Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
  • A61C5/00—Filling or capping teeth
  • A61C5/40—Implements for surgical treatment of the roots or nerves of the teeth; Nerve needles; Methods or instruments for medication of the roots
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K6/00—Preparations for dentistry
  • A61K6/50—Preparations specially adapted for dental root treatment
  • A61K6/54—Filling; Sealing
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents

Definitions

• Described herein is an endodontic treatment of an infected root canal with a drug delivery system.
• Endodontic treatments usually involve cleaning and enlarging the endodontic cavity space ("ECS"), also known as the root canal system of a human tooth.
• ECS endodontic cavity space
• the unprepared root canal is usually a narrow channel that runs through the central portion of the root of the tooth.
• Cleaning and enlargement of the ECS can be necessitated by the death or necrosis of the dental pulp, which is the tissue that occupies that space in a healthy tooth.
• This tissue can degenerate for a multitude of reasons, which include tooth decay, deep dental restorations, complete and incomplete dental fractures, traumatic injuries or spontaneous necrosis due to the calcification and ischemia of the tissue, which usually accompanies the ageing process. Similar to a necrotic or gangrenous appendix, the complete removal of this tissue is paramount, if not urgent, because of the subsequent development of infections or dental abscesses, septicemia, and even death.
• the root canal system of a human tooth is often narrow, curved and calcified, and can be extremely difficult to negotiate or clean.
• the conventional endodontic or root canal instruments currently available are frequently inadequate in the complete removal of the pulp and the efficient enlargement of the ECS.
• they are usually predisposed to breakage, causing further destruction to the tooth.
• Broken instruments are usually difficult, if not impossible to remove, often necessitating the removal of the tooth.
• Injury to the tooth which occurs as the result of a frank perforation or alteration of the natural anatomy of the ECS, can also lead to failure of the root canal and tooth loss.
• the unprepared root canal of the tooth usually begins as a narrow and relatively parallel channel.
• the portal of entry or the orifice and the portal of exit or foramen are relatively equal in diameter.
• the endodontic cavity preparation generally includes progressively enlarging the orifice and the body of the canal, while leaving the foramen relatively small. The result is usually a continuous cone-shaped preparation.
• Implants are indicated when tooth structure is not adequate, or when a tooth is damaged beyond endodontic repair. Device placement immediately following tooth extraction lessens bone resorption and is thus appropriate when the prognosis of the native tooth is poor.
• implants have proven more durable than endodontically repaired teeth, with greater than 95 percent survival reported.
• implants are costly and beyond the means of a large fraction of the patient population.
• An alternative to treating root canal infection would be to treat the infected root canal with a local drug delivery device.
• the delivery system could be implanted in the dentin, in the pulp chamber, the root canal and/or at external areas of the root canal tooth.
• the drug delivery device would deliver medicaments for an external period of time that provides relief for the patient and eliminate or reduce the infectious organisms.
• Taft (1858) did propose a therapeutic concept of managing pulpal problems directed at maintaining pulpal vitality and the formation of a "boney deposit” (secondary reparative dentin or irritational dentin in present terminology and concept) to protect the pulp and allow it to heal.
• Weitzel (1879) proposed the use of cold to try to determine if the pulp was irreversibly inflamed or required removal. This was one of the first correlations with diagnostic testing and pulpal status, which was followed shortly by Brophy (1880) and the use of heat to determine vitality or non-vitality. Interestingly, this type of testing has not changed in 130 years, however, we have a somewhat better understanding of the neurophysiology of pain and the meaning of the responses to these stimuli (Hargreaves 2002).
• the vascular phase corresponds to the very first events of the inflammatory process. Following tissue irritation, the arterioles undergo a constriction mediated by autonomous nervous fibers, lasting no longer than 5s (Fachin et al. 2009). This is immediately followed by constriction, promotion of vasodilatation by endogenous chemical mediators, in the arteriolar at first, with resulting increase in the vascular hydrostatic pressure (hyperemia). As more and more blood goes through the vessels, both capillary vessels and venules become dilated. The action of chemical mediators and the increased intravascular pressure also promote an increase in vascular permeability, leading to exudation and edema (Van Hassel 1971 ; Trowbridge & Emiing 1997).
• pulpal hyperemia a diagnostic category that tells present-day clinicians that something can be done to salvage the dental pulp and secure healing
• pulpal hyperemia a diagnostic category that tells present-day clinicians that something can be done to salvage the dental pulp and secure healing
• pulpal hyperemia a diagnostic category that tells present-day clinicians that something can be done to salvage the dental pulp and secure healing
• pulpal hyperemia a diagnostic category that tells present-day clinicians that something can be done to salvage the dental pulp and secure healing
• pulpal hyperemia clinically characterized by provoked, temporary, localized, low-intensity pain.
• this tissue is closely related to the dentin, forming the dentin-pulp complex
• the pulp can be affected by multiple and varied irritations to the dentin (Mjor & Levik 1975; Mjor & Ferrari 2002; Buyukgural et al. 2008).
• Hyperemia is a condition derived from a set of physical, chemical and bacterial aggressions produced by cavity preparation, restorative materials and caries disease.
• Several authors (Fry et al. 1960; Mosteller 1962; Mjor & Levik 1975) have discussed whether hyperemia can be treated by using topical corticosteroids on dentin and have suggested that it is possible to prevent this hypersensitive reaction with topical application of the medication on the dentin prior to restoration.
• Ciarlone & Pashley (1992) are in accordance with this viewpoint when they affirm that drugs can be used as a conservative mode of treatment during the initial phases of pulpal inflammation, capitalizing on dentinal permeability.
• the root canal treatment may not be necessarily be the first line of treatment for teeth diagnosed with reversible pulpitis.
• Steroids or more appropriately glucocorticoids form a class of drugs that interfere with the production or release of mediators that activate or sensitize nociceptors.
• Glucocorticoids are known to reduce the inflammatory response by suppressing vasodilatation, neutrophil migration and phagocytosis and by inhibiting the formation of arachidonic acid from neutrophil and macrophage-cell membrane phospholipids, thereby blocking the cyclo-oxygenase and lipoxygenase pathways and respective synthesis of prostaglandins and leukotrienes
• glucocorticoids have been used to reduce postoperative pain following endodontic procedures. Applications have been primarily in the root canal when treatment involves a tooth with a vital, yet inflamed pulp (Rogers et al. 1999). If used in cases of pulpal necrosis there seems to be poor absorption of the drug when using the root canal as the route of administration. Other studies have actually addressed the systemic use of corticosteroids on postoperative pain (Krasner & Jackson 1986). Generally the systemic use will reduce the severity of the pain.
• Prostaglandin E2 and interleukin- 8 concentrations were determined by enzyme immunoassay. Results demonstrated a significantly (p ⁇ 0.05) lower concentration of prostaglandin E2 compared to the saline group at day 1. There were no significant (p > 0.05) differences between the two groups at day 3. The pulpal concentrations of prostaglandin E2 were reduced at 1 day after the intraosseous injection of Depo-Medrol.
• corticosteroids The therapeutic effect of corticosteroids is based on their action on the synthesis of lipocortin and vasocortin, inhibiting the formation of edema and A 2 phospholipasis enzymes, respectively. By inhibiting this enzyme, membrane phospholipids cannot be converted into aracdonic acid. Therefore, the synthesis of prostaglandins and prostacyclins (the
• an anti-inflammatory agent inhibits edema, vasodilatation and the chemotactic effects on leukocytes.
• corticosteroids will act on histamine, heparin, and bradikinin, which are important chemical mediators in the initial phases of acute inflammation(Fry et al. 1960; Rittner, et al. 2003).
• the activation of the kinin system results in the release of bradikinin norpeptide.
• This vasoactive agent can induce arteriolar dilatation, increase venule permeability and cause pain (Ciarlone & Pashley 1992;Trowbridge & "Emling 1997; Rittner, et al. 2003).
• Depo-Medrol type of drug when might the use of Depo-Medrol type of drug be indicated?
• practitioners either had to treat the emergency patient with irreversible pulpitis (knowing strong analgesics may not completely alleviate the pain if the tooth was left untreated) or reschedule the patient early the next day, complicating an already full schedule.
• One situation would be when there is an inordinate number of emergency patients, and all cannot be clinically treated due to lack of time or staff support. This situation however would be unusual in today's practice.
• Another example may be when the tooth exhibits unusual coronal/root anatomy or partially calcified canals, not allowing the practitioner to debride the root canal or canals adequately due to time constraints. Another situation may be anesthetic failure where all options have been exhausted but the dentin or pulp cannot be entered due to extreme pain. Whichever the case an intraosseous injection of Depo-Medrol (X-Tip TM Intraosseous Anesthesia System - Dentsply Tulsa Dental Specialities, Tulsa, OK, USA) can clinically reduce the patient's pain to
• the challenges would be, in this case, could 1 ) a greater amount of time be obtained prior to needing definitive intervention; or 2) could the use of some type of drug in this manner actually enable healing to occur.
• Figure 1 demonstrates one suitable drug delivery device.
• Figure 2 demonstrates additional examples of suitable drug delivery devices.
• Figure 3 shows histology images of posts implanted into bone comparing a poly(L-lactic acid) bone pin and an identical poly(DTE carbonate) pin.
• Figure 4 shows a drug eluting plug placed into a tooth having pulpitis where the plug does not go into the pulp chamber.
• the drug eluting plug is capped by a restorative.
• Figure 5 shows a drug eluting plug placed into a tooth having pulpitis where the plug reaches into the pulp chamber.
• the drug eluting plug is capped by a restorative.
• Figure 6 shows one drug delivery devices that is a depot like device containing the treatment or polymer/anti-microbial system where a drug eluting plug is at least partially encapsulated by a restorative material.
• pulp infections are notoriously difficult to treat, pulpectomy is most often the therapeutic option of choice.
• clinical success with non-endodontic antimicrobial eluting medical devices suggests similar approaches for sparing root pulps. Because patients irrationally fear root canal procedures, most will likely be willing to try to any therapy that postpones the dreaded "root canal”.
• Described herein is a method of treating pulpitis in a mammal, comprising the steps of removing a portion of a tooth to expose an inflamed root, and applying a drug to the exposed root, where the application of the drug is done by an extended release drug delivery device.
• Described herein is a method of treating pulpitis in a mammal, comprising the steps of applying a drug to a tooth having an inflamed root where the root is not exposed, wherein application of the drug is done by an extended release drug delivery device.
• the system could be a depot like device as shown in Figure 6 containing the treatment or polymer/antimicrobial system.
• This system of Figure 6 is a drug eluting plug that is placed inside a restoration or restorative material. The drug eluting plug can reach into the pulp chamber or end outside the pulp chamber as shown in Figure 4.
• the first is the least invasive.
• the endodontist drills a small whole in the bone supporting the tooth and places a pre-formed, pre-sterilized drug delivery depot loaded degradable or non-degradable polymer.
• the device might be placed through a syringe similar to DBX delivery as shown in Figure 1.
• polymer/antimicrobial system and /or polymer anti-inflammatory system within the root canal and the infected pulp with partial pulpectory to create a larger reservoir space if necessary.
• the ideal outcome would be a capped, fully functional tooth with bacteria-free pulp. Presumably, the tooth would remain healthier and the traditional root canal procedure postponed.
• a fourth approach would be to place a drug depot that is in contact with dentin tubules.
• the tubules are a natural path for the delivery of the therapeutic to the infected pulp.
• the fifth approach would be to place a drug depot that is in contact with the tooth below the gum line.
• the tubules are a natural path for the delivery of the therapeutic to the infected pulp.
• Multiblock polyester copolymers developed as degradable suture materials synthesized from monomers selected from glycolic acid, lactic acid, caprolactone, ethylene glycol, dioxanone, trimethylene carbonate, and tartaric acid
• Homopolymers and copolymers of lactic and glycolic acid are the most clinically used degradable polymers in the medical device industry. Vendors include DURECT, PURAC, Zeus, Secant Medical, NatureWorks, and SurModics Pharmaceuticals (soon to be divested).
• SurModics offers PLGA microparticle formulations that degrade in hours to years, depending upon the formulation. Crystalline PLA and PGA degrade more slowly, and PLGA 50:50 polymers degrade more quickly than pure PLA or PGA due to their amorphous nature.
• suture monomers primarily PLA isomers, ⁇ -caprolactone, p-dioxanone, and trimethylenecarbonate
• TMC trimethylene carbonate
• DLLA D,L-lactide
• CL ⁇ -caprolactone
• Kohn and colleagues used Combinatorial Polymer Science and Rapid Throughput Characterization techniques to identify property variations within a different polymer families. Kohn maintains combinatorial libraries of degradable polymers based upon tyrosine-derived polyarylate and tyrosine-derived carbonate at Rutgers. By varying monomer composition and polymerization conditions, elution can be controlled and degradation rate predicted.
• Known cleared medical devices utilizing the tyrosine-based polyarylates and rifampin/minocycline combination as a coating are shown in Figure 2 and include the PIVIT ABTM Antimicrobial-Coated Surgical Mesh (CR Bard), the AIGISRx ® and AIGISRx ® Flat Cardiac Rhythm Medical Device (CRMD) Anti- Bacterial Envelope, and the AIGISRx ® ST antibacterial product for surgical repair of damaged or ruptured soft tissue. While the TYRX products use a combination of antibiotics, other polymer formulations in this family can similarly be used to deliver other antimicrobial agents.
• Trident Biomedical, Inc. unlike TYRX, has no cleared medical product.
• Trident licensee REVA Medical evaluated tyrosine-based polycarbonate in human clinical trials of its coronary stent.
• Existing licenses for interventional cardiology and ophthalmic applications is driving commercialization of these polymers.
• the company is developing a fracture fixation device based upon histology showing lesser inflammation compared with a PLA pin. This observation makes a root sparing device placed in the bone attractive.
• In vivo performance of a poly(L-lactic acid) bone pin (Left) and an identical poly(DTE carbonate) pin (Right) are shown in Figure 3. From J. Kohn et al. / Biomaterials 28 (2007) 4171-4177. Both pins were round with smooth surfaces and had exactly matched implant dimensions.
• the histology images were obtained 900 days post implantation and represent cross sections of the pin, showing the bone response around the implant. See text for additional details.
• the elution profile might be appropriate for eradication of root infection.
• Incept LLC developed applications using in situ polymerizable PEG macromer chemical systems similar to those originally developed at Focal Inc. (now Genzyme).
• the DuraSeal system may well be amenable to delivering antibiotics simply by dissolving antibiotic into one of the barrels of the two barrel syringe used to deliver Duraseal.
• Incept may control use of the polymer system for certain dental applications.
• Hydrogel articles suitable for use herein may be advantageously used in dentistry, for example, in occluding root canals.
• a root canal has been cleaned and disinfected, the resulting passageway is occluded to prevent bacterial contamination.
• un- crosslinked rubber-type materials such as Gutta-Percha, are used to plug these openings.
• Gutta-Percha has no inherent form-fitting property and must be mechanically forced into the canal.
• a rod of substantially dehydrated hydrogel material may be cut to size and introduced into the root canal, where it is allowed to hydrate, swell, and lock into place to form a tight fit.
• the hydrogel is expected to provide an effective barrier against oral fluids, food material, and bacteria. If a substantially non- degradable hydrogel is selected, long term occlusion may be provided. Alternatively, an absorbable material may be used if it is desirable that natural tissues replace the hydrogel over a period of time.”
• degradable polymers include various copolymers and terpolymers fabricated with polyethylene glycol (PEG) and suture monomers (Innocore, PolyVation BV, SurModics, Philipps-Universitat (Germany), GA/LA/CL/PEG), polybutylene terephthalate (PBT) (OctoPlus, PEG/PBT), polyhydroxyalkanoate (PHA) (Tepha/MIT, Poly-4-hydroxybutyrate), neutral and charge-modified PVA-g-PLGA polyesters (Philipps-Universitat), poly (ester amide) (Medivas/DSM Biomedical/Cornell), poly(ortho ester) (AP Pharma), Poly(anhydride ester) (Kathryn Uhrich, Rutgers University/ Polymerix Corporation), Poly(ester urethane) (Bezwada Biomedical; DSM Biomedical; Bionic Technologies Australia/PolyNovo), and Poly (ester ethy
• inorganic cements can act as supporting matrixes for drugs or polymer containing drug formulations.
• Inorganic cements such as Portland or Aalborg cement could provide the requirements for an extended release drug device.
• Microspheres loaded with an antibiotic/ steroid like demeclocycline hydrochloride / triamcinolone acetonide, are prepared according to example 2 of Gibson et al [US 6,291 ,013], but with one of demeclocycline hydrochloride or triamcinolone acetonide, or both in combination instead of Coumarin-6 as the active agent(s).
• the microspheres are mixed with a liquid carrier before administration.
• the liquid carrier is aqueous based with a preferred hydrogel composition, like a polysaccharide, PVA, PVP, polyacrylic acid and the like.
• composition 4 the gel and microparticles are placed into a ceramic material in the shape of cylinder with one end open and one end closed.
• the cylinder is filled with the gel and microparticles composition and the open end is placed in the pulp chamber.
• the ceramic material can be composed of dental composite material.
• composition 4 is directly injected into the pulp chamber or at the root end.
• microspheres of EXAMPLE 1 are suspended in the same sodium hyaluronate carrier and placed within the same syringe as are used for the DBX ® Putty Demineralized Bone Matrix (Dentsply Implants, Waltham MA), bone cement or Mineral trioxide aggregate (MTA) (Dentsply Tulsa).
• the microspheres are suspended in the DBX putty, bone cement or MTA itself.
• composition is placed at the root end or as a pulp capping material.
• EXAMPLE 3 Direct delivery of therapeutic preparation to inflamed pulp.
• the affected tooth is prepared for standard root canal procedure, but after the tooth is uncapped, the inflamed pulp is not completely excised. Instead, the preparation of EXAMPLE 1 or 2 is injected into the pulp chamber, with partial removal of the pulp if necessary to create room for the putty or MTA. The tooth is sealed per standard root canal procedure.
• Particle 1 Poly(DL-lactide) (DL-PL) microspheres loaded with demeclocycline hydrochloride are prepared according to example 2 of Gibson et al [US 6,291 ,013], but with the dispersed phase containing 10.5g DL-PL and 0.525g demeclocycline hydrochloride dissolved in 168.0 g of dichloromethane ("DCM").
• DCM dichloromethane
• Particle 2 Poly(DL-lactide) (DL-PL) microspheres loaded with triamcinolone acetonide are prepared according to example 2 of Gibson et al [US 6,291 ,013], but with the dispersed phase containing 10.5g DL-PL and 0.525g triamcinolone acetonide dissolved in 168.0 g DCM.
• Particles of each type are suspended in sodium hyaluronate carrier at 2%, w/w, particle/HA carrier before administration.
• the therapeutic preparation is preferably placed within the bone feeding the tooth root so as to leave the crown of the tooth intact but can also be placed within the dentin or ECS after opening the tooth but not removing the infected root or as a pulp capping material or after some amount of necrotic pulp is removed.
• a therapeutic preparation made at 1 -10%, w/w, drug-loaded particle/HA carrier, or more preferably, 2-5%.
• An amount of therapeutic preparation that achieves local concentrations of each drug within the tooth root in excess of 1 -10ug/ml over about a 48 hour time period, or more preferably over about a 120 hour time period, or more preferably over about a 2 week period, or more preferably over about a 4 week period, or more preferably over about an 8 week period.
• Minocycline hydrochloride microspheres are suspended in sodium hyaluronate carrier or in the MTA, bone cement or DBX material at 2%, w/w, particle/HA carrier.
• the therapeutic preparation of embodiment 1 or 2 is used in combination with a restorative material placed within the dentin or ECS after opening the tooth.
• the restorative material can be delivered concomitantly with the therapeutic preparation or after delivery of the therapeutic preparation.
• Material having acceptable physical properties e.g., Dyract ® flow, DENTSPLY DeTrey, Germany
• Other known restorative materials are suitable for use herein.

Landscapes

• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Organic Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• Rheumatology (AREA)
• Neurosurgery (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Communicable Diseases (AREA)
• Pain & Pain Management (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Oncology (AREA)
• Surgery (AREA)
• Dentistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Dental Tools And Instruments Or Auxiliary Dental Instruments (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Priority Applications (3)

Applications Claiming Priority (2)

Publications (1)

Family

ID=54359294

Family Applications (1)

Country Status (4)

Cited By (4)

Citations (4)

Family Cites Families (5)

• 2015
  • 2015-04-29 WO PCT/US2015/028305 patent/WO2015168292A1/en not_active Ceased
  • 2015-04-29 CA CA2947421A patent/CA2947421C/en active Active
  • 2015-04-29 JP JP2016565173A patent/JP6644709B2/ja not_active Expired - Fee Related
  • 2015-04-29 EP EP15785553.7A patent/EP3137011A4/en not_active Withdrawn

Patent Citations (4)

Non-Patent Citations (1)

Also Published As

Similar Documents

Legal Events