CA2012208C

CA2012208C - Method of treating periodontitis

Info

Publication number: CA2012208C
Application number: CA 2012208
Authority: CA
Inventors: Julius Ozick
Original assignee: Individual
Current assignee: Individual
Priority date: 1989-03-27
Filing date: 1990-03-15
Publication date: 2001-05-22
Anticipated expiration: 2010-03-15
Also published as: CA2012208A1

Abstract

A method of treatment for periodontitis comprises the administration of a topical or systemic pharmaceutical composition containing at least one retinoid compound.
Preferred retinoids include Vitamin A aldehyde, Vitamin A
acid, Vitamin A esters, isotretinoin, etretinate and acitretin.

Description

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 .T ~ ~~ ~i2208 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:

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 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 r ~0lzzo8 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) The structures of the preferred retinoids are shown below:

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 ic~~ ctc~ c:c3 x3C \ \ \ \ \ C~2'~S
etretinate cx30 ~ cx~
ca= cup cap .
x~c \ ~ \ \ ~\ cooH acitretin I~
ctc~o~cs~

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, *Trade-mark B

zotzzoe 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.).
*Trade-mark B

2t~ 1228 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.

~~ 12208 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 ao~2zoa 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.

Claims

1. Use of a topical or systemic pharmaceutical composition containing at least one retinoid compound, for treating a patient suffering from periodontitis.

2. Use according to claim 1, wherein said retinoid compound is selected from the group consisting of Vitamin A aldehyde, Vitamin A acid, Vitamin A
esters, isotretinoin, etretinate and acitretin.

3. Use according to claim 1, wherein said composition comprises at least one retinoid compound and a pharmaceutically acceptable inert carrier or vehicle.

4. Use according to claim 1, wherein said composition is a systemic composition and is used in an amount sufficient to provide a daily retinoid dosage of from about 0.1 to about 5.0 mg/kg of patient body weight.

5. Use according to claim 4, wherein said daily dosage is from about 0.5 to about 2.0 mg/kg of patient body weight.

6. Use according to claim 1, wherein said composition is a systemic composition in the form of a capsule, tablet, caplet, liquid, suspension or lozenge.

7. Use according to claim 1, wherein said composition is a topical composition containing from about 0.01 to about 0.1% by weight of at least one retinoid compound.

8. Use according to claim 7, wherein said composition contains from about 0.025 to about 0.05% by weight of at least one retinoid compound.

9. Use according to claim 1, wherein said composition is a topical composition in the form of a slow release patch adhered to the periodontal tissues.

10. Use according to claim 1, wherein said composition is a topical composition comprising a liquid solution of at least one retinoid.

11. Use according to claim 1, wherein said composition is a topical composition in the form of a toothpaste or tooth gel.

12. Use according to claim 1, wherein said composition is a topical composition in the form of filaments of food grade plastic incorporating at least one retinoid and suitable for insertion into the gingival crevices.

13. Use according to claim 1, wherein said composition is an emulsion of at least one retinoid in a sticky vehicle.

14. Use according to claim 13, wherein said composition is in the form of a chewing gum.

15. Use of at least one retinoid compound for the preparation of a topical or systemic pharmaceutical composition for treating a patient suffering from periodontitis.

16. Use according to claim 15, wherein said retinoid compound is selected from the group consisting of Vitamin A aldehyde, Vitamin A acid, Vitamin A
esters, isotretinoin, etretinate and acitretin.

17. Use according to claim 15, wherein said composition comprises at least one retinoid compound and a pharmaceutically acceptable inert carrier or vehicle.

18. Use according to claim 15, wherein said composition is a systemic composition in the form of a capsule, tablet, caplet, liquid, suspension or lozenge.

19. Use according to claim 15, wherein said composition is a topical composition containing from about 0.01 to about 0.1% by weight of at least one retinoid compound.

20. Use according to claim 19, wherein said composition contains from about 0.025 to about 0.05% by weight of at least one retinoid compound.

21. Use according to claim 15, wherein said composition is a topical composition in the form of a slow release patch adhered to the periodontal tissues.

22. Use according to claim 15, wherein said composition is a topical composition comprising a liquid solution of at least one retinoid.

23. Use according to claim 15, wherein said composition is a topical composition in the form of a toothpaste or tooth gel.

24. Use according to claim 15, wherein said composition is a topical composition in the form of filaments of food grade plastic incorporating at least one retinoid and suitable for insertion into the gingival crevices.

25. Use according to claim 15, wherein said composition is an emulsion of at least one retinoid in a sticky vehicle.

26. Use according to claim 15, wherein said composition is in the form of a chewing gum.