JP2901707B2 - 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
JP-A-63-77806 discloses a denture stabilizer 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 comprises: [A] a repeating unit derived from vinylpyrrolidone; and [B] a repeating unit derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms. Is contained in a molar ratio of 70:30 to 99: 1.

The second mucoadhesive according to the present invention comprises: [A] a repeating unit derived from vinylpyrrolidone; [B] a repeating unit derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms; C] a copolymer [II] containing a repeating unit derived from a vinyl compound having a side chain of 4 or less carbon atoms in a molar ratio of 20:30:78 to 98: 1: 1. I have.

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 copolymer [I] of [A] vinylpyrrolidone and [B] a vinyl compound having an alkyl side chain having 5 or more carbon atoms.

Examples of such vinyl compounds include vinyl carboxylate compounds, acrylate compounds, and methacrylate compounds.

Specific examples of the vinyl carboxylate compound having 5 or more carbon atoms include, for example, vinyl caproate,
Examples include vinyl ethylhexanoate, vinyl caprylate, vinyl caprate, vinyl laurate, 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 methacrylate compound having an alkyl side chain having 5 or more carbon atoms, preferably 5 to 25 carbon atoms, include 2-ethylhexyl methacrylate, octyl methacrylate, isooctyl methacrylate, isodecyl methacrylate, lauryl methacrylate, tridecyl methacrylate, and methacrylic acid. And stearyl acid.

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 obtained by copolymerizing vinylpyrrolidone and a vinyl compound having an alkyl side chain having 5 or more carbon atoms as described above. At this time, in addition to the above compounds, a compound [D] selected from lower alkyl vinyl ether, acrylic acid, methacrylic acid, itaconic acid, acrylamide and acrylamide derivatives may be copolymerized. 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 such a copolymer [I], a conventional addition polymerization method may be used, and it is not particularly limited. For example, vinylpyrrolidone and a vinyl compound having a side difference of 5 or more carbon atoms may be used. Is subjected to radical polymerization by heat and light.

At this time, peroxides such as benzoyl peroxide and hydrogen peroxide, azobis such as azobisisobutyronitrile, 4,4'-azobis-4-cyanovaleric acid, benzoin, benzoin methyl ether The polymerization can be carried out using a polymerization initiator such as benzoin such as benzoin, phenylketone such as dimethoxyphenylacetophenone, diethoxyphenylacetophenone, and benzophenone such as benzophenone and benzoylbenzoic acid.

The polymerization may be performed in any state such as bulk polymerization, solution polymerization, suspension polymerization, and emulsion polymerization.

The copolymer [I] thus obtained is composed of: [A] a repeating unit derived from vinylpyrrolidone, and [B] a repeating unit derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms. In a molar ratio of 70:30 to 99: 1, preferably 85:15 to 95: 5.

When the copolymer [I] contains a repeating unit derived from the compound [D] as described above, [A] a repeating unit derived from vinylpyrrolidone, and [B] a carbon number of 5 or more. A repeating unit derived from a vinyl compound having an alkyl side chain of: and a repeating unit derived from the compound [D] at 20:30:50
9898: 1: 1, preferably 45:15:40 to 90: 5: 5.

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 [III].

The polymer [III] used in the present invention has at least 1
It comprises 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 include vinyl acetate and vinyl siloxane.

In addition, acrylic acid compounds having a side chain having 4 or less carbon atoms such as methyl acrylate, ethyl acrylate, n-butyl acrylate, t-butyl acrylate, isobutyl acrylate, and 2-hydroxyethyl acrylate may also be used. it can.

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 preferred.

Polymer [III] 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 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 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. It consists of a copolymer [II] obtained by polymerization.

Examples of the [B] vinyl compound having an alkyl side chain having 5 or more carbon atoms and [C] the vinyl compound having a side chain having 4 or less carbon atoms are the same as the above-mentioned copolymer [I]. [B] vinyl compound and [C] vinyl compound.

Further, in addition to these, the compound [D] as described above may 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.

The copolymer [II] thus obtained comprises: [A] a repeating unit derived from vinylpyrrolidone; [B] a repeating unit derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms; [C] a repeating unit derived from a vinyl compound having a side chain having 4 or less carbon atoms in a molar ratio of 20:30:78 to 98: 1: 1, preferably 40:15:45 to 80: 5: 10. Contained in.

When the copolymer [II] contains a repeating unit derived from the compound [D] as described above, [A] a repeating unit derived from vinylpyrrolidone, and [B] an alkyl having 5 or more carbon atoms. A repeating unit derived from a vinyl compound having a side chain, [C] a repeating unit derived from a vinyl compound having a side chain having 4 or less carbon atoms, and [D] a repeating unit derived from a compound, : 30: 7
8:78 to 97: 1: 1: 1, preferably in a molar ratio of 40: 15: 45: 45 to 80: 5: 10: 10.

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 [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 a repeating unit derived from a vinyl compound having a side chain having 5 or more carbon atoms, a side chain alkyl group is bonded in a graft form, and thus has hydrophobicity. Therefore, when such a mucoadhesive comprising the copolymer [I] or the copolymer [II] is used as, for example, a denture stabilizer, the repeating unit derived from the hydrophilic [A] compound is excessively absorbed by 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): 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] 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] 100 g of vinylpyrrolidone, [B] 23 g of vinyl laurate, and a polymerization initiator azobisisobutyronitrile were copolymerized in a nitrogen stream at 60 ° C for 8 hours. Copolymer [I] -1 was obtained.

 Table 1 shows the composition of the obtained copolymer.

60% by weight of this copolymer [I] -1, 20% by weight of ethanol, 15 parts of purified water and 5 parts of polyethylene glycol 400
A mucoadhesive 1 consisting of 1% by weight was prepared. For the obtained mucoadhesive 1, the wet tack was determined according to ASTM D2979-71.
Using a probe tack tester, the amount of dissolution in hot water at 37 ± 2 ° C. after 24 hours was measured, and the results are shown in Table 2 together with the overall evaluation.

Example 2 [A] 100 g of vinylpyrrolidone, [B] 2-acrylic acid
149 g of ethylhexyl and 20 g of vinyl laurate were copolymerized using a polymerization initiator azobisisobutyronitrile under a nitrogen stream at 60 ° C. for 8 hours to obtain a copolymer [I].
-2 was obtained.

 Table 1 shows the composition of the obtained copolymer.

60% by weight of this copolymer [I] -2, 25% by weight of ethanol, 10 purified water and 5% polyethylene glycol 400
A mucoadhesive 2 consisting of weight% was prepared. Table 2 shows the tack, the amount of dissolution, and the overall evaluation of the obtained mucoadhesive 2 when wet.

Example 3 [A] 100 g of vinylpyrrolidone, [B] 20 g of vinyl laurate, and [C] 70 g of vinyl acetate were prepared by using a polymerization initiator azobisisobutyronitrile in a nitrogen stream at 60 ° C. The copolymer was copolymerized for 8 hours to obtain a copolymer [II].

 Table 1 shows the composition of the obtained copolymer.

A mucoadhesive 3 comprising 60% by weight of this copolymer [II], 25% by weight of ethanol, 10 purified water and 5% by weight of polyethylene glycol 400 was prepared. Table 2 shows the tack, dissolution amount, and overall evaluation of the obtained mucoadhesive agent 3 when wet.

Comparative Example 1 A mucoadhesive consisting of 75% by weight of polyvinyl acetate and 25% by weight of ethanol was prepared. Table 2 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 2 in the same manner as in Example.

──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-63-115805 (JP, A) JP-A-61-73648 (JP, A) JP-A-63-77806 (JP, A) 55351 (JP, A) (58) Field surveyed (Int. Cl. ⁶ , DB name) A61K 6/00 A61K ⁶ /08-6/083

Claims (4)

(57) [Claims] (1) a repeating unit derived from vinylpyrrolidone (A) and a repeating unit (B) derived from a vinyl compound having an alkyl side chain having 5 or more carbon atoms, A mucoadhesive comprising the copolymer [I] in a molar ratio. 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 repeating unit derived from [A] vinylpyrrolidone, [B] 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 vinyl compound having 4 or less carbon atoms. A mucoadhesive comprising a copolymer [II] containing a repeating unit derived from a vinyl compound having a chain in a molar ratio of 20:30:78 to 98: 1: 1. 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.