Drug delivery from the oral cavity: focus on a novel mechatronic delivery device

Dental drug delivery systems have been used for a long time, in particular for the local therapy of diseases affecting the oral cavity. Research today concentrates on the design of formulations to increase their retention time. Even today, however, prosthetic devices incorporating drug delivery are rarely used. Mainly, they are focused on prophylaxis and the release of antibacterial agents. However, as buccal delivery, because of its undeniable advantages, has become popular for systemic drug delivery, and prolonged well-controlled release has been identified as beneficial, especially for chronic diseases, a new class of delivery systems is evolving: highly miniaturized computerized delivery systems, integrated into a dental appliance. Dental delivery systems today are used in two ways: the main application is the local treatment of diseases affecting the oral cavity itself like periodontitis or fungal infections. The second is for systemic drug delivery.     

Nanodrug delivery systems in dentistry: a review on current status and future perspectives

The present review provides an insight into various potential areas of dentistry that are being invaded by nanotechnology based drugs and drug delivery systems. Current treatments for diseases of dental and oral structures rely on the use of classical pharmacological agents which, in some cases are limited by low efficacy and lack of selectivity to target cells. However, various nanostructures in drug delivery and their challenges in the field of dentistry have not been reviewed so far in the literature. The different treatment opportunities of importance include caries control restorations, tooth remineralisation, management of dentinal hypersensitivity, dental caries vaccine, management of oral biofilm, root canal disinfection, local anaesthesia and periodontal infection. The authors have also identified few dental applications demanding extensive research to emerge as a promising therapeutic strategy. We conclude by claiming that dentistry should follow the trend of probing matter at nanoscale to achieve a predictable treatment outcome.     

Sustained-release drug delivery of antimicrobials in controlling of supragingival oral biofilms

Introduction: Dental caries, a bacterial biofilm-associated disease, is a prevalent oral health problem. It is a bacterial biofilm-associated disease. Conventional means of combating this disease involves oral hygiene, mostly tooth brushing. Supplementary means of prevention and treatment is often necessary. The use of sustained-release delivery systems, locally applied to the oral cavity appears to be one of the most acceptable avenues for the delivery of antimicrobial agents.

Area covered: The development and current approaches of local sustained delivery technologies applied to the oral cavity for treatment and prevention of dental caries is discussed. The use of polymeric drug delivery systems, varnishes, liposomes and nanoparticles is presented.

Expert opinion: The use of local sustained-release delivery systems applied to the oral cavity has numerous clinical, pharmacological and toxicological advantages over conventional means. Various sustained-release technologies have been suggested over the course of several years. The current research on oral diseases concentrates predominantly on improving the drug delivery. With progress in pharmaceutical technology, sophisticated controlled-release platforms are being developed. The sustained release concept is innovative and there are few products available for the benefit of all populations. Harmonizing academic research with the dental industry will surely expedite the development and commercialization of more products of such pharmacological nature.     

Lectin-mediated drug delivery in the oral cavity

The delivery of therapeutic agents to, or via, the oral cavity is limited by the efficient removal mechanisms that exist in this area. Lectins are proteins or glycoproteins that bind to specific sugar residues, and can, therefore, interact with the glycoconjugates present on cell surfaces or salivary mucins. Endogenous lectins could also be used as points of attachment for carbohydrate-containing delivery systems. This review considers the possibility of using lectins as targeting agents within the oral cavity and reports on some of the limited number of studies completed to date. As lectins are multifunctional molecules, the possibility of using them as both targeting and therapeutic agents is considered. Lectin-containing delivery systems are a potential innovation for targeted and prolonged therapy within the oral cavity, but considerations such as toxicity and cost will need to be addressed before their routine use becomes a reality.     

Matrix- and reservoir-based transmucosal delivery systems

Traditionally, per-oral delivery has been the primary route of administration for therapeutic agents targeting systemic delivery. However, oral administration subjects these compounds to extensive presystemic elimination, which may include gastrointestinal degradation, metabolism, or first-pass clearance via the liver, and may ultimately result in poor bioavailability. Parenteral routes, such as intravenous or intramuscular, permit therapeutic agents to gain direct entry into the systemic circulation and, therefore, reach the intended site of action more rapidly. Unfortunately, this mode of drug administration entails numerous disadvantages, including the requirement for close medical supervision and the need for specialized equipment. Transmucosal absorption of nitroglycerin from solutions through the oral cavity was demonstrated in the mid-nineteenth century, and since that time various conventional drug delivery systems for oral mucosal delivery have been proposed and have achieved clinical application. Technologic advances in biomaterials and techniques have resulted in the formulation of novel designs more pertinent to the oral cavity, meeting the challenges of the physicochemical properties of the drug entity itself and achieving the therapeutic aims of the drug delivery system. Issues of patient compliance and convenience have recently resulted in a trend toward once-a-day administration regimens, requiring drugs with high potency and sustained effect. Such drugs usually have a short biologic half-life, exhibit poor permeability and solubility, and are susceptible to enzymatic degradation. However, because of the advantages of delivering a drug through the oral mucosa, these drugs are viable candidates for delivery via this route. Many investigators have studied the potential of transmucosal delivery through the oral cavity, and the oral mucosa is increasingly being considered as a plausible route for many drug classes. Sublingual tablets, oral lozenges, chewing gum systems, and other dosage forms represent potential drug delivery systems for the oral mucosa, but most of the literature has not discussed information on specific drug delivery systems and their challenges. This article examines the anatomy, physiology, and absorption properties of the oral mucosal environment; explores the considerations for a transmucosal system; reviews these types of systems; and evaluates and proposes matrix and reservoir transmucosal applications.     

Peptides in oral diseases

The oral cavity is home to numerous viruses and micro-organisms recognized as having a role in various oral diseases as well as in infections in other parts of the body. Indeed, in general a microbial infection underlies or is believed to underlie the ample spectrum of oral diseases, from tooth enamel decay to periodontal lesions, from candidiasis to virus-induced oral squamous cell carcinomas, and bullous autoimmune oral disorders. This clinico-pathological context stresses the need of targeted therapies to specifically kill infectious agents in a complex environment such as the oral cavity, and explains the current interest in exploring peptide-based therapeutic approaches in oral and dental research. Here, we review the therapeutic potential of antimicrobial peptides such as LL-37, beta defensins, adrenomedullin, histatins, and of various peptides modulating gene expression and immuno-biological interaction(s) in oral diseases.     

Intraoral drug delivery

The oral availability of many drugs is poor because of the pH of the stomach, the presence of enzymes, and extensive first-pass metabolism. Traditionally, these drugs have been administered as parenteral drug delivery systems, which invariably leads to poor patient compliance. This has made the pharmaceutical industry look for alternative routes of drug delivery. One possible route is via the oral cavity. This review compares the many different and novel drug delivery systems that have been developed for absorption through the oral cavity as well as those that undergo quick disintegration or dissolution in the oral cavity. Systems for oral delivery include mucoadhesive patches, films and tablets, as well as quick-disintegrating wafers, tablets and films. There are many examples of drugs that have been formulated into intraoral absorptive drug delivery systems as well as quick-disintegrating drug delivery systems. The fact that most of the research being conducted on intraoral drug delivery systems is driven by pharmaceutical manufacturers demonstrates the need for such drug delivery systems. As we begin to discover more about oral mucosal drug delivery, and develop much more sophisticated drug delivery systems, many more drugs will be formulated as intraoral systems. There is no doubt that the need for these systems is real, and many classes of drugs could benefit from this noninvasive type of drug delivery. The challenge now is to synthesize drug moieties that exhibit increased absorption across the oral mucosa and are more potent in their action. Intraoral drug delivery systems are possibly one of the very few drug delivery systems that seem to be ahead of the development of new drug compounds that are effectively absorbed across tissue membranes.     

Recent developments in the use of bioadhesive systems for delivery of drugs to the oral cavity

The delivery of therapeutic agents to, or via, the oral cavity is limited by the efficient removal mechanisms that exist in this area. Bioadhesive formulations have been developed to allow prolonged localized therapy and enhanced systemic delivery. The oral mucosa however, while avoiding first-pass effects, is a formidable barrier to drug absorption, especially for "biopharmaceutical" products arising from the recent innovations in genomics and proteomics. Bioadhesive polymers are typically hydrophilic macromolecules containing numerous hydrogen-bonding groups. Second-generation bioadhesives include modified or new polymers that allow enhanced adhesion and/or drug delivery, along with site-specific ligands such as lectins. Over the last 20 years, a range of bioadhesive formulations have been developed for the oral cavity, but only comparatively few have found their way onto the market. This review will consider some recent developments in the use of bioadhesive buccal systems, notably the development of new polymers, advanced delivery systems, and the exploitation of the multifunctional properties of some bioadhesives.     

Intraoral delivery of antimicrobials

Antimicrobial therapies for oral diseases have been in use for centuries, but have undergone rapid changes in the last decade. In the coming years, antimicrobial strategies will become more sophisticated and efficacy will be greatly improved as new therapeutic technologies emerge. New delivery systems for common antimicrobials and novel agents to modulate the immune system, as well as biofilm formation and maturation, may be on the horizon. This review describes the development and the application of intraoral antimicrobial drug delivery in the oral environment. Current clinical uses of antimicrobials as well as future approaches to the treatment and prevention of oral infectious diseases are discussed.     

Effect of chitosan on a periodontal pathogen Porphyromonas gingivalis

Local delivery systems of antimicrobial agents for treatment of the periodontal diseases received considerable attention during the past decade due to the disadvantages of the systemic administration. An ideal formulation should exhibit ease of delivery, a good retention at the application site, and a controlled release of the drug. The application of bioadhesive gels provides a long stay in the oral cavity, adequate drug penetration, high efficacy and acceptability. In dentistry and oral medicine, various applications of chitosan, which is a bioadhesive polymer have been proposed due to its favorable properties such as biocompatibility and biodegradability. The aim of this study was to determine the antimicrobial activity of chitosan formulations either in gel or film form against a periodontal pathogen, Porphyromonas gingivalis. The viscosity, bioadhesive properties and antimicrobial activity of chitosans at different molecular weight and deacetylation degree were evaluated in the absence or presence of chlorhexidine gluconate (Chx), incorporated into the formulations at 0.1 and 0.2% concentrations. The flow property of the gels were found to be suitable for topical application on the oral mucosa and to syringe into the periodontal pocket. Bioadhesion of the gels and films examined ex-vivo using fresh porcine buccal mucosa showed that both the film and gel formulations exert bioadhesive properties and was not affected by incorporation of Chx. Chitosan is shown to have an antimicrobial activity against P. gingivalis and this was higher with high molecular weight chitosan. The combination of chitosan with Chx showed a higher activity when compared to that of Chx alone, which would provide Chx application at lower concentrations thus avoiding its unwanted side effects. Chitosan films and gels seem to be promising delivery systems for local therapy of periodontal diseases with its bioadhesive property and antimicrobial activity.     

New developments and opportunities in oral mucosal drug delivery for local and systemic disease

The oral mucosa's accessibility, excellent blood supply, by-pass of hepatic first-pass metabolism, rapid repair and permeability profile make it an attractive site for local and systemic drug delivery. Technological advances in mucoadhesives, sustained drug release, permeability enhancers and drug delivery vectors are increasing the efficient delivery of drugs to treat oral and systemic diseases. When treating oral diseases, these advances result in enhanced therapeutic efficacy, reduced drug wastage and the prospect of using biological agents such as genes, peptides and antibodies. These technologies are also increasing the repertoire of drugs that can be delivered across the oral mucosa to treat systemic diseases. Trans-mucosal delivery is now a favoured route for non-parenteral administration of emergency drugs and agents where a rapid onset of action is required. Furthermore, advances in drug delivery technology are bringing forward the likelihood of transmucosal systemic delivery of biological agents.     

肠道菌群失调与口腔疾病研究概述——以儿童龋齿为例

众所周知,微生物菌群失调与人体多种疾病密切相关。口腔和肠道作为人体两大微生物栖息地,在微生物相关疾病中发挥着重要作用。尽管口腔和肠道是通过胃肠道连接的连续区域,但由于口腔-肠道屏障的存在,口腔和肠道微生物分布得到很好的隔离。然而,在口腔-肠道屏障功能障碍的情况下,口腔微生物群可以转移到肠黏膜。相反,肠道菌群失调也会对口腔微生物组成造成一定影响。口腔到肠道和肠道到口腔的微生物易位可以重塑彼此的微生物生态系统,最终调节机体生理功能和病理过程。然而迄今为止,口腔-肠道微生物的相互作用在口腔疾病中的发病机制一直未被充分认识。本文中,我们将重点介绍口腔-肠道微生物串扰在口腔疾病及儿童龋齿中的作用,为后续通过操纵肠道微生物治疗口腔疾病和儿童龋齿提供理论依据。     

蜂胶治疗口腔疾病的药理作用和临床应用现状

本对近年来蜂胶用于治疗口腔疾病的有关报道作一总结，概括论述了蜂胶的抗病原微生物、抗炎镇痛、抗溃疡、镇静麻醉以及其它药理作用和毒性评价，并对其治疗龋齿病、牙体病、牙髓病、牙周组织病、口腔粘膜病等类口腔疾病的临床疗效进行了整理归纳，同时对蜂胶作为一种高效天然药材应用于口腔疾病的独特优势和应用前景作出了展望。     

Drug Delivery Systems for Intraperitoneal Therapy

Disorders associated with the peritoneal cavity include peritoneal adhesions and intraperitoneal (IP) malignancies. To prevent peritoneal adhesions, physical barrier devices are used to prevent organs from contacting other structures in the abdomen and forming adhesions, or pharmacological agents that interfere with adhesion formation are administered intraperitoneally. IP malignancies are other disorders confined to the peritoneal cavity, which are treated by combination of surgical removal and chemotherapy of the residual tumor. IP drug delivery helps in the regional therapy of these disorders by providing relatively high concentration and longer half-life of a drug in the peritoneal cavity. Various studies suggest that IP delivery of anti-neoplastic agents is a promising approach for malignancies in the peritoneal cavity compared to the systemic administration. However, IP drug delivery faces several challenges, such as premature clearance of a small molecular weight drug from the peritoneal cavity, lack of target specificity, and poor drug penetration into the target tissues. Previous studies have proposed the use of micro/nanoparticles and/or hydrogel-based systems for prolonging the drug residence time in the peritoneal cavity. This commentary discusses the currently used IP drug delivery systems either clinically or experimentally and the remaining challenges in IP drug delivery for future development.     

Preparation and characterisation of polymeric films containing propolis

Propolis is a natural resinous substance, with a high polyphenol content, produced by honeybees and characterized by antimicrobial, anti-inflammatory and antioxidant properties, which make it useful for different therapeutic applications, especially in the stomatological field in the treatment of mild buccal diseases. The aim of this study was to prepare some polymeric film formulations for local delivery of propolis into the oral cavity. For this purpose, a commercial propolis fluid extract and three extracts (dry, ethanolic, glyceric) obtained from raw propolis were previously characterized with regard to their polyphenolic fraction composition and their antimicrobial properties against Candida albicans, Escherichia coli and Staphylococcus aureus strains. Commercial fluid extract, judged the most suitable in terms of polyphenol content and antimicrobial activity, was then incorporated into alginate, alginate-chitosan and agar films, prepared using a casting-solvent evaporation technique, which were finally evaluated in terms of thickness, total polyphenol content, in vitro polyphenol release profiles, swelling behaviour and antimicrobial properties. Our results demonstrate that polymeric films can be proposed as new propolis vehicles in the treatment of dental and buccal diseases.     

Matrices and scaffolds for drug delivery in dental, oral and craniofacial tissue engineering

Current treatments for diseases and trauma of dental, oral and craniofacial (DOC) structures rely on durable materials such as amalgam and synthetic materials, or autologous tissue grafts. A paradigm shift has taken place to utilize tissue engineering and drug delivery approaches towards the regeneration of these structures. Several prototypes of DOC structures have been regenerated such as temporomandibular joint (TMJ) condyle, cranial sutures, tooth structures and periodontium components. However, many challenges remain when taking in consideration the high demand for esthetics of DOC structures, the complex environment and yet minimal scar formation in the oral cavity, and the need for accommodating multiple tissue phenotypes. This review highlights recent advances in the regeneration of DOC structures, including the tooth, periodontium, TMJ, cranial sutures and implant dentistry, with specific emphasis on controlled release of signaling cues for stem cells, biomaterial matrices and scaffolds, and integrated tissue engineering approaches.     

九佛开展小学生口腔健康教育及窝沟封闭预防龋病和牙周病效果评价

目的评价在学校开展口腔健康教育及窝沟封闭预防牙周病和龋病的效果。方法将应行六龄齿窝沟封闭的390名学生进行分组,一组对照组及两组实验组。由于各种原因家长不同意实施六龄齿窝沟封闭术,也无系统的开展口腔健康教育活动的78名学生为对照组。把余下的312名学生随机分为两组实验组。实验组一为系统的开展健康教育活动及行六龄齿窝沟封闭术的学生。实验组二是只对学生及家长宣教六龄齿行窝沟封闭的重要性,单纯行六龄齿窝沟封闭术而无系统的开展口腔健康教育活动的学生。半年、一年复查口腔健康知识、健康行为、牙周健康及患龋情况。结果实施健康教育后,在口腔健康知识知晓率、行为改善率及牙周健康状况几方面,实验组一取得的效果明显高于对照组与实验组二,差异有统计学意义（P〈O．05）。行六龄齿窝沟封闭术后,实验组一与实验组二复查均无患龋。结论以学校为基础开展口腔健康教育及六龄齿窝沟封闭术对预防龋病和牙周病具有重要的意义。     

Solubility enhancers for oral drug delivery

With recent progress in high throughput screening of potential therapeutic agents, the number of poorly water-soluble drug candidates has risen sharply and formulating for poorly water-soluble compounds for oral delivery now presents one of the most frequent and greatest challenges to scientists in the pharmaceutical industry. Many new drugs and potential therapeutic compounds under investigation possess high lipophilicity, poor water solubility, and low oral bioavailability. Furthermore, development of improved oral dosage forms for currently marketed drugs can also enhance their therapeutic value. Oral delivery systems designed for poorly water-soluble drugs include micelles with surfactants, microemulsions, self-emulsifying/microemulsifying drug delivery systems (SEDDS/SMEDDS), solid dispersions, microspheres and cyclodextrin inclusion complexes. These delivery systems have been shown to enhance oral bioavailability and therapeutic effects of poorly water-soluble drugs mainly by improving the poor solubility. As a consequence of extensive research, various oral delivery systems for poorly water-soluble agents are being developed in clinical phases worldwide. New formulation technologies and multidisciplinary expertise may lead to development of advanced and effective oral drug delivery systems applicable to a wide range of poorly water-soluble drugs in the near future.