CA2275049A1 - Drug delivery composition for dental applications - Google Patents
Drug delivery composition for dental applications Download PDFInfo
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- CA2275049A1 CA2275049A1 CA002275049A CA2275049A CA2275049A1 CA 2275049 A1 CA2275049 A1 CA 2275049A1 CA 002275049 A CA002275049 A CA 002275049A CA 2275049 A CA2275049 A CA 2275049A CA 2275049 A1 CA2275049 A1 CA 2275049A1
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- chlorhexidine
- biologically active
- drug delivery
- release
- active agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/60—Preparations for dentistry comprising organic or organo-metallic additives
- A61K6/69—Medicaments
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K6/00—Preparations for dentistry
- A61K6/70—Preparations for dentistry comprising inorganic additives
- A61K6/71—Fillers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0063—Periodont
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- General Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Inorganic Chemistry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A drug delivery composition is disclosed that can achieve the sustained release of biologically active agents. Preferred is a composition having a dental application in the root canals and pulp chambers of teeth. A particularly preferred composition is a non-biodegradable device capable of achieving the sustained release of antimicrobial agents. The composition can be formed into insert devices, that can be used to treat and prevent endodontic diseases and conditions. The insert devices are especially useful in treating and preventing diseases such as periradicular periodontitis, apical abscess and external inflammatory root resorption, all of which require drug delivery to the root canals and pulp chambers of the affected teeth. Preferably, the composition contains chlorhexidine and its salts , that can be released to sustain high concentrations in root canals of teeth over a period of up to three months.
Description
Title DRUG DELIVERY COMPOSITION FOR DENTAL APPLICATIONS
FIELD OF THE INVENTION
The present invention pertains to a drug delivery composition, suitable for sustained release of one or more biologically active agents.
BACKGROUND OF THE INVENTION
A. Endodontic Disease and Treatment Endodontic disease is a process in which the dental pulp tissue and the tissues supporting the tooth become affected by infection from oral microorganisms invading the tooth. Endodontic disease is a frequent occurrence that affects approximately 70% of the populations in countries with well developed dental care modes, and by estimate, over 95% of the populations in other parts of the world. Endodontic disease is one of the major causes of tooth loss in these populations.
Endodontic disease is an all-inclusive term for a variety of clinical conditions, that are forms of either pulpitis or periradicular periodontitis.
Pulpitis is an inflammation of the dental pulp that can be caused by mechanical, physical and microbial stimuli. If the stimulus is not eliminated in the early stages of pulpitis, the disease process escalates beyond potential repair, and leads to pulpal necrosis. Frequently at this stage, oral microorganisms infect the necrotic pulp and the pulp space inside the tooth, consisting of the pulp chamber and root canals. If allowed to persist, this root canal infection causes the onset of periradicular periodontitis, an infective disease of the tissues that support the tooth, the periodontal ligament and alveolar bone. Symptoms that may be encountered in the various stages of the disease process frequently lead to the loss of the affected tooth. Untreated or intractable root canal infection ultimately leads to tooth loss.
Periradicular periodontitis can be treated by debridement of the infected pulp tissue and disinfection of the root canal. Disinfection of the root canal is achieved by a combination of three modalities: (i) instruments (files and reamers) are used to debride the pulpal tissue and enlarge the root canal; (ii) antimicrobial irrigating solutions, mainly sodium hypochlorite, are used to flush debris, digest tissue remnants, and kill microorganisms; and (iii) antimicrobial medicaments are applied to the root canal between consecutive treatments to kill surviving microorganisms. Such treatment is effective and it results in complete healing of the diseased sites in 46% to 93% of the cases (Friedman S, in: Essential Endodontology (Q~rstavik D & Pitt Ford TR, eds.) Blackwell Science, Oxford (1998)). Absence of healing, or treatment failure, is mainly attributed to residual root canal infection (Sjogren U, et al., Int. Endodon.
J. 30: 297-306 (1997)).
Root canal microorganisms can persist in spite of the aforementioned procedures, mainly when harbored in root canal irregularities and dentinal tubules, where they may be inaccessible to the instruments, irrigants and medicaments. Thus the ability of the instruments to disinfect the root canal is minimal (Bystrom A &
Sundqvist G, Scand. J. Dent. Res. 89:321-328 (1981); Dalton BC, et al., J. Endodon. 24:763-(1998)), and even the irrigants are insufficient to do so predictably (Sjogren U, et al., Int.
Endodon. J. 30: 297-306 (1997)). Most of the available root canal medicaments, such as camphorated paramonochlorphenol or iodine potassium iodide are strongly antimicrobial;
however, they are effective for only hours, and after they expire, microorganisms can repopulate the root canal (Bystrom A, et al., Endod. Dent. Traumatol. 1:170-175 (1985)).
Another commonly used root canal medicament, calcium hydroxide, can be effective for weeks (Bystrom A, et al., Endod. Dent. Traumatol. 1:170-175 (1985)); however, it is not very effective against specific enteric bacteria (f~rstavik D & Haapasalo M, Endod. Dent.
Traumatol. 6:142-149 (1990)), that are frequently associated with failures of root canal treatment (Sundqvist G, et al., Oral Surg. 85:86-93 (1998)). The ability of calcium hydroxide to kill microorganisms harbored in the dentinal tubules also is questionable (Heling I, et al., Int. Endod. .I. 25:15-19 (1992)).
FIELD OF THE INVENTION
The present invention pertains to a drug delivery composition, suitable for sustained release of one or more biologically active agents.
BACKGROUND OF THE INVENTION
A. Endodontic Disease and Treatment Endodontic disease is a process in which the dental pulp tissue and the tissues supporting the tooth become affected by infection from oral microorganisms invading the tooth. Endodontic disease is a frequent occurrence that affects approximately 70% of the populations in countries with well developed dental care modes, and by estimate, over 95% of the populations in other parts of the world. Endodontic disease is one of the major causes of tooth loss in these populations.
Endodontic disease is an all-inclusive term for a variety of clinical conditions, that are forms of either pulpitis or periradicular periodontitis.
Pulpitis is an inflammation of the dental pulp that can be caused by mechanical, physical and microbial stimuli. If the stimulus is not eliminated in the early stages of pulpitis, the disease process escalates beyond potential repair, and leads to pulpal necrosis. Frequently at this stage, oral microorganisms infect the necrotic pulp and the pulp space inside the tooth, consisting of the pulp chamber and root canals. If allowed to persist, this root canal infection causes the onset of periradicular periodontitis, an infective disease of the tissues that support the tooth, the periodontal ligament and alveolar bone. Symptoms that may be encountered in the various stages of the disease process frequently lead to the loss of the affected tooth. Untreated or intractable root canal infection ultimately leads to tooth loss.
Periradicular periodontitis can be treated by debridement of the infected pulp tissue and disinfection of the root canal. Disinfection of the root canal is achieved by a combination of three modalities: (i) instruments (files and reamers) are used to debride the pulpal tissue and enlarge the root canal; (ii) antimicrobial irrigating solutions, mainly sodium hypochlorite, are used to flush debris, digest tissue remnants, and kill microorganisms; and (iii) antimicrobial medicaments are applied to the root canal between consecutive treatments to kill surviving microorganisms. Such treatment is effective and it results in complete healing of the diseased sites in 46% to 93% of the cases (Friedman S, in: Essential Endodontology (Q~rstavik D & Pitt Ford TR, eds.) Blackwell Science, Oxford (1998)). Absence of healing, or treatment failure, is mainly attributed to residual root canal infection (Sjogren U, et al., Int. Endodon.
J. 30: 297-306 (1997)).
Root canal microorganisms can persist in spite of the aforementioned procedures, mainly when harbored in root canal irregularities and dentinal tubules, where they may be inaccessible to the instruments, irrigants and medicaments. Thus the ability of the instruments to disinfect the root canal is minimal (Bystrom A &
Sundqvist G, Scand. J. Dent. Res. 89:321-328 (1981); Dalton BC, et al., J. Endodon. 24:763-(1998)), and even the irrigants are insufficient to do so predictably (Sjogren U, et al., Int.
Endodon. J. 30: 297-306 (1997)). Most of the available root canal medicaments, such as camphorated paramonochlorphenol or iodine potassium iodide are strongly antimicrobial;
however, they are effective for only hours, and after they expire, microorganisms can repopulate the root canal (Bystrom A, et al., Endod. Dent. Traumatol. 1:170-175 (1985)).
Another commonly used root canal medicament, calcium hydroxide, can be effective for weeks (Bystrom A, et al., Endod. Dent. Traumatol. 1:170-175 (1985)); however, it is not very effective against specific enteric bacteria (f~rstavik D & Haapasalo M, Endod. Dent.
Traumatol. 6:142-149 (1990)), that are frequently associated with failures of root canal treatment (Sundqvist G, et al., Oral Surg. 85:86-93 (1998)). The ability of calcium hydroxide to kill microorganisms harbored in the dentinal tubules also is questionable (Heling I, et al., Int. Endod. .I. 25:15-19 (1992)).
The disadvantage exists, therefore, that the current root canal treatment modalities, including instruments, irrigants and medicaments, are insufficient to predictably disinfect the root canal.
As the final step in root canal treatment, the canal is filled and the tooth crown rerstored, to prevent future ingress of microorganisms and recurrent infection subsequent to treatment. The goal of resisting microbial ingress is particularly challenging, considering that the root canal treated teeth are expected to function for the patientis lifetime, while being constantly at risk of microbial ingress through leakage in the margins of the restorations, and invasion of dentinal tubules from infected sites in the gums and periodontal defects. Currently used root filling materials do not effectively resist microbial ingress (Friedman S, et al., .l. Endodon. 23:557-561 (1997);
Friedman S, et al. J. Dent. Res. abstract 78:206 (1999)), and therefore, they do not provide sufficient protection against recurrent root canal infection. Consequently, infection of the filled root canal, and resulting treatment failure, can occur even if a previous root canal infection was effectively eliminated, and also in teeth that were not infected prior to root filling.
Such recurrent infection, or treatment failure, leads to tooth loss in about 23% of the cases (Petersson K, et al., Endod. Dent. Traumatol. 5:153-158 (1989)).
The further disadvantage exists, therefore, that the currently used root filling materials do not prevent treatment failure from microbial ingress and propagation in the filled root canal.
In response to the shortcomings of the aforementioned conventional modalities for root canal disinfection, researchers have explored possibilities to employ chlorhexidine and its salts as a root canal medicament. Chlorhexidine effectively kills oral microorganisms when applied to treat gum disease (Oosterwaal PJM, et al., J. Clin.
Periodontol. 18:97-100 (1991); Schaeken MJM, et al., J. Dent. Res. 70:150-153 (1991)), and it is effective against microorganisms that cause periradicular periodntitis, including enteric bacteria (Henessey T.D., J. Periodont. Res. 8 suppl. 12:61-67 (1973);
Emilson C.G., Scand. J. Dent. Res. 85:255-265 (1977)) that can resist the action of other medicaments (Q~rstavik D & Haapasalo M, Endod. Dent. Traumatol. 6:142-149 (1990)).
The antimicrobial efficacy of chlorhexidine equals that of the conventional root canal irrigants and medicaments (Delany G.M. et al., Oral Surg. 53:518-523 (1982);
Ohara P.K. et al., Endod. Dent. Traumatol. 9:95-100 (1993); Vahdaty A. et al., Endod. Dent.
Traumatol. 9:243-248 (1993); Jeansonne M.J. & White R.R. ,J. Endodon. 20:276-(1994); Siqueira J.F. & de Uzeda M. J. Endodon. 23:167-169 (1997); Barbosa C.A.M. et al., J. Endodon. 23:297-300 (1997); Heling I. & Chandler M.P. Int Endod J 31:8-(1998); Kuruvilla J.R. & Kamath M.P. J. Endodon. 24:472-476 (1998); Ayhan H.
et al., Int. Endod. J. 32:99-102 (1999); D'Arcangelo C. et al., J. Endodon. 25:351-353 (1999)).
Unlike the other medicaments, however, chlorhexidine binds to the oral tissues including dentin (Emilson C.G. et al., J. Periodont. Res. 8 suppl. 12:17-21 (1973)). The bound chlorhexidine may kill microorganisms that approach the dentin surface, and it may alter the physical and chemical properties of the dentin surface to prevent microbial colonization (Emilson C.G. et al., J. Periodont. Res. 8 suppl. 12:17-21 (1973)). and affects residual antimicrobial activity of the dentin surface (Parsons GJ, et al., Oral Surg.
49:455-459 (1980)). Root canal dentin demonstrates a short-term residual antimicrobial activity after exposure to chlorhexidine for several minutes (White RR, et al., J. Endodon.
23:229-231 ( 1997); Jung S, et al., J. Endodon. 25:288 abstract ( 1999));
however, to predictably resist microbial ingress and prevent recurrent infection in the long term, a substantive antimicrobial activity must be induced. To predictably affect substantive antimicrobial activity, the canal has to be exposed to chlorhexidine for a longer time than afforded by irrigation alone (Heling I. et al., Int. Endod. ,I. 25:20-24 (1992)), preferably for one week (Komorowski R & Friedman S, J. Endodon. 23:263 abstract (1997)).
The substantive antimicrobial activity cannot be induced by any other conventionally used root canal medicament, nor can it be induced by a short term irrigation of the root canal with chlorhexidine.
The further disadvantages exist, therefore, that the commonly used root canal medicaments, and even chlorhexidine used as an irrigant, cannot induce substantive antimicrobial activity in the root canal.
As the final step in root canal treatment, the canal is filled and the tooth crown rerstored, to prevent future ingress of microorganisms and recurrent infection subsequent to treatment. The goal of resisting microbial ingress is particularly challenging, considering that the root canal treated teeth are expected to function for the patientis lifetime, while being constantly at risk of microbial ingress through leakage in the margins of the restorations, and invasion of dentinal tubules from infected sites in the gums and periodontal defects. Currently used root filling materials do not effectively resist microbial ingress (Friedman S, et al., .l. Endodon. 23:557-561 (1997);
Friedman S, et al. J. Dent. Res. abstract 78:206 (1999)), and therefore, they do not provide sufficient protection against recurrent root canal infection. Consequently, infection of the filled root canal, and resulting treatment failure, can occur even if a previous root canal infection was effectively eliminated, and also in teeth that were not infected prior to root filling.
Such recurrent infection, or treatment failure, leads to tooth loss in about 23% of the cases (Petersson K, et al., Endod. Dent. Traumatol. 5:153-158 (1989)).
The further disadvantage exists, therefore, that the currently used root filling materials do not prevent treatment failure from microbial ingress and propagation in the filled root canal.
In response to the shortcomings of the aforementioned conventional modalities for root canal disinfection, researchers have explored possibilities to employ chlorhexidine and its salts as a root canal medicament. Chlorhexidine effectively kills oral microorganisms when applied to treat gum disease (Oosterwaal PJM, et al., J. Clin.
Periodontol. 18:97-100 (1991); Schaeken MJM, et al., J. Dent. Res. 70:150-153 (1991)), and it is effective against microorganisms that cause periradicular periodntitis, including enteric bacteria (Henessey T.D., J. Periodont. Res. 8 suppl. 12:61-67 (1973);
Emilson C.G., Scand. J. Dent. Res. 85:255-265 (1977)) that can resist the action of other medicaments (Q~rstavik D & Haapasalo M, Endod. Dent. Traumatol. 6:142-149 (1990)).
The antimicrobial efficacy of chlorhexidine equals that of the conventional root canal irrigants and medicaments (Delany G.M. et al., Oral Surg. 53:518-523 (1982);
Ohara P.K. et al., Endod. Dent. Traumatol. 9:95-100 (1993); Vahdaty A. et al., Endod. Dent.
Traumatol. 9:243-248 (1993); Jeansonne M.J. & White R.R. ,J. Endodon. 20:276-(1994); Siqueira J.F. & de Uzeda M. J. Endodon. 23:167-169 (1997); Barbosa C.A.M. et al., J. Endodon. 23:297-300 (1997); Heling I. & Chandler M.P. Int Endod J 31:8-(1998); Kuruvilla J.R. & Kamath M.P. J. Endodon. 24:472-476 (1998); Ayhan H.
et al., Int. Endod. J. 32:99-102 (1999); D'Arcangelo C. et al., J. Endodon. 25:351-353 (1999)).
Unlike the other medicaments, however, chlorhexidine binds to the oral tissues including dentin (Emilson C.G. et al., J. Periodont. Res. 8 suppl. 12:17-21 (1973)). The bound chlorhexidine may kill microorganisms that approach the dentin surface, and it may alter the physical and chemical properties of the dentin surface to prevent microbial colonization (Emilson C.G. et al., J. Periodont. Res. 8 suppl. 12:17-21 (1973)). and affects residual antimicrobial activity of the dentin surface (Parsons GJ, et al., Oral Surg.
49:455-459 (1980)). Root canal dentin demonstrates a short-term residual antimicrobial activity after exposure to chlorhexidine for several minutes (White RR, et al., J. Endodon.
23:229-231 ( 1997); Jung S, et al., J. Endodon. 25:288 abstract ( 1999));
however, to predictably resist microbial ingress and prevent recurrent infection in the long term, a substantive antimicrobial activity must be induced. To predictably affect substantive antimicrobial activity, the canal has to be exposed to chlorhexidine for a longer time than afforded by irrigation alone (Heling I. et al., Int. Endod. ,I. 25:20-24 (1992)), preferably for one week (Komorowski R & Friedman S, J. Endodon. 23:263 abstract (1997)).
The substantive antimicrobial activity cannot be induced by any other conventionally used root canal medicament, nor can it be induced by a short term irrigation of the root canal with chlorhexidine.
The further disadvantages exist, therefore, that the commonly used root canal medicaments, and even chlorhexidine used as an irrigant, cannot induce substantive antimicrobial activity in the root canal.
Hence, a major therapeutic goal is the development of a vehicle to deliver chlorhexidine to root canals for extended periods of time, to (i) kill residual root canal microorganisms; and (ii) induce substantive antimicrobial activity that can prevent microbial ingress and recurrent infection subsequent to treatment, and consequent treatment failure.
B. Use of Sustained-release Pharmaceutical Compositions in the Treatment of Endodontic and Other Diseases To allow long-term delivery of medicaments to specific sites for medical and dental treatment applications, researchers have developed sustained-release pharmaceutical compositions that can be inserted into the target site and slowly release the medicament contained within them. The most investigated devices for sustained release comprise incorporation of a medicament into a polymeric matrix, which is then shaped into a convenient form for insertion in the target site. Specifically, Friedman M
(U.S. Pat. No. 5,002,769) discloses a sustained-release device containing chlorhexidine for use in treatment of periodontal disease. This sustained-release device incorporates a biodegradable polymer to be used as a periodontal implant. This device is more effective than calcium hydroxide in disinfection of root canal dentin in bovine teeth (Heling I, et al., Int. Endod. J. 25:15-19 (1992)). Bovine root canals medicated with this device show resistance to microbial colonization in vitro, in contrast to canals medicated with calcium hydroxide (Heling I, et al., Int. Endod. J. 25:20-24 (1992)). Such substantive antimicrobial activity may inhibit the recurrence of infection subsequent to treatment, and lower the rate of treatment failures.
The biodegredable sustained-release device is not well suited for a root canal application inside the tooth. The minimal amount of fluids present in the root canal, if any, is insufficient to degrade the polymer carrier and release the chlorhexidine.
Furthermore, the device may not be completely degraded when it is time to permanently fill the root canal, and the clinician cannot verify whether fragments of the polymer device still remain in the root canal or not.
Loesche WJ (U.S. Pat. No. 4,568,535) discloses an ethylcellulose based, non-biodegradable periodontal implant; however, this non-biodegradable sustained-release composition contains metronidazole for periodontal use, and it is not suitable for endodontic use.
Due to the strong, positive charge of chlorhexidine and the consequent binding capability, many polymers used for sustained drug delivery become unsuitable for chlorhexidine. For example, cellulose acetate phthalate, used for sustained release of metronidazole, strongly binds with chlorhexidine resulting in undetectable release of chlorhexidine (Wu XY & Lee PI, unpublished data). Chlorhexidine is also incompatible with many pharmaceutical excipients that are used to plasticize the polymers, such as dibutyl phthalate, diamyl phthalate, diisobutyl carbonyl phthalate, butyl diglycol carbonate, and tricresyl phosphate. These characteristics of chlorhexidine make the formulation of the delivery composition difficult.
Moreover, preparing a device with a shape and size suitable for insertion into root canals, while maintaining considerable mechanical strength, is another challenge.
The disadvantage exists, therefore, that the aforementioned sustained-release compositions are unsuitable for delivery of chlorhexidine for endodontic use, to disinfect infected root canals and render them resistant to recurrent infection in the long term.
Hence, a major therapeutic goal is the development of a sustained-release composition that (i) releases the drug by a mechanism rather than by biodegradation; (ii) is sized in conformity with the small dimensions of root canals; (iii) is capable of delivering chlorhexidine for weeks to disinfect infected root canals and render them resistant to recurrent infection; and (iv) can be retrieved at the end of the medication period without residual debris remaining in the root canal.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical compositions suitable for dental therapy, preferably for placement in the root canals and pulp chambers of teeth, and capable of treating root canal infection and preventing recurrent infection subsequent to completion of treatment.
Broadly stated, the present invention involves a drug delivery composition comprising a cylindrical device containing at least one biologically active agent wherein the device has a polymer matrix core which can be coated or not coated by another polymer or by the same polymer. The polymer matrix core may contain other pharmaceutical excipients, such as fillers like starches and binders like polyvinyl pyrrolidone. The device may be manufactured with one end thicker or wider than the other end to conform with the shape of the dental root canal and pulp chamber.
In detail, the invention provides a sustained-release composition that permits the sustained release of biologically active agents such as antimicrobial agents or anti-inflammatory agents in a root canal and pulp chamber of a tooth, and that comprises an essentially needle-like device specifically adapted for implementation in a root canal of a patientis tooth. The device contains an effective amount of at least one biologically active agent such as antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs, a polymer matrix and a polymer film coating being optional.
The invention also provides a method of preparing the device that contains at least one biologically active agent, the method comprising:
(1) obtaining a mixture of a suitable polymer and other pharmaceutical excipients;
(2) mixing the polymer mixture with at least one biologically active agent;
(3) molding the mixture to form a cylindrical or needle-like shape; and (4) coating the core matrix with a polymer film; with step (4) being optional.
The invention further provides a method of administering at least one biologically active agent to a root canal and pulp chamber of a patientis tooth in need of such an agent, which comprises administering to the patient an essentially needle-like device specifically adapted for implementation in a dental root canal, wherein the device contains an effective amount of at least one biologically active agent such as antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs.
Brief Description of the Drawings Figure 1 shows the short-term concentrations of chlorhexidine released from the delivery composition using three different formulations.
Figure 2 shows the cumulative amount of chlorhexidine released from the delivery composition of formulation 2, that was removed from the solution and placed in a fresh buffer solution after 17 hours.
Figure 3 shows the long-term release rates of chlorhexidine for delivery compositions using four different formulations.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The sustained-release drug delivery composition of the invention is a water-permeable polymeric solid that is cast in a cylindrical or needle-like form. Such a sustained-release composition is formed from solid polymers or solidification of gel-like polymers.
The sustained-release drug delivery composition of the invention is formed to contain biologically active agents, including antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs, preferably chlorhexidine salts or tetracyclines, most preferably chlorhexidine salts. Such sustained-release drug delivery composition is cylindrical or needle-like, preferably needle-like and specially adapted to allow its insertion into the root canals and pulp chamber of the teeth of patients.
The nature of the preferred components of the sustained-release drug delivery composition of the invention is described in greater detail below.
I. The Components of the Drug Delivery Composition of the Invention As herein aforementioned, the present invention pertains to a sustained-release drug delivery composition comprising a suitable device containing at least one biologically active agent. The contained agents include antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs. Any one of these agents may be incorporated into the drug delivery composition alone or in combination with one or more of the other agents.
A. The Polymeric Matrix Core of the Composition The core in the drug delivery composition of the invention comprises a polymer matrix. In order to provide a non-degradable polymeric matrix for sustained-release of biologically active agents, it is preferable to employ a polymeric matrix composed of water-permeable polymer. Such polymer matrices do not undergo significant degradation when the device is inserted into the root canal of a tooth or any other target site and thus are retrievable at the end of the medication period or whenever desired. Such polymer matrices are preferably comprised of cellulose derivatives such as ethylcellulose, methylcellulose, methylpropyl cellulose; polyurethanes;
silicone rubbers;
polyesters; polyamides; gutta percha; and polysaccharides, most preferably ethylcellulose. Such matrix core also may be comprised of pharmaceutical excipients such as fillers, binders, pigments, flavours, preservatives, and colours.
B. The Polymeric Coating of the Composition The device of the drug delivery composition of the invention also may comprise a coating. In order to provide a non-degradable polymeric coating for sustained-release of biologically active agents, it is preferable to employ a polymeric coating composed of water-permeable polymer. Such polymer coating does not undergo significant degradation when the device is inserted into the root canal of a tooth or any other target site and thus is retrievable at the end of the medication period or whenever desired. Such polymer coating is preferably comprised of cellulose derivatives such as ethylcellulose, methylcellulose, methylpropyl cellulose; polyurethanes;
silicone rubbers;
polyesters; polyamides; gutta percha; polysaccharides, polyethylene;
polypropylene;
acrylic polymers; and waxes, most preferably ethylcellulose .Such coating also may be comprised of pharmaceutical excipients such as fillers, binders, pigments, flavours, preservatives, or colours.
The sustained-release drug delivery composition of the invention may contain inert excipients to improve the ease of insertion of the device or to wet the device.
For example, inert excipients may include water, saline, glycerol, propyl glycol, ethanol, and buffer solutions.
C. Biologically Active Agents of the Composition The biologically active agents of the sustained-release drug delivery composition of the invention include antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs, preferably chlorhexidine salts or tetracyclines, most preferably chlorhexidine salts. Chlorhexidine in liquid or solid state can be incorporated in the sustained-release drug delivery composition, provided as a free base or salt of chlorhexidine, preferably as a salt of chlorhexidine, most preferably as chlorhexidine acetate or gluconate. Any one of the aformentioned biologically active agents may be incorporated into the drug delivery composition alone or in combination with one or more of the other agents.
The sustained-release drug delivery composition of the invention also may contain biologically active agents outside of the device for immediate action of therapy.
Such biologically active agents may include antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs, preferably chlorhexidine salts or tetracyclines, most preferably chlorhexidine salts.
II. Process for Formulation of the Drug Delivery Composition A method for the formulation of the sustained-release drug delivery composition of the invention containing at least one biologically active agent is provided below.
Water-permeable polymers including cellulose and derivatives such as ethylcellulose, methylcellulose, methylpropyl cellulose; polyurethanes;
silicone rubbers;
polyesters; polyamides; gutta percha; and polysaccharides, most preferably ethylcellulose are dissolved in a suitable solvent or solvent mixture preferably alcohols or ethyl acetate, most preferably ethanol. One or more pharmaceutical excipients such as fillers (e.g., starches, lactose, cellulose, bicalcium phosphate) and binders (e.g., polyvinyl pyrrolidone, starches, sucrose, lactose, glucose, Acacia) are introduced into the polymer solution.
Biologically active agents including antimicrobial agents and/or anti-inflammatory agents, preferably chlorhexidine salts or tetracyclines, most preferably chlorhexidine salts, are dissolved or dispersed in the polymer solution forming a homogeneous solution or suspension.
In general, the ratio of the chlorhexidine in the polymer solution will vary from 1 g chlorhexidine to 2 to 5 g polymer. Most of the solvent is evaporated in a fumehood at room temperature, and the remaining gel-like mixture is transferred to a mold to form the needle-like device and allowed to dry completely at room temperature.
The prototype device was manufactured as described above with a length of 17 mm and a diameter of 0.6 to 0.8 mm. The weight of the device was approximately 8 mg including 2 to 3 mg of chlorhexidine. Four different formulations were used in this work, to manufacture compositions with different drug loading and drug release mechanisms.
In order to be inserted into a root canal of a patientis tooth to treat or prevent periradicular endodontic disease, the device of the sustained-release drug delivery composition of the invention is preferably needle-like having a diameter in the range from 0.1 to 4.0 mm, and preferably having a diameter in the range from 0.2 to 1.0 mm, most preferably approximately 0.25 mm. It is desirable to employ devices having a length in the range from 1 to 18 mm, and is preferably in the range from 6 to 15 mm, most preferably approximately 12 mm. Such device may be manufactured with a variety of diameters and lengths to suit different tooth dimensions. Such device may be tapered with one end thicker or wider than the other end to conform with the shape of the dental root canal and pulp chamber, the preferred taper not exceeding 4% so that if the device is 12 mm long and the tip at one end is 0.25 mm then the tip at the other end is 0.73 mm.
Devices having such dimensions and, therefore, suitable for insertion into the root canal of a patientis tooth may be employed to treat or prevent periradicular endodontic disease.
Having now generally described this invention, the same will be better understood by reference to certain specific examples which are included herein for purposes of illustration only and are not intended to limit the scope of the invention, unless specified.
Preparation and Evaluation of the Sustained-release Drug Delivery Composition Various grades of ethylcellulose (Ethocel, Dow Chemical) of different molecular weights, namely V 100, V45, and V 10 were dissolved in absolute ethanol to form a 10 wt % solution with different weight ratio of V100/V45N10. A typical ratio was 5/10/1. The pharmaceutical excipient starch (Aldrich) was introduced to the polymer solution. The weight of starch used was 40% to 50% of the dry ethylcellulose used. The biologically active agent chlorhexidine acetate was dissolved or dispersed in the polymer solution to form a mixture containing 20% to 50% chlorhexidine in the total solid mass.
After most of the solvent was evaporated at room temperature in a fumehood, the remaining gel-like mixture was transferred into a mold and dried at room temperature to form the needle-like device having a length of 17 mm and a diameter of 0.6 to 0.8 mm.
The weight of the device was about 8 mg including 2 to 3 mg of chlorhexidine acetate. A
coating was applied over the core by dipping the core into a solution comprising 8%
ethylcellulose in ethanol and drying at room temperature.
Four different formulations were prepared all having different drug loading and drug release mechanisms, as follows: ( 1 ) Formulation 1 - the chlorhexidine concentration was 30%, no filler was added and no coating was applied; (2) Formulation 2 - the chlorhexidine constituted 45 wt % of the solid core composition, no filler was added but the core was coated with 8% ethylcellulose; (3) Formulation 3 - it was similar to formulation 2 except for the addition of starch as the filler; and (4) Formulation 4 - it was also similar to formulation 2 except for being coated twice.
In another different formulation, the core of the drug delivery composition containing chlorhexidine gluconate was prepared using PEG8000 and PEG400. A
coating comprising 8% ethylcellulose in butanol/ethyl acetate (30:70 w/w) was applied over the core.
In vitro Drug Release Short-term Drug Release Test Each device of the drug delivery composition was immersed into 3.0 ml of 0.05 M buffer solution (pH = 7.4) in a cuvette at 37 °C with vigorous stirring. The amount of drug released into the solution was continuously monitored with a diode array spectrophotometer (Hewlett-Packard 8452A). The measurement lasted for more than 20 hours, with a sampling interval of 10 minutes.
Long-term Drug Release Test Each device of the drug delivery composition was immersed in 0.35 ml deionized water in a small glass tube (SO mm long, internal diameter 5 mm) without stirring. The glass tubes were placed into a water bath at 37 °C. Every 24 hours, the drug concentration in the medium was determined by spectrophotometry. The devices were immediately patted dry, and immersed into fresh deionized water in a separate tube.
Subsequent release tests were then continued.
Results As shown in Fig. 3, the drug was released quickly from the device of formulation 1 with most of it consumed within 2 to 3 days; therefore, formulation 1 is ruled out because of too rapid release. For the device of formulation 4, the drug release rate was very low; therefore, formulation 4 may be suitable for an extended application, but its antimicrobial effectiveness needs to be verified in further investigations. The drug release profiles of the devices of formulations 2 and 3 are more desirable because their initial burst establishes an effective drug level in the solution, and the following slow but steady release is sufficient to sustain the drug concentration at a therapeutic level. A
release rate greater than 0.02 mg/day can last 40 days or longer.
In vitro Substantive Antimicrobial Activity Tests Objective Two tests were carried out to asses the substantive antimicrobial activity of root dentin after interaction with chlorhexidine as follows: (1) short-term irngation of root canals as conventionally performed in endodontic practice; and (2) prolonged immersion of root canals.
Methodology The method of Q~rstavik D & Haapasalo M (Endod. Dent. Traumatol.
6:142-149 (1990)) was modified to prepare a bovine root model for the antimicrobial tests. The root was cut with a rotating diamond saw into 5 mm long segments, or specimens, each with an external diameter of approximately 7 mm. The root canals of the specimens were enlarged with an ISO 033 round bur, to standardize the internal diameter to 3.3 mm. The smear layer was removed from the root canal wall with 17% EDTA.
The specimens were sterilized separately by autoclaving three times in test tubes containing brain heart infusion (BHI) broth for 30 minutes at 121 °C, coated with nail varnish on the outer surfaces, and mounted with sticky wax at the bottom of Petri dishes.
In the short-term irngation test the root canal of each specimen was irrigated for 5 minutes with 10 ml of one of the following test solutions:
Group 1 - liquid 0.2% chlorhexidine gluconate; Group 2 - 5.25% sodium hypochlorite; Group 3 -sterile saline. Solutions were dispensed with sterile syringes, while the excess was evacuated with high power suction.
In the prolonged immersion test the root canal of each specimen was completely immersed with one of the following test solutions: Group 4 - liquid 0.2%
chlorhexidine gluconate; Group 5 - 5.25% sodium hypochlorite; Group 6 -sterile saline;
Group 7 - distilled water with the device of the drug release composition of the invention inserted into the canal. The specimens were then incubated at 37 °C for 7 days while adding fresh solutions daily (in Group 7 distilled water was added).
After drying the canals, they were inoculated with a suspension of E.
faecalis (ATCC 29212) in BHI broth for a period of 3 weeks. A fresh inoculum was added every other day to maintain microbial viability.
After inoculation the specimens were rinsed with sterile water and dried.
Sterile round burs, ISO sizes 035, 037, 040, and 042 were used sequentially to enlarge the canals and thus recover dentin samples ranging in depth from 0.1 mm to 0.45 mm. The dentin samples obtained with each bur were collected in a separate test tube containing 3 ml of sterile BHI broth, and incubated for 24 hours at 37 °C. The optical density of the broth, proportional to the number of viable bacteria present in the dentin sample, was measured in a spectrophotometer at 540 nm. The mean and standard deviation optical density values were calculated for each group and statistically analyzed.
Results Table 2. Optical density of the broth (mean ~ SD) as an indication of microbial growth (n = 10 for Groups 1-6, n = 2 for Group 7).
Group Dentin depth (mm) 0.1 0.2 0.35 0.45 1 0.720.12 0.760.07 0.760.10 0.840.06 2 0.640.13 0.660.10 0.650.09 0.730.10 3 0.650.16 0.620.07 0.690.08 0.710.08 4 0.0110.003 0.0150.005 0.0090.005 0.00960.005 0.530.09 0.690.14 0.770.16 0.670.21 6 0.690.25 0.590.17 0.660.21 1.060.21 7 / non detectablenon detectable/
Specimens from Group 1 demonstrated high optical density values that did not differ from those observed for Groups 2, 3, 5 and 6. In contrast, specimens from Group 4 (prolonged immersion with liquid 0.2% chlorhexidine gluconate) demonstrated significantly lower optical density values than those observed for all other groups. This finding was consistent for all the dentin depths sampled. Specimens from Group demonstrated significantly lower optical density values at dentin depths of 0.2 mm and 0.35 mm.
General Discussion From the results of the studies chlorhexidine, such as contained in the drug delivery compsition of the invention, appears to be an effective root canal medicament capable of reducing the potential for infection of the root dentin.
The drug delivery composition is suitable for sustained-release of chlorhexidine over short and long periods of time, ranging from hours to months.
The sustained-release drug delivery composition of the invention is very suitable for insertion into root canals of teeth for the following reasons:
(i) the device of the composition of the invention does not become degraded over time, therefore there is no concern about residual fragments of it remaining in the root canal and interfering with the root filling procedure;
(ii) insertion and removal of the device of the composition of the invention is simple and does not require any instrumentation or procedures additional to the conventional ones used routinely in root canal treatment;
(iii) activation of the release of the chlorhexidine in the root canal does not require the presence of vital tissue, only an initial immersion of the root canal with any fluid, preferably chlorhexidine aqueous solution.
As will be realized from the above description and results, the sustained release of chlorhexidine into the root canal and pulp chamber of the tooth is a preferred way of treating periradicular endodontic diseases and preventing root canal re-infection subsequent to treatment.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples, and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Table 1. Comparison of the drug delivery composition of the invention with relevant US patents.
Patent Materials Drugs) Shape/DeviceApplications Degradable #
05,226,434 dental periodontics No floss 05,002,769 implant periodontics Yes 05,438,076PMMA/MAA CPK film-formingperiodontics, No oral or (Eudragit), polymer dermatological fungal EC solution infections, endodontics coating the paper point 05,213,615 polymer cariology No in solution 05,614,223PHEMA/MAA fluoridetablets, attached to No teeth as core; enzyme capsules, PHEMA/MMA inhibitor.globules, half as membrane football, veneers or thick films 05,451,424polyurethaneCHX extrusion Yes 04,685,883 microspheres,periodontics Yes slabs (adhesive) 04,568,535Ethylcellulosemetroni-implant periodontics No dazole 05,019,096polyurethane,AgNO, coating film on catheters,No silicones,CHX gloves. No PLA Yes Our devicecomposite CHX or needle-likeendodontics No of various other polymers antibacte-rial agents
B. Use of Sustained-release Pharmaceutical Compositions in the Treatment of Endodontic and Other Diseases To allow long-term delivery of medicaments to specific sites for medical and dental treatment applications, researchers have developed sustained-release pharmaceutical compositions that can be inserted into the target site and slowly release the medicament contained within them. The most investigated devices for sustained release comprise incorporation of a medicament into a polymeric matrix, which is then shaped into a convenient form for insertion in the target site. Specifically, Friedman M
(U.S. Pat. No. 5,002,769) discloses a sustained-release device containing chlorhexidine for use in treatment of periodontal disease. This sustained-release device incorporates a biodegradable polymer to be used as a periodontal implant. This device is more effective than calcium hydroxide in disinfection of root canal dentin in bovine teeth (Heling I, et al., Int. Endod. J. 25:15-19 (1992)). Bovine root canals medicated with this device show resistance to microbial colonization in vitro, in contrast to canals medicated with calcium hydroxide (Heling I, et al., Int. Endod. J. 25:20-24 (1992)). Such substantive antimicrobial activity may inhibit the recurrence of infection subsequent to treatment, and lower the rate of treatment failures.
The biodegredable sustained-release device is not well suited for a root canal application inside the tooth. The minimal amount of fluids present in the root canal, if any, is insufficient to degrade the polymer carrier and release the chlorhexidine.
Furthermore, the device may not be completely degraded when it is time to permanently fill the root canal, and the clinician cannot verify whether fragments of the polymer device still remain in the root canal or not.
Loesche WJ (U.S. Pat. No. 4,568,535) discloses an ethylcellulose based, non-biodegradable periodontal implant; however, this non-biodegradable sustained-release composition contains metronidazole for periodontal use, and it is not suitable for endodontic use.
Due to the strong, positive charge of chlorhexidine and the consequent binding capability, many polymers used for sustained drug delivery become unsuitable for chlorhexidine. For example, cellulose acetate phthalate, used for sustained release of metronidazole, strongly binds with chlorhexidine resulting in undetectable release of chlorhexidine (Wu XY & Lee PI, unpublished data). Chlorhexidine is also incompatible with many pharmaceutical excipients that are used to plasticize the polymers, such as dibutyl phthalate, diamyl phthalate, diisobutyl carbonyl phthalate, butyl diglycol carbonate, and tricresyl phosphate. These characteristics of chlorhexidine make the formulation of the delivery composition difficult.
Moreover, preparing a device with a shape and size suitable for insertion into root canals, while maintaining considerable mechanical strength, is another challenge.
The disadvantage exists, therefore, that the aforementioned sustained-release compositions are unsuitable for delivery of chlorhexidine for endodontic use, to disinfect infected root canals and render them resistant to recurrent infection in the long term.
Hence, a major therapeutic goal is the development of a sustained-release composition that (i) releases the drug by a mechanism rather than by biodegradation; (ii) is sized in conformity with the small dimensions of root canals; (iii) is capable of delivering chlorhexidine for weeks to disinfect infected root canals and render them resistant to recurrent infection; and (iv) can be retrieved at the end of the medication period without residual debris remaining in the root canal.
SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical compositions suitable for dental therapy, preferably for placement in the root canals and pulp chambers of teeth, and capable of treating root canal infection and preventing recurrent infection subsequent to completion of treatment.
Broadly stated, the present invention involves a drug delivery composition comprising a cylindrical device containing at least one biologically active agent wherein the device has a polymer matrix core which can be coated or not coated by another polymer or by the same polymer. The polymer matrix core may contain other pharmaceutical excipients, such as fillers like starches and binders like polyvinyl pyrrolidone. The device may be manufactured with one end thicker or wider than the other end to conform with the shape of the dental root canal and pulp chamber.
In detail, the invention provides a sustained-release composition that permits the sustained release of biologically active agents such as antimicrobial agents or anti-inflammatory agents in a root canal and pulp chamber of a tooth, and that comprises an essentially needle-like device specifically adapted for implementation in a root canal of a patientis tooth. The device contains an effective amount of at least one biologically active agent such as antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs, a polymer matrix and a polymer film coating being optional.
The invention also provides a method of preparing the device that contains at least one biologically active agent, the method comprising:
(1) obtaining a mixture of a suitable polymer and other pharmaceutical excipients;
(2) mixing the polymer mixture with at least one biologically active agent;
(3) molding the mixture to form a cylindrical or needle-like shape; and (4) coating the core matrix with a polymer film; with step (4) being optional.
The invention further provides a method of administering at least one biologically active agent to a root canal and pulp chamber of a patientis tooth in need of such an agent, which comprises administering to the patient an essentially needle-like device specifically adapted for implementation in a dental root canal, wherein the device contains an effective amount of at least one biologically active agent such as antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs.
Brief Description of the Drawings Figure 1 shows the short-term concentrations of chlorhexidine released from the delivery composition using three different formulations.
Figure 2 shows the cumulative amount of chlorhexidine released from the delivery composition of formulation 2, that was removed from the solution and placed in a fresh buffer solution after 17 hours.
Figure 3 shows the long-term release rates of chlorhexidine for delivery compositions using four different formulations.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The sustained-release drug delivery composition of the invention is a water-permeable polymeric solid that is cast in a cylindrical or needle-like form. Such a sustained-release composition is formed from solid polymers or solidification of gel-like polymers.
The sustained-release drug delivery composition of the invention is formed to contain biologically active agents, including antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs, preferably chlorhexidine salts or tetracyclines, most preferably chlorhexidine salts. Such sustained-release drug delivery composition is cylindrical or needle-like, preferably needle-like and specially adapted to allow its insertion into the root canals and pulp chamber of the teeth of patients.
The nature of the preferred components of the sustained-release drug delivery composition of the invention is described in greater detail below.
I. The Components of the Drug Delivery Composition of the Invention As herein aforementioned, the present invention pertains to a sustained-release drug delivery composition comprising a suitable device containing at least one biologically active agent. The contained agents include antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs. Any one of these agents may be incorporated into the drug delivery composition alone or in combination with one or more of the other agents.
A. The Polymeric Matrix Core of the Composition The core in the drug delivery composition of the invention comprises a polymer matrix. In order to provide a non-degradable polymeric matrix for sustained-release of biologically active agents, it is preferable to employ a polymeric matrix composed of water-permeable polymer. Such polymer matrices do not undergo significant degradation when the device is inserted into the root canal of a tooth or any other target site and thus are retrievable at the end of the medication period or whenever desired. Such polymer matrices are preferably comprised of cellulose derivatives such as ethylcellulose, methylcellulose, methylpropyl cellulose; polyurethanes;
silicone rubbers;
polyesters; polyamides; gutta percha; and polysaccharides, most preferably ethylcellulose. Such matrix core also may be comprised of pharmaceutical excipients such as fillers, binders, pigments, flavours, preservatives, and colours.
B. The Polymeric Coating of the Composition The device of the drug delivery composition of the invention also may comprise a coating. In order to provide a non-degradable polymeric coating for sustained-release of biologically active agents, it is preferable to employ a polymeric coating composed of water-permeable polymer. Such polymer coating does not undergo significant degradation when the device is inserted into the root canal of a tooth or any other target site and thus is retrievable at the end of the medication period or whenever desired. Such polymer coating is preferably comprised of cellulose derivatives such as ethylcellulose, methylcellulose, methylpropyl cellulose; polyurethanes;
silicone rubbers;
polyesters; polyamides; gutta percha; polysaccharides, polyethylene;
polypropylene;
acrylic polymers; and waxes, most preferably ethylcellulose .Such coating also may be comprised of pharmaceutical excipients such as fillers, binders, pigments, flavours, preservatives, or colours.
The sustained-release drug delivery composition of the invention may contain inert excipients to improve the ease of insertion of the device or to wet the device.
For example, inert excipients may include water, saline, glycerol, propyl glycol, ethanol, and buffer solutions.
C. Biologically Active Agents of the Composition The biologically active agents of the sustained-release drug delivery composition of the invention include antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs, preferably chlorhexidine salts or tetracyclines, most preferably chlorhexidine salts. Chlorhexidine in liquid or solid state can be incorporated in the sustained-release drug delivery composition, provided as a free base or salt of chlorhexidine, preferably as a salt of chlorhexidine, most preferably as chlorhexidine acetate or gluconate. Any one of the aformentioned biologically active agents may be incorporated into the drug delivery composition alone or in combination with one or more of the other agents.
The sustained-release drug delivery composition of the invention also may contain biologically active agents outside of the device for immediate action of therapy.
Such biologically active agents may include antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs, preferably chlorhexidine salts or tetracyclines, most preferably chlorhexidine salts.
II. Process for Formulation of the Drug Delivery Composition A method for the formulation of the sustained-release drug delivery composition of the invention containing at least one biologically active agent is provided below.
Water-permeable polymers including cellulose and derivatives such as ethylcellulose, methylcellulose, methylpropyl cellulose; polyurethanes;
silicone rubbers;
polyesters; polyamides; gutta percha; and polysaccharides, most preferably ethylcellulose are dissolved in a suitable solvent or solvent mixture preferably alcohols or ethyl acetate, most preferably ethanol. One or more pharmaceutical excipients such as fillers (e.g., starches, lactose, cellulose, bicalcium phosphate) and binders (e.g., polyvinyl pyrrolidone, starches, sucrose, lactose, glucose, Acacia) are introduced into the polymer solution.
Biologically active agents including antimicrobial agents and/or anti-inflammatory agents, preferably chlorhexidine salts or tetracyclines, most preferably chlorhexidine salts, are dissolved or dispersed in the polymer solution forming a homogeneous solution or suspension.
In general, the ratio of the chlorhexidine in the polymer solution will vary from 1 g chlorhexidine to 2 to 5 g polymer. Most of the solvent is evaporated in a fumehood at room temperature, and the remaining gel-like mixture is transferred to a mold to form the needle-like device and allowed to dry completely at room temperature.
The prototype device was manufactured as described above with a length of 17 mm and a diameter of 0.6 to 0.8 mm. The weight of the device was approximately 8 mg including 2 to 3 mg of chlorhexidine. Four different formulations were used in this work, to manufacture compositions with different drug loading and drug release mechanisms.
In order to be inserted into a root canal of a patientis tooth to treat or prevent periradicular endodontic disease, the device of the sustained-release drug delivery composition of the invention is preferably needle-like having a diameter in the range from 0.1 to 4.0 mm, and preferably having a diameter in the range from 0.2 to 1.0 mm, most preferably approximately 0.25 mm. It is desirable to employ devices having a length in the range from 1 to 18 mm, and is preferably in the range from 6 to 15 mm, most preferably approximately 12 mm. Such device may be manufactured with a variety of diameters and lengths to suit different tooth dimensions. Such device may be tapered with one end thicker or wider than the other end to conform with the shape of the dental root canal and pulp chamber, the preferred taper not exceeding 4% so that if the device is 12 mm long and the tip at one end is 0.25 mm then the tip at the other end is 0.73 mm.
Devices having such dimensions and, therefore, suitable for insertion into the root canal of a patientis tooth may be employed to treat or prevent periradicular endodontic disease.
Having now generally described this invention, the same will be better understood by reference to certain specific examples which are included herein for purposes of illustration only and are not intended to limit the scope of the invention, unless specified.
Preparation and Evaluation of the Sustained-release Drug Delivery Composition Various grades of ethylcellulose (Ethocel, Dow Chemical) of different molecular weights, namely V 100, V45, and V 10 were dissolved in absolute ethanol to form a 10 wt % solution with different weight ratio of V100/V45N10. A typical ratio was 5/10/1. The pharmaceutical excipient starch (Aldrich) was introduced to the polymer solution. The weight of starch used was 40% to 50% of the dry ethylcellulose used. The biologically active agent chlorhexidine acetate was dissolved or dispersed in the polymer solution to form a mixture containing 20% to 50% chlorhexidine in the total solid mass.
After most of the solvent was evaporated at room temperature in a fumehood, the remaining gel-like mixture was transferred into a mold and dried at room temperature to form the needle-like device having a length of 17 mm and a diameter of 0.6 to 0.8 mm.
The weight of the device was about 8 mg including 2 to 3 mg of chlorhexidine acetate. A
coating was applied over the core by dipping the core into a solution comprising 8%
ethylcellulose in ethanol and drying at room temperature.
Four different formulations were prepared all having different drug loading and drug release mechanisms, as follows: ( 1 ) Formulation 1 - the chlorhexidine concentration was 30%, no filler was added and no coating was applied; (2) Formulation 2 - the chlorhexidine constituted 45 wt % of the solid core composition, no filler was added but the core was coated with 8% ethylcellulose; (3) Formulation 3 - it was similar to formulation 2 except for the addition of starch as the filler; and (4) Formulation 4 - it was also similar to formulation 2 except for being coated twice.
In another different formulation, the core of the drug delivery composition containing chlorhexidine gluconate was prepared using PEG8000 and PEG400. A
coating comprising 8% ethylcellulose in butanol/ethyl acetate (30:70 w/w) was applied over the core.
In vitro Drug Release Short-term Drug Release Test Each device of the drug delivery composition was immersed into 3.0 ml of 0.05 M buffer solution (pH = 7.4) in a cuvette at 37 °C with vigorous stirring. The amount of drug released into the solution was continuously monitored with a diode array spectrophotometer (Hewlett-Packard 8452A). The measurement lasted for more than 20 hours, with a sampling interval of 10 minutes.
Long-term Drug Release Test Each device of the drug delivery composition was immersed in 0.35 ml deionized water in a small glass tube (SO mm long, internal diameter 5 mm) without stirring. The glass tubes were placed into a water bath at 37 °C. Every 24 hours, the drug concentration in the medium was determined by spectrophotometry. The devices were immediately patted dry, and immersed into fresh deionized water in a separate tube.
Subsequent release tests were then continued.
Results As shown in Fig. 3, the drug was released quickly from the device of formulation 1 with most of it consumed within 2 to 3 days; therefore, formulation 1 is ruled out because of too rapid release. For the device of formulation 4, the drug release rate was very low; therefore, formulation 4 may be suitable for an extended application, but its antimicrobial effectiveness needs to be verified in further investigations. The drug release profiles of the devices of formulations 2 and 3 are more desirable because their initial burst establishes an effective drug level in the solution, and the following slow but steady release is sufficient to sustain the drug concentration at a therapeutic level. A
release rate greater than 0.02 mg/day can last 40 days or longer.
In vitro Substantive Antimicrobial Activity Tests Objective Two tests were carried out to asses the substantive antimicrobial activity of root dentin after interaction with chlorhexidine as follows: (1) short-term irngation of root canals as conventionally performed in endodontic practice; and (2) prolonged immersion of root canals.
Methodology The method of Q~rstavik D & Haapasalo M (Endod. Dent. Traumatol.
6:142-149 (1990)) was modified to prepare a bovine root model for the antimicrobial tests. The root was cut with a rotating diamond saw into 5 mm long segments, or specimens, each with an external diameter of approximately 7 mm. The root canals of the specimens were enlarged with an ISO 033 round bur, to standardize the internal diameter to 3.3 mm. The smear layer was removed from the root canal wall with 17% EDTA.
The specimens were sterilized separately by autoclaving three times in test tubes containing brain heart infusion (BHI) broth for 30 minutes at 121 °C, coated with nail varnish on the outer surfaces, and mounted with sticky wax at the bottom of Petri dishes.
In the short-term irngation test the root canal of each specimen was irrigated for 5 minutes with 10 ml of one of the following test solutions:
Group 1 - liquid 0.2% chlorhexidine gluconate; Group 2 - 5.25% sodium hypochlorite; Group 3 -sterile saline. Solutions were dispensed with sterile syringes, while the excess was evacuated with high power suction.
In the prolonged immersion test the root canal of each specimen was completely immersed with one of the following test solutions: Group 4 - liquid 0.2%
chlorhexidine gluconate; Group 5 - 5.25% sodium hypochlorite; Group 6 -sterile saline;
Group 7 - distilled water with the device of the drug release composition of the invention inserted into the canal. The specimens were then incubated at 37 °C for 7 days while adding fresh solutions daily (in Group 7 distilled water was added).
After drying the canals, they were inoculated with a suspension of E.
faecalis (ATCC 29212) in BHI broth for a period of 3 weeks. A fresh inoculum was added every other day to maintain microbial viability.
After inoculation the specimens were rinsed with sterile water and dried.
Sterile round burs, ISO sizes 035, 037, 040, and 042 were used sequentially to enlarge the canals and thus recover dentin samples ranging in depth from 0.1 mm to 0.45 mm. The dentin samples obtained with each bur were collected in a separate test tube containing 3 ml of sterile BHI broth, and incubated for 24 hours at 37 °C. The optical density of the broth, proportional to the number of viable bacteria present in the dentin sample, was measured in a spectrophotometer at 540 nm. The mean and standard deviation optical density values were calculated for each group and statistically analyzed.
Results Table 2. Optical density of the broth (mean ~ SD) as an indication of microbial growth (n = 10 for Groups 1-6, n = 2 for Group 7).
Group Dentin depth (mm) 0.1 0.2 0.35 0.45 1 0.720.12 0.760.07 0.760.10 0.840.06 2 0.640.13 0.660.10 0.650.09 0.730.10 3 0.650.16 0.620.07 0.690.08 0.710.08 4 0.0110.003 0.0150.005 0.0090.005 0.00960.005 0.530.09 0.690.14 0.770.16 0.670.21 6 0.690.25 0.590.17 0.660.21 1.060.21 7 / non detectablenon detectable/
Specimens from Group 1 demonstrated high optical density values that did not differ from those observed for Groups 2, 3, 5 and 6. In contrast, specimens from Group 4 (prolonged immersion with liquid 0.2% chlorhexidine gluconate) demonstrated significantly lower optical density values than those observed for all other groups. This finding was consistent for all the dentin depths sampled. Specimens from Group demonstrated significantly lower optical density values at dentin depths of 0.2 mm and 0.35 mm.
General Discussion From the results of the studies chlorhexidine, such as contained in the drug delivery compsition of the invention, appears to be an effective root canal medicament capable of reducing the potential for infection of the root dentin.
The drug delivery composition is suitable for sustained-release of chlorhexidine over short and long periods of time, ranging from hours to months.
The sustained-release drug delivery composition of the invention is very suitable for insertion into root canals of teeth for the following reasons:
(i) the device of the composition of the invention does not become degraded over time, therefore there is no concern about residual fragments of it remaining in the root canal and interfering with the root filling procedure;
(ii) insertion and removal of the device of the composition of the invention is simple and does not require any instrumentation or procedures additional to the conventional ones used routinely in root canal treatment;
(iii) activation of the release of the chlorhexidine in the root canal does not require the presence of vital tissue, only an initial immersion of the root canal with any fluid, preferably chlorhexidine aqueous solution.
As will be realized from the above description and results, the sustained release of chlorhexidine into the root canal and pulp chamber of the tooth is a preferred way of treating periradicular endodontic diseases and preventing root canal re-infection subsequent to treatment.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples, and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims rather than the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Table 1. Comparison of the drug delivery composition of the invention with relevant US patents.
Patent Materials Drugs) Shape/DeviceApplications Degradable #
05,226,434 dental periodontics No floss 05,002,769 implant periodontics Yes 05,438,076PMMA/MAA CPK film-formingperiodontics, No oral or (Eudragit), polymer dermatological fungal EC solution infections, endodontics coating the paper point 05,213,615 polymer cariology No in solution 05,614,223PHEMA/MAA fluoridetablets, attached to No teeth as core; enzyme capsules, PHEMA/MMA inhibitor.globules, half as membrane football, veneers or thick films 05,451,424polyurethaneCHX extrusion Yes 04,685,883 microspheres,periodontics Yes slabs (adhesive) 04,568,535Ethylcellulosemetroni-implant periodontics No dazole 05,019,096polyurethane,AgNO, coating film on catheters,No silicones,CHX gloves. No PLA Yes Our devicecomposite CHX or needle-likeendodontics No of various other polymers antibacte-rial agents
Claims (4)
1. A sustained-release drug delivery composition comprising a device containing at least one biologically active agent wherein the device has a polymer matrix with or without coating.
2. A method for preparing the device containing at least one biologically active agent, the method comprising:
(1) Mixing of a suitable polymer and other pharmaceutical excipient(s);
(2) Combining the polymer mixture with at least one biologically active agent;
(3) Molding of the mixture to form a cylindrical or needle shape; and (4) Coating the core matrix with a polymer film, with step (4) being optional.
(1) Mixing of a suitable polymer and other pharmaceutical excipient(s);
(2) Combining the polymer mixture with at least one biologically active agent;
(3) Molding of the mixture to form a cylindrical or needle shape; and (4) Coating the core matrix with a polymer film, with step (4) being optional.
3. A method for treatment and prevention of periradicular endodontic disease by using a sustained-release drug delivery composition according to any one of claims 1 to 2.
4. A method of administering an effective amount of chlorhexidine or another biologically active agent to a patient in need of such an agent, which comprises providing to said patient as essentially needle-like device adapted for insertion in a root canal and pulp chamber of a tooth of the patient, said device comprising:
(1) an effective amount of chlorhexidine or another biologically active agent, wherein said effective amount is an amount sufficient for the treatment and prevention of periradicular endodontic disease;
(2) a water-permeable polymer matrix consisting of ethylcellulose, another derivative of cellulose or a derivative of polysaccharides, wherein the polymer matrix is present in an amount sufficient to release chlorhexidine or another biologically active agent without undergoing degradation when placed in water or another liquid;
(3) a water-permeable polymer coating consisting of ethylcellulose, another derivative of cellulose or a derivative of polysacharides, wherein the polymer coating is present in an amount sufficient to release chlorhexidine or another biologically active agent without undergoing degradation when placed in a water or another liquid;
(4) biologically active agents outside of the device for immediate action of therapy, wherein the biologically active agents consist of antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs;
(5) a needle-like shape and dimensions adapted for implementation in the root canals and pulp chambers of teeth of patients.
(1) an effective amount of chlorhexidine or another biologically active agent, wherein said effective amount is an amount sufficient for the treatment and prevention of periradicular endodontic disease;
(2) a water-permeable polymer matrix consisting of ethylcellulose, another derivative of cellulose or a derivative of polysaccharides, wherein the polymer matrix is present in an amount sufficient to release chlorhexidine or another biologically active agent without undergoing degradation when placed in water or another liquid;
(3) a water-permeable polymer coating consisting of ethylcellulose, another derivative of cellulose or a derivative of polysacharides, wherein the polymer coating is present in an amount sufficient to release chlorhexidine or another biologically active agent without undergoing degradation when placed in a water or another liquid;
(4) biologically active agents outside of the device for immediate action of therapy, wherein the biologically active agents consist of antimicrobial agents like chlorhexidine, triclosan, clindamycin, tetracyclines, doxycycline, metronidazole, and penicillins, or anti-inflammatory agents such as corticosteroids, flurbiprofen, piroxicam, indomethacin, and other non-steroidal anti-inflammatory drugs;
(5) a needle-like shape and dimensions adapted for implementation in the root canals and pulp chambers of teeth of patients.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002275049A CA2275049A1 (en) | 1999-06-17 | 1999-06-17 | Drug delivery composition for dental applications |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002275049A CA2275049A1 (en) | 1999-06-17 | 1999-06-17 | Drug delivery composition for dental applications |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2275049A1 true CA2275049A1 (en) | 2000-12-17 |
Family
ID=30774351
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002275049A Abandoned CA2275049A1 (en) | 1999-06-17 | 1999-06-17 | Drug delivery composition for dental applications |
Country Status (1)
| Country | Link |
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| CA (1) | CA2275049A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2698149A1 (en) | 2012-08-17 | 2014-02-19 | Sanovel Ilac Sanayi ve Ticaret A.S. | Topical Aqueous Pharmaceutical Compositions of Flurbiprofen and Chlorhexidine |
-
1999
- 1999-06-17 CA CA002275049A patent/CA2275049A1/en not_active Abandoned
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2698149A1 (en) | 2012-08-17 | 2014-02-19 | Sanovel Ilac Sanayi ve Ticaret A.S. | Topical Aqueous Pharmaceutical Compositions of Flurbiprofen and Chlorhexidine |
| WO2014027976A1 (en) | 2012-08-17 | 2014-02-20 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Topical aqueous pharmaceutical compositions of flurbiprofen and chlorhexidine |
| EP2865370A1 (en) | 2012-08-17 | 2015-04-29 | Sanovel Ilac Sanayi ve Ticaret A.S. | Topical aqueous pharmaceutical compositions of flurbiprofen and chlorhexidine |
| EP3834815A1 (en) | 2012-08-17 | 2021-06-16 | Sanovel Ilac Sanayi Ve Ticaret A.S. | Topical aqueous pharmaceutical compositions of flurbiprofen and chlorhexidine |
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