Note: Descriptions are shown in the official language in which they were submitted.
1 336682
A METHOD OF TREATING CONDITIONS OF TEETH AND THEIR SUPPORTING TISSUE
FIELD OF lNV~NLlON
The present invention relates to the use of sulphated saccharides for
the treatment of conditions of teeth and tooth-supporting tissue.
TECHNICAL BACKGROUND
Both gingivitis and periodontitis are inflammatory diseases caused by
plaque formation on the teeth. Chronic periodontitis often leads to
destruction of the tissues supporting the teeth. Plaque can be de-
fined as a soft bacteria-contAinine coating on the surface of a
tooth. When a tooth is not clean, plaque formation will commence and
this will lead to gingivitis in the gingival area.
The inflammation of the gingiva leads to the formation of the gingi-
val sulcus, and a gingival pocket is formed. Clear evidence that
plaque is responsible for gingivitis was derived from the induction
of experimental gingivitis (H. L0e et al., J. Periodontology 36 : 177-
187, 1965). Starting from a state of clinical gingival health, all
participants developed gingivitis within 10 to 21 days after elimina-
tion of oral hygiene procedures. After reinstating plaque control,
the gingiva returned to a normal condition within seven days.
Gingivits is characterizered by swelling and redness of the free
gingival margin. Bleeding is caused by, for example, toothbrushing
and gentle probing by a dentist. There is a loss in the connective
tissue tone, which tends to open the gingival sulcus. The disease
process may be combatted by either eliminating the plaque or by
altering the environment by ch~nging the composition of the plaque.
In order to colonize a surface, bacteria must be able to adhere to
the surface in question. The mucous epithelium of the oral cavity is
constantly renewed, so that bacteria adhering to the mucosal surface
2 1 336682
will tend to be sloughed off together with the outer layer of dead
cells of the epithelium, thus preventing bacterial invasion of the
living tissue underneath the dead epithelial cells. On the other
hand, the dental surface constitutes a firm non-living base to which
bacteria effectively adhere. The bacterial colonies on the dental
surface (plaque), especially at the gingival margin and in the sub-
gingival region, are not removed by any similar process, resulting in
an antibacterial immune reaction from the surrounding tissue evident
as a chronic inflammation of the gingival tissue. Under normal and
healthy conditions this inflammatory reaction is mild, with a delica-
te balance being struck between colonizing bacteria and antibacterial
effect.
Inflammation of the gingiva due to bacterial colonization of the
dental surfaces is therefore an important initial stage of periodon-
titis. If the bacterial colonies (plaque) are not removed, accumula-
tion of bacteria along the gingival margin or in the dento-gingival
region will lead to increased gingival inflammation and destruction
of the periodontal membrane possibly followed by bone resorption.
Eventually a periodontal pocket develops in which more bacteria
accumulate, resulting in increased inflammation and infection proper
of the tissue so as to lead to a more pronounced degradation of the
tooth-supporting tissue.
Wherever there is a plaque coated surface, calcium ions can take part
in chemical reactions, giving rise to formation of calculus. Calculus
can be found on the tooth surface as supra-gingival or subgingival
deposits. These deposits must be removed in order to maintain normal
gingival conditions.
A characteristic of periodontal infection is that once bacteria/-
plaque have established themselves (i.e. infected) firmly in a perio-
dontal pocket, the natural humoral defense mechanisms are not capableof dealing with the infection, and the plaque may turn into hard
deposits, i.e. calculus.
1 336682
Apart from the general inflammation caused by the presence of bac-
teria/plaque, the release of hydrolytic enzymes like hyaluronidase,
desoxyribonuclease, collagenase and proteases probably contributes to
the destruction of dental tissue.
The severity of tissue damage probably depends on the antigen/anti-
body reaction of the organism as well as the degree of retention of
inflammatory products in the periodontal pockets. Accumulation of
mediators of local inflammation accelerates the process. In most
cases the process is slow, with immunoinfiltration of the gingival
tissue and formation of granulation tissue which contains inflamma-
tory cells. Occasionally, this slow progression is superseded by
acute exacerbations with accumulation of inflammatory cells and
release of lysosomal enzymes. Such exacerbations are probably due to
changes in the bacterial flora.
Juvenile periodontitis differs from the above marginal periodontitis
only by an early onset, and by often involving certain groups of
teeth and being accompanied by a much lesser degree of plaque for-
mation. It begins in late childhood, resulting in a pronounced loss
of the teeth's supporting tissue, and it too is an infectious disease
on a par with other periodontal diseases.
Current periodontal therapy is directed towards the removal of bac-
terial plaque and calculus deposits - subgingival and supragingival
plaque. These goals are usually achieved by means of scaling and
polishing, instruction in oral hygiene procedures, periodontal sur-
gery where indicated and periodic maintenance.
Another option for treatment which remains to be fully evaluated isthe possibility of disrupting the subgingival microflora in such a
way that supragingival plaque control becomes less important. One
potential approach to such a treatment is intensive intermittent
disruption using local or systemic antimicrobial agents, examples of
which are metronidazole, tetracycline and erythromycin. Such agents
may also be used for irrigation of the periodontal pockets. The
potential effect is based on the concept that alteration of the
~ 4 l 336682
subgingival microflora at appropriate intervals may be sufficient to
prevent the development of an ecosystem suitable to the reestablish-
ment of pathogens in adequate levels for disease initiation. Another
approach is bacterial substitution, replacing potential pathogens
with bacteria which occupy the same ecological niche but have a redu-
ced pathogenic potential.
Still another approach is the use of chemical agents which will alter
plaque and subgingival microflora sufficiently to prevent gingivitis
or the development of gingivitis into parodontitis.
A vast number of chemical agents have been evaluated as potential
antiplaque/antigingivitis agents. The first generation agents are
antibacterial agents with limited effectiveness. These agents are
effective as antibacterials in vitro, but are either not retained
intra-orally or they are rapidly released. Therefore, they inhibit
the bacteria for a short period of time, after which time bacteria
growth is resumed. Their clinical effect is limited unless the agents
are used frequently, i.e. four to six times a day. This group in-
cludes topical antibiotics, oxygenating compounds, quaternary ammo-
nium compounds, phenolic compounds, and sanguinarine. The second
generation agents are effective not only in vitro but also in vivo,
due to their retention and release kinetics. At present, chlorhexi-
dine and chlorhexidine analogues are the primary second generation
compounds, and stannous fluoride may also qualify as belonging to
this group.
Penicillin, tetracycline, erythromycin, polymyxin B, kanamycin,
metronidazole and spiromycin have been used for anti-plaque treat-
ment. However, the potential for the development of bacterial re-
sistance and hypersensitivity reactions should limit the use of
antibiotics for plaque control purposes. In general, antibiotics may
hold great promise for specific bacterial diseases in the oral cavi-
ty, but they appear to be inappropriate for the routine control of
supragingival plaque and associated diseases.
~~ 5 l 336682
Quaternary ammonium compounds are cationic surface agents which are
capable of reducing surface tension, absorbing to negatively charged
surfaces and disrupting membranes. Plaque reducing effects have been
reported with benzethonium chloride and cetylpyridinium chloride at
0.1%, when used four times daily. Side effects with quaternary ammo-
nium compounds have included both ulcerations and discomfort.
Phenolic compounds have a long history of use in the oral cavity as
either a mouthwash or as throat lozenges. A commercial preparation
(Listerine~) of thymol, eucalyptol, methyl salicylate, benzoic acid
and boric acid has shown a certain plaque reducing effect as compared
to a placebo. It is not clear whether the degree of plaque inhibition
due to this agent is of long-term value in the prevention of parodon-
titis.
Sanguinarine, a benzophenanthradine alkaloid, has recently been
reported to be potentially useful as a plaque control agent. Prelimi-
nary studies indicate that sanguinarine is capable of providing some
reduction and prevention of plaque and gingivitis.
Chlorhexidine gluconate in 0.1 - 0.2X solutions and 1X gels have been
shown to exert an effective plaque inhibiting and anti-gingivitis
effect, when used short-term. A few long-term studies with chlor-
hexidine gluconate have also shown promising effects against plaque
formation. The oral use of chlorhexidine has been associated with
staining of the teeth and tongue and a bitter taste, and longer use
often gives rise to alterations of the mucosa. Owing to the cationic
nature of the compound, it is difficult to mask the taste by addition
of flavoring agents without affecting the biological activity. Other
agents such as alexidine and octenidine are structurally similar to
chlorhexidine, and appear have a comparable effect.
In summary, treatment of gingivitis and periodontitis has mainly been
prophylactic, emphasizing the importance of removing calculus and
dental plaque and generally improving oral hygiene by mechanical
means such as toothbrushing using fluoride-cont~ining toothpastes
etc., and using dental floss, toothpicks and the like. When neces-
ç 1 336682 73578-1
sary, surglcal methods have been used ln order to reduce the depth
of the perlodontal pockets. Systemlc or topical antlbacterlal
treatment wlth tetracycline or the like has also been shown to
have some effect, especially during acute lnfectious episodes, and
finally, lrrigating or rinsing the mouth with antiseptics such as
chlorohexidine has been shown to exert a certain, if llmlted,
effect, especlally on glnglvltis and plaque formatlon. However,
none of these treatments are entirely satisfactory as they either
requlre a hlgh degree of patlent compllance and/or do not possess
a high degree of efflclency.
SUMMARY OF THE INVENTION
It has surprisingly been found that sulphated
saccharides, in particular sucralfate, exert a highly beneficlal
effect on a variety of dental conditions and diseases when applled
topically on teeth or gingiva.
Accordingly, in one aspect, the preset invention relates
to the use of a sulphated saccharide or a salt or a complex
thereof as an ingredient in a topical preparation for the
prophylaxis or treatment of diseases or conditlons of the tooth or
tooth-supporting tissue. In the following, such diseases or
conditlons are occaslonally referred to as dental diseases or
conditions.
In another aspect, the present lnventlon provldes for
the use of topical preparation comprising an aluminium complex of
sulphated sucrose ln admlxture wlth a sultable dllvent or carrler
for the prophylaxis or treatment of diseases or condltlons of the
teeth or tooth-supporting tlssue selected from dental carles,
,~
6~ 1 336682 73578-1
dental plaque, glnglvltls, perlodontltlæ, alveolltls, pulpltls,
post-extractlve or post-surglcal wounds, tooth eruptlon, bone
resorptlon, prosthetlc lrrltatlon, cysts or neoplasms orlglnatlng
ln the tooth-supportlng tlssue, and bacterlal, mycotlc and vlral
oral lnfectlons.
In another aspect, the present lnventlon provldes for
the use of a toplcal preparatlon comprlslng a sulphated sucrose
for the prophylaxls or treatment of glnglvltls, the preparatlon
contalnlng 1-15% by welght of the salt of sulphated sucrose ln
admlxture wlth a sultable dlluent or carrler.
In yet another aspect the preæent lnventlon provldes a
toothpaste preparatlon comprislng a prophylactlcally or
therapeutlcally effectlve amount of an alumlnlum complex of
sulphated sucrose, whlch ls ln the range of 0.01-75% by welght ln
admlxture wlth a sultable dlluent or carrler.
In a further aspect the present lnventlon provldes a
mouthwash comprlslng a æolutlon or suspenælon of a propylactlcally
or therapeutlcally effectlve amount of an alumlnlum complex of
sulphated sucrose, whlch ls 0.01-75% by welght, and a flavourlng
agent.
In another aspect the present lnventlon provldes a
chewlng gum comprlslng an alumlnlum complex of sulphated sucrose
ln an amount of 0.01-75% by welght and a conventlonal chewlng gum
base selected from the group conslstlng of chlcle and synthetlc
rubbers.
In a further aspect the present lnventlon provldes a
paste or gel sultable for use as a denture flxatlve or for
lnsertlon lnto perlodontal pockets, the paste or gel comprlslng a
6b l 3 3 6 ~ 8 2 73578-1
prophylactlcally or therapeutlcally effectlve amount of an
alumlnlum complex of sulphated sucrose, whlch ls ln the range of
0.01-75% by welght, and at least one materlal selected from the
group conslstlng of pectln, gelatlne a methylcellulose.
The present lnventlon also lncludes the use of the above
descrlbed toothpaste preparatlons, mouthwashes and chewlng gums
for the prophylaxls or treatment of dlseases of condltions of the
tooth or tooth-supportlng tlssue
In contradlstlnctlon to the known means of treatlng or
preventlng dental condltlons, excellent results have been obtalned
accordlng to the present lnventlon, by uslng a sulphated
saccharlde such as sucralfate, ln connectlon wlth dlseases such as
glnglvltls, perlodontltls, alveolltls, and lnfectlons such as oral
candida.
Sucralfate has prevlously been lndlcated for the
treatment of gastrlc and duodenal ulcers (cf. US 3,432,489; EP
161816; EP 192640) and for the treatment of emesls and dlarrhoea
ln dogs and cats (cf. EP 133880). In radlolabelled form,
sucralfate has also been used as a dlagnostic agent for the
lmaglng of gastrolntestlnal mucosa since, as
1 336682
mentioned above, the substance binds selectively to ulcerated areas
in the stomach and upper small intestine (cf. EP 107209).
The American Journal of Gastroenterology, 80(3), 1985, pp. 206-209;
"Sucralfate: Nonulcer Uses" suggests the use of sucralfate for a
variety of applications apart from the treatment of gastric and
duodenal ulcer, including the treatment of chemotherapy induced
stomatitis (1 g sucralfate/15 ml glycerol), post-sclerotic ulcer,
reflux oesophagitis and bile reflux oesophagitis as well as for
counteracting the ulcerogenic effects of aspirin. Also, Ferraro and
Mattern, Drug Intell. Clin. Pharm. 18, 1984, p. 153, report the use
of a sucralfate suspension for treating chemotherapy-induced mouth
ulcers (stomatitis), utilizing the ability of sucralfate to adhere to
ulcers (vide above). However, there is no indication that sucralfate
may be used for other purposes than treating mucosal ulcers. Similar-
ly, EP 136 100 suggests the possible use of a sucralfate suspension
for treating ulcers in the mouth but does not indicate any non-ulcer
use of the substance.
EP 230 023 describes pharmaceutical compositions comprising sulpha-
ted oligosaccharides for wound healing. This disclosure indicates the
use of these substances for the enhancement of healing of wounds in
collagen con~inine tissues, including skin and bone. It refers in
particular to skin ulcers characterized by breaches or ruptures of
the skin barrier. It is stated in the disclosure that polysulphated
saccharides are believed to be involved in the stimulation of migra-
tion of repair cells, such as fibroblasts, into the wound site,resulting in neovascularization. It is further stated that sucralfate
gives rise to inflammatory reactions, and that wound healing with
neovascularization and fibroblast (rather than macrophage) migration
was not observed with sucralfate. It is also stated that a low level
of 0.1 to 1 mg/ml of the polysulphated saccharide is preferred in
order to avoid local haemorrage or inflammation at the wound site. In
contradiction to this, excellent anti-inflammatory effects have been
obtained according to the present invention by using sucralfate
topically on the gingiva. The disclosure also mentions that poly-
sulphated saccharides may be used to promote bone healing, and that
rro le ~ Aft~
- 8 l 336682
because of this healing effect they are believed to be suitable for
use in or as prosthesic devices, for treatment of periodontal disease
and in artificial skin. Periodontal disease in this context would
seem to be speculatively listed because of the claimed bone healing
effect.
Thus, the above references do not indicate that sucralfate or other
polysulphated saccharides exert anti-inflammatory effects, anti-
plaque effects, or that they stabilize or strengthen cell surfaces
and intercellular matrices, including the epithelial and mucosal
surfaces. On the contrary, the above mentioned EP 230 023 states that
sucralfate actually contributes to inflammation. In view of the
results hitherto obtained, which show binding of sucralfate to woun-
ded mucosal surfaces, it is considered surprising that sucralfate,
and probably the entire group of polysulphated saccharides, may be
used for indications not involving wounded or ulcerated oral mocosa,
but rather inflammatory diseases such as gingivitis and parodontitis,
and for preventing plaque and calculus formation in the gingival
pocket.
It has been observed that one sulphated saccharide, sucralfate, when
used internally in the treatment of gastric ulcers, binds preferenti-
ally to the surface of the ulcer. It is currently believed that this
is a property which is common to sulphated saccharides and that it is
the result of an ability of sulphated saccharides to bind to proteo-
glycans and hyaluronic acid, which are the components of the surface
of many cells and protect or stabilize them so that the cell surface
remains intact. In other cases, e.g. in connective tissue, including
gingiva, hyaluronic acid and proteoglycans form a protective matrix
in which cells are embedded. Furthermore, it is known that certain
sulphated saccharides, e.g. heparan sulphate, dextran sulphate and
xylose sulphate, are hyaluronidase inhibitors. Hyaluronidases are
enzymes which catalytically cleave the glycosidic bonds of hyaluronic
acid. The decomposition of hyaluronic acid by hyaluronidases there-
fore leads to exposure of the cells to damage from various agents
such as pathogens and inflammatory substances. It has been demonstra-
ted (P.M. Bartold and R.C. Page, J. Oral Path. 15, 1986, pp. 367-374;
- 9 1 336582
K.S. Last et al., Archs Oral Biol . 30 (3), 1985, pp. 275-281) that
the presence of degradation products of hyaluronic acid in crevicular
fluid present in the periodontal pockets are correlated with clinical
signs of periodontitis. Thus, it is assumed that by inhibiting hyalu-
ronidase, sulphated saccharides promote the regeneration of tissue bypromoting the regeneration of the layer or matrix containing hya-
luronic acid and proteoglycans. Sulphated saccharides such as sucral-
fate may also modify or inhibit inflammatory reactions and/or stimu-
late tissue regenerative processes by other not yet fully understood
mechanisms.
The non-aluminium complexed form of sucralfate is a salt of sucrose
octakis(hydrogen sulphate), which is a very strongly negatively
charged entity. It is contemplated that the effects of sucralfate and
other sulphated saccharides can in part be ascribed to these strong
electrostatic forces. They may be important in preventing pellicle
formation on tooth surfaces, and they may also play an important role
in the modification and protection of the cell surface. It is be-
lieved that a normal or healthy cell surface has a strong electro-
negative charge, which is disturbed when the cell surface is im-
paired. Sucrose octakis(hydrogen sulphate) salts and other sulphatedsaccharide moieties may act as electronegative charges which can
reestablish the negative surface charge of the "wounded cell area",
and thereby exert a cell protecting, wound healing and anti-inflamma-
tory effect.
Vitamin C and sucralfate would seem to be related in several aspects.
Chemically, they are both structurally related to glucose and other
hexoses. At the tissue level, both compounds are associated with the
synthesis of intercellular substances, including collagen, and it is
known that vitamin C stimulates the synthesis of sulphated proteogly-
canes. Depletion of vitamin C leads to scurvy, which is characterizedby, among other things, impaired wound healing and gingivitis. In
clinical studies it has been possible to demonstrate a close rela-
tionship between gingivitis and vitamin C intake. Sucralfate has been
demonstrated to enhance wound healing and to improve gingivitis when
applied topically. Recently, vitamin C has also been associated with
lo 1 336682
immunoenhancing, anti-inflammatory and anti-allergic effects. The
anti-inflammatory effect of vitamin C is, among other things, a
result of inhibition of myeloperoxidase and aryl sulphatase activity,
and possibly also the elimination of free radicals. It is contempla-
ted that sucralfate may possess the same properties as vitamin C withrespect to antioxidant effect and inhibition of myeloperoxidase and
other enzymes which play a role in inflammatory processes.
Sucralfate has been shown to have a plaque reducing and modifying
effect when used topically in the oral cavity. The mechanisms in-
volved in the formation of plaque are still little understood. Theadhesive interaction involved in plaque formation appears to be very
complex, as may be deduced a priori from the wide variations in the
chemical composition of the acquired pellicle and interbacterial
matrix. The constituents of saliva, such as high molecular glycopro-
teins, may play an important role in the removal of bacteria from themouth by inhibiting bacterial attachment to oral surfaces. These
findines (Embery & Sdhogg, Proc. of a workshop on saliva-dental
plaque and enamel surface interactions, Strasbourg, Ed. R.M. Frank &
S.A. Leach, pp. 185-194, October 1981) suggest that saliva, by mimic-
ing the bacterial binding sites on teeth and the epithelial cellsurfaces, may competitively inhibit bacterial attachment. It is
contemplated that sucralfate, via a modulating/stimulating effect on
glucosaminoglycanes and hyaluronic acid either directly or via
inhibition/stimulation of various enzymes, enhances the ability of
salivary components to mask bacterial binding sites and to induce
bacterial aggregation, thereby diminishing or preventing plaque
formation, in the gingival sulcus/pocket. Lectin-like interactions
also appear of importance in the aggregation and attachment of oral
bacteria. It has furthermore been observed that there is a similarity
between the GAG (glycosaminoglycans) in mixed dental plaque and
calculus and gingival tissues, suggesting that periodontal breakdown
may be a factor in the accumulation of GAG in subgingival calculus.
Inhibition of GAG breakdown by sucralfate will thus prevent the
formation of plaque and calculus. Furthermore, the group of compounds
belonging to the glycosaminoglycanes has proved to be a useful model
series with which to study the binding properties of hydroxyapatite.
11 1 336682
The binding of hydroxyapatite is enhanced by calcium ions and in-
hibited by fluoride, and it is electrostatic in nature. It is there-
fore not unlikely that modifications of GAG's by sucralfate and other
polysulphated saccharides can interfere with initial pellicle for-
mation and the binding of bacteria to the surface of the teeth.
In a further aspect, the present invention relates to a method of
preventing or treating dental diseases or conditions, the method com-
prising topically applying on teeth or tooth-supporting tissue, a
prophylactically or therapeutically effective amount of a sulphated
saccharide or a salt or a complex thereof.
DETAILED DISCLOSURE OF THE INVENTION
The sulphated saccharide used in accordance with the invention may be
a monosaccharide, for instance xylose, fructose or glucose, an oligo-
saccharide, in particular a disaccharide such as sucrose, lactose,
maltose or cellobiose, or a polysaccharide such as dextran, heparan,
dermatan, proteodermatan, hyaluronic acid, heparin, chondroitin,
amylose, glucosamine, glucosaminoglycan and a mucopolysaccharide or a
subunit thereof.
In certain cases, it may be an advantage to use the sulphated saccha-
ride in combination with another wound-healing substance such as a
non-sulphated polysaccharide, for instance hyaluronic acid, vide Ex-
ample 3.
The saccharide is preferably a polysulphated or persulphated sac-
charide, which means that two or more sulphur-cont~ining moieties may
be present as substituents on the carbohydrate moiety.
In some cases, the sulphated saccharide may be complexed with or form
a salt with a metal, e.g. an alkali or alkaline earth metal such as
Na, K, Ca, Sr, Mg or Ba, or Al, Zn, Cu, Ga, Bi and Mn, or with an
organic base. The salts are preferably selected from those which are
sparingly soluble in water, in order to obtain a slow release effect
- 1 336682
12
- when they are used topically in the oral cavity. The currently pre-
ferred metal is aluminium, optionally in the form of aluminium
hydroxide. In the sulphated saccharide, aluminium complexes with the
sulphate moiety. Thus, a preferred class of sulphated saccharides is
aluminium disaccharide polysulphates of which the currently most pre-
ferred substance is sucralfate.
Sucralfate may be represented by the following formula:
CH20R
CH OR
/ ~ ~CH20R
H OR OR H
R - S03 [A12 (OH) 5]
The substance may, for instance, be prepared as disclosed in US
3,432,489 by reacting a 1-10% aqueous solution of a disaccharide
polysulphate or an alkali metal or alkaline earth metal salt thereof
with a 1-lOZ aqueous solution contAining aluminium ions, preferably
AlCl(OH)2 at room temperature and a pH of 4-4.5. The disaccharide
polysulphate is prepared by reacting a disaccharide with ClS03H,
H2S04 or H2S04-C5H5N-
Sucralfate may also be termed sucrose octakis(hydrogen sulphate)aluminium complex. Its CAS number is 54182-58-0. The commercial
product is a white powder which is practically insoluble in water and
most organic solvents; it is soluble in acids and alkalis. In prac-
tice, there may be slight variations in the chemical composition, for
example due to the fact that the sulphation may be slightly incomple-
te, giving a product that may e.g. contain a certain proportion of
molecules which are not octasulphated (persulphated), but which
instead are sulphated to a lesser degree, for example heptasulphated.
Such minor variations in the commercial product are well known and
1 336682
13
are reflected in the fact that the aluminium content in commercial
products may range from 17 to 21% and the sulphur content from 9.5 to
12.5%. In the present context, the term "sucralfate" also comprises
such generally accepted minor variations.
Apart from sulphated saccharides, it is contemplated that other sub-
stances may show a similar therapeutic or prophylactic activity in
connection with dental diseases and conditions as defined above. Ex-
amples of such substances are ketotifen and chromoglycate and other
antiallergic agents known to act on and stabilize cell surfaces, such
agents also being suspected of inhibiting the activity of hyaluroni-
dase.
Although there may be cases where the sulphated saccharide may be
administered as such, it will typically be compounded with one or
more pharmaceutically acceptable carriers or excipients to be pres-
ented in a form which is suitable for topical application to teeth ortooth-supporting tissue. It will usually be in the form of a fluid,
semi-fluid, semi-solid or solid preparation such as a solution,
suspension, powder, paste, gel, cream, salve, dental fixative, perio-
dontal implant, chewing gum, chewable tablet, effervescent tablet or
lozenge.
The topical preparation may be formulated in accordance with conven-
tional pharmaceutical practice with pharmaceutical excipients conven-
tionally used for topical applications such as alginate, pectin,
gelatin and derivatives thereof, cellulose derivatives such as methyl
cellulose, carboxymethyl cellulose or oxidised cellulose, guar gum,
acacia gum, karaya gum, tragacanth gum, locust bean gum, bentonite,
agar, carbomer, bladderwrack, ceratonia, dextran and derivatives
thereof, ghatti gum, hectorite, ispaghula husk, polyvinylpyrrolidone,
silica and derivatives thereof, such as silicates, xanthan gum, ka-
olin, chalk, dicalcium phosphate, alumina, pyrophosphate, talc,starch and derivatives thereof, paraffin, water, vegetable and animal
oils, isopropyl myristate, polyethylene, polyethylene oxide, poly-
ethylene glycol and polyethylene glycol esters, polypropylene glycol,
glycerol, ethanol, propanol, propylene glycol, glycols, alcohols,
- 14 l 336682
fatty alcohols, fixed oils, sodium, potassium, aluminium, magnesium
or calcium salts (such as the chloride, carbonate, bicarbonate,
citrate, gluconate, lactate, acetate, gluceptate or tartrate), rub-
bers (artifical or natural) such as chicle, polyisobutylene, etc.,
sorbitane esters, quaternary ammonium salts, salts of fatty acids and
polysorbates.
The preparation of the invention may also contain conventional addi-
tives such as thickeners, emulsifiers, anionic, cationic and
non-ionic surfactants, stabilizing agents, preservatives, abrasives,
flavouring agents, etc.
A mouthwash is an example of a solution or suspension form of the
preparation of the invention. In such a preparation, the vehicle is
typically a mixture of water and an alcohol, in particular ethanol or
isopropanol. Generally, the ratio of water to alcohol is in the range
of from about 1:1 to about 20:1, preferably from 3:1 to 20:1, by
weight. The alcohol content preferably constitutes about 20-40 X by
weight of the vehicle. The total amount of water-alcohol mixture in
this type of preparation is typically in the range of from about 70
to about 98 % by weight of the preparation. The pH of such liquid and
other preparations of the invention is generally in the range of from
about 5 to about 8.
The mouthwash may further contain about 1-5 X by weight of a non-
ionic surfactant selected from the group consisting of block polymers
of ethylene oxide, mixed polymers of propylene oxide and ethylene
oxide, polyoxyethylene hexitan mono-higher fatty acid esters contai-
ning 10-80 moles of ethylene oxide per mol, and higher fatty acid
mono- and di-ethanol amides and mixtures thereof.
The typical surfactant contains at least 10-80 Z by weight of hy-
drophylic units of polyoxyethylene and the hydrophobic radical such
as polyoxypropylene which preferably has a molecular weight of about
3250, as in the mixed polymers of propylene oxide and ethylene oxide.
In a preferred embodiment of the invention, the mouthwash contains
from about 0.1 to about 10 X by weight of sucralfate. A typical
~ 15 l 336682
mouthwash contains 10 X by weight of glycerine, 25 X by weight of
ethanol, 0.5-2 X by weight of surfactant(s), 0.5 X by weight of fla-
vouring agents, and 0.1-10 X by weight, e.g. 5 X by weight, of su-
cralfate, the rc ~inder of the composition being water.
It has surprisingly been found that a preparation which is particu-
larly effective for prophylactic purposes may be prepared by mixing
the sulphated saccharide with a toothpaste preparation. The sulphated
saccharide has been found to be compatible with toothpaste prepara-
tions of the type commonly available as commercial toothpastes, and
can thus be used on a regular basis for the prevention of e.g.
inflammatory and plaque-related conditions.
A toothpaste will usually contain polishing agents, surfactants, gel-
ling agents and other excipients such as flavouring and colouring
agents. The polishing agent may be selected from those which are
currently employed for this purpose in dental preparations. Suitable
examples are water-insoluble sodium or potassium metaphosphate,
hydrated or anhydrous dicalcium phosphate, calcium pyrophosphate,
zirconium silicate or mixtures thereof. Particularly useful polishing
agents are various forms of silica, especially silica xerogels such
as are described in U.S. patent No. 3,538,230. The polishing agent is
generally finely divided, with a particle size smaller than 10 ~m,
for example 2-6 ~m. The polishing agent may be employed in an amount
of 10-99X by weight of the toothpaste. Typically the toothpaste
preparations will contain 20-75X of the polishing agent.
A suitable surfactant is normally included in the toothpaste prepara-
tions. The surfactant is typically a water-soluble non-soap synthetic
organic detergent. Suitable detergents are the water-soluble salts
of: higher fatty acid monoglyceride monosulphates (for example sodium
hydrogenated coconut fatty acid monoglyceride monosulphate); higher
alkyl sulphates (for example sodium lauryl sulphate); alkylaryl-
sulphonates (for example sodium dodecylbenzene-sulphonates); and
higher alkyl sulphoacetates (for example sodium lauryl sulphoace-
tate). In addition, there may be employed saturated higher aliphatic
acyl amides of lower aliphatic amino carboxylic acids having 12-16
~ 16 l 336682
carbon atoms in the acyl radical and in which the amino acid portion
is derived from the lower aliphatic saturated monoaminocarboxylic
acids having 2-6 carbon atoms, such as fatty acid amides of glycine,
sarcosine, alanine, 3-aminopropanoic acid and valine, in particular
the N-lauryl, myristoyl and palmitoyl sarcosinate compounds. Con-
ventional non-ionic surfactants may also be included if desired.
The surface active materials are generally present in an amount of
about 0.05-10%, typically about 0.5-5Z, by weight of the toothpaste
preparation.
Typically the liquids of the toothpaste will comprise mainly water,
glycerol, sorbitol, propylene glycol or mixtures thereof. An advan-
tageous mixture is water and glycerol, preferably with sorbitol. A
gelling agent such as natural or synthetic gums and gum-like materi-
als, e.g. Irish Moss or sodium carboxymethylcellulose, may be used.
Other gums which may be used are gum tragacanth, polyvinyl-pyrroli-
done and starch. They are usually used in an amount up to about 10%,
typically about 0.5-5%, by weight of the toothpaste.
The pH of a toothpaste is substantially neutral, such as a pH of
about 6-8. If desired, a small amount of a pH-regulating agent, e.g.
a small amount of an acid such as citric acid or an alkaline material
may be added.
The toothpaste may also contain other materials such as soluble
saccharin, flavouring oils (e.g. oils of spearmint, peppermint,
wintergreen), colouring or whitening agents (e.g. titanium dioxide),
preservatives (e.g. sodium benzoate), emulsifying agents, silicones,
alcohol, menthol and chlorophyll compounds (e.g. sodium copper chlo-
rophyllin).
The content of sucralfate or other sulphated saccharide in the tooth-
paste of the above type or types discussed below will normally be in
the range of 1-20X by weight, calculated on the weight of the total
toothpaste composition, such as in the range of 5-20% by weight, in
particular about 10-20% by weight such as 12-18% by weight. The
~ 17 l 336682
latter ranges are especially indicated for toothpastes which are used
for treatment of gingivitis and periodontosis. It is, however, also
interesting to provide toothpastes having a lower content of sucral-
fate which will often predominantly be adapted for preventive or
prophylactic purposes. For such purposes, sucralfate content ranges
from about 0.1 to about 5Z by weight may be interesting.
A special type of toothpaste are toothpastes which are substantially
clear gels. Such toothpastes may either contain no polishing agents
at all or may contain the polishing agent in such finely divided form
that the gels will still appear substantially clear. Such gel tooth-
paste types may either be used per se or may be combined with tooth-
pastes containing polishing agents as discussed above.
There are, of course, numerous examples of special toothpastes or
dentifrices adapted for special purposes or with special advantages.
Thus, e.g., EP 280077 describes a toothpaste which contains stabili-
zed dicalcium phosphate dihydrate, resulting in a high water absorp-
tion capacity and an adequate viscosity at low abrasive content; US
4,618,488 discloses stable toothpastes, in particular transparent
toothpastes, which contain amourphous silica and/or silicate abrasi-
ve with specific surface areas, resulting in long term stability of
the transparency of the toothpaste; US 4,632,826 discloses a tooth-
paste, the polishing agent of which is constituted by a combination
of silicagel and/or precipitated silica and weakly calcined alumina
mixture, resulting in a toothpaste with low scratching and abrasion
effect and with high storage stability; US 4,721,614 discloses a
toothpaste which contains sodium bicarbonate as sole abrasive, thus
avoiding excessive abrasive properties and retaining a good storage
stability; US 4,702,905 and US 4,716,034 disclose toothpastes which
are resistent to syneresis in contact with polyolefin packaging,
which toothpastes are thus suitable for packaging in e.g. laminate
tubes, mechanical dispensers and flexible sachets; US 4,599,363
discloses a method for wetting and dispersing powders for toothpaste
preparations in turbulent liquid medium, the method preventing for-
mation of lumps and loss of powdered solids and resulting in high
quality toothpaste compositions; US 4,701,319 discloses a toothpaste
1 336682
- 18
which has good stability, viscocity and processing properties, the
toothpaste containing abrasive, carboxyvinyl polymer, and a carragee-
nan humectant.
It will be understood that these are only a few examples of tooth-
paste or dentifrice compositions into which a sulphated sachharide,
in particular sucralfate, may be incorporated in the manner described
above to obtain the surprising advantages characteristic to the
present invention, and that the person skilled in the art would be
able to compose any kind of suitable toothpaste or dentifrice compo-
sition based on literature references such as the ones given aboveand the specific information contained herein about suitable manners
for incorporating sulphated saccharides in particular sucralfate into
such compositions.
The incorporation of sucralfate or other sulphated saccharide in a
toothpaste preparation and other dental or oral preparations may be
performed in many different ways. Often, it will be preferred to form
a suspension of sucralfate and combine the sucralfate suspension with
the other preparation ingredients in paste form. Alternatively, dry
sucralfate powder may be mixed with the other preparation components,
either first with the dry preparation constituents and subsequently
with liquid or semi-liquid preparation constituents, or sucralfate
powder per se can be incorporated in an otherwise finished prepara-
tion.
In general, it is preferred that the sucralfate powder is added
together with the polishing material or dentifrice. It has also been
established, see also below, that the size of sucralfate particles in
a toothpaste is an important factor. Thus, it is preferred that at
least 95 Z by weight of the sucralfate in the toothpaste has a par-
ticle size of below 250 ~m.
A suitable example of a sucralfate-containing toothpaste would be a
modified version of a commercially available toothpaste with a su-
cralfate content of 1-20 X by weight, the toothpaste part being
composed from the following components (expressed as parts by
- 19 1 336682
weight): 10.1 parts 98 X w/w glycerin, 0.35 parts sodium carboxymet-
hyl cellulose, 0.3 parts sodium saccharin, 0.01 parts TiO2, 58.5
parts of a 70 X w/w aqueous solution of sorbitol, 3.0 parts polyethy-
lene glycol 600, 0.4 parts sodium fluorophosphate, 0.1 parts sodium
fluoride, 0.004 parts blue colourant, 18.0 parts SiO2 polishing
agent, 4.2 parts ultrafine SiO2 thickening agent (Tixosil), 0.1 parts
calcium hydrogen phosphate dihydrate, 1.3 parts of a 90 X solution
of C12 18 alkyl sodium sulphate ester, 3.0 parts water, and 0.7 parts
flavouring agent (such as peppermint or spearmint flavour).
A typical general procedure for making sucralfate-containing denti-
frice products such as toothpaste is, in a first step, to disperse
the gelling agent in the appropriate humectant and mix and add deio-
nized water and sweetener followed by mixing to form a gel phase;
and then, in a second step to add polishing material together with
sucralfate to the gel phase and mix to form a homogeneous product
and continuing mixing under vacuum; and finally, in a third step, to
add surfactant and flavour and mix under vacuum to obtain the finis-
hed products. In this procedure, the reason for adding sucralfate
together with the polishing agent is that earlier addition before the
gel phase is prepared may create a composition which is too thick
for efficient mixing. Following preparation, the product may be
packed in a suitable container such as a pressurized container or a
collapsable, e.g. aluminum, lead or plastic, tube.
In this connection it should be mentioned that while the incorpora-
tion of sucralfate or other water-insoluble or sparingly water-so-
luble sulphated saccharides is best performed as described herein
taking into consideration the physical and chemical properties of the
sulphated saccharide in particular the particle size considerations
mentioned below, the incorporation of water-soluble sulphated sac-
charides, such as sodium and potassium salts of sucrose oktakis(hydrogen sulphate) in toothpastes or dentifrices or other prepara-
tions discussed herein will normally be extremely simple and will
ordinarily consist in the addition of the sulphated saccharide to the
preparation or to constituents thereof in either dry or dissolved
form.
~ Tr~
- 20 l 336682
For certain purposes, such as "pocket filling materials", denture
fixatives and other preparations which are to stay for prolonged
periods in contact with wounded or infected areas, the preparation is
advantageously one which is capable of adhering to the gingiva,
periodontal sulcus/pocket, tooth enamel, dentine, root cement or
tooth-supporting tissue on which it is applied, in order to ensure a
sufficiently intimate contact between the active substance and the
surface in question for a sufficient period of time to obtain an
efficient localized action of the sulphated saccharide. Such adhesive
properties may be obtained by for example incorporating suitable high
molecular weight materials such as pectin, gelatine and methylcellu-
lose into the preparation, preferably together with a non-aqueous
liquid vehicle such as a medium chain triglyceride, e.g. a trigly-
ceride comprising acid moieties of a length of about 12-18 carbon
atoms.
The preparation may further be one which is biodegradable, meaning
that it is capable of being degraded in the body outside the diges-
tive tract. The biodegradable material present in the preparation is
one which gives rise to degradation products which are readily elimi-
nated from the body by being metabolized at the cellular level or bydisintegrating into smaller components which are eliminated via the
kidneys or metabolized in the liver etc. Examples of useful biodegra-
dable materials are synthetic polymers such as polyglycolic acid,
polyacetic acid, polylactic acid or copolymers thereof, polycarbo-
nates, polyacetals, polyketals, polyorthoesters, etc., as well asnatural polymers such as proteins, e.g. gelatin and collagen, or
polysaccharides, e.g. dextran, agarose, pectin, starch, alginates,
hyaluronic acid, etc. The biodegradability of the preparation is
considered to be particularly advantageous when the preparation is in
the form of a periodontal implant, as this would obviate the necessi-
ty of surgically removing the implant after the treatment is comple-
ted.
Periodontal implants may be prepared by moulding, pressing, extrud-
ing, etc. in a manner known per se and subsequently formed into any
_ 21 l 336682
desired shape such as a film, thread, strip, wedge or sponge. Prepa-
rations for insertion into periodontal pockets are, however, prefer-
ably in the form of a paste or gel, a suitable quantity of which is
introduced into the pocket by means of a suitable instrument such as
a syringe.
A chewing gum may be prepared by incorporating the sulphated saccha-
ride into a conventional chewing gum base contAining chicle or a syn-
thetic rubber. Similarly, chewable tablets may be prepared by com-
pounding the sulphated saccharide with one or more conventional ex-
cipients such as sorbitol, xanthan gum, etc.
The pharmacologically active element in sucralfate is probably thenon-aluminium complexed sodium and/or potassium salt of sucrose
octakis(hydrogen sulphate). Since such a salt is soluble in water, it
would seem that a small particle size would be an important factor
when preparing formulations of the sparingly soluble sucralfate. One
way of achieving a small sucralfate particle size is by means of
milling, grinding or disintegrating apparatus, e.g. a three roll
mill, where the sucralfate powder is ground, preferably together with
a suitable liquid vehicle having a viscosity adapted to effectively
suspend the resulting fine particles, and preferably a relatively low
vapour pressure so that no excessive evaporation with resulting
agglomeration of the fine particles will occur, such as a polyal-
cohol, for example glycerin or polyethylene glycol. The resulting
preparation will normally contain up to 60-70% by weight of sucral-
fate particles with a fairly uniform particle size of about 5-lO ~m
or less (for 95% by weight of the sucralfate), the particles being
substantially evenly suspended in the vehicle. Such a paste can then
be further suspended in any suitable pharmaceutical preparation using
well known pharmaceutical methods. Another starting point for a small
particle size sucralfate formulation is sucralfate "filter cake",
which is sucralfate contAining about 50% by weight of water, and with
a particle size of about 5-10 ~m or less. This material can be mixed
with, for instance, a water-miscible liquid which has a relatively
low vapour pressure, such as glycerin, in order to prevent the water
from evaporating, and the sucralfate particles will retain their
1 336682
22
small size. Another important factor to take into consideration when
preparing formulations of sucralfate and other sulphated saccharides
is the strong negative charge of salts of sucrose octakis(hydrogen
sulphate), and probably of most sulphated saccharides. The pharmaco-
logical effect of sucralfate, salts of sucrose octakis(hydrogensulphate) and other sulphated saccharides probably depends on this
negatively charged entity, and the pharmacological effect of the drug
may be reduced by the presence of positively charged mono- and diva-
lent ions in the vehicle.
The topical preparation to be used for the present purpose generally
comprises the sulphated saccharide in an amount of 0.001-99%, typi-
cally 0.01-75X, more typically 0.1-20%, especially 1-10% by weight of
the total preparation. In particular, when the sulphated saccharide
is sucralfate, a preferred concentration thereof in the preparation
is often from 0.5-50%, especially 0.5-25Z, especially 1-15X, such as
1-10%. It is suitably applied 1-10 times a day, dependent on the type
and severity of the condition to be treated. Preparations for appli-
cation in periodontal pockets, however, are preferably applied at
regular intervals during the entire treatment period.
The preparation may contain other active agents than the sulphated
saccharide, such as antibiotics, antibacterial or antimicrobial
agents, antiviral agents, antimycotic agents, bacteriostatic agents
(e.g. sulphonamides), antiseptic agents, disinfectants, local anes-
thetics or analgesics, antiinflammatory agents, antineoplastic agents
and anticaries agents (e.g. fluoride).
As mentioned above, the sulphated saccharide is indicated for use in
connection with any dental disease or condition initially involving
bacterial colonization, inflammation and/or infection of the teeth or
tooth-supporting tissue. The sulphated saccharide may thus be used
for treating or preventing dental caries, dental plaque or calculus,
gingivitis, periodontitis, alveolitis, pulpitis and osteomyelitis. It
has further been shown that the sulphated saccharide may be useful
for preventing post-extractive, post-surgical or post-traumatic
wounds or bone resorption, prosthetic irritation, irritation, inflam-
23 l 336682
mation or infection associated with tooth eruption or extraction,cysts and neoplastic conditions originating in the tooth-supporting
tissue, and bacterial, mycotic and viral oral infections, and it has
been shown to be effective in the treatment of oral infections such
as candida.
The invention is further illustrated by the following non-limiting
examples.
EXAMPLE 1
A topical paste preparation for insertion into periodontal pockets
and as fixative for dentures was prepared from the following ingredi-
ents:
Sucralfate* 30 g
Pectin 10 g
Gelatin 10 g
15 Carboxymethylcellulose 10 g
Medium-chain triglycerides 60 g
* Provided by Abic Laboratories, Israel, in finely divided form (par-
ticle size: 95Z by weight <250 ~m).
The finely divided sucralfate was thoroughly mixed with the other
ingredients in finely divided form. The medium-chain triglycerides
were added to the resulting powder to a suitable paste-like consis-
tency and a substantially homogeneous dispersion of the particulate
components.
EXAMPLE 2
A topical paste preparation for insertion into periodontal pockets
and as fixative for dentures was prepared from the following ingredi-
ents:
- 24 l 336682
Sucralfate * 10 g
Gelatin 10 g
Pectin 10 g
Medium-chain triglycerides 15 g
5 Hydrogenated coconut oil15 g
* Provided by Farmos Pharmaceutical, Finland, 95% by weight < 250~m.
The finely-divided sucralfate was thoroughly mixed with the pectin
and gelatine in finely divided form. The medium-chain triglycerides
and hydrogenated coconut oil were added to the resulting powder to a
suitable paste-like consistency and a substantially homogeneous dis-
persion of the particulate components.
EXAMPLE 3
A topical paste preparation for insertion into infected periodontal
pockets was prepared from the following ingredients:
15 Sucralfate * 30 g
Tetracycline 3 g
Hyaluronic acid **0.3 g
Pectin 10 g
Gelatin 10 g
20 CMC 10 g
Medium-chain triglycerides 60 g
* Provided by Farmos Pharmaceutical, Finland, 95Z by weight <250 ~m.
** Obtained from human umbilical cord (Sigma)
The finely divided sucralfate was thoroughly mixed with the other
ingredients in finely divided form. The medium-chain triglycerides
were added to the resulting powder to a suitable consistency and a
substantially homogeneous dispersion of the particulate components.
1 336682
_ 25
EXAMPLE 4
A topical gel preparation was prepared by mixing 15 g of sucralfate
powder (supplemented by Guilini Chemie, West Germany, 95Z by weight
<250 ~m) with 15 ml of 3% HCl. The mixture formed a translucent ad-
hesive gel.
EXAMPLE 5
A topical gel preparation was made by melting 50 g of gelatine and
mixing into it 20 g of the same sucralfate powder as in Example 4.
EXAMPLE 6
A toothpaste preparation was prepared by mixing 15 g of the same
sucralfate powder as used in Example 4 with 15 ml of glycerol and
adjusting the paste to the desired consistency by adding glycerol
after 2 days.
EXAMPLE 7
A toothpaste preparation was prepared by mixing 10 g of sucralfate
(provided by Guilini Chemie, U. Germany, 95X by weight <250 ~m)
powder with 12 ml of water. This mixture was subsequently mixed with
12 g of a toothpaste containing polishing agent (Colgate "Blue
Mint").
EXAMPLE 8
A toothpaste preparation was made by mixing 10 g of sucralfate powder
with 70 g of a base prepared in advance and comprising:
~ 26 l 336682
Sodium monofluorphosphate 0.38 %
Sodium fluoride 0.11 %
Sorbitol (70% sol) 58 %
Silicon dioxide 18 %
Glycerine (98%) 10.1 %
Polyethylene glycol (PEG 600) 3 %
Sodium lauryl phosphat 1.3 %
Sodium saccharine 0.3 %
Dicalcium phosphat 0.1 X
Titanium dioxide 0.01 Z
Tixocil 4 X
Flavour 0.7 Z
and adjusting the consistency by adding distilled water.
EXAMPLE 9
A toothpaste was prepared by mixing:
Aluminium abrasive 35 %
Sterile water 29.3 %
Glycerine 22 X
Sucralfate * 10 X
Hydroxyethylcellulose (Natrosol 250 M) 1.4 %
Polyethylene glycol 40 di-isostearat 1 X
Flavour K91-4037 1 %
Sodium saccharine 0.4 %
* Micronized sucralfate (10 ~m) provided by Guilini Chemie, W. Germa-
ny
- 27 l 336682
EXAMPLE 10
A chewing gum was prepared by heating a commercial chewing gum to
100C and then stirring 10Z by weight of sulcrafate powder into the
melted gum base. The gum base had the following composition:
Hydrogen peroxide (solid) 5 mg
Sorbitol 285 mg
Mannitol 7 mg
Saccharin 0.7 mg
Another sucralfate chewing gum was prepared in the same manner using
a gum based on chicle, sorbitol, dicalcium phosphate and saccharine.
EXAMPLE 11
Clinical trials
A) A paste according to Example 3 was used for treating 10 cases of
periodontitis accompanied by 5-10 mm deep, infected (i.e. cont~ining
pus) periodontal pockets by introducing the paste into pockets by
means of a spatula, after scaling the calculus from the root surface.
The paste was left in the pockets for a week, after which the treat-
ment was repeated.
On examination 2 days after the initial treatment there was no longer
any pus or inflammation of the gingiva and the patients did not com-
plain of any pain or irritation. The depth of the periodontal pockets
was observed to be reduced. After 2 weeks it was observed that the
mobile teeth had become more firmly fixed into the alveole and there
were no clinical signs of inflammation.
It was concluded that this paste preparation is suitable for treating
periodontic disease accompanied by infected periodontal pockets and
loosening of the affected teeth. The sticky paste prevents the infec-
tion of the cleaned pocket.
- 28 1 336682
B) A paste according to Example 1 was used substantially as described
under A) with the exception that the treated periodontal pockets were
not infected, as determined by the absence of pus. As in A), the
number of treated patients was 10.
After a few days the clinical signs of inflammation, bleeding and
oedema had disappeared, the depth of periodontal pockets had been
reduced, the treated teeth had become immobile, and none of the
patients had experienced clinical side effects of the treatment. 2
weeks later, the depths of the periodontal pockets had been further
reduced.
It is therefore concluded that the paste according to Example 1 is
well-suited for treating periodontal pockets, the more so as the
patients' gingiva were no longer painful, so that they could resume
brushing their teeth and otherwise maintaining a normal oral hygienic
standard.
C) The preparation of Example 2 was used for treating 24 cases of
periodontitis in which the patients had periodontal pockets of a
depth of up to 5-6 mm. After depuration and cleaning the teeth, the
gel was injected into the periodontal pockets by means of a syringe
provided with a blunt needle.
When e~. in~d 2 days later, the patients had not experienced any pain
after the treatment, and the inflammation of the gingiva was reduced
to an extent normally observed only after a weeks treatment.
D) A toothpaste as described in Example 6 was used in the treatment
of 100 cases of gingivitis by carefully applying, both with and
without initial prophylactic polishing and scaling, the paste on the
gingival margin for about 2 minutes using a soft bristled toothbrush.
This treatment was repeated two or more times daily for several weeks
(maximum treatment period 6 months).
1 336682
_ 29
On examination after a few days an almost healthy gingival mucosa was
observed, and 50 of the patients who used the toothpaste for longer
periods up to six months showed none of the discolorations of the
teeth and of the tongue associated with the use of chlorohexidine and
antibiotics.
E) A toothpaste according to Example 7 and Example 9 were used by 150
patients (75 patients for each toothpaste) constantly or intermit-
tently for periods of from 3 to 12 months (median 6 months), as a
sole treatment for gingivitis. The toothpastes were used morning and
evening, the gingival margin being brushed horizontally with a soft
bristled toothbrush. The patients were instructed to not rinse their
mouth until one minute after brushing. As a sole treatment, this
resulted in healthy gingiva with no bleeding and swelling, and a
remarkable reduction in subgigival deposits of plaque and calculus
has been shown, resulting in a firm binding of the gingiva margin,
and thereby effectively preventing further progression of periodontic
disease.
F) Another 50 patients used the toothpaste of Example 9, but contai-
ning only 2% sucralfate instead of 12Z sucralfate. The patient cate-
gory and the use of the toothpaste were identical with the above-
mentioned Example 11 E), and the anti-gingivitis effect was the same,
indicating that even a low concentration of 2% sucralfate in a denti-
frice would seem to be sufficient as a gingivitis-preventing
treatment.
G) Pastes according to Example 1 and Example 2 were used as a denture
fixative. Twenty patients with difficult upper dentures used the
pastes for periods of up to one year. The pastes have resulted in a
good fixation of the dentures and have had the additional advantages
of being tasteless, providing a long-lasting (up to 12 hours) gluing
effect and functioning as a kind of shock absorbing paste, with very
little irritation of the gums and mucosa. The pastes have also been
used as glue in immediate dentures (immediately after extraction of
teeth), and have given rise to a very quick healing of the gums.
1 336682
H) The paste of Example 2 and the gel of Example 4 have been used in
about 20 cases of third lower molar eruptions, applying them under
the mucosal flap. They have resulted in a good anti-inflammatory
effect equivalent to the effect seen following the use of chlorohexi-
dine and antibiotics such as Nebaticine.
I) The paste of Example 2 has been used in 25 cases of third lower
molar extractions, placed on a gauze mesh, and there has been no
incidence of dry sockets alveolitis.
J) The gel of Example 5 was filled into impression-type syringes.
Before use, the syringes were heated to 70C in a water-bath, the gel
being used to fill out periodontal pockets. About 10 patients have
been treated, and the effect has been good, with a marked anti-in-
flammatory effect and the pocket being well protected from contamina-
tion.
K) The gel preparation of Example 4 was used in the gingival margin
and left for 1-2 days, in 50 patients with severe gingivitis with
swelling and bleeding, the patients thus being unable to maintain
proper oral hygiene. They were instructed not to brush their teeth.
Inspection after one day showed a remarkable healing of the gingivi-
tis, making it possible to institute the relevant dental treatmentwithout discomfort. The gel acquires a rubber-like consistency and
can thus easily be removed when necessary.
L) The gel of Example 4 has also been used on dentures as a fixative,
and it has in a few cases been applied topically on the infected area
in the treatment of oral candida infections. It has also been used
following minor surgery in the oral cavity in about 20 cases, being
applied on the wound area and providing pain relief and an anti-
inflammatory and wound healing effect.
- 31 l 335682
EXAMPLE 12
For the curative management of patients with deep periodontal pockets
(more than about 5 mm), which constitute about 20Z of all periodonto-
sis cases, it is probably necessary to have a method of treatment
which can remove the subgingival bacterial plaque formation and keep
the dental surface free of new plaque formation for a period of time
which is sufficiently long to allow the gingival tissue to normalize
and the contact epithelium to be re-created and attach to the tooth.
For that purpose, a special cleaning system based on a modified
ultra-sonic Odontoson (3 N Special, Lennart Goof A/S, Usser0d M011e,
2990 H0rsholm, Denmark), has been developed. The apparatus is modi-
fied by placing a water jet-pipe nearly parallel with the ultrasonic
needle, in such a way that the water jet stream is directed alongside
the ultrasonic needle, hitting the point of the needle. With this
construction, it is possible to direct both the ultrasonic needle and
the water jet stream into the periodontal pocket simultaneously. The
combined effect of the ultrasonic needle being carefully moved over
the surface of the pocket and the tooth surface while the water
vigorously hits the tip of the needle has shown to be very effective
in removing bacterial plaque from the surface of the teeth. The
amount of water needed is approximately 30-50 ml per minute. The
cleaning effect is significantly improved by adding sucralfate in a
concentration of approximately O.1-lX by weight to the flushing
water. The addition of sucralfate also significantly delays the
formation of new bacterial plaque, and it is helpful in guiding the
dentist when removing the subgingival plaque, in that the water stops
foaming when the plaque is completely removed.
Six patients with advanced parodontitis and periodontal pockets of a
depth of 8-12 mm were treated with the above mentioned cleaning
system. Sucralfate 0.1% by weight, in the form of Antepsin Granulate,
Farmos, was added to the flushing water. This treatment was repeated
at appropriate intervals for up to 4 weeks. In all six cases there
was a nearly complete healing of the periodontotic condition. Another
six patients with the same grade of parodontitis underwent the same
_ 32 l 336682
cleaning of the periodontal pockets followed by injection of a su-
cralfate paste (Example 2) using a syringe with a blunt needle. After
7 to 14 days, the deep periodontal pockets had nearly disappeared and
the patients were classified as being greatly improved with respect
to parodontitis. Inflammatory signs and symptoms had completely
disappeared and at a follow up after 4 months, there were no signs of
reappearance of parodontitis.
EXAMPLE 13
Sucralfate has been shown to be highly effective as an anti-inflamma-
tory agent and moderately effective as a plaque reducing agent when
used as a mouthwash.
In a study comprising 13 adults (aged 19-46 years) a 2X by weight
aqueous suspension of sucralfate was used 2-3 times daily as a mouth-
wash for a period of 12 days. No other oral hygiene was allowed
during this test period. Before the start of the study, the partici-
pants' teeth were polished and it was controlled that none of the
participants had severe gingivitis or calculus. The test persons
received 200 ml of mouthwash flavored with peppermint, and were
instructed to rinse the mouth with 10 ml 2-3 times a day. At the
start of the study and after 8 and 12 days, plaque control was made
with Diaplak, and gingival bleeding was controlled using a periodon-
tal probe to investigate the orifice of the gingival crevice. None of
the test persons felt any discomfort during the test period, and none
experienced foetor ex ore. The results below summarize measurements
of the gingival index (L0e, 1967, J. Periodont. 38: 38-44), and
plaque index assessed according to the method of Bay ~ Ainemo.
The mean plaque index before start and before polishing was 0.69, and
1.17, respectively, indicating a very minor increase in dental plaque
score during the test period. The condition of the gingivae after 12
days of sucralfate mouthwash as the only means of oral hygiene was
perfect, with no signs of beginning inflammatory changes, and the
gingival score was 0 for all 13 test persons. Those persons who
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smoked developed discoloration of the teeth, but apart form this
discoloration there were no side effects.
From previous experience it is known that withdrawal of all mechani-
cal oral hygiene procedures in individuals with healthy gingivae for
a period of 2-4 weeks will result in clinically detectable gingivi-
tis. On this basis, it can be concluded that topical administration
of sucralfate in the mouth exerts a beneficial effect, in that su-
cralfate is capable of effectively preventing the development of
gingivitis.
EXAMPLE 14
Double-blind r~ndo i~ed comparison of a sucralfate dentifrice against
a chlorhexidine dentifrice (active control), and a blue minty gel
dentifrice (passive control), in adults with mild gingivitis
The objective of this study was to compare the effect of a ~0X su-
cralfate dentifrice (Example 9) on established gingivitis and plaque
with a blue minty gel (negative control), and Corsodyl~ Gel denti-
frice (positive control, 10X chlorhexidine). The subjects were selec-
ted from patients attending a general dental practice. Forty-eight
(48) subjects meeting the inclusion criteria were randomly allocated
to one of the three groups. The subjects were instructed to use only
the allocated dentifrice and toothbrush (Oral B~ 35), using enough
toothpaste to cover the head of the brush and to brush for one minute
morning and night, and to use no other oral hygienic procedures. The
subjects received no prophylaxis before the start of the trial.
Scoring system
The following 6 teeth were scored: 6+, 2+, +4, 4-, -2, -6. Swelling
was scored at the gingival papilla meseally to the teeth. The gingi-
val index (GI) was scored from 0-3 using the Quikly-Hein GI index,
and the plaque index (PI) was scored from 0-5. Pockets were measured
by probing. For each tooth, probing was carried out using 3 scores
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buccaly (distally, midale and meseally) and one score orally
(midale). Plaque was scored using the Lambster modification of the
Quigley-Hein plaque index after disclosing the teeth with Diaplak
(erythrosine). The figures shown below are the sum of all 24 measure-
ments for each index.
The above-described procedure was used at week three (3) and at week
six (6) examinations.
Results
Baseline scores obtained at the first visit for swelling, gingivitis,
plaque and pocket depths showed that all 48 patients had slight
inflammatory changes and mild gingivitis.
At each of the three week and at the six week examinations, the
effect of the test dentifrices was evaluated on 37 patients. The
effect on gingivitis and plaque formation, respectively, is expressed
as the change in the gingival index (GI) and the plaque index (PI)
(calculated as post/pre x 100) during the test period. The effect
obtained over the first three week period is calculated for patients
attending the three week visit, and correspondingly, the effect for
the six week period is calculated for patients attending the six week
visit. Tables 1 and 2 give the mean values for the three groups.
Table 1
Mean gingival index (GI)
Placebo Chlorhexidine Sucralfate
0 - 3 weeks: 109Z 101X 88X
0 - 6 weeks: 110% 100% 90%
_ 35 1 335682
Table 2
Mean plaque index (PI)
Placebo Chlorhexidine Sucralfate
0 - 3 weeks: 91X 71% 83X
0 - 6 weeks: 94Z 84% 92%
The acceptability and effect of the toothpaste was evaluated by
asking the patients at the three week visit about taste, staining of
the teeth and tendency to gingival bleeding while brushing. The
results are shown in Table 3.
Table 3
Ratings for taste, staining and bleeding
Number of patients
Placebo Chlorhexidine sucralfate
Taste: Good 9 0 6
Average 6 2 4
Bad 0 10 0
Staining: Less 0 1 2
No change 13 2 8
More 2 9 0
Bleeding: Less 3 1 4
No change 11 11 6
More 1 0 0
36 1 7`3~82
Conclusion
Chlorhexidine had some effect on plaque formation, and at the three
week visit the plaque index for chlorhexidine was reduced to 71Z of
the baseline findings. Chlorhexidine gave no reduction in the gingi-
val index. The sucralfate dentifrice showed a moderate but consistentbeneficial effect on the gingivae. During the first three weeks of
the test period the gingival index with sucralfate was reduced from a
mean of 1.23 to a mean of 1.08, indicating that most of the bleeding
sites had disappeared. There was also some effect of sucralfate on
plaque formation.
The sucralfate dentifrice was generally very well accepted. It was
rated as having a good taste and was reported by some of the test
persons to give less bleeding. Nearly all of the patients were posi-
tive with respect to continued use of the sucralfate dentifrice. A
few patients reported spontaneously that the sucralfate dentifrice
had a beneficial effect on tobacco stains.
Chlorohexidine was nearly llnAni ously rated as having a bad taste and
giving rise to discolouring of the teeth, leading to four out of
sixteen test persons using chlorhexidine dropping the test.
With few exceptions, the subjects using chlorhexidine would not
continue using this test dentifrice.
