JPH01242519A - Oral cavity sanitary composition - Google Patents

Abstract

PURPOSE: To obtain the subject composition useful for suppressing the growth of bacteria on surfaces of teeth by compounding a cationic antibacterial substance and a polymer having pendant polyalkylene-oxide side chains. CONSTITUTION: This composition is composed of (A) a cationic antibacterial substance, preferably a polybiguanide or its salt, especially bis-biguanide, i.e., chlorhexidine and (B) a polymer having recurring units of formula I and formula II X and Y are each a (substituted) hydrocarbyl; Z is CHR<1> CHR<2> or (CH2 )m [R<1> and R<2> are each H or a hydrocarbyl; (m)=2-10]; R<3> is H, a hydrocarbyl or an acyl; L and M are each a direct bond or a group of atoms; (n)=1-60; (p) and (q) are each 1-4}, in which A is contained in an amount of 0.001-10wt.%, especially 0.01-0.1wt.% and B is in an amount of 0.05-30wt.%, especially 0.2-2wt.%. It is preferable that a structure of formula I is induced by addition polymerization of a polymerizable olefinic unsaturated carboxylic acid, and a structure of formula II is induced by polymerization of an addition- polymerizable olefinic unsaturated ester or amide.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides oral hygiene compositions.
com-position) and on tooth surfaces.

A highly desirable result is obtained by preventing the sticky deposition of dental plaque on the surfaces of mammalian (especially human) teeth. Due to the presence of dental plaque, when caries-inducing or other types of bacteria grow, the tooth surface becomes colonized and deposits are formed, which adhere firmly to the tooth surface.

The deposition of dental plaque on the tooth surface is considered to be one of the early stages in the progression of dental caries and periodontal ligament disease.

Many attempts have been made to prevent plaque deposition and remove plaque from tooth surfaces. For example, the use of brushes, dental floe
ss) and the use of oral irrigation (oralirriga)
tor) and interdental irritants (tor) and interdental irritants (tor) and interdental irritants (tor)
Attempts have been made to use timu-1ator). However, such treatments are not completely successful and often require supplementary regular treatment by a dentist.

EP 0.182.523A discloses that certain pharmaceutical compositions (a) contain caries-causing microorganisms or other microorganisms commonly found in the oral cavity, on the surface of teeth or in dentures (s); highly effective in preventing or significantly reducing (b) the cohesive deposition of dental plaque resulting from such microorganisms on the tooth surfaces; is disclosed.

The preparation of polymers for use in certain pharmaceutical compositions is described in the aforementioned EP 182,523A.

Chlorhexidine is a cationic antiseptic that has been widely used by doctors as a topical antibacterial agent for over 20 years: its preparation is described in British Patent No. 705.838. It has been reported that chlorhexidine can be used as a disinfectant in the oral cavity and that under certain circumstances chlorhexidine can clearly stain teeth (
Loe et al., Journal of Periodonta
l Re5search+ Vol 5+ No. 79-83
(1970)). Such stain
g) seems to be a common property of cationic disinfectants. Such contamination has been shown to result from the reaction of cationic disinfectants with food ingredients, especially tannin-rich food ingredients such as coffee, tea or red wine (Addy et al., Journal of Periodontal R
e5earch, Vol 9+ pages 134-140).

We have now treated certain surfaces, such as teeth or hydroxyapatite, with a combination of both (a) certain polymers with suspended polyalkylene oxide side chains and ('b) cationic antimicrobial substances. Surprisingly, treated tooth surfaces exhibit great anti-adhesive and antibacterial properties against certain oral microorganisms, i.e. the above combination reduces the so-called biocontamination of tooth surfaces. ”(“bio-
It was recognized that it is possible to suppress "fouling").

In fact, in the presence of the above-mentioned polymers, a uniform antibacterial effect is obtained even when the tooth surface is treated with a solution of a low concentration of antibacterial substance. Furthermore, the present inventors have surprisingly found the following; namely, (i) in the presence of the polymer, even when a larger amount of chlorhexidine is absorbed on the tooth surface, the above-mentioned chlorhexidine-induced (ii) certain cationic antimicrobial substances;
For example, the antibacterial properties of chlorhexidine and alexidine are
increase on the denture surface when the denture surface is treated with an acidic polymer, such as Polymer 93W (see below) and the antimicrobial substances mentioned above, or a combination thereof;
and (iii) composite reinforcing agent (res tora Li
on) For example, Occlusin (RT
M), Opalux, Silx (
Silux) and Valux (Va 1ux) P2O
It has been found that where such substances tend to be contaminated by cationic antimicrobial agents, such contamination is at least reduced in the presence of said polymers. At least the front teeth
It will be appreciated that such a reduction in contamination is particularly desirable for (ior tooth).

According to the invention: (i) at least one cationic antimicrobial substance;
Oral hygiene compositions are provided comprising an effective amount of i) at least one polymer having one or more pendant polyalkylene oxide groups.

Examples of cationic antibacterial substances that can be used in the present invention include:
In particular, benzalkonium chloride, bispyridine amines such as octe-nidine or preferably poly-biguanides such as alexidine, more preferably bis-biguanides such as chlorhexidine.
exidine).

In book I11 of the present invention, “polybiguanide” (“pol biguanide”)
The term "y-biguanide") refers to the general formula (I
): means a compound having a large number of in-ct+ain biguanide residues or a tautomer thereof. The antibacterial substances used in the present invention typically contain 2.3 or 4
There are several such intrachain residues. However, at least enough of said residues may be present to provide a major portion of the repeat units of a high molecular weight polymer, such as a polymer of molecular weight up to about 10,000.

It will be appreciated that when polybiguanides are used in the present invention, they may be present as free bases;
However, it is preferred that the polybiguanide is present as a salt thereof, for example as an acetate or a hydrochloride, and in particular as a bis-biguanide, i.e. chlorhexidine, having the structure shown below - formula (■): 1,6 known to
-di(4-chlorophenyl-diguanido)hexane, it is more preferably present as digluconate.

If a polybiguanide, such as chlorhexidine, is used in the present invention in the free base form, the polybiguanide may be in the form of a mixture (eg, as a salt) on the tooth surface as a salt with an acidic polymer as described below.

The reasons why the oral hygiene composition of the present invention exhibits a large antibacterial effect are considered to be as follows: (i) an increase in the amount of chlorhexidine absorbed on the tooth surface and/or (ii) an increase in the amount of chlorhexidine absorbed on the tooth surface. the absorbed concentration changes, so that more chlorhexidine is available for antibacterial action on the tooth surface; and/or (ij) the orientation of the absorbed chlorhexidine on the tooth surface changes. and/or (iv.
) Formation of ion pairs between the cationic antimicrobial substance and the acid anion of the polymer (if present).

In the compositions of the present invention, the large number of hydrogen bonds and biguanide cations between the polymers may contribute to the aforementioned increase in the amount of absorbed chlorhexidine or change in absorption concentration or orientation.

The polymer constituting the oral hygiene composition of the present invention is preferably acidic; "acidic" means that it contains at least one carboxylic acid group bonded to the polymer backbone. However, the polymer may be amphoteric, basic or neutral, although this is not preferred.

Preferably, the one or more pendant polyalkylene oxide groups attached to the polymers making up the oral hygiene compositions of the present invention are ethylene oxide groups. However, at least some of them may be other poly(lower) alkylene oxide groups, such as polypropylene oxide groups.

Examples of polymers constituting the oral hygiene compositions of the present invention include one or more repeating units of the general structure A: □
One or more repeating units of Y − ((ZO) , , R3) − [in the above, structure A
X, which may be the same or different in the repeating units of structure B, and Y, which may be the same or different in the repeating units of structure B, each represent a hydrocarbyl or substituted hydrocarbyl residue. group and provides the backbone of the polymer; Z is -CIIR'-CIIR2- or -(CH2)lI
when Z is -CIIR'-CIIR"-, R1 is present in the same repeating unit of structure B (if n or q is 2 or more) or in a different repeating unit of structure B. can be the same or different and are hydrogen or a hydrocarbyl group, and R2 is (n or q) in the same repeating unit of structure B.
(2 or more) or can be the same or different in different repeating units of structure B;
and hydrogen or a hydrocarbyl group, provided that R1 and R in a single group -CIIR'-CIIR"-0-
2 cannot both be hydrocarbyl groups; or can be different, and
hydrogen or a hydrocarbyl group or an acyl group derived from an alkanoic acid having up to 5 carbon atoms; m, if present, is a number from 2 to 10; n is from 1 to 6
p is a number from 1 to 4; q is a number from 1 to 4; each (Co2)1) group is linked to a hydrocarbyl residue via one or more intermediate groups; p is a number from 1 to 4; q is a number from 1 to 4; is attached to a group or can be different;
and one or more direct bonds or one or more of the groups of atoms (each of the groups of atoms being one or more of the atoms for connecting the C(hH) group and the X group); provided that there are more than two (GO, H
) groups shall not be able to be linked directly to the same carbon atom in the group is linked to the building residue Y and, when q is 2 to 4, can be linked by the group M to the same or different carbon atom of the group Y; M is in the repeating unit of structure B may be the same or different and one or more direct bonds or one or more of the groups of atoms (each group of atoms is (
ZO), providing a chain of one or more atoms for linking the group and Yi), with the proviso that there are more than two (zO), M is the same carbon atom in the group Y shall not be able to be directly bonded to Z
is -CH2-CH-, the ratio is 1:20 to 20:1].

Preferably, R1 and R2, when present, are both hydrogen.

When R1 or R2 is a hydrocarbyl group, it is preferably a lower alkyl group, more preferably a methyl group.

R3 is preferably a lower alkyl group, more preferably a methyl group.

When Z is -(CH2)--, m is preferably 4; in this case, -(ZO)- is readily formed from tetrahydrofuran.

In the above definition for the polymers contained in the compositions of the invention, it is provided that at least some of the carboxyl groups in the repeating units of general structure A correspond to the anion of the salt CO2-<
It should be noted that these also include polymers which have been converted, as far as the ratio of carboxyl groups to -20- groups is concerned, into -CO,H groups; the corresponding cations are, for example, ammonium ( N)I'. ) or alkaline earth metals or preferably alkali metals (e.g. Na
"+K").

However, the cation can be derived from the cationic antimicrobial substance itself; in fact, if the cationic antimicrobial substance is present as a salt of an acidic polymer, thereby eliminating the substantial presence of free chlorhexidine in the oral cavity. pollution will be further reduced.

- In the C-like structure A, each carboxyl group is represented by [i.e., the linking entity
) to the hydrocarbyl residue. p
is 2 to 4, each carboxyl group can be bonded by L to the same carbon atom in the group X, and when L represents two or more intermediate groups, the group X may be bonded to the same or different carbon atoms in; however,
It is of course not possible for more than two carboxyl groups to be bonded directly to the same carbon atom of the group X (this assumes that X has at least 2 carbon atoms; however, if It should be understood that those containing only one atom are also encompassed by the present invention).

In principle, L can represent up to four separate intermediate groups in structure A (if p is 4). L can be the same or different in the repeat unit of structure A.

When L represents a group of one or more atoms, each group providing a bonded chain of atoms, said bonding chain typically includes one or more carbon atoms, each group providing a bonded chain of atoms. eg carbon atoms in the aryl ring) and/or heteroatoms (particularly N and/or 0). Bonds that can be provided by L include the following: , □i@ , ) ” In the above, apart from the case of a direct bond, the upper bond is bonded to X and the lower bond is bonded to the carboxyl group. However, in the present invention it is preferred that L is one or more direct bonds, so that each carboxyl group is directly bonded to a carbon atom in the polymer backbone.

In structure A, p is preferably 1 or 2, more preferably l (L can thus represent one or at most two intermediate groups).

In structure B, each (ZO), R' group is denoted by M, and has one or more direct bonds and one or more groups of atoms, each of which (ZO
) providing a chain of one or more atoms for linking the fiR group and the Y group (i.e., by the linking entity)
linked to a hydrocarbyl residue. When q is 2 to 4, each (zO), R group can be bonded by M to the same carbon atom in the group Y, and M represents two or more intermediate groups. may be bonded to the same or different carbon atoms in the group Y; however, more than two (20) R' groups may of course be bonded directly to the same carbon atom in the group Y. (In this case, it is assumed that Y has at least 2 carbon atoms; however, it should be understood that cases where Y contains only 1 carbon atoms are also encompassed by the present invention. be).

M can be the same or different in the repeat unit of structure B.

Although M may represent one or more direct bonds, in the present invention M may be a group of one or more atoms, each group of atoms providing a bonded chain of atoms. Preferred; such a linking chain will normally contain one or more carbon atoms (which may include, for example, carbon atoms in a ring, such as benzyl ether) and/or heteroatoms (particularly N and/or O). M
An example of a particularly preferred linking chain provided by is the hand linked to (ZO)nR').

In structure B, q is preferably l or 2, more preferably 1 (therefore M is 1 or at most 2
).

Structure A preferably represents a repeating unit derived by addition polymerization (usually free radical initiated addition polymerization) of a polymerizable olefinically unsaturated carboxylic acid. Examples of such unsaturated carboxylic acids are maleic acid (fumaric acid), itaconic acid, hydroxyglycine or preferably acrylic acid.

Structure B combines an unsaturated carboxylic acid (or an esterifying or amidizing derivative thereof, such as an acid chloride or anhydride) with a hydroxy compound of the formula HO (ZO), R3 (to form an ester) or 2) 12N ( ZO),.

Preferably it represents a repeating unit derived from the (usually free radical initiated) polymerization of an addition polymerizable olefinically unsaturated ester or amide formed by reaction of R3 with an amine (forming an amide).

The acid that can induce structure B is acrylic acid or methacrylic acid,
In particular, the latter is preferable, and when an ester or amide derivative of methacrylic acid is used, respectively,
The following structure is obtained for B: The acidic polymer contained in the oral hygiene composition of the invention has a ratio of acidic residues to suspended polyalkylene oxide residues of about 6=1. (in the case of polyethylene glycol in which each side chain has a molecular weight of about 350, ie so-called PEG-350).

The polymer used in the present invention is the aforementioned European Published Patent No. 0.1
No. 82,523A, the disclosure of which is incorporated herein by reference.

In the oral hygiene compositions of the present invention, the concentration of at least one polymer present in the composition is typically from about 0.05 to 30% by weight, based on the weight of the composition. the preferred concentration is about 0.1-5% by weight, more preferably 0.2-2% by weight.

The concentration of at least one antimicrobial substance in the oral hygiene composition of the present invention is about 0.001 to 1, based on the weight of the composition.
O weight percent; preferred concentration is about 0.001-1.0
% by weight, more preferably 0.01 to 0.1% by weight
It is.

In the oral hygiene composition of the present invention, it is preferred that the amount of polymer is greater than the amount of antimicrobial substance. However, it is also possible to have more antimicrobial substances present than in the polymer.

Although the oral hygiene compositions of the present invention typically contain one type of polymer, two or more such polymers may be present in the composition.

Compositions of the present invention having ratios of antimicrobial material to polymer such that undesired reactions are eliminated can be prepared by one skilled in the art by extensive experimentation.

The oral hygiene compositions of the present invention are generally compatible with the antimicrobial efficiency of cationic antimicrobial substances, such as chlorhexidine.
Contains a pharmaceutically acceptable vehicle. In order to maintain the efficiency of chlorhexidine, it is necessary to adjust its concentration in a particular vehicle, and appropriate concentrations can be determined experimentally by those skilled in the art.

Suitable conventional pharmaceutically acceptable vehicles that may be used in the oral hygiene compositions of the present invention include; water, ethanol (in which case water or a water/ethanol mixture is often humectants such as propylene glycol, isopropanol, glycerin and sorbitol; cellulose derivatives such as hydroxypropyl and hydroxyethylcellulose, polyoxypropylene/polyoxyethylene block copolymers [so-called ``poloxamers'' (“
'Poloxamers')] For example, Symbelonic ('Poloxamers')]
Synperonic) PE 39/70 and PE
Gelling agents such as F87; certain gel stabilizers such as polyvinylpyrrolidone; sweeteners such as sodium saccharin; preservatives such as cetylpyridinium chlorite and certain lower alkyl parahydroxy-benjiates; polyoxy surfactants such as ethylene isohexadecyl ether (200); and certain dyes and flavoring agents, such as those listed on the approved EEC and FD&C lists. It will be appreciated that the vehicle will be selected so as not to interfere with the effectiveness of the oral hygiene compositions of the invention; in particular, anionic substances such as anionic cellulose derivatives or anionic symberonics are not preferred.

The oral hygiene compositions of the present invention contain (and are compatible with) an effective amount of the polymer and an antimicrobial substance, optionally
It may be in the form of a conventional pharmaceutically acceptable oral hygiene formulation. Examples of such formulations include, inter alia, oral rinses (mo
utwash), rinse, irrigatol solution, abrasive and non-abrasive gel toothpaste (de
ntifrice), interdental irritants (interdent
al stimulators or coatings, chewing gums, lozenges, breath fresheners, foams and sprays.

Examples of the present invention are shown below. Before the example number (D”
The symbol "CT" indicates that this is a comparative example.

In most of the examples below, the standard bacteria is Oral Bacterium Strep Cocus dan77.
tococus mutans ) NCTC 10
449 was used. This bacterium is called Rioflo M
Plain Heart Infusion in odel C 30 Fer-menter
Infusion) (RHI) (Oxoid products). A 750 ml pot containing 350 ml of bacterial suspension was used. Bacteria is 0
．． Diluted at a dilution rate of 1/h, supplied with an air flow of 0.241/min and stirred at a stirring speed of 300 rpm.
Grown at 7°C. A sample (approximately 20 d) of bacterial suspension was taken from the incubator for each experiment. Bacteria were centrifuged at 4000 rpm for 10 minutes and washed with denatured Ringer.
Salt solution (0.54 g/l NaCI2; 0.02
g/IKcI; 0.03 g/ECaC12; and 0.75 g g/l sodium mercaptoacetate)
The cells were resuspended in denatured Ringer's salt solution and diluted (X 10). The approximate bacterial concentration in the diluted salt solution was 10''/l.

Strebutococcus Michiol
usmitior ) NCTC 7864 was grown in 100 ml plain heart infusion broth for 24 hours in batch culture. The culture was then centrifuged at 350 rpm for 30 minutes and the pellet was washed twice by resuspending in saline and centrifuging. The cell concentration of the bacterial suspension was then adjusted to approximately 10'-10'' cells/l.

Whole saliva was used in another example.

(absortion surface) hydroxyapatite powder [calcium phosphate dibasic Ca+o(O
Hydroxyapatite discs were prepared by compressing and sintering H)z(POa)6 (Heidrich product) at 1100°C. During the experiment, this disk was
It was reused after heating at °C for 2 hours.

Hydroxyapatite discs containing a gold plate were treated for 2 minutes at room temperature with a solution of a polymer, eg Polymer 93W (1 w/v %) in a 1:1 (by volume) mixture of industrial denatured alcohol/water. The discs were cleaned by immersing them in a container containing running water at approximately 15°C and shaking 5 times.

An aqueous solution of chlorhexidine and an INS solution of alexidine were separately adsorbed for a period of time onto the surface of hydroxyapatite discs treated with polymers, if appropriate (compared to untreated discs). used in the test). The discs were then washed by immersing them in a running water container and shaking 5 times.

The polymer referred to above as "Polymer 93W" is the EP
This is an acidic polymer prepared by the method described in Example 5 of No. 182523. (Other acidic polymers were prepared in a similar manner). Polymer 93W has a molar ratio of 6:1
methacrylic acid and PEG 350 MAt residues.

The term "PEG 350MAt" refers to polyethylene oxide with a molecular weight of approximately 350, capped with methoxy and methacryloyl groups, i.e., CH2.C(CH3)C00(CH2CH20), C
It means I+3 (n-8).

PEG 150M8t, PEG 1000MAt and PEG 2000MAt each have a molecular weight of 15
0.1000 and 2000, representing similar polyethylene oxides.

Polymer Mll is similar to EP 182,523 except that hydroxy-terminated PEG is used instead of amino-terminated PEG.
It was prepared by a method similar to that described in Example 15 of the issue.

Loeffler's Methylene Blue (Loeffler's
Meth - Triangle - 95% ethyl alcohol (30d), methylene blue (0.3g) and water (100d).

EXAMPLE 11 - These examples demonstrate that Polymer 93W retains its anti-adhesive properties in the presence of absorbed chlorhexidine.

1% by weight of hydroxyapatite discs in polymer 93W
Treated with a solution and then treated with some antibacterial substance for a period of time. The thus treated discs were immersed in a bacterial suspension (30 mg) in a Petri dish for 2 hours.

The discs were removed from the bacterial suspension and washed by immersing them in a container of running water and shaking 5 times.

Bacteria attached to the discs were stained using Loeffler's methylene blue. The reduction in bacterial adhesion was determined by microscopic examination.

The results obtained are shown in Table 1.

From Table 1, it can be seen that chlorhexidine and alexidine do not reduce the anti-adhesion rate of polymer 93W deposited on hydroxyapatite disks.

Anti-adhesion rate (χ)(
゛^8ゞ) is shown by the following equation: (a) If the polymer does not reduce the area of the surface covered by bacteria, then AAχ=ゞ” x 100
= O and (b) if the polymer prevents bacteria from adhering to the surface, then the surface χ−”−′ X 100
It will be understood that = 100×.

Similar results were obtained when specimens of materials commonly used in the manufacture of dental prosthetic devices, as described below, were treated with Polymer 93W and then exposed to chlorhexidine to Streptococcus mithiol NCTC 7864.

All of these implementations are chlorhexidine polymer 93
We show that the antibacterial effect of certain concentrations of chlorhexidine is enhanced on hydroxyapatite when used in the presence of W.

A solution of chlorhexidine was absorbed onto sterilized hydroxyapatite discs treated with Polymer 93W.

S, Al2 cells were collected from the incubator and then incubated for 40 minutes.
Diluted 100 times in BHI agar at °C. The inoculated agar was coated onto the HAP disks.

Agar-coated discs were incubated overnight at 37°C. Bacterial growth in agar was rated on a scale of 0 (no growth) to 10 (control).

Since each hydroxyapatite disk surface was in each case contacted with the same number of bacteria, the anti-adhesive properties did not influence the results obtained; ie only the antibacterial effect was measured. From the results shown in Table 2, it can be seen that by combining Polymer 93W and chlorhexidine, a greater antibacterial effect can be obtained than when chlorhexidine itself is applied at the same chlorhexidine concentration.

In Comparative Examples (CT) 2, 3.4 and 5, the discs were not treated with Polymer 93W. Comparative Example 2 is a blank test; in Comparative Example 2A, the disk was coated with polymer 93W.
I just processed it.

Table -λ- These examples demonstrate the anti-fouling and anti-microbial effects obtained by using a combination of polymer and chlorhexidine and that such a combination gives better results than the individual components. .

Sterilized hydroxyapatite discs were coated with polymer 93W.
Treatment with w/vX solution followed by a concentration of chlorhexidine solution. The discs were then incubated in fresh whole saliva for 1 hour at 37°C and then washed by immersion in a running water container and shaking 5 times. Excess water was removed from the disk surface by contacting the edge of each disk with filter paper.

BH1 agar containing 0.04 w/v χ bromocresol green (which makes bacterial growth on white hydroxyapatite discs visible to the naked eye) was pipetted onto the discs at 40 °C. , an F2 layer of agar was formed on the disk surface.

The discs were then incubated overnight at 37°C.

The results are shown in Table 3.

In Comparative Examples 6 to 10, the treatment with Polymer 93W was omitted. In Comparative Example 11, Polymer 93W was used, but chlorhexidine was not used.

From Li Meng Table 3, a certain concentration of chlorhexidine, for example 0.
For 01 and 0.001%, it can be seen that the presence of polymer 93W increases the bactericidal and/or bacterial growth prevention effect of chlorhexidine. Comparative Example II shows that bacterial growth is reduced due to the antifouling properties of the polymer itself.

These examples demonstrate that treating hydroxyapatite disks with certain polymers (a) increases the amount of chlorhexidine absorbed by the disks, and (b) reduces subsequent cleaning treatment. shows that the retention of absorbed chlorhexidine is improved.

-Methacryloyl chloride (0.58 mol) of poly17-B3 and B18 was added to toluene (600 d) cooled in a water bath, Jeff
)"360" or °"2070" (0.5 mol) and 2,6-lutidine (0.56 mol) over a period of 2 hours.

A large amount of white precipitate formed. After the reaction mixture was left to stand for 3 hours, the white precipitate was filtered off and washed with toluene. The filtrate was evaporated under reduced pressure and the residue was kept under vacuum to remove volatiles. The properties of the product (yield 80-90%) were determined by infrared absorption spectroscopy and nuclear magnetic resonance spectroscopy.

The amino end group-containing products from the two reactions (respectively,
u360'' and ``2070'' with terminal butoxy or methoxy groups) are separately converted into their N-methacryloyl derivatives and then copolymerized with methacrylic acid in the manner described in EP O, 1825238, Example 11. did.

The hydroxyapatite discs were pre-equilibrated in double-distilled water (double distilled) for 1 hour. The discs were removed from the water, the water was absorbed onto filter paper, dried and kept at room temperature for about 30 minutes. Its UV reflectance scan (ref 1e-ctance
5can) was performed. The optical density (absorbance) at 266 nm (0,0,) was typically about 0.9.

Discs with 0,D,significantly different from this value were excluded.

The acceptable discs were prepared in l w/d solution of polymer (l:1/I
MS: water) for 5 minutes. The disks were removed from the polymer solution, immersed in running water and shaken five times, allowed to absorb water onto the filter paper, allowed to dry, and allowed to stand for 30 minutes before being scanned.

Each of the polymer-coated discs was treated with an aqueous solution of chlorhexidine (0,
02-)Vχ) (The 0 disk which had been immersed in a 15t tank for 1 hour was washed as described above, left to stand for 30 minutes and then scanned.Then the disk was placed in a washing tank (12
00d) for 1 hour, dried by filter paper absorption,
The sample was allowed to stand for 0 minutes and then scanned.

DM Hachihe M: N N-Dimethyl 1-2-aminoethyl methacrylate HA^: Methacrylic acid i^: PEG maleate: Polyethylene glycol PI"G:
Polypropylene glycol dief 360: n-C
, Hz(OCHzCllz)40c)1zCH(CH3
)OCToCIl(CHz)Nl12;Chef2070
: CHzOCHtCIbO(CII□Cll0),
CI□Cl1(CH3)NH2 In the above, n is "'2070
” has a molecular weight of about 2000, and R=
H or CH3, and the ratio of H:CH is about 7:3; Aryl-PEG: Ethoxylated allyl alcohol; However, for BIO, the side chain methacrylate or methacrylamide derivative shown in the table is Existed as structure B; B10: Contains a terminal hydroxyl group.

The U, V scans were performed using a Unican 5P1750 UV spectrophotometer.

The "optical density difference" values shown in Table 4 were obtained from this scan.

It can be seen from Tables 4 and 5 that the acidic polymer significantly increases the amount of chlorhexidine absorbed. Most hydroxyapatite coated with acidic polymers absorbs more chlorhexidine from its 0.02 w/vχ solution than the neat hydroxyapatite surface absorbs chlorhexidine from its 2−/vχ solution. In other words, the absorption of chlorhexidine was improved by more than 100 times.

No improvement in the absorption amount of chlorhexidine was observed for the basic polymer (Polymer 73) and the neutral polymer (Polymer 812). Similarly, polymethacrylic acid did not increase the absorption of chlorhexidine, indicating that it is the PEG (or PPG) chains, and not the carboxyl groups, that have the effect of increasing absorption.

The results of the cleaning tests showed that after 1 hour of cleaning, about 23% of the initially absorbed chlorhexidine was absorbed onto the bare (uncoated) hydroxyapatite, whereas on the polymer-coated circles. It can be seen that it is about 80% for the board. - At night, after washing, the amount of absorbed chlorhexidine remaining on the uncoated HAP discs, if any, was below the detectable limit; for the polymer-coated discs. Approximately 50-60% of the amount of chlorhexidine originally absorbed remained absorbed. It can therefore be seen that the polymer-coated discs absorb more chlorhexidine than the uncoated discs and are not easily removed by washing from the polymer-coated disc surface.

These examples, with reference to Examples 10-20 and 6-9 above, demonstrate that antibacterial properties (at certain cyclohexidine concentrations) can be achieved without increased contamination. Indicates that it increases.

The vertical hydroxyapatite disks were pre-equilibrated in double-distilled water for 1 hour. Pre-equilibrated discs with 1% (w/v) of polymer
Immersed for 5 minutes in a 1% solution in aqueous solution or IMS:water (1:1) mixture. The discs were removed from the polymer solution and washed by immersing them in a container of running water and shaking 5 times. The cleaned discs were then treated with 15 ml of an aqueous solution of chlorhexidine (chlorhexidine concentrations are shown in Table 6).
immersed in it for 5 minutes. The disks were removed from the aqueous chlorhexidine solution and then immersed in a 15 d tea warm solution for 1 hour at room temperature.

The discs were removed from the tea solution and washed as described above.

The immersion and washing operations in chlorhexidine solution and tea warm solution were repeated three times, in each case using fresh chlorhexidine solution and tea solution.

After this soaking and washing cycle, the discs were soaked in tea warm solution overnight. The discs were then cleaned as described above, dried at room temperature for 1 hour, and then evaluated for contamination on the discs.

The tea solution was prepared by pouring 500 d of boiling water onto two tea bags. Remove the tea bag after 5 minutes,
The tea solution was cooled to room temperature. The tea solution was filtered using standard filter paper and stored at 4°C until use.

The contaminated disks prepared by the above-mentioned common operations were prepared in Examples 10-
The samples were scanned using a UV/visible reflectance spectrophotometer as described in Section 20 and compared to a blank (disc without absorption of chlorhexidine).

FIG. 1 shows a typical UV-absorbance curve thus obtained. In Figure 1, a - bare hydroxyapatite disc; b = brown - blank (no tea hot liquid treatment); c, d, e =
Tea/chlorhexidine treatment; chlorhexidine concentrations are 0.002%, 0.02% and 0.2%, respectively.

The polymers listed in Table 6, the chemical composition of which is shown in Table 5, were investigated for their effect on the formation of chlorhexidine stains in the presence of tea. The polymer is I M
Absorbed separately from a 1% (-v) solution in S/water (1:1). Chlorhexidine 0.2%, 0.02%
and 0.002% solution was used.

A UV/visible reflectance spectrophotometer was used to scan the disk and measure 0, D, at 266, 410 and 510 nm. Brown - 0.0 for blank. were also measured at these wavelengths and these values were subtracted from discs treated with chlorhexidine or polymer/chlorhexidine.

Table 6 shows the results at 510 nm. These results are expressed as a ratio to brown-blank=1.0. 26
Similar results were obtained at 6 nm and 410 nra. In Comparative Example 18, the polymer was omitted; ie, chlorhexidine itself was used.

From Table 6, it can be seen that at the two higher chlorhexidine concentrations (i.e. 0.2% and 0.02%), the amount of contamination caused by the treatment of HAP discs due to the presence or type of polymer is found to be virtually unaffected. The minimum applied concentration of chlorhexidine (i.e. 0.002%
), the contamination is significantly reduced for most of the examples, and the degree of contamination is equal to or below the lowest level when the disc is brought into contact with the tea hot liquid. However, it will be seen from the results of Examples 10-20 and 6-9 that for approximately the same contamination as the control, more chlorhexidine is absorbed by the polymer and exhibits greater antimicrobial efficacy.

These examples show that when hydroxyapatite (HAP) discs were treated with a mixture of chlorhexidine and polymer 93W, the HAP discs were significantly reduced compared to when HAP discs were treated with a chlorhexidine solution alone. This shows that the amount of chlorhexidine absorbed onto the surface increases.

Polymer 93W EMS? Yongtl! (2w/vχ) and an appropriate aqueous solution of lorhexidine (0.04in/v2) were mixed at a volume ratio of 1=1. The hydroxyapatite discs were left in the above mixture for one hour and then washed five times with water. Example 1 The amount of chlorhexidine absorbed onto the disc
UV reflectance was measured with a spectrophotometer (optical density was measured at 266 nm) as described in 0-20.

In Comparative Examples 20 and 21, the disks were
Treated with 0.2% and 0.02% solutions of chlorhexidine in a 1:1 (by volume) mixture of MS and water for 1 hour.

The results obtained are shown in Table 7. It can be seen from Table 7 that by treating HAP with the Polymer-93W/chlorhexidine mixture, more chlorhexidine is absorbed than when treated with the chlorhexidine solution alone.

These examples demonstrate increased bactericidal "kill" when using the Polymer-93W/chlorhexidine mixture compared to using chlorhexidine solution alone.

The disks prepared in Examples 30-31 were washed with water overnight and then subjected to the S-Sakyrus agar overlay test. The discs were placed in Petri dishes and covered with BHI agar (25 ml). grown in the incubator and in Ringer's salt solution.
Pipette 100 μl of 5-liter diluted 100 times onto the agar and spread it evenly.
Grow overnight at 7°C;
The "lawn'") and the "clear zone" where no bacteria are present were investigated and measured. The results obtained are shown in Table 8. Bands are expressed as % of disk area.

It is understood that if the % of the ``Area of the disk where bacteria do not grow'' in Table 1 is 100 or more, this indicates that the inhibitory effect extends beyond the periphery of the disk and into the agar layer. will be done.

It can be seen from Table 8 that the polymer/chlorhexidine mixture has a greater bactericidal effect than chlorhexidine alone.

11 Kosai 2nd Ward These examples are anti-adhesive compounds (anti-adh
e-sive con+pound), polymer 93W
The combination of chlorhexidine and chlorhexidine has been shown to reduce the amount of contamination that occurs on various surfaces within the oral environment compared to chlorhexidine alone. These surfaces are made of teeth, composite reinforcing materials,
For example, it consists of Occlusin and Opalux and methacrylate-based resins commonly used in the manufacture of dental prostheses (hereinafter referred to as "PR" for convenience).

Immediately after the ligament was pulled out, residual flesh pieces were removed from the tooth with a scalpel, and the tooth was tumbled in a 50% sodium hypochlorite solution for 20 minutes, and the surface was washed with distilled water.

These teeth and the teeth containing reinforcing material were sonicated in alcohol for 10 minutes and then dried.

A sample of DR (25 mm x 10 intestines x 3 layers) and a disk sample of the composite reinforcing material were washed in alcohol and dried.

Pox-a: 1% and 5% of polymer 93W (Ig) in a mixture of industrial denatured alcohol (50d) and water (50m). Volume b: Chlorhexidine aqueous solution (0.2%, 0.02% and 0.002%) c: Polymer 93W and A suitable mixture of chlorhexidine was prepared.

d: Collect a sample (20d) from each of the six volunteers,
Human saliva was obtained by centrifugation at 25,000 rpa+ for 20 minutes and pooling.

e: A commercially available tea sample (80g) was mixed with distilled water (80mffi).
) for 2 minutes, the resulting liquid was cooled to room temperature, and the remaining tea leaves were filtered off to prepare a hot tea liquid.

Pressure value The surface of each locust bean was treated with a saliva sample for 10 minutes. Excess saliva was removed by washing.

In Examples 34-49, the surface was subjected to a first treatment for 10 minutes, the surface was washed with distilled water, subjected to a second treatment for 10 minutes, rinsed and soaked in tea hot liquid for 1 hour; this step was repeated. The samples were placed in the tea bath overnight and the entire process was repeated daily for 5 days.

In Examples 50 to 65, the first treatment was performed for 5 minutes, and the second treatment was performed for 5 minutes.
The same 5-day procedure as above was carried out, except that the above treatment was omitted and the samples were treated with the appropriate mixture of Polymer 93W and chlorhexidine.

Surface contamination was visually compared to the same surface treated with water alone and rated on the following scale: 0: no contamination, i.e. O when treated with water (control); 1: Slightly contaminated 2: Moderately contaminated 3: Severely contaminated 4: Extremely contaminated The meanings of the abbreviations in Tables 9, 10 and 11 are as follows: 0C= 2 Oclusin OP Opalux T = Teeth PR = Prosthetic Resin A = 0.5% Polymer 93W AA = 1% Polymer 93W B = Water X = 0.1% Chlorhexidine X X = 0.2 〃 Y = 0.01 〃 Y Y =0.02 〃 Z=0.0O1〃 Z Z =0.002,.

W = 0.0001, / Yu-"L-Ura-ojo"JhiJLi Man-Yu-Yu-Yu-Ura-Daiichi■" Table 9 shows that at low concentrations (for example, 0.002%) of chlorhexidine, dental It has been found that contamination of reinforcing agents, teeth or prosthetic resins is reduced if the surface is first treated with certain polymers. Furthermore, from Examples 46 to 49, the surface was treated with chlorhexidine and then polymer 9
It can be seen that when treated with 3W, the contamination is reduced to the level of the control case.

Table 1O shows the results obtained when Oclusin and Opalux surfaces were treated with a mixture of chlorhexidine and Polymer 93W. At cyclohexidine concentrations of 0.01% and below, the contamination of Occlusin is significantly reduced to the level of the control; the same is observed for Ovalux.

Table 11 shows the results obtained when tooth surfaces and prosthetic resins were treated with a mixture of chlorhexidine and Polymer 93W. The trend of reduction in contamination is similar for Oclusin and Opalux.

When performing the above evaluation on teeth with Occlusin prosthesis, the tooth and the prosthesis are slightly contaminated to the same degree, further reducing the contour of the prosthesis.

[Brief explanation of the drawing]

FIG. 1 is a curve showing the relationship between the wavelength of ultraviolet light and the absorbance of the disk.

Claims (1)

[Claims] 1. Containing an effective amount of (i) at least one cationic antimicrobial substance; and (ii) at least one polymer having pendant polyalkylene oxide side chains. Composition for oral hygiene. 2. The composition according to claim 1, wherein the cationic antibacterial substance is polybiguanide or a salt thereof. 3. The composition according to claim 2, wherein the polybiguanide is a bis-biguanide. 4. The composition of claim 3, wherein the bis-biguanide is chlorhexidine. 5. At least one polymer has a general structure A: ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ has one or more repeating units and a general material structure B: ▲ has a mathematical formula, a chemical formula, a table, etc. One or more repeating units of ▼ [in the above, structure A
X, which may be the same or different in the repeating units of structure B, and Y, which may be the same or different in the repeating units of structure B, each represent a hydrocarbyl or substituted hydrocarbyl residue. group and provides the main chain of the polymer; Z is -CHR^1-CHR^2- or -(CH_2)_
m; when Z is -CHR^1-CHR^2-, R^1 is present in the same repeating unit of structure B (if n or q is 2 or more) or in a different repeating unit of structure B; can be the same or different in the same repeating units of structure B and are hydrogen or hydrocarbyl groups, and R^2 in the same repeating units of structure B (where n or q is or in different repeating units of structure B and are hydrogen or hydrocarbyl groups, with the proviso that
R^1 in a single unit -CHR^1-CHR^2-O-
and R^2 cannot both be hydrocarbyl groups;
or more) or may be the same or different in different repeating units of structure B and derived from hydrogen or hydrocarbyl groups or alkanoic acids having up to 5 carbon atoms. m is a number from 2 to 10; n is a number from 1 to 60; p is a number from 1 to 4; q is a number from 1 to 4; each (CO_2H) group is linked to a hydrocarbyl residue X via one or more intermediate groups L, and when p is 2 to 4, a group L can be the same or different in the repeating unit of structure A, and may be linked to one or more direct bonds or groups of atoms. (each group of atoms provides a chain of one or more atoms for linking the (CO_2H) group and the X group), with the proviso that more than two (CO_2
H) Groups shall not be able to be linked directly to the same carbon atom in the group is linked to the building residue Y and, when q is 2 to 4, can be linked by the group M to the same or different carbon atom of the group Y; M is in the repeating unit of structure B may be the same or different and one or more direct bonds or one or more of the groups of atoms (each group of atoms is (
providing a chain of one or more atoms for linking the group Y), provided that more than two (ZO)_n groups shall not be able to be directly bonded to atoms; the ratio between the number of -CO_2H groups and the number of (ZO) groups is, in particular,
When Z is -CH_2-CH_2-, 1:20-2
0:1]. 6. If Z is -CHR^1-CHR^2-, then R^
6. The composition of claim 5, wherein both 1 and R^2 are hydrogen. 7. The composition according to claim 5, wherein R^3 is a methyl group. 8. In structure A, L is a direct bond, -CH_2-, -
CH_2-CH_2-, -CH_2-CH=, -NH-
CO-, CONHCH(CH_3)- or -CONHC
6. The composition of claim 5, which is H(OH)-. 9. The composition according to claim 5, wherein in structure A, p is 1 or 2. 10. In structure B, M is -COO- or -CONH
- The composition according to claim 5. 11. Claim 5, wherein in structure B, q is 1 or 2.
Compositions as described. 6. The composition of claim 5, wherein 12, A or B represents a repeating unit derivable by addition polymerization of a polymerizable olefinically unsaturated carboxylic acid or an ester or amide derivative thereof. 13. The composition according to claim 12, wherein the polymerizable olefinically unsaturated carboxylic acid is acrylic acid or methacrylic acid. 14. Containing a pharmaceutically acceptable vehicle which is water, ethanol, humectants, gelling agents, gel stabilizers, sweeteners, preservatives, surfactants or approved dyes or fragrances. Composition of. 15. Oral cleaning solutions, rinses, irrigatol solutions, gel toothpastes, denture cleaners, coated dental floss, coated or impregnated toothbrush bristles, interdental irritants or coatings, chewing gum, sweetened tablets, press fresheners, Composition according to claim 1, in the form of a foam or spray.