CA2947421C - Endodontic treatment with long term drug delivery system - Google Patents
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- 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
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- 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
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- A61K6/00—Preparations for dentistry
- A61K6/60—Preparations for dentistry comprising organic or organo-metallic additives
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- 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
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Abstract
Disclosed is an endodontic treatment of an infected root canal with a drug delivery system in order to prevent the need for a root canal treatment of a patient.
Description
2 PCT/US2015/028305 Endodontic Treatment with Long Term Drug Delivery System TECHNICAL FIELD
[0001] Described herein is an endodontic treatment of an infected root canal with a drug delivery system.
BACKGROUND
[0002] Endodontic treatments usually involve cleaning and enlarging the endodontic cavity space ("ECS"), also known as the root canal system of a human tooth. 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.
[0001] Described herein is an endodontic treatment of an infected root canal with a drug delivery system.
BACKGROUND
[0002] Endodontic treatments usually involve cleaning and enlarging the endodontic cavity space ("ECS"), also known as the root canal system of a human tooth. 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.
[0003] The root canal system of a human tooth is often narrow, curved and calcified, and can be extremely difficult to negotiate or clean. Indeed, 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. Furthermore, 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.
[0004] 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 TU L-1040.WO
diameter. To accommodate complete cleaning and filling of the canal and to prevent further infection, the canal must usually be prepared. The endodontic cavity preparation ("ECP") 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.
diameter. To accommodate complete cleaning and filling of the canal and to prevent further infection, the canal must usually be prepared. The endodontic cavity preparation ("ECP") 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.
[0005] Bacterial colonization of the dental pulp chamber leads to inflammation and apical periodontitis. Once infected, the root canal is most often treated by pulpectomy as described above, sterilization, obturation, and capping to resolve the periodontitis and restore normal tooth function. While the therapeutic root canal procedure is highly successful (greater than eighty percent survival five-years post implant), the repaired tooth no longer functions with normal physiology and is more susceptible to future problems. Some such restored teeth last a lifetime;
most eventually require further intervention when the tooth fails mechanically or becomes reinfected. Repeated root canal procedures are also quite successful, but many treated teeth ultimately require extraction, followed by placement of either a bridge or permanent implant.
most eventually require further intervention when the tooth fails mechanically or becomes reinfected. Repeated root canal procedures are also quite successful, but many treated teeth ultimately require extraction, followed by placement of either a bridge or permanent implant.
[0006] 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. Not surprisingly, implants have proven more durable than endodontically repaired teeth, with greater than 95 percent survival reported. However, implants are costly and beyond the means of a large fraction of the patient population.
[0007] 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.
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.
[0008] Systemic antibiotic therapy is not feasible for eradicating root pulp infections because the local drug concentration required cannot be obtained without exceeding toxic systemic TUL-1040.WO
levels due to inadequate collateral blood supply. However, polymeric drug delivery technologies have been used successfully to achieve high local concentrations of drug without increasing systemic concentrations to toxic levels. While drug-eluting coronary stents are the most successful commercial application of this concept, several lesser known products deliver antiseptic and antibiotic antimicrobial agents.
levels due to inadequate collateral blood supply. However, polymeric drug delivery technologies have been used successfully to achieve high local concentrations of drug without increasing systemic concentrations to toxic levels. While drug-eluting coronary stents are the most successful commercial application of this concept, several lesser known products deliver antiseptic and antibiotic antimicrobial agents.
[0009] Various approaches used in non-endodontic medical applications appear feasible for dental applications. The most straight forward method is placement of a pre-formed, pre-sterilized depot of antibiotic loaded degradable polymer within bone that feeds the root. The second approach is in-situ polymerization of a degradable polymer/antimicrobial system within the same bone. The third approach would be more destructive to the natural anatomy of the tooth but easiest for practitioners to implement, i.e., in-situ placement of a degradable polymer/antimicrobial and/or anti-inflammatory system within the root canal or pulp chamber or dentinal tooth structure and the infected pulp (with partial pulpectory to create a larger reservoir space if necessary). None of these techniques precludes standard root canal procedure should they fail, but all could be effective in sparing the root and postponing ore eliminating the need for traditional therapies.
[0010] Diagnostic challenges in the determination of the presence or absence of pulpal disease and its extent have been the subject of controversy for decades. Early writings from around the world indicate that there was recognition of the relationship between caries, pulpal inflammation and pain. Fu His (2953 BC) is credited with one of the earliest surviving descriptions of several types of toothache, including pain caused by cold and mastication (Goodis 2002). Pliny the Elder (23-79 AD) advised that a toothache could be relieved by chewing the root of the hyocyamus soaked in vinegar; or the roots of the plantain, the latter of which are known to possess antimicrobial and anti-inflammatory properties (Gomez-Flores et al.
2000). The focus during this era was pain management and not so much reduction of inflammation as a prelude to healing.
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2000). The focus during this era was pain management and not so much reduction of inflammation as a prelude to healing.
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[0011] Various remedies for the management of pain only existed during the next several hundred years and consisted of tooth trephination, pulp extirpation, and cautery (both heat and chemicals). Yet to our knowledge no one focused on a non-intervention type of pain/inflammation management. 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).
(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).
[0012] Once clinicians felt that they could have an idea of vitality or non-vitality, the use of antiseptic substances to cover the exposed pulp with the intent to encourage healing were espoused. What was not understood at that time in history were the mechanisms of pulpal inflammation and its spread and ability of the pulp to respond favorably or unfavorably to specific stimuli or treatments (Van Hassel 1971 ¨ circumferential spread of inflammation versus the strangulation theory [Amir & Gutmann 2001]). In essence these individuals were faced with the same dilemma that we face today, and that being our inability to reliably determine the status of the dentinal pulp following injury or trauma. In particular, to be able to interpret accurately signs and/or symptoms or lack thereof in the presence of dental caries, restorative tooth treatment, periodontal disease, and tooth trauma and relate them accurately to the pathophysiological status of the dental pulp. Recently there was an attempt to do this and to clarify the present-day diagnostic criteria and their interpretation (Newton et al. 2009; Levin et al 2009). Achieving consensus in this regard was however illusive.
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[0013] Inflammation in the dental pulp is a local reaction of vascular tissues characterized by loss of liquid and blood cells to the extravascular environment or interstice.
This reaction may be induced by biological, physical or chemical agents (Trowbridge & Emling 1997;
Accorinte et al 2008). 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 & Emling 1997).
This reaction may be induced by biological, physical or chemical agents (Trowbridge & Emling 1997;
Accorinte et al 2008). 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 & Emling 1997).
[0014] In the pulp tissue, the first stage of potentially reversible inflammation (a diagnostic category that tells present-day clinicians that something can be done to salvage the dental pulp and secure healing) is known as pulpal hyperemia, clinically characterized by provoked, temporary, localized, low-intensity pain. Given that 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 (MAI- & Levik 1975; MAI- & Ferrari 2002; 130y0kgOral et al. 2008).
Moreover, due to the intimate relation between these tissues and the dentinal permeability, molecules of medications, such as corticosteroids, applied on the exposed dentin, may diffuse through the dentinal tubules, with the potential to provide a therapeutic effect, alleviating the painful symptom (Fry et al. 1960; Pashley 1996).
Moreover, due to the intimate relation between these tissues and the dentinal permeability, molecules of medications, such as corticosteroids, applied on the exposed dentin, may diffuse through the dentinal tubules, with the potential to provide a therapeutic effect, alleviating the painful symptom (Fry et al. 1960; Pashley 1996).
[0015] Since the 1960s, corticosteroids have been used on dentin in order to diminish dentinal hypersensitivity, pulpal hyperemia and in some cases used as direct pulp capping agents (Clarke K et al. 1981). In fact during the period of 1965-1974 studies were published in Italy, Germany, Poland, France and Czechoslovakia that used corticosteroids to manage pulpal TUL-1040.WO
inflammation, however substantial clinical directives were not evident and the studies published were at the lowest level of evidence-based directives.
inflammation, however substantial clinical directives were not evident and the studies published were at the lowest level of evidence-based directives.
[0016] 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 at. 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. However, it should be pointed out that, although this practice has been recommended, most studies that investigated the action of topical corticosteroids in endodontic applications evaluated the direct use of these drugs on the pulp to minimize inflammation or pain (Negm 2001; Rodd & Boissonade 2005).
Furthermore, there still remains the challenge in the clinician's ability to accurately distinguish between mere sensitivity and reversible pulpitis, and reversible and irreversible pulpitis.
Furthermore, there still remains the challenge in the clinician's ability to accurately distinguish between mere sensitivity and reversible pulpitis, and reversible and irreversible pulpitis.
[0017] Recently, however Frost (2011) published a paper that detailed a study using a corticosteroid/antibiotic dressing as an indirect pulp capping material on teeth diagnosed as having reversible pulpitis (no obvious exposure and the material was placed on the cavity floor following caries removal). The criteria for this diagnosis were clearly detailed and any pulps that were exposed during excavation were eliminated from the study. In his sample, 454 teeth were treated in this manner of which 435(96%) needed two treatment visits and 19(4%) need three treatment visits. Subsequent interventions included root canal treatment on 43(10%) of the teeth, extraction on 21(5%) of the teeth and 14(3%) received additional dressing with the medicament. Median survival time of the teeth was 6 years. The author indicated, based on these findings, the root canal treatment may not be necessarily be the first line of treatment for teeth diagnosed with reversible pulpitis.
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[0018] Steroids or more appropriately glucocorticoids forrn 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 (Hargreaves & Seltzer 2002). Contemporarily, the 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. Studies have also evaluated the intramuscular use of dexamethasone or the intraosseous or intraligamentary injection of methylprednisolone acetate (Depro Medrol) (Kaufman et al. 1994; Gallatin et al. 2000; lsett et al. 2003).
Abstracts of studies [Gallatin & !sett respectively] below:
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 (Hargreaves & Seltzer 2002). Contemporarily, the 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. Studies have also evaluated the intramuscular use of dexamethasone or the intraosseous or intraligamentary injection of methylprednisolone acetate (Depro Medrol) (Kaufman et al. 1994; Gallatin et al. 2000; lsett et al. 2003).
Abstracts of studies [Gallatin & !sett respectively] below:
[0019] The purpose of this prospective, double-blind, randomized study was to evaluate pain reduction using an intraosseous injection of slow-releasing methylprednisolone in teeth with irreversible pulpitis. Forty subjects presenting for emergency treatment completed the study.
Each subject had a tooth with a clinical diagnosis of irreversible pulpitis with actively associated moderate to severe pain. After local anesthesia was attained, the subjects were randomly assigned to receive an intraosseous injection of either 1.0 ml of Depo-Medrol (40 mg) or 1.0 ml of sterile saline (control). No endodontic therapy was begun at the initial appointment. The subjects received ibuprofen and Tylenol #3 and completed a 7-day questionnaire on pain, percussion pain, and analgesic medications taken each day. Over the 7-day observation period, the subjects who received the intraosseous injection of Depo-Medrol reported significantly (p <
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0.05) less pain and percussion pain while taking significantly (p < 0.05) fewer pain medications.
Clinically the intraosseous injection of Depo-Medrol could be used to temporarily alleviate the symptoms of irreversible pulpitis until definitive treatment can be rendered.
Each subject had a tooth with a clinical diagnosis of irreversible pulpitis with actively associated moderate to severe pain. After local anesthesia was attained, the subjects were randomly assigned to receive an intraosseous injection of either 1.0 ml of Depo-Medrol (40 mg) or 1.0 ml of sterile saline (control). No endodontic therapy was begun at the initial appointment. The subjects received ibuprofen and Tylenol #3 and completed a 7-day questionnaire on pain, percussion pain, and analgesic medications taken each day. Over the 7-day observation period, the subjects who received the intraosseous injection of Depo-Medrol reported significantly (p <
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0.05) less pain and percussion pain while taking significantly (p < 0.05) fewer pain medications.
Clinically the intraosseous injection of Depo-Medrol could be used to temporarily alleviate the symptoms of irreversible pulpitis until definitive treatment can be rendered.
[0020] The purpose of this prospective, randomized, doubleblind study was to evaluate the pulpal concentrations of prostaglandin E2 (PGE2) and interleukin-8 (1L-8) in untreated teeth with irreversible pulpitis after the administration of an intraosseous injection of Depo-Medrol. Forty emergency patients with a clinical diagnosis of irreversible pulpitis experiencing moderate to severe pain participated. After receiving local anesthesia, patients randomly received, in a double-blind manner, an intraosseous injection of either 1 ml of Depo-Medrol (40 mg) (20 patients) or 1 ml of sterile saline placebo (control) (20 patients). No endodontic treatment was initiated. At 1 or 3 days after the intraosseous injection, the teeth were extracted and the pulpal tissue harvested. 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.
[0021] The therapeutic effect of corticosteroids is based on their action on the synthesis of lipocortin and vasocortin, inhibiting the formation of edema and A2 phospholipasis enzymes, respectively. By inhibiting this enzyme, membrane phospholipids cannot be converted into aracdonic acid. Therefore, the synthesis of prostaglandins and prostacyclins (the cyclooxygenase route) as well as the synthesis of leukotrienes (the lypooxygenase route) that should follow, are blocked (Trowbridge & Emling 1997; Manchikanti 2002).
According to Rittner, et al. (2003), the production of bradikinin and prostaglandins could regulate the onset of pain.
Nakanishi, et al. (2001) point out that pulpal fibroblasts and macrophages can participate in the production of prostaglandins by means of cyclooxygenase-2 expression in the pulpal inflammation, and both can be involved in the pathogenesis of pulpitis. That is why the TU L-1040.WO
application of an anti-inflammatory agent inhibits edema, vasodilatation and the chemotactic effects on leukocytes. Moreover, 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).
According to Rittner, et al. (2003), the production of bradikinin and prostaglandins could regulate the onset of pain.
Nakanishi, et al. (2001) point out that pulpal fibroblasts and macrophages can participate in the production of prostaglandins by means of cyclooxygenase-2 expression in the pulpal inflammation, and both can be involved in the pathogenesis of pulpitis. That is why the TU L-1040.WO
application of an anti-inflammatory agent inhibits edema, vasodilatation and the chemotactic effects on leukocytes. Moreover, 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).
[0022] Considering the clinical relevance of prevention in the development of irreversible pulp inflammation and the scarcity of more recent studies attesting the hypothesis that corticosteroid anti-inflammatory medication is effective under these circumstances, the pursuit of studies to examine both this opportunity and one in which the pulp is diagnosed at least in the early stages of irreversible pulpitis should be pursued. Options for clinical applications of various anti-inflammatory drugs in a multitude of ways should be examined, for example on exposed crown or root dentin; after removal of the infected layer of dentin without pulpal exposure (known today as indirect pulp capping); on the dentin following crown preparation or other extensive restorative procedures; placement directly on an exposed pulp, whether in the crown or root;
and placement into the cancellous bone if signs or symptoms of initial periradicular periodontitis are present (Gutmann et al. 2009). The latter approach was advocated by Gallatin et al. (2000) under certain circumstances. They felt that from a clinician's point of view it might be as quick to place a dental dam and perform a pulpotomy or pulpectomy. Therefore, when might the use of Depo-Medrol type of drug be indicated? In the past practitioners either had to treat the emergency patient with irreversible pulpit's (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. There are situations that arise, admittedly rarely, when the intraosseous injection of Depo-Medrol could be used to temporarily alleviate symptoms of irreversible pulpitis until definitive treatment can be rendered. 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-TipTm Intraosseous Anesthesia System - Dentsply Tulsa Dental Specialities, Tulsa, OK, USA) can clinically reduce the patient's pain to manageable levels, up to 7 days, before needing root canal treatment. 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.
BRIEF DESCRIPTION OF THE DRAWINGS
and placement into the cancellous bone if signs or symptoms of initial periradicular periodontitis are present (Gutmann et al. 2009). The latter approach was advocated by Gallatin et al. (2000) under certain circumstances. They felt that from a clinician's point of view it might be as quick to place a dental dam and perform a pulpotomy or pulpectomy. Therefore, when might the use of Depo-Medrol type of drug be indicated? In the past practitioners either had to treat the emergency patient with irreversible pulpit's (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. There are situations that arise, admittedly rarely, when the intraosseous injection of Depo-Medrol could be used to temporarily alleviate symptoms of irreversible pulpitis until definitive treatment can be rendered. 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-TipTm Intraosseous Anesthesia System - Dentsply Tulsa Dental Specialities, Tulsa, OK, USA) can clinically reduce the patient's pain to manageable levels, up to 7 days, before needing root canal treatment. 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.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Figure 1 demonstrates one suitable drug delivery device.
[0024] Figure 2 demonstrates additional examples of suitable drug delivery devices. A:
propylene mesh; B: Coating (Polymer and antibiotics).
propylene mesh; B: Coating (Polymer and antibiotics).
[0025] 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.
[0026] Figure 4 shows a drug eluting plug D 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 C.
[0027] Figure 5 shows a drug eluting plug D placed into a tooth having pulpitis where the plug reaches into the pulp chamber. The drug eluting plug is capped by a restorative C.
[0028] 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 D is at least partially encapsulated by a restorative material C.
SUMMARY
SUMMARY
[0029] Because pulp infections are notoriously difficult to treat, pulpectomy is most often the therapeutic option of choice. However, 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".
Date Recue/Date Received 2022-06-03
Because patients irrationally fear root canal procedures, most will likely be willing to try to any therapy that postpones the dreaded "root canal".
Date Recue/Date Received 2022-06-03
[0030] 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.
[0031] 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.
[0031a] Described herein is a composition for extended release drug delivery of an antimicrobial agent and/or an anti-inflammatory for use in treating pulpitis by placement of the composition in a root canal, pulp chamber, and/or dentin, wherein the composition is composed of a hydrogel polymer containing microparticles or nanoparticles that contain the antimicrobial agent and/or the anti-inflammatory, wherein the composition is placed in a preformed carrier.
DETAILED DESCRIPTION
[0031a] Described herein is a composition for extended release drug delivery of an antimicrobial agent and/or an anti-inflammatory for use in treating pulpitis by placement of the composition in a root canal, pulp chamber, and/or dentin, wherein the composition is composed of a hydrogel polymer containing microparticles or nanoparticles that contain the antimicrobial agent and/or the anti-inflammatory, wherein the composition is placed in a preformed carrier.
DETAILED DESCRIPTION
[0032] Successful treatment of dental pulp infection depends upon adequate local concentration of antimicrobial agent or an anti-inflammatory agent for adequate time.
Systemic drug therapy is not feasible because of the limited blood supply to the pulp through base of the root. However, polymeric drug delivery technologies have been used successfully to achieve high local concentrations of drug while minimally affecting systemic concentrations. While drug-eluting coronary stents are the most successful commercial application of this concept, several lesser known products deliver antiseptic and antibiotic antimicrobial agents.
Systemic drug therapy is not feasible because of the limited blood supply to the pulp through base of the root. However, polymeric drug delivery technologies have been used successfully to achieve high local concentrations of drug while minimally affecting systemic concentrations. While drug-eluting coronary stents are the most successful commercial application of this concept, several lesser known products deliver antiseptic and antibiotic antimicrobial agents.
[0033] Various approaches used in non-endodontic medical applications appear feasible for delivery of antimicrobial agents and or steroidal agents to the root pulp.
1. Placement of a pre-formed, pre-sterilized depot of antibiotic loaded degradable polymer within bone that feeds the root 2. In-situ polymerization of a degradable polymer/antimicrobial system within the same bone.
Date Recue/Date Received 2022-06-03 TUL-1040.WO
3. A polymer/antimicrobial system of a polymer/antimicrobial system within the root canal (possibly including pulp chamber) and the infected pulp (with partial pulpectory to create a larger reservoir space if necessary).
4. A polymer/antimicrobial system within the dentin of the tooth 5. A polymer/antimicrobial system placed in the area surrounding of the tooth All of the systems described could also contain anti-inflammatory agent as well. The system could be a depot like device as shown in Figure 6 containing the treatment or polymer/anti-microbial 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.
1. Placement of a pre-formed, pre-sterilized depot of antibiotic loaded degradable polymer within bone that feeds the root 2. In-situ polymerization of a degradable polymer/antimicrobial system within the same bone.
Date Recue/Date Received 2022-06-03 TUL-1040.WO
3. A polymer/antimicrobial system of a polymer/antimicrobial system within the root canal (possibly including pulp chamber) and the infected pulp (with partial pulpectory to create a larger reservoir space if necessary).
4. A polymer/antimicrobial system within the dentin of the tooth 5. A polymer/antimicrobial system placed in the area surrounding of the tooth All of the systems described could also contain anti-inflammatory agent as well. The system could be a depot like device as shown in Figure 6 containing the treatment or polymer/anti-microbial 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.
[0034] The first is the least invasive. In this procedure, 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.
[0035] The second approach, in-situ polymerization or liquid-solid phase change of a degradable or non-degradable polymer/antimicrobial and /or polymer anti-inflammatory system within the same bone, is more versatile in that drug agents can differ from patient to patient but would require a higher level of skill to control the reaction. While dentists are used to light activated chemistry, this method would likely use a redox initiator.
[0036] The third approach would be more destructive to the natural anatomy of the tooth but easiest for practitioners to implement in that it slightly modifies the current root canal procedure.
Instead of placing the depot in bone feeding the root, the practitioner places the 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.
TU L-1040.WO
Presumably, the tooth would remain healthier and the traditional root canal procedure postponed.
Instead of placing the depot in bone feeding the root, the practitioner places the 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.
TU L-1040.WO
Presumably, the tooth would remain healthier and the traditional root canal procedure postponed.
[0037] 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 tubules are a natural path for the delivery of the therapeutic to the infected pulp.
[0038] 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.
[0039] It is important to note that none of these techniques precludes the standard root canal procedure should they fail, but all could be effective in sparing the root and postponing ore eliminating the need for traditional therapies.
Polymer Technologies for Drug Delivery
Polymer Technologies for Drug Delivery
[0040] Degradable polymers intended for local drug release were described in the 1980s and commercialized in the succeeding years. While many consider the drug eluting coronary stent the epitome of drug-eluting polymer systems for medical applications, commercialization of additional coated devices has proven more difficult and time consuming than once expected.
Nonetheless, several cleared antimicrobial agent-eluting products might be effective as infected root treatments, including = Degradable sutures (polyglactin 910, poliglecaprone 25,polydioxanone)/Triclosan = Periodontal disease depot (PLGA/ minocycline, PLA/doxycycline)
Nonetheless, several cleared antimicrobial agent-eluting products might be effective as infected root treatments, including = Degradable sutures (polyglactin 910, poliglecaprone 25,polydioxanone)/Triclosan = Periodontal disease depot (PLGA/ minocycline, PLA/doxycycline)
[0041] In addition, several cleared devices as drug-eluting (antibiotic, antimicrobial, and other agent) coatings use polymer/antimicrobial systems that might be readily adapted to a root-sparing treatment. Additional drug-eluting polymers in various states of commercialization also appear amenable to the application, including the following.
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= 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 = Polymers clinically used to deliver antibiotics from devices in contact with tissue, including tyrosine-derived polyarylate and polyanhyd ride = Polymers evaluated in human clinical trials but not yet included on a cleared device, including tyrosine-derived polycarbonate, polyhydroxyalkanoate, poly(ester amide), and poly(ortho ester) = Polymers evaluated in pre-clinical models but that would likely face higher regulatory hurdles, including poly(anhydride-ester), poly(propylene fumarate), branched polyesters (neutral and charge-modified poly(vinyl alcohol)-graft- poly(lactic-co-glycolic acid) polyesters), poly(ethylene carbonate), 1,3-trimethylene carbonate, poly(ether amide), degradable polyethylenimine, poly(ester urethanes)
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= 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 = Polymers clinically used to deliver antibiotics from devices in contact with tissue, including tyrosine-derived polyarylate and polyanhyd ride = Polymers evaluated in human clinical trials but not yet included on a cleared device, including tyrosine-derived polycarbonate, polyhydroxyalkanoate, poly(ester amide), and poly(ortho ester) = Polymers evaluated in pre-clinical models but that would likely face higher regulatory hurdles, including poly(anhydride-ester), poly(propylene fumarate), branched polyesters (neutral and charge-modified poly(vinyl alcohol)-graft- poly(lactic-co-glycolic acid) polyesters), poly(ethylene carbonate), 1,3-trimethylene carbonate, poly(ether amide), degradable polyethylenimine, poly(ester urethanes)
[0042] Of these, two commercial products (triclosan-treated sutures and antibiotic-loaded suture materials (PLGA, PDLLA) used to treat periodontal disease), two commercial polymer systems used clinically to deliver antibiotics (Degradable suture materials and Tyrosine-derived polyarylates), and four primarily academic drug eluting polymer programs in various states of commercialization appear the most promising, these being 1.) Tyrosine-derived carbonate 2.) Poly(propylene fumarate) 3.) Polyanhydride and 4.) Poly(anhydride-ester).
Other degradable and/or water soluble materials such as matrix proteins (e.g. collagen), polysaccharides, water soluble poly(vinyl alcohol), and poly(ester urethane) might well work.
Polymer Systems for Drug Delivery
Other degradable and/or water soluble materials such as matrix proteins (e.g. collagen), polysaccharides, water soluble poly(vinyl alcohol), and poly(ester urethane) might well work.
Polymer Systems for Drug Delivery
[0043] Monomers from the suture industry: glycolide, L-Iactide and its isomers, c-caprolactone, p-dioxanone, and trimethylenecarbonate (Various Sources) TU L-1040.W0 Bezwada describes five key lactone-based monomers used in the absorbable suture industry in his White Paper, "Synthetic Absorbable Polyesters." In addition to the polymers used in the commercial Triclosan eluting suture products, numerous additional copolymers originally developed for a suture application reported to deliver antibiotics in academic literature. Some are currently used on commercial products for applications ranging from periodontal disease treatment to orthopedic implants.
) 0 a Glycolide poly[glyc ol id e]
Den. TM
-,y0 0 0 _ ____________________ T
0 _ n L (-) Lactide poIAL L act d e]
p -Diaxanone poly[p-dioxanone]
PDSTm o 0 poi** rolactc=nei Caprolactone 0 õi ii Trim ethyl en ecarbon ate poly[Trim eery I enecarb nate]
Synthetic absorbable ho mop oly esters .
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Glycolic Acid/Lactic Acid (Various Sources)
) 0 a Glycolide poly[glyc ol id e]
Den. TM
-,y0 0 0 _ ____________________ T
0 _ n L (-) Lactide poIAL L act d e]
p -Diaxanone poly[p-dioxanone]
PDSTm o 0 poi** rolactc=nei Caprolactone 0 õi ii Trim ethyl en ecarbon ate poly[Trim eery I enecarb nate]
Synthetic absorbable ho mop oly esters .
TU L-1040.WO
Glycolic Acid/Lactic Acid (Various Sources)
[0044] 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.
= 4 a S. 2 - ____________ - PIA 4111111110111111~MINV 100 100 _________________________ P GA 0 =eilolirtvi Of Witt Half-life cut months) of various ratios of PLA and PGA as copolymers implanted in rat tissue.
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.
= 4 a S. 2 - ____________ - PIA 4111111110111111~MINV 100 100 _________________________ P GA 0 =eilolirtvi Of Witt Half-life cut months) of various ratios of PLA and PGA as copolymers implanted in rat tissue.
[0045] Additional suture monomers (primarily PLA isomers, E-caprolactone, p-dioxanone, and trimethylenecarbonate) have also been used to control suture degradation rate.
Feijen and colleagues report that the rate of in vitro degradation of trimethylene carbonate (TMC) copolymerized with D,L-lactide (DLLA) or c-caprolactone (CL) varied by two orders of magnitude, depending on polymer composition.
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Tyrosine-Derived Polyarylate, Tyrosine-Derived Carbonate
Feijen and colleagues report that the rate of in vitro degradation of trimethylene carbonate (TMC) copolymerized with D,L-lactide (DLLA) or c-caprolactone (CL) varied by two orders of magnitude, depending on polymer composition.
TU L-1040.WO
Tyrosine-Derived Polyarylate, Tyrosine-Derived Carbonate
[0046] 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.
1 .. ..... _ 1 = =
=
= =4 = =
= = * = =
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*0 * A * a . =
4, = . * a A - A A a AA
* 9*,41416 A 6 I CIO eas. 440 4'al, i I
i e ..- ..-AJA.a ,*A- -*
!
i 44 1 rt xlet j AO
1 al -_,..0x4iiiittaig**Asirsit AAAAA AAA* 4.ttss 6 6 t A Air* A A A. oll 4L4 A & 4 ilki I Time __________________________________________ OW
R ' : -. 'y ' ' 0+ Wary ,: 1, i .:,..:!v , - , - :...,-,!.
= ' -, ! Age 1 i: , = ' . : ' . ',r * n' * * I..., * .'µ
'*a * : t *¨ a i 'alle i .
Kohn assigned most of the relevant patents to Rutgers University, which in turn licensed tyrosine-based polyarylates IP to TYRX, Inc. and tyrosine-based polycarbonate to Trident Biomedical, Inc. TYRX additionally licensed from Baylor College of Medicine and the University of Texas M. D. Anderson Cancer Center combination drug patents including the combination of rifampin and minocycline to address postsurgical infection and fibrosis. Known cleared medical devices utilizing the tyrosine-based polyarylates and rifampin/minocycline combination as a TU L-1040.WO
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.
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.
1 .. ..... _ 1 = =
=
= =4 = =
= = * = =
s * 4 1 4,0A.- 0 * - = fr .6 A - = 4 ' 1 A a ai =====4'.
*0 * A * a . =
4, = . * a A - A A a AA
* 9*,41416 A 6 I CIO eas. 440 4'al, i I
i e ..- ..-AJA.a ,*A- -*
!
i 44 1 rt xlet j AO
1 al -_,..0x4iiiittaig**Asirsit AAAAA AAA* 4.ttss 6 6 t A Air* A A A. oll 4L4 A & 4 ilki I Time __________________________________________ OW
R ' : -. 'y ' ' 0+ Wary ,: 1, i .:,..:!v , - , - :...,-,!.
= ' -, ! Age 1 i: , = ' . : ' . ',r * n' * * I..., * .'µ
'*a * : t *¨ a i 'alle i .
Kohn assigned most of the relevant patents to Rutgers University, which in turn licensed tyrosine-based polyarylates IP to TYRX, Inc. and tyrosine-based polycarbonate to Trident Biomedical, Inc. TYRX additionally licensed from Baylor College of Medicine and the University of Texas M. D. Anderson Cancer Center combination drug patents including the combination of rifampin and minocycline to address postsurgical infection and fibrosis. Known cleared medical devices utilizing the tyrosine-based polyarylates and rifampin/minocycline combination as a TU L-1040.WO
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.
[0047] Trident Biomedical, Inc., unlike TYRX, has no cleared medical product.
However, 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. I 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.
Polv(propvlene fumarate),
However, 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. I 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.
Polv(propvlene fumarate),
[0048] Poly(propylene fumarate), an unsaturated linear polyester based on fumaric acid, and its crossslinked derivatives are studies as bone void fillers and biomaterial scaffolds F1'aThajCle'"y 11r0A-1 Poly(Propylene Fumarate) TUL-1040.WO
As such, the material degradation is slow. A photocrosslinked poly(propylenefumarate) (PPF)/poly(N-vinyl pyrrolidone) (PVP) matrix was reported to release three different ophthalmic model drugs for over 200 days [Hacker MC, Haesslein, A, Ueda H, Foster WJ, Garcia CA, Ammon DM, Borazjani RN, Kunzler JF, Salamone JC, Mikos AG. Biodegradable fumarate-based drug-delivery systems for ophthalmic applications. Journal of Biomedical Materials Research Part A, 88A (2009) 976-989].
b) Acetazolamide Dichkrphonamide limaiol rnaleate Z
1 103 lb- AZ 5% 100 -A- op 10% f ,,;,, .. :100 -4P- TM 5%
oso $ -e- AZ 2.5% ' -1- DP 5%
BO j i 80 Bo Bo 1 ,,,,i, m 60 ,=.'. 60 i - , * , I
Time plays]
, (a) Absolute () and (b) rdative (%) cumulative =mans of acetazolanide (AZ):
dichlorphenarride (DP), and &mad =lean? (rkt) released from phott),.. NistialKed !11 =.1"0' manices of diffesent comixmaion (Table I): (0) AZ 2.5%, (0) rm 5%.1.)ata represent means SD for If .. 3.
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Polyanhydride
As such, the material degradation is slow. A photocrosslinked poly(propylenefumarate) (PPF)/poly(N-vinyl pyrrolidone) (PVP) matrix was reported to release three different ophthalmic model drugs for over 200 days [Hacker MC, Haesslein, A, Ueda H, Foster WJ, Garcia CA, Ammon DM, Borazjani RN, Kunzler JF, Salamone JC, Mikos AG. Biodegradable fumarate-based drug-delivery systems for ophthalmic applications. Journal of Biomedical Materials Research Part A, 88A (2009) 976-989].
b) Acetazolamide Dichkrphonamide limaiol rnaleate Z
1 103 lb- AZ 5% 100 -A- op 10% f ,,;,, .. :100 -4P- TM 5%
oso $ -e- AZ 2.5% ' -1- DP 5%
BO j i 80 Bo Bo 1 ,,,,i, m 60 ,=.'. 60 i - , * , I
Time plays]
, (a) Absolute () and (b) rdative (%) cumulative =mans of acetazolanide (AZ):
dichlorphenarride (DP), and &mad =lean? (rkt) released from phott),.. NistialKed !11 =.1"0' manices of diffesent comixmaion (Table I): (0) AZ 2.5%, (0) rm 5%.1.)ata represent means SD for If .. 3.
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Polyanhydride
[0049] Brem and colleagues described a polyanhydride for delivery of drug to the brain in the late 1980s. In 1996, FDA cleared the Gliadel Wafer, a polyandhydride loaded with carmustine, for newly-diagnosed high-grade malignant glioma patients as an adjunct to surgery and radiation. Septacin, a polyand hydride loaded with gentamicin, developed for the treatment of osteomyelitis showed promise but never achieved commercial success, possibly due to sub-zero storage temperatures required for long-term stability. Krasko and colleagues described a polyanhydride gel containing gentamicin for the treatment of osteomyelitis but reported large increases in release drug release rate when the polymer was stored warmer than -17 C.
However, the elution profile might be appropriate for eradication of root infection.
.-- _ 0 _____________________________________________________ Time (days) -*--17C -41- 4C 4 weeks -ea- 4C 12 weeks 25C 4 weeks -ef- 25C7 weeks 37C 1 day Gentamicin gulbte release *km irradiated P(SA-RA) 3:7 loaded with 20% dnig ,t, ,r,cd at differen te;:lurcs. Tbc.,i,.-ntnnicia sulfate rele:se and detection we le pet/brined urAer COrlditiOrIS ribed Fig. 1. Sar,-,plei;
mired under freezing (I- 17 nej seivcc4 7:7 control. 'The ti',:perinient was performed in duplicate and the standard deviation did not exceed &8%.
TUL-1040.WO
Ta D!,:tdation kinetic constants and total degradation time 1br disks 2em.i =2 mni) as a fu..v..lion of the polymer network composition Polyanhydride cLiasposition (mmIlt) Deg: 1 lotion time ys) oh(M4) 13 x 10- 2 P0,1 sa' PH) 8.4x 10-3 496
However, the elution profile might be appropriate for eradication of root infection.
.-- _ 0 _____________________________________________________ Time (days) -*--17C -41- 4C 4 weeks -ea- 4C 12 weeks 25C 4 weeks -ef- 25C7 weeks 37C 1 day Gentamicin gulbte release *km irradiated P(SA-RA) 3:7 loaded with 20% dnig ,t, ,r,cd at differen te;:lurcs. Tbc.,i,.-ntnnicia sulfate rele:se and detection we le pet/brined urAer COrlditiOrIS ribed Fig. 1. Sar,-,plei;
mired under freezing (I- 17 nej seivcc4 7:7 control. 'The ti',:perinient was performed in duplicate and the standard deviation did not exceed &8%.
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Ta D!,:tdation kinetic constants and total degradation time 1br disks 2em.i =2 mni) as a fu..v..lion of the polymer network composition Polyanhydride cLiasposition (mmIlt) Deg: 1 lotion time ys) oh(M4) 13 x 10- 2 P0,1 sa' PH) 8.4x 10-3 496
50/5U 11MS A)Ipoly(CPP: CP11) 54x1O4 78 75/2:7 r.,,I1,1:NIS:1 i..:poly(C,P11) 1.9x10-3 22 : ) ;7525) 3.0 x 10 -4 138 Covq.:,)MSA.: AIStA) (75:25) 1.9x10 3 22 PEG Macromer [0050] Incept LLC developed applications using in situ polymerizable PEG
macromer chemical systems similar to those originally developed at Focal Inc. (now Genzyme).
_______________________________________ H2C¨C¨C 04CH2CH20)-g¨C=---CH2 140iCH20120 tH PEG diacrylate a Poly(ethylene glycol) ?H3 II CH3 (PEG) H2C=--c¨C---0-+Cii2CH20)-C¨C ---"=; H2 PEG dimethacrylate
macromer chemical systems similar to those originally developed at Focal Inc. (now Genzyme).
_______________________________________ H2C¨C¨C 04CH2CH20)-g¨C=---CH2 140iCH20120 tH PEG diacrylate a Poly(ethylene glycol) ?H3 II CH3 (PEG) H2C=--c¨C---0-+Cii2CH20)-C¨C ---"=; H2 PEG dimethacrylate
[0051] 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.
However, Incept may control use of the polymer system for certain dental applications.
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Dental Applications [0062] Hydrogel articles suitable for use herein may be advantageously used in dentistry, for example, in occluding root canals. Generally, after a root canal has been cleaned and disinfected, the resulting passageway is occluded to prevent bacterial contamination. Often un-crosslinked rubber-type materials, such as Gutta-Percha, are used to plug these openings.
Gutta-Percha, however, has no inherent form-fitting property and must be mechanically forced into the canal.
[0063] In accordance with the principles of the present disclosure, 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."
[US 6,605,294. Methods of using in situ hydration of hydrogel articles for sealing or augmentation of tissue or vessels.]
[0054] The principals at Incept are currently at Ocular Therapeutix adapting the system for ophthalmic drug delivery applications, thus providing another possible source of the macromers.
Additional Polymer Systems Potentially Suitable for Drug Delivery [0055] Commercialization and widespread use of products using other degradable polymers is lacking for various reasons, but all might be appropriate for antimicrobial delivery and could be revisited if necessary.
[0056] Other degradable polymers include various copolymers and terpolymers fabricated with polyethylene glycol (PEG) and suture monomers (Innocore, PolyVation By, SurModics, Philipps-Universitat (Germany), GA/LA/CUPEG), polybutylene terephthalate (PBT) (OctoPlus, PEG/PBT), polyhydroxyalkanoate (PHA) (Tepha/MIT, Poly-4-hydroxybutyrate), neutral and TUL-1040.w0 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 ethylenimine) (Exploit Technologies Private Limited).
Cement matrices [0057] Other materials such as 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.
[0058] Preparation of antibiotic/corticosteroid loaded into a biodegradable material, preferably, poly(DL-lactide) (DL-PL) microspheres.
[0059] 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).
[0060] 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.
[0061] Optionally 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.
[0062] Optionally composition 4 is directly injected into the pulp chamber or at the root end.
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[0063] EXAMPLE 2 [0064] Preparation of readily injectable putty of antibiotic/corticosteroid loaded microspheres.
[0065] The 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). Alternatively, the microspheres are suspended in the DBX
putty, bone cement or MTA itself.
[0066] The composition is placed at the root end or as a pulp capping material.
[0067] EXAMPLE 3 Direct delivery of therapeutic preparation to inflamed pulp.
[0068] 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.
[0069] Embodiment 1.
[0070] 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 dichloronnethane ("DCM").
[0071] 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.
[0072] Particles of each type are suspended in sodium hyaluronate carrier at 2%, w/w, particle/HA carrier before administration.
[0073] 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 TUL-1040.WO
opening the tooth but not removing the infected root or as a pulp capping material or after some amount of necrotic pulp is removed.
[0074] Related claims [0075] DL-PL microparticles loaded with drug at a mass fraction ranging from 0.1-10%, w/w, drug/polymer, or more preferably, 1-5%.
[0076] Microparticles fabricated with a distribution centered on 375 50um diameter, with 85%
of particles having diameter ranging between 200-500um.
[0077] A therapeutic preparation made at 1-10%, w/w, drug-loaded particle/HA
carrier, or more preferably, 2-5%.
[0078] A therapeutic preparation from which drug release that occurs over about a 24 hour time period, or more preferably 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.
[0079] An amount of therapeutic preparation that achieves local concentrations of each drug within the tooth root in excess of 1-bug/m1 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.
[0080] Embodiment 2.
[0081] 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.
[0082] Embodiment 3.
[0083] 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, TUL-1040.WO
DENTSPLY DeTrey, Germany) can optionally include the drug-loaded microparticles. Other known restorative materials are suitable for use herein.
,
However, Incept may control use of the polymer system for certain dental applications.
TU L-1040.WO
Dental Applications [0062] Hydrogel articles suitable for use herein may be advantageously used in dentistry, for example, in occluding root canals. Generally, after a root canal has been cleaned and disinfected, the resulting passageway is occluded to prevent bacterial contamination. Often un-crosslinked rubber-type materials, such as Gutta-Percha, are used to plug these openings.
Gutta-Percha, however, has no inherent form-fitting property and must be mechanically forced into the canal.
[0063] In accordance with the principles of the present disclosure, 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."
[US 6,605,294. Methods of using in situ hydration of hydrogel articles for sealing or augmentation of tissue or vessels.]
[0054] The principals at Incept are currently at Ocular Therapeutix adapting the system for ophthalmic drug delivery applications, thus providing another possible source of the macromers.
Additional Polymer Systems Potentially Suitable for Drug Delivery [0055] Commercialization and widespread use of products using other degradable polymers is lacking for various reasons, but all might be appropriate for antimicrobial delivery and could be revisited if necessary.
[0056] Other degradable polymers include various copolymers and terpolymers fabricated with polyethylene glycol (PEG) and suture monomers (Innocore, PolyVation By, SurModics, Philipps-Universitat (Germany), GA/LA/CUPEG), polybutylene terephthalate (PBT) (OctoPlus, PEG/PBT), polyhydroxyalkanoate (PHA) (Tepha/MIT, Poly-4-hydroxybutyrate), neutral and TUL-1040.w0 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 ethylenimine) (Exploit Technologies Private Limited).
Cement matrices [0057] Other materials such as 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.
[0058] Preparation of antibiotic/corticosteroid loaded into a biodegradable material, preferably, poly(DL-lactide) (DL-PL) microspheres.
[0059] 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).
[0060] 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.
[0061] Optionally 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.
[0062] Optionally composition 4 is directly injected into the pulp chamber or at the root end.
TUL-1040.WO
[0063] EXAMPLE 2 [0064] Preparation of readily injectable putty of antibiotic/corticosteroid loaded microspheres.
[0065] The 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). Alternatively, the microspheres are suspended in the DBX
putty, bone cement or MTA itself.
[0066] The composition is placed at the root end or as a pulp capping material.
[0067] EXAMPLE 3 Direct delivery of therapeutic preparation to inflamed pulp.
[0068] 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.
[0069] Embodiment 1.
[0070] 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 dichloronnethane ("DCM").
[0071] 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.
[0072] Particles of each type are suspended in sodium hyaluronate carrier at 2%, w/w, particle/HA carrier before administration.
[0073] 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 TUL-1040.WO
opening the tooth but not removing the infected root or as a pulp capping material or after some amount of necrotic pulp is removed.
[0074] Related claims [0075] DL-PL microparticles loaded with drug at a mass fraction ranging from 0.1-10%, w/w, drug/polymer, or more preferably, 1-5%.
[0076] Microparticles fabricated with a distribution centered on 375 50um diameter, with 85%
of particles having diameter ranging between 200-500um.
[0077] A therapeutic preparation made at 1-10%, w/w, drug-loaded particle/HA
carrier, or more preferably, 2-5%.
[0078] A therapeutic preparation from which drug release that occurs over about a 24 hour time period, or more preferably 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.
[0079] An amount of therapeutic preparation that achieves local concentrations of each drug within the tooth root in excess of 1-bug/m1 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.
[0080] Embodiment 2.
[0081] 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.
[0082] Embodiment 3.
[0083] 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, TUL-1040.WO
DENTSPLY DeTrey, Germany) can optionally include the drug-loaded microparticles. Other known restorative materials are suitable for use herein.
,
Claims (7)
1. A composition for extended release drug delivery of an antimicrobial agent and/or an anti-inflammatory for use in treating pulpitis by placement of the composition in a root canal, pulp chamber, and/or dentin, wherein the composition is composed of a hydrogel polymer containing microparticles or nanoparticles that contain the antimicrobial agent and/or the anti-inflammatory, and wherein the composition is placed in a preformed carrier.
2. A composition for use according to claim 1 where the antimicrobial agent and/or the anti-inflammatory release for longer than 1 day.
3. A composition for use according to claim 1 where the antimicrobial agent and/or the anti-inflammatory release for between 2 days and 6 months.
4. A composition for use according to any one of claims 1 to 3 where the preformed carrier is composed of the hydrogel polymer, an inorganic material, a degradable material, a polymeric material, and an elastomer, including combinations thereof.
5. A composition for use according to claim 4 where the preformed carrier material is radiopaque.
6. A composition for use according to any one of claims 1 to 5, wherein the composition is for application to a tooth having an inflamed root where the root is exposed.
7. A composition for use according to any one of claims 1 to 5, wherein the composition is for application to a tooth having an inflamed root where the root is not exposed.
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PCT/US2015/028305 WO2015168292A1 (en) | 2014-04-29 | 2015-04-29 | Endodontic treatment with long term drug delivery system |
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US20200405916A1 (en) * | 2018-03-20 | 2020-12-31 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Regeneration of vital tooth pulp |
CN114469863B (en) * | 2021-11-26 | 2023-09-26 | 南方医科大学南方医院 | Use of sterol liposomes as drug delivery systems for dental pulp and dentin |
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DE4019617A1 (en) * | 1990-06-20 | 1992-01-02 | Thera Ges Fuer Patente | IMPLANTABLE ACTIVE SUBSTITUTE MATERIAL |
JP2959833B2 (en) * | 1990-11-06 | 1999-10-06 | ライオン株式会社 | Sustained-release oral disease therapeutic agent and method for producing the same |
DE19962470A1 (en) * | 1999-12-22 | 2001-07-12 | Schulz Hans Herrmann | Use of chemotherapy drugs |
US20090148486A1 (en) * | 2005-04-28 | 2009-06-11 | Helen Lu | Compositions and methods for treating pulp inflammations caused by infection or trauma |
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