Intraoral Drug Delivery Research Articles

Intraoral Drug Delivery: Highly Thiolated κ-Carrageenan as Mucoadhesive Excipient.

This study aims to design a novel thiolated κ-carrageenan (κ-CA-SH) and evaluate its potential as an excipient for the design of mucoadhesive drug delivery systems. Native κ-carrageenan (κ-CA) was thiolated with phosphorous pentasulfide in sulfolane and characterized via 1H NMR, FTIR, as well as Ellman's test. Cytotoxicity was assessed via resazurin assay. In vitro release of the model drug, benzydamine hydrochloride, was determined. Tensile and mucosal residence time studies were performed on buccal and small intestinal mucosa. Mucoadhesive features were investigated via rheological studies with freshly isolated porcine mucus. Thiolated κ-CA (κ-CA-SH) with 1213.88 ± 52 µmol/g thiol groups showed no cytotoxicity at a concentration of 1% (m/v) and low cytotoxicity up to 2% (m/v). Benzydamine hydrochloride showed slow release in solution for both polymers. Tensile studies on buccal and intestinal mucosa showed an up to 2.7-fold and 7.7-fold enhancement in the maximum detachment force (MDF) and total work of adhesion (TWA) of κ-CA-SH vs. κ-CA, respectively. The κ-CA-SH exhibited an up to 4.4-fold improved dynamic viscosity with mucus and significantly prolonged residence time on mucosa compared to native κ-CA. Since highly thiolated κ-CA shows a slow release of positively charged active pharmaceutical ingredients and enhanced mucoadhesive properties, it might be a promising excipient for local drug delivery in the oral cavity.

Smart intraoral systems for advanced drug delivery

AbstractDrug administration through the oral cavity is considered to be a convenient, effective, and time‐saving strategy in the clinic with high safety and quick onset, especially for patients with needle fear and swallowing difficulties. Without the degradation in gastrointestinal tract and first‐pass metabolism, the intraoral drug delivery system turns out to be an attractive option for macromolecule absorption, which will provide a promising platform for the successful delivery of protein, peptide, nucleic acid, and polysaccharide. Nevertheless, limited bioavailability, short retention time, and poor reproducibility pose a major hurdle to the further application of conventional intraoral drug delivery systems. Recent advances in chemical, material, and engineering techniques bring great opportunities to improve intraoral system fabrication and applications, owing to the high biocompatibility and functional diversity. In this review, we systematically summarize the recent development of smart intraoral drug delivery systems, including fast dissolving oral films, medicinal chewing gum systems, intraoral mucoadhesive systems, physical assisted systems, intelligent intraoral device, and chemically assisted systems. Moreover, the challenges and prospects for clinical and industrial applications of current strategies are well discussed. It is believed that the smart intraoral system would serve as a promising candidate to improve human life in the near future.

MMP-8-Responsive Polyethylene Glycol Hydrogel for Intraoral Drug Delivery

Currently available drug delivery systems for oral diseases suffer from short retention time and poor local concentrations at the target site. A biodegradable stimulus-responsive hydrogel was synthesized in the present study to evaluate its application as an environmentally sensitive carrier for on-demand intraoral drug delivery. The hydrogel was synthesized from diacrylate-containing polyethylene glycol–based scaffolds and a cysteine-terminated peptide crosslinker (CGPQG↓IWGQC) via a Michael-type addition reaction. Because CGPQG↓IWGQC can be cleaved by matrix metalloproteinase 8 (MMP-8), minocycline hydrochloride, bovine serum albumin, or an antibacterial peptide (KSL) was incorporated into the scaffolds to evaluate the MMP-8-responsive release behavior of the on-demand drug delivery system. Hydrogel characterization and gelation kinetics were examined with gel time, Fourier-transform infrared spectroscopy, scanning electron microscopy, and measurements of rheologic parameters. Degradation behavior and MMP-8-responsive drug release were performed by high-performance liquid chromatography and protein-specific assay. Biocompatibility evaluation indicated that the hydrogels were noncytotoxic. Antibacterial testing demonstrated that the released drugs were able to maintain bioactivity. Taken together, these results suggest that the MMP-8-sensitive hydrogel is a promising candidate for on-demand intraoral localized drug delivery. Because MMP-8 is one of the most important biomarkers for periodontitis, the MMP-8-responsive hydrogel has potential to be used for in situ adaptive degradation in response to chronic periodontitis and peri-implantitis. This notion has to be tested in animal models of periodontal disease.

Polymeric drug delivery systems for intraoral site-specific chemoprevention of oral cancer.

Oral cancer is among the most prevalent cancers in the world. Moreover, it is one of the major health problems and causes of death in many regions of the world. The traditional treatment modalities include surgical removal, radiation therapy, systemic chemotherapy, or a combination of these methods. In recent decades, there has been significant interest in intraoral site-specific chemoprevention via local drug delivery using polymeric systems. Because of its easy accessibility and clear visibility, the oral mucosa is amenable for local drug delivery. A variety of polymeric systems-such as gels, tablets, films, patches, injectable systems (e.g., millicylindrical implants, microparticles, and in situ-forming depots), and nanosized carriers (e.g., polymeric nanoparticles, nanofibers, polymer-drug conjugates, polymeric micelles, nanoliposomes, nanoemulsions, and polymersomes)-have been developed and evaluated for the local delivery of natural and synthetic chemopreventive agents. The findings of in vitro, ex vivo, and in vivo studies and the positive outcome of clinical trials demonstrate that intraoral site-specific drug delivery is an attractive, highly effective and patient-friendly strategy for the management of oral cancer. Intraoral site-specific drug delivery provides unique therapeutic advantages when compared to systemic chemotherapy. Moreover, intraoral drug delivery systems are self-administrable and can be removed when needed, increasing patient compliance. This article covers important aspects and advances related to the design, development, and efficacy of polymeric systems for intraoral site-specific drug delivery. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1383-1413, 2018.

Biophysical and biological characterization of intraoral multilayer membranes as potential carriers: A new drug delivery system for dentistry

The current study developed through layer-by-layer deposition a multilayer membrane for intraoral drug delivery and analyzed the biochemical, functional, and biological properties of this membrane. For that purpose, we designed a three-layer chlorhexidine-incorporated membrane composed by pure chitosan and alginate. The biochemical, functional, and biological properties were analyzed by the following tests: degradation in saliva medium; controlled drug release; water absorption, mass loss; pH analysis; and biocompatibility through fibroblast cell viability by MTT assay. All tests were conducted at three different periods (24, 48 and 72hours). The results demonstrated that hybrid membranes composed by alginate and chitosan with glycerol had greater water absorption and mass loss in buffer solution and in artificial saliva. The controlled drug release test revealed that the hybrid membrane exhibited greater drug release (0.075%). All chlorhexidine-incorporated membranes reduced the cell viability, and chitosan membranes with and without glycerol did not interfere with fibroblast viability. The biochemical and biophysical characteristics of the designed membranes and the findings of cell viability tests indicate great potential for application in Dentistry.

An intra-oral drug delivery system design for painless, long-term and continuous drug release

To supplement traditional intravenous injections and other drug delivery pathways, we propose an intra-oral implant system that can allow relatively non-invasive procedures for a drug loading pathway into human blood throughout the maxillary spongy bone. Due to lack of periodontal ligaments and the pulp structure, continuous and steady drug release throughout dental implants may minimize pain, and have therapeutic applications for patients who frequently undergo invasive procedures for conditions such as diabetes mellitus (DM). First we design the intra-oral drug delivery system (DDS) modules based on dental implant fixtures. After the fixture is implanted into the maxilla, the drug is loaded into the DDS structures which are replaceable for drug reloading, replacement or further sterilization. Two different DDS modules are investigated: mechanical and piezoelectric. The mechanical DDS module embedded in the prosthetic abutment combines rotation and screw-driven feeding for drug delivery may achieve quantitative release with an accuracy up to 10μl. On the other hand, the piezoelectric DDS module can output stable volumes over at least 10min with a maximum flow rate of 2.5ml/min, which is adequate for clinical applications. We also use finite element simulations to evaluate the bearing stress around the dental fixture, and the drug flux line during drug release. The bearing stress during drug release is less than 1MPa, which is about 1/10 of the occlusal force. Furthermore, in animal experiments, it is found that insulin release through this DDS module may decrease blood sugar value within 5min, which is as fast as traditional intra-venous injections, and last for 20min. However, more evaluations and improvements are still needed to establish clinical practice and standard procedures, including the development of wireless control techniques and neat module integration.

In vitro evaluation of thio-poly acrylic acid for intraoral delivery

Context: Intraoral drug delivery as mucosal delivery pathway provides a huge platform in the pharmaceutical field.Objective: Combining mucoadhesiveness and controlled release of thio-poly acrylic acid as advanced excipient for buccal drug delivery.Materials and methods: Mediated by carbodiimide, cysteine was covalently attached to poly acrylic acid. This thiomer was assessed with regard to cytotoxicity, stability, mucoadhesion, and rheology as well as release behavior of Lidocaine.Results: Stability assays of thio-poly acrylic acid were complying with United States Pharmacopeia requirements. Mucoadhesion assay such as tensile (total work of adhesion), bioadhesion, rotating cylinder revealed as this thiomer was superior in comparison to non-thiolated poly acrylic acid with 7.61-fold, 2.8-fold, 5.61-fold improvement, respectively without any toxic effect. The cell viability exhibited over 90% after incubation time of 3 h and 24 h respectively. Lidocaine release showed 1.98-fold more controlled release over 3 h in comparison to unmodified poly acrylic acid.Conclusion: Taken the findings in consideration, thio-poly acrylic acid provides excellent stability, controlled release, and superior mucoadhesive features. The prolonged residence time of thio-poly acrylic acid represents a pillar in the buccal drug delivery.

Synthesis and characterization of thiolated β-cyclodextrin as a novel mucoadhesive excipient for intra-oral drug delivery

The objective of the present study was to synthesize and characterize cysteamine conjugated β-cyclodextrin (β-CD-Cys) as a novel mucoadhesive oligomeric excipient for intra-oral drug delivery. β-CD-Cys conjugates were obtained in a two-step synthetic pathway, whereby, vicinal diol groups of the oligomer were oxidized using increasing concentrations of sodium-per-iodate (NaIO4), prior to the covalent coupling of cysteamine via reductive amination. Quantification of immobilized thiol groups through Ellman's test revealed 561.56±81μmol/g, 1054.26±131μmol/g and 1783.92±201μmol/g of free thiol groups attached to the oligomer backbone depending on the extent of oxidation. β-CD-Cys conjugates at concentrations of 0.5% (m/v) showed no toxic effects on Caco-2 cells within 72h. Furthermore, β-CD-Cys conjugates displayed a 4-fold improved water solubility compared to the parent oligomer. β-CD-Cys conjugates (β-CD-Cys561, β-CD-Cys1054 and β-CD-Cys1783) showed 2.86-, 15.09- and 49.08-fold improved retention time on porcine intestinal mucosa and 9.66-, 16.43- and 34.51-fold improved on the porcine buccal mucosa, respectively. Formation of inclusion complexes of miconazole nitrate and β-CD-Cys1054 resulted in 150-fold increased solubility of miconazole nitrate. According to these results, it seems that β-CD-Cys conjugates might provide a new promising tool for delivery of poorly water soluble therapeutic agents, such as miconazole nitrate for intra-oral delivery.

Formulation and optimization of fast dissolving intraoral drug delivery system for clobazam using response surface methodology.

Clobazam is a newer 1,5-benzodiazepine used for the treatment of epilepsy. It is better tolerated and less sedating than other benzodiazepines. Absorption of the drug can be impacted by oral fast dissolving dosage form; this may have implications for epilepsy in pediatrics and those having difficulty in swallowing tablets/capsules resulting in improved patient compliance. The purpose of the present investigation was to formulate and optimize clobazam oro-dissolving tablets by direct compression method using response surface methodology (RSM). Oro-dispersible tablets of clobazam were prepared by direct compression method using crospovidone (2-6%) as a superdisintegrant, microcrystalline cellulose (MCC) (20-40%) was used as diluents along with directly compressible mannitol to enhance mouth feel. A 32 full factorial design was applied to investigate the combined effect of two formulation variables: amount of crospovidone and MCC over the independent variables disintegration time, wetting time and percent drug release. Disintegration time showed by all formulations was found to be in the range of 24.3-193 s based on evaluation parameters the formulation containing 6% of crospovidone and 30% of MCC showed promising performance against all other formulations. The results demonstrated that the RSM could efficiently be applied for the formulation of clobazam oro-dispersible tablets; therefore, constitute an advance in the management of epileptic attacks.

Fast-dissolving intra-oral drug delivery systems

Background: Fast-dissolving delivery systems address the needs of populations requiring special attention, such as paediatric and geriatric patients. Difficulty in swallowing medicines is often encountered by these patients, leading to non-compliance with medication. This results in ineffective treatment. Fast-dissolving delivery systems, besides overcoming these difficulties, offer additional advantages such as more rapid drug absorption, extension of patent life of existing drugs, elimination of the need for water, and increased ease of taking medicines while travelling and for patients with restricted water intake. Objective: To review researchers, companies and institutions involved in fast-dissolving tablet technology to understand the unique pharmacotherapeutic need of relevant age groups and to encourage development of new fast-dissolving systems for existing drugs. Method: A detailed analysis of prominent research in this field is presented, giving special emphasis to patented activities and developments anticipated in the near future. Conclusion: Freeze-drying remains at the apex of fast-dissolving tablet technologies, but new-generation technologies involving compaction methods can produce robust, versatile tablets with exceptional qualities, extending the application of this dosage form.

Development of a GC-MS assay for the determination of fentanyl pharmacokinetics in rabbit plasma after sublingual spray delivery.

Development of a GC-MS assay for the determination of fentanyl pharmacokinetics in rabbit plasma after sublingual spray delivery.

Biocompatible flow sensor with integrated solvent concentration measurement

The concept and development of two microsensors for application in an intraoral drug delivery system (DDS) that has the size of two molar teeth is presented. The microsensors add intelligence to the DDS: a flow sensor measuring the mass flow of the drug solution and a concentration sensor detecting when the drug pill inside the DDS is going to be exhausted. Both sensors are monolithically integrated on one sensor chip having dimensions of 5mm×3mm×1mm. The flow sensor is optimized for a measuring range of 50μl/h. The concentration sensor is able to measure concentrations which are around the solubility limit of the used drug substance. The sensor we report here provides the opportunity to dynamically measure the concentration in the close vicinity of the location where the mass flow is measured. Thus, the combined sensor is not only able to measure the flux of the drug solution but is also able to determine the flux of a dissolved substance in real time.

Intelligent intraoral drug delivery microsystem

The authors report on the concept and development of an intelligent intraoral drug delivery microsystem, that provides an alternative approach for the treatment of addiction and chronic diseases. The drug delivery system (DDS) comprises a medication replacement reservoir, a medication release mechanism, a built-in intelligence, a remote control, microsensors, and microactuators. It is thus able to release the medication in a controlled manner according to the patient needs. The emphasis of this article is on the application of sensors and microfluidic components in a real microsystem and also showing some details of two system components, namely, the osmotic pump and the flow sensor. The motivation for the microfluidic approach, the concept of the DDS, the requirements for this specific application, and the arising problems will be presented and discussed. Regarding the sensors and actuators, the problems mainly concern size and power consumption. A major challenging aspect of microfluidic component development is to avoid clogging of small channels because of particles and recrystallization of saturated fluids.

Study of the clinical usefulness of a dental drug system for selective reduction of mutans streptococci using a case series

The aim of this study was to evaluate the clinical efficacy and safety of a dental drug delivery system (3DS) for the selective reduction of mutans streptococci. Twenty patients with high levels of mutans streptococci in saliva participated. The efficacy of 0.2% chlorhexidine (CHX) delivered by 3DS in reducing the salivary levels of mutans streptococci compared with total streptococci and lactobacilli was investigated. Each subject was treated by professional mechanical tooth cleaning (PMTC) and subsequently individual trays with CHX for 5 min. Salivary bacterial samples were taken at the baseline and weeks 1-12. A significant reduction in the colony count of mutans streptococci was observed during the first 4 weeks compared with the baseline count, while no significant decrease in the count of total streptococci or lactobacilli was found during 12 weeks. In particular, the proportion of mutans streptococci in total streptococci remained low after 12 weeks. Our results indicate that the new 3DS used in combination with PMTC appears to be a promising intraoral drug delivery system which, when used with a low CHX concentration selectively, effectively reduces mutans streptococci in the oral cavity with no adverse effects.

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.

A polymeric device for delivery of anti-microbial and anti-fungal drugs in the oral environment: effect of temperature and medium on the rate of drug release

Objectives. The use of drug delivery systems in dentistry is a relatively new area of research with the exception of fluoride ion release from polyalkenoate cements and their predecessor silicate cements. The present study is based on the use of a bio-compatible material ethylene vinyl acetate copolymer (EVA) that enables constant release of drugs of therapeutic levels over extended periods of time at doses suitable for the treatment of oral conditions. Method. Polymer casting solutions were made by dissolving EVA and the drug in the ratio of 40:1 in 70 ml of dichloromethane at 38 °C for 6 h. Thin square films of 3×3 cm 2 with a thickness of 1 mm were cut from the dry sheet obtained by solvent evaporation technique. Drug loaded samples were extracted for a minimum of 14 days in 10 ml medium (double distilled water or water/ethanol (4:1)) which was replaced daily. Spectral measurements were made to follow changes in optical densities (OD) during release kinetics. Effect of temperature (24 and 37 °C) on the rate of drug release was studied and the energies of activation (Δ E ≠) were calculated using Arrehenius equation for the diffusion (translocation) of molecules of tetracycline hydrochloride (TTH), doxycycline hydrochloride (DOH), and chlorhexidine diacetate (CDA) in water as extracting medium. Effect of extracting medium (water and water/ethanol (4:1)) was also investigated on the rate of drug release measurements at 24 °C. Results. Analysis of variance of the data revealed that significantly enhanced rates were observed at the higher temperature (37 °C) and when extracting medium was changed to water/ethanol (4:1) for TTH, DOH and CDA ( p<0.0015). The enhanced rate values seem to be due to the formation of channels in the polymer. The largest activation energy (21.83 kcal mol −1) observed for CDA was interpreted as due to the highest average molecular weight (626) compared to TTH (481) and DOH (481). Significance. These in vitro rate of drug release measurements will provide a basis for establishing a novel approach (treatment modality) for sustained intra-oral drug delivery over extended time periods using laboratory methods and materials that are readily available to dentists.

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.

Chitosan and sodium alginate based bioadhesive tablets for intraoral drug delivery.

Bioadhesive tablets for intraoral drug delivery were prepared by directly compressing the drug with a mixture of chitosan and sodium alginate in weight ratios of 4:1, 1:1 and 1:4, and the adhesion and release characteristics of the prepared systems were evaluated in vitro and in vivo. Ketoprofen was used as a model drug. The magnitudes of the adhesion force of chitosan/alginate tablets were observed to be comparable to that of Aftach, which is a typical commercial preparation of an oral mucosal adhesive tablet. Increasing the chitosan content in the tablets resulted in a decrease in the release rate of ketoprofen. When the tablets were administered to the sublingual site of rabbits, ketoprofen from the tablets with chitosan/alginate was rapidly absorbed without an initial sharp peak. Furthermore, the plasma concentration curves for the tablet with a 1:4 chitosan/alginate ratio showed a sustained release 3 h after administration. The data presented suggest that tablets prepared from chitosan and alginate are potential candidates for intraoral drug delivery.

An intraoral drug delivery system

Topical drug therapy for ulcerative and vesiculobullous diseases of the oral mucosa has generally proved unsatisfactory because of the turbulent and changing nature of the oral cavity. The construction and use of an intraoral drug delivery system using custom carriers to deliver topical medication is described. The delivery system presented overcomes many of the obstacles associated with topical drug administration for oral lesions and provides a therapeutic alternative to systemic agents.