Note: Descriptions are shown in the official language in which they were submitted.
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METHOD OF TREATMENT FOR PERIODONTITIS
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to methods of treating
periodontal disease.
2. Description of the Prior Art
The term "periodontal disease" actually encompasses
a number of diseases that affect the supporting tissues of
the teeth. The periodontium consists of the investing and
supporting tissues of the tooth, and consists of the gingiva,
the periodontal ligament, the cementum and the alveolar
bone. The periodontium is subject to morphological and
functional variations, to changes associated with age and to
pathology.
The term gingivitis refers to an inflammation of
the gingival tissue. Recent research on periodontal disease
shows that not all patients with gingivitis progress to
periodontal disease. However, gingivitis may be the first
sign of oncoming periodontal disease and most, if not all,
periodontal disease has an accompanying gingivitis.
Periodontitis is defined as inflammation involving
the gingival unit (gingiva and alveolar mucosa) and extends
to the periodontal ligament, alveolar bone, and cementum.
Periodontitis involves loss of clinical attachment and
radiographic loss of bone. The conversion clinically from
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gingivitis to periodontitis reflects the progression,
histopathologically, from the established stage to the
advanced stage of the periodontal lesion.
The vast body of evidence indicates that the
primary cause of both gingivitis and periodontitis is
bacterial activity. Bacteria attach to the tooth surface at
and slightly under the gingival margin. They colonize and
form an organized mass that is referred to as bacterial
plaque. This plaque, if allowed to remain, brings about
inflammatory changes in the tissues. The pathogenic
potential of plaque can vary from one individual to another
and from tooth to tooth within an individual. The reaction
of the host tissues to this bacterial attack is through an
inflammatory and immunologic defense mechanism.
Prophylactic measures to maintain good oral hygiene
and keep teeth and gums in a relatively plaque-free state are
important in the prevention of most treatable forms of
periodontal disease. The patient's own brushing, flossing
and utilization of certain antiseptic mouthwashes which may
be of value in controlling plaque are supplemented by
professional scaling and root planing treatments.
Once active periodontitis develops, however, a
variety of treatment modalities have been utilized to combat
the disease and prevent its progression. These include
periodontal surgery: e.g., curettage, givgivectomy, flap or
pocket elimination and the modified Widman flap procedure:
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and chemotherapy, particularly local and systemic antibiotic
treatment. The antibiotic agents most frequently used are
the tetracyclines and metronidazole. Excellent reviews of
current knowledge regarding periodontal disease in general
and periodontitis in particular, as well as conventional
treatment methods, include V.J. Iacono, NYS Dent. J.,
53:24-29 (1987); T.J. O'Leary et al., J. Periodont.,
59:306-310 (1988): L. Saxen, Int. Dent. J., 35:291-296
(1985): W.C. Hurt et al., Baylor Dent. J., 32:17-19 (1988).
The conventional methods currently utilized to
treat periodontal disease suffer from a number of significant
drawbacks. Surgical reduction of periodontal pockets can
expose roots, cause sensitivity, and result in poor esthetics
by a lengthening of the clinical crown and altering the
gingival contours. Surgical treatment does not guarantee
that the disease process will not recur to the detriment of
the patient's dentition.
Antibiotic therapy is not usually totally
successful, particularly in advanced cases, probably because
the site of action of periodontal disease is not accessible
to a sufficient concentration of drug at the base of the
periodontal pocket to completely halt the disease process.
Anti-microbial solutions have been introduced through
irrigating devices to the periodontal pocket with some
success, but are not curative. Sustained systemic
administration of antibiotics such as tetracyclines is
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inadvisable because of the potentially serious side effects
and the possibility of giving rise to antibiotic-
resistant infections.
New, more effective approaches to the treatment of
periodontal disease, particularly periodontitis, are actively
being sought.
SUMMARY OF THE INVENTION
It is the object of the present invention to
provide a method of treatment for periodontitis which
overcomes the aforementioned drawbacks of prior art methods
and may be practiced by patients at home as well as utilized
by professional dental practitioners. In keeping with this
object, and others that will become apparent hereinafter,
the present invention resides in the administration to
patients suffering from periodontitis of therapeutic amounts
of Vitamin A or any one of its derivatives or analogs,
hereinafter collectively referred to as "retinoids". The
retinoids may be administered systemically or by topical
application at the disease site.
Any of a variety of conventionally available,
orally acceptable retinoid preparations can be utilized for
systemic therapy, as well as any other pharmaceutically
acceptable preparation containing one or more retinoids as
its active ingredient together with an inert carrier or
vehicle. The retinoids can be applied locally by injection
into the periodontal pocket, through the use of irrigating
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devices, fitted with blunt hypodermic needles, by the
application of retinoid-containing patches to the disease
site, or any other conventional method for effectively
bringing and maintaining a topical pharmaceutical agent in
contact with its tissue site of action.
DETAILED DESCRIPTION OF THE INVENTION
The present invention deals with a conceptual
change in approach to the treatment of periodontal disease.
Rather than attempting to eradicate or suppress the growth of
the literally hundreds of microbial species found in the
mouth, and particularly in plaque, the novel method is
directed to treating the target tissues of the host (the
periodontal tissues) so as to render them less susceptible
and more resistant to the pathological effects of the
microbial population.
Accordingly, the present invention resides in the
administration to a patient suffering from periodontitis of a
topical or systemic pharmaceutical composition comprising as
its active ingredient at least one retinoid compound.
Preferred retinoids for use in the present invention include:
Vitamin A aldehyde (retinal, retinene)
Vitamin A acid (tretinoin, retinoic acid)
Vitamin A esters (e. g., retinyl palmitate)
isotretinoin
etretinate
acitretin (free acid of etretinate)
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The structures of the preferred retinoids are shown
below:
CH7 CH7 CH7
I
\ \ \ cHo Vitamin A a'dehyde
~CH7 .
~~//''i
~7
~z ~2 ~~3
I I i
,\ \ ,\ \ v\ c~x Vitamin A acid
.I
I ~1
C~3
i H3 i I7 Cx1
,\ \ 9\ \ ~\ coo~cH~l~~~~3 reti ny1 palmi tate
CH7 C~7 CH7
I
\ \ \ \ ~ isotretinoin
cock
7
«7
ic~~ ctc~ c:c3
x3C \ \ \ \ \ C~2'~S
etretinate
cx30 ~ cx~
ca= cup cap .
x~c \ ~ \ \ ~\ cooH acitretin
I~
ctc~o~cs~
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A number of the preferred retinoids specified
above are commercially available in approved oral or topical
preparations: for example, ACCUTANE* (isotretinoin) and
TEGISON* (etretinate) capsules from Roche Laboratories,
Nutley, New Jersey; RETIN-A* (tretinoin) cream from Ortho
Pharmaceutical Corp., RARITAN*, New Jersey; and numerous
oral and topical compositions containing Vitamin A
derivatives.
A preferred daily dosage range for retinoids
administered orally (i.e., systemically by the oral route) to
treat periodontitis in accordance with the present invention
is from about 0.1 to about 5.0 mg/kg of body weight,
typically given over a period of from about 10 to about 20
weeks as an initial course of treatment. A more preferred
dosage range is from about 0.5 to about 2.0 mg/kg daily. The
daily dosage can be administered in one to four equally
divided doses.
The preferred concentration range of retinoids in
topical preparations used in the methods of the present
invention is from about 0.01 to about 0.1% by weight, with a
more preferred range of about 0.025 to about 0.05%. The
exact concentration depends greatly upon the delivery method
and topical vehicle chosen, which in turn affects the amount
of drug available to the periodontal tissues.
Suitable oral preparations for use in the methods
of the present invention include any conventional oral
pharmaceutical dosage forms (e. g., capsules, tablets,
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caplets, liquids, suspensions, lozenges, and the like)
containing as their active ingredients one or more retinoid
compounds, preferably in such amount that one to four dosage
units will comprise a daily oral dosage of retinoids coming
within the range set forth above. These oral dosage forms
may include any conventional vehicles, carriers, excepients,
binders, flavoring agents and other suitable inactive
ingredients known to those skilled in the pharmaceutical
arts. Moreover, the oral dosage forms may comprise active
ingredients in addition to the retinoid compounds, e.g.,
orally effective antibiotics or other agents useful in the
treatment of periodontitis or its sequelae.
Topical compositions for local treatment of
affected periodontal tissues may include conventional,
commercially available creams, ointments and gels containing
Vitamin A, Vitamin A esters and other retinoid derivatives,
to the extent that those products may be safe and acceptable
for oral use in terms of toxicity, taste and consistency. In
general, any topical vehicle compatible with the retinoids
and acceptable for use in the mouth may be used in
formulating topical compositions for practicing the novel
treatment methods. Particularly suitable vehicles are
topical dental pastes of the type commonly utilized for
oral corticosteroid compositions, e.g., ORABASE* (Colgate-
Hoyt Laboratories, Caton, Mass.), and anhydrous ointment
bases such as AQUAPHOR* (Beiersdorf Inc. Norwalk, Conn.).
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Topical treatment with retinoids may also be
provided through the use of irrigation devices associated
with blunt hypodermic needles inserted in the periodontal
crevices, with orally acceptable solutions of the retinoids
used in the irrigation reservoir. Slow release patches
containing retinoids may also be applied to the gingivae,
similar to patches currently utilized for transdermal
administration of nitroglycerin and other cardiovascular
treatment agents.
Emulsions of retinoids in sticky vehicles, such as
gum arabic, may be formulated and adhered to the affected
tissues, or made into chewing gum to provide a sustained
release of treatment agent. Similarly, the retinoid
compounds can be dissolved in food grade plastic made into
thin filaments to be inserted in the gingival crevices. This
method has been suggested with respect to tetracycline
therapy. Therapeutic toothpastes or gels can also be
provided containing retinoids for regular hygienic use by
patients.
Where higher tissue concentrations of the retinoids
are deemed necessary to provide effective therapy to the
affected periodontal tissues, sterile parenteral solutions of
one or more retinoids may be injected directly into the
gingivae. Such solutions may be prepared with any
conventional injectable vehicles for oral use in which the
retinoids are soluble.
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In general, any systemic or local methods of
administration capable of providing effective therapeutic
amounts of the active retinoid agents to achieve the goal of
protecting the periodontal tissues from microbial assault may
be utilized in practicing the method of the present
invention.
The retinoids have been previously utilized to
treat or prevent hyperkeratotic dermatoses such as severe
acne, psoriasis and lichen planus, and to reverse dysplasia
of oral leukoplakia. Vitamin A and other retinoids can also
reverse the abnormal differentiation of epithelial tissues in
Vitamin A deficient animals and in organ cultures. In animal
models, retinoids have been shown to delay the appearance,
retard the growth, and cause regression of certain cancers,
and clinical trials have been conducted evaluating the role
of agents such as isotretinoin in cancer chemotherapy. But
there has been no prior disclosure of the utility of
retinoids in the treatment of periodontitis or related
conditions.
Treatment of periodontal tissues with retinoids in
accordance with the methods of the invention renders the
tissues less susceptible to the pathological effects of
periodontal bacteria, particularly the cytopathic species
which cause greatest tissue degeneration. These treatment
methods may be practiced prophylactically in patients prone
to periodontitis or to treat mild, moderate or advanced cases
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of the disease. Beneficial results can generally be expected
within the first ten to twenty-week course of treatment, and
treatment can be renewed if regression occurs following the
first course.
It has thus been shown that there are provided
methods which achieve the various objects of the invention
and which are well adapted to meet the conditions of
practical use.
As various possible embodiments might be made of
the above invention, and as various changes might be made in
the embodiments set forth above, it is to be understood that
all matters herein described are to be interpreted as
illustrative and not in a limiting sense.
What is claimed as new and desired to be protected
by Letters Patent is set forth in the following claims.
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