vinyl carbonyl group.

Examples of such macromonomers include polymethyl methacrylate having a methacryloyl group at the end, polystyrene having a methacryloyl group at the end, polybutyl acrylate having a methacryloyl group at the end, and styrene/acrylonitrile having a methacryloyl group at the end. , silicone having a methacryloyl group at the end.

Among these, polymethyl methacrylate having a methacryloyl group at the end is preferably used.

In the present invention, a macromonomer having a weight average molecular weight of 500 to 20,000, preferably 2,000 to 10,000 is used. In addition, when using such macromonomers,
It may be used after being dissolved, dispersed, or emulsified in an organic solvent such as water, toluene, methyl ethyl ketone, ethyl acetate, lower alcohol, tetrahydrofuran, acetone, or a mixed solvent thereof.

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

In order to obtain such a copolymer [In], the [A] compound and a macromonomer may be subjected to addition polymerization, and there are no particular limitations. For example, peroxides such as benzoyl peroxide, hydrogen peroxide, etc., azobis compounds such as abbisisobutyronitrile, 4-4°-azobis-4cyanovaleric acid, etc., benzoin, benzoin methyl ether, etc. Radical polymerization can be carried out by heat and light using a polymerization initiator such as benzoins, phenyl ketones such as dimethoxyphenylacetophenone, jetoxyphenylacetophenone, benzophenone, benzophenones such as benzoylbenzoic acid, etc. . At this time, the polymerization may be carried out by any of bulk polymerization, solution polymerization, suspension polymerization, and emulsion polymerization.

In the polymerization, the [A] compound and the above macromonomer are used in a weight ratio of 70:30 to 99 liters, preferably 85:15 to 98:2.

The average molecular weight of the copolymer [I] thus obtained is preferably 20,000 to 1,500,000.

The third mucoadhesive according to the present invention is composed of the above-mentioned polymer [V
] may be included.

When polymer [V] is added to the third mucoadhesive,
Copolymer [I] is 20-99% by weight, preferably 50-9%
0% by weight, polymer [V] is 1 to 80% by weight, preferably 1
It is used in amounts of 0 to 50% by weight.

The fourth mucoadhesive according to the present invention includes: [A] at least one compound selected from the group consisting of lower alkyl vinyl ether, acrylic acid, methacrylic acid, itaconic acid, acrylamide, and acrylamide derivatives, and [D] weight average A macromonomer with a molecular weight of 500 to 2oooo and having a vinyl group at the end and a vinyl compound having a side chain with [C] carbon number of 4 or less at a weight ratio of 98:l:l to 20:30:78. It consists of a copolymer [IV] obtained by polymerization.

Such [A] compound, [D] comacromonomer C]
Specifically, as the vinyl compound, the above-mentioned copolymer [
I], [I[], [A] compound similar to [I], [D]
Comacromonomer [C] Vinyl compounds can be mentioned.

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

At this time, [A] compound, [D comacromonomer and [
C] The vinyl compound has a weight ratio of 98:1:1 to 20:3
0:78 preferably 80:2:10 to 40:15:45
used in amounts of

The copolymer [IV] obtained in step 2 preferably has an average molecular weight of 20,000 to 1,500,000.

The fourth mucoadhesive according to the present invention is the above-mentioned polymer [V
] may be included. When polymer [V] is added, copolymer [IV] is 20 to 99% by weight, preferably 50 to 90% by weight, and polymer [V] is 1 to 80% by weight, preferably 10 to 50% by weight. used in amounts of

Copolymer [I] used as a mucoadhesive in the present invention,
In [II], [■ and [IV], the above [A
] Lower alkyl vinyl ether, acrylic acid, methacrylic acid, itaconic acid, acrylamide, and repeating units derived from acrylamide derivatives exhibit hydrophilicity. Further, in the repeating unit derived from the compound [B] or the macromonomer [D], a side chain alkyl group or a polymer segment is bonded in a grafted manner, and therefore it has hydrophobicity. Therefore, such a copolymer [I]
When a mucoadhesive consisting of or [I[] or [■] or [IV] is used, for example, as a denture stabilizer, the repeating unit derived from the hydrophilic [A] compound swells moderately with water, resulting in oral mucosa. The repeating unit derived from the hydrophobic [B] compound or [D] macromonomer has an affinity for the denture palate (usually made of acrylic resin).

Furthermore, since it has water resistance, it does not dissolve into the mouth and has excellent cushioning properties (elasticity).

In addition to the copolymer described above, the mucoadhesive agent according to the present invention may contain the following additives as appropriate.

(1) Solvent (softener): ethanol, purified water, polyethylene glycol, glycerin, propylene glycol, sorbitol, triethyl citrate, etc. (2) Plasticizer: beeswax, wood wax, candelilla wax, carnauba wax, White petrolatum, non-toxic oil wax such as liquid paraffin, (3) Emulsifier: glycerin fatty acid ester such as glycerin monostearate, sorbitan fatty acid ester such as sorbitan monostearate, (4) Filler: carbonic acid Calcium, calcium phosphate, talc, etc. (5) Adhesion aids...cellulose derivatives such as CMC,
Polyacrylic acid or its metal salt (6) Flavoring agents, fragrances, etc.

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

Effects of the Invention The mucoadhesive of the present invention is a copolymer [I] or [I[] or [III] having both a hydrophobic unit and a hydrophilic unit.
or [IV], it adheres well to mucous membranes, is water resistant, does not elute with moisture, and is stable in use. Furthermore, it has an affinity for non-mucous membranes such as acrylic resin, and has excellent cushioning properties over a long period of time.

EXAMPLES The present invention will be explained below with reference to Examples, but the present invention is not limited to these Examples.

Example 1 [A] 100g of ethyl vinyl ether, 10g of acrylic acid
Copolymerization was carried out using 0 g and 70 g of [B] dinylic laurate and a polymerization initiator abbisisobutyronitrile at 60°C in a nitrogen stream for 8 hours to form a copolymer [I
] was obtained.

The composition of the obtained copolymer is shown in Table-1.

This copolymer [I] 60% by weight, ethanol 25% by weight
, purified water 10% by weight and polyethylene glycol 40
Mucoadhesives 1 were prepared consisting of 0 and 5% by weight. For the obtained mucoadhesive l, the tack when wet was determined by ASTM.
Measurement was carried out using a probe tack tester according to D2979-71, and the amount of dissolution after 24 hours in 37±2°C warm water was measured, and the results are shown in Table 1 along with the overall evaluation.

Example 2 [A] 100 g of ethyl vinyl ether, 10 g of acrylic acid
0g [D] Methyl methacrylate macromonomer AA-
6 (methacrylic terminal polymethyl methacrylate manufactured by Toagosei Kagaku Kogyo ■) in a nitrogen stream,
Copolymerization was carried out at 0°C for 8 hours to form a copolymer [I[[]
I got it.

A mucoadhesive agent 2 was prepared consisting of 660% by weight of this copolymer [II[]6, 25% by weight of ethanol, 10% by weight of purified water, and 5% by weight of polyethylene glycol 400. Table 1 shows the tackiness, dissolution amount, and 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. Evaluations are shown in the same way as in the examples.
Shown in 1.

Comparative Example 2 Evaluation of a mucoadhesive agent made of 100% by weight of polyethylene oxide is shown in Table 1 in the same way as in Examples.

Table-1

Claims (8)

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