Critical evaluation of permeation enhancers for oral mucosal drug delivery

Background: Drug delivery via oral mucosa is an alternative method of systemic administration for various classes of therapeutic agents. Among the oral mucosae, buccal and sublingual mucosae are the primary focus for drug delivery. Buccal delivery offers a clear advantage over the peroral route by avoidance of intestinal and hepatic first-pass metabolism. However, despite offering the possibility of improved systemic drug delivery, buccal administration has been utilized for relatively few pharmaceutical products so far. One of the major limitations associated with buccal delivery is low permeation of therapeutic agents across the mucosa. Various substances have been explored as permeation enhancers to increase the flux/absorption of drugs through the mucosa, but irritation, membrane damage, and toxicity are always associated with them and limit their use. A clinically accepted permeation enhancer must increase membrane permeability without causing toxicity and permanent membrane damage. To date, the information available on oral mucosal permeation enhancement is much less than transdermal enhancement, though oral mucosa is more resistant to damage than other mucosal membranes. This article reviews the various categories of permeation enhancers for oral mucosal drug delivery, their mechanism of action, their usefulness, and the limitations associated with their use. Conclusion: To optimize the concentration of enhancer to limit its toxicity while facilitating an enhancing effect reproducibly will be a big challenge for future developments. Advances in permeability modulation and formulation with appropriate enhancers can provide for effective and feasible buccal drug delivery for many drugs, which otherwise have to be injected or ingested with water.     

Buccal Drug Delivery Systems

Buccal administration offers certain unique advantages for the drugs which cannot be easily or efficiently administered by oral or intravenous route. However, transbucccal delivery receiived relatively little attention and few well-controlled studies of buccal mucosa permeability have been conducted. The oral mucosa provides a protective covering for the underlying tissue, being as a barrier for microorganisms and toxins. This article extensively reviews the histology of buccal mucosa, permeation studies (both invitro and in vivo) of buccal drug delivery system, their development and various types of techniques and devices available for the delivery of drugs through buccal mucosa.     

Buccal Drug Delivery Systems

Abstract

Buccal administration offers certain unique advantages for the drugs which cannot be easily or efficiently administered by oral or intravenous route. However, transbucccal delivery receiived relatively little attention and few well-controlled studies of buccal mucosa permeability have been conducted. The oral mucosa provides a protective covering for the underlying tissue, being as a barrier for microorganisms and toxins. This article extensively reviews the histology of buccal mucosa, permeation studies (both invitro and in vivo) of buccal drug delivery system, their development and various types of techniques and devices available for the delivery of drugs through buccal mucosa.     

Design and evaluation in vitro of controlled release mucoadhesive tablets containing chlorhexidine

This investigation deals with the development of buccal tablets containing chlorhexidine (CHX), a bis-bis-guanide with antimicrobial and antiseptic effects in the oral cavity, and able to adhere to the buccal mucosa to give local controlled release of drug. A mucoadhesive formulation was designed to swell and form a gel adhering to the mucosa and controlling the drug release into the oral cavity.

Some batches of tablets were developed by direct compression, containing different amounts of hydroxypropylmethylcellulose (HPMC) and carbomer; changing the amount ratio of these excipients in formulations, it is possible easily modulate the mucoadhesive effect and release of drug. The in vitro tests were performed using the USP 26/NF paddle apparatus, a specifically developed apparatus, and a modified Franz diffusion cells apparatus. This last method allows a simultaneous study of drug release rate from the tablets and drug permeation through the buccal mucosa.

Similar tests have also been carried out on a commercial product, Corsodyl gel^®, in order to compare the drug release control of gel with respect to that of the mucoadhesive tablet, as a formulation for buccal delivery of CHX. While the commercial formulation does not appear to control the release, the formulation containing 15% w/w methocel behaves the best, ensuring the most rapid and complete release of the drug, together with a negligible absorption of the active agent as required for a local antiseptic action in the oral cavity.     

Expression of P-glycoprotein and CYP3A4 along the porcine oral-gastrointestinal tract: implications on oral mucosal drug delivery

Objectives: To characterize the expression of Pgp and CYP3A4 along the oral-gastrointestinal (GI) tract for understanding the potential roles of CY3A4 and Pgp in oral mucosal drug delivery.

Design: Porcine buccal mucosa, sublingual mucosa, esophagus and jejunum, ileum and colon tissues were used for studying the mRNA and protein expression of CYP3A4 and Pgp. mRNA and protein were determined using real-time quantitative polymerase chain reaction (PCR) and western blot, respectively. The expression levels of CYP3A4 and Pgp in different segments of oral-GI tract were compared.

Results: Levels of Pgp mRNA were significantly lower (14–40 times lower) in buccal and sublingual mucosa than that in intestine. In contrast, higher levels of CYP3A4 mRNA were observed in the oral mucosa as compared to that in intestine, but the difference was not statistically different. The levels of Pgp protein along the oral-GI tract followed the order: sublingual ～buccal ～esophagus < jejunum ～ileum ～ colon while the expression of CYP3A4 protein in the oral mucosa was similar to that in intestine.

Conclusion: Expression of Pgp in oral mucosa is lower than that in intestine, while the expression of CYP3A4 in oral mucosa is similar to that in intestine. Because of lower Pgp in oral mucosa, oral mucosal drug delivery can be used as an alternative strategy to avoid the coordination of Pgp and CYP3A4 metabolism in drug absorption. However, CYP3A4-dependent metabolism may play a role in oral mucosal drug delivery as in per oral-GI absorption.     

Design and Evaluation In Vitro of Controlled Release Mucoadhesive Tablets Containing Chlorhexidine

ABSTRACT

This investigation deals with the development of buccal tablets containing chlorhexidine (CHX), a bis-bis-guanide with antimicrobial and antiseptic effects in the oral cavity, and able to adhere to the buccal mucosa to give local controlled release of drug. A mucoadhesive formulation was designed to swell and form a gel adhering to the mucosa and controlling the drug release into the oral cavity.

Some batches of tablets were developed by direct compression, containing different amounts of hydroxypropylmethylcellulose (HPMC) and carbomer; changing the amount ratio of these excipients in formulations, it is possible easily modulate the mucoadhesive effect and release of drug. The in vitro tests were performed using the USP 26/NF paddle apparatus, a specifically developed apparatus, and a modified Franz diffusion cells apparatus. This last method allows a simultaneous study of drug release rate from the tablets and drug permeation through the buccal mucosa.

Similar tests have also been carried out on a commercial product, Corsodyl gel^®, in order to compare the drug release control of gel with respect to that of the mucoadhesive tablet, as a formulation for buccal delivery of CHX. While the commercial formulation does not appear to control the release, the formulation containing 15% w/w methocel behaves the best, ensuring the most rapid and complete release of the drug, together with a negligible absorption of the active agent as required for a local antiseptic action in the oral cavity.     

Mucoadhesive polymers for buccal drug delivery

Raising the concept of mucoadhesion in the 1980s, the use of mucoadhesive polymers for buccal drug delivery has been the subject of interest. Buccal route is one of the non-invasive routes comprising several advantages such as targeting the specific tissue (I), bypassing the first-pass effect (II) as well as higher patient compliance (III) and higher bioavailability (IV) have rendered administration route feasible for a variety of drugs. This review highlights the use of mucoadhesive polymers in buccal drug delivery. An overview of the oral mucosa’s anatomy, theories of mucoadhesion as well as mucoadhesive polymers is given within this review. Furthermore, recent advantages in mucoadhesive polymers according to the variety of drug delivery forms are presented.     

Polymers for Mucoadhesive Drug Delivery System: A Current Status

To overcome the relatively short gastrointestinal (GI) time and improve localization for oral controlled or sustained release drug delivery systems, bioadhesive polymers that adhere to the mucin/epithelial surface are effective and lead to significant improvement in oral drug delivery. Improvements are also expected for other mucus-covered sites of drug administration. Bioadhesive polymers find application in the eye, nose, and vaginal cavity as well as in the GI tract, including the buccal cavity and rectum. This article lays emphasis mainly on mucoadhesive polymers, their properties, and their applications in buccal, ocular, nasal, and vaginal drug delivery systems with its evaluation methods.     

Polymers for mucoadhesive drug delivery system: a current status

To overcome the relatively short gastrointestinal (GI) time and improve localization for oral controlled or sustained release drug delivery systems, bioadhesive polymers that adhere to the mucin/epithelial surface are effective and lead to significant improvement in oral drug delivery. Improvements are also expected for other mucus-covered sites of drug administration. Bioadhesive polymers find application in the eye, nose, and vaginal cavity as well as in the GI tract, including the buccal cavity and rectum. This article lays emphasis mainly on mucoadhesive polymers, their properties, and their applications in buccal, ocular, nasal, and vaginal drug delivery systems with its evaluation methods.     

Aloin delivery on buccal mucosa: ex vivo studies and design of a new locoregional dosing system

Context: Chemoprevention of potential malignant disorders or cancerous lesions that affect oral mucosae requires extended duration of treatment. Locoregional delivery of natural products could represent a promising strategy for this purpose.

Objective: To investigate the aptitude of aloin to permeate through, or accumulate in, the buccal mucosa and to develop a new prolonged oro-mucosal drug delivery system.

Materials and methods: Permeation/accumulation of aloin from Curacao Aloe (containing 50% barbaloin) was evaluated ex vivo, using porcine buccal mucosa as the most useful model to simulate human epithelium. Oro-mucosal matrix tablets were prepared by dispersing aloin (10% w/w) in Eudragit® RS 100 as, biocompatible, low permeable, pH-independent, and non-swelling polymer. The prepared tablets were evaluated for drug–polymer compatibility, weight variation, drug uniformity content, diameter, thickness, hardness, friability, swelling, mucoadhesive strength, and drug release.

Results: Aloin has low tendency to cross buccal mucosa, permeation is marginal, and high drug amounts remain entrapped into the epithelium. Matrix tablets characteristics were in agreement with pharmacopoeial requirements. Drug release showed highly reproducible Higuchian profile. Delivery through matrix tablets promoted drug accumulation in the mucosal tissue.

Discussion and conclusion: Following application of matrix tablets on porcine buccal mucosa, the amount of discharged drug recovered in the tissue should be sufficient to produce the desired effects, providing therapeutic drug levels directly at the site of action. Aloin-loaded tablets are valid candidates for prevention/treatment of potentially malignant disorders and oral cancer and could potentially lead to clinically relevant drug delivery system as coadjuvant of conventional chemotherapy/radiation therapy.     

Preface for buccal drug delivery theme issue

During the past years, buccal drug delivery has attracted the attention of researchers looking for alternative delivery routes of administration. As an alternative to oral drug delivery, the buccal mucosal route avoids the passage through the acidic gastric environment, intestinal and bacterial enzymatic activity, absorption issues associated with the intestinal epithelium (e.g. P-glycoprotein efflux), and the first pass metabolism of the liver. Therefore, the buccal route could be a good delivery route for macromolecules and other drugs not compatible with the gastrointestinal tract environment. This “Buccal Drug Delivery” special edition of Drug Development and Industrial Pharmacy aims to bring together a range of different aspects relevant to the growing field of buccal drug delivery. The special edition includes thorough reviews of the literature, as well as original research articles touching on most prominent features related to buccal drug delivery systems, such as the move toward the use of nanotechnology in different ways to facilitate buccal drug delivery with the potential to prompt future product developments.     

In vitro comparative evaluation of monolayered multipolymeric films embedded with didanosine-loaded solid lipid nanoparticles: a potential buccal drug delivery system for ARV therapy

Drug delivery via the buccal route has emerged as a promising alternative to oral drug delivery. Didanosine (DDI) undergoes rapid degradation in the gastrointestinal tract, has a short half-life and low oral bioavailability, making DDI a suitable candidate for buccal delivery. Recent developments in buccal drug delivery show an increased interest toward nano-enabled delivery systems. The advantages of buccal drug delivery can be combined with that of nanoparticulate delivery systems to provide a superior delivery system. The aim of this study was to design and evaluate the preparation of novel nano-enabled films for buccal delivery of DDI. Solid lipid nanoparticles (SLNs) were prepared via hot homogenization followed by ultrasonication and were characterized before being incorporated into nano-enabled monolayered multipolymeric films (MMFs). Glyceryl tripalmitate with Poloxamer 188 was identified as most suitable for the preparation of DDI-loaded SLNs. SLNs with desired particle size (PS) (201?nm), polydispersity index (PDI) (0.168) and zeta potential (?18.8?mV) were incorporated into MMFs and characterized. Conventional and nano-enabled MMFs were prepared via solvent casting/evaporation using Eudragit RS100 and hydroxypropyl methylcellulose. Drug release from the nano-enabled films was found to be faster (56% versus 20% in first hour). Conventional MMFs exhibited higher mucoadhesion and mechanical strength than nano-enabled MMFs. SLNs did not adversely affect the steady state flux (71.63?±?13.54?µg/cm²?h versus 74.39?±?15.95?µg/cm²?h) thereby confirming the potential transbuccal delivery of DDI using nano-enabled MMFs. Nano-enabled buccal films for delivery of DDI can be successfully prepared, and these physico-mechanical studies serve as a platform for future formulation optimization work in this emerging field.     

Potential mucoadhesive dosage form of lidocaine hydrochloride: II. In vitro and in vivo evaluation

The aim of this study was to develop a controlled release buccal mucoadhesive delivery system for systemic delivery of lidocaine hydrochloride as a model drug. In vitro release and buccal permeation as well as in vivo permeation of LDHCL patches were evaluated. The drug release and the permeability of the drug through porcine buccal mucosa were evaluated using Franz diffusion cell. In vivo evaluation of patches was carried out on rabbits as an animal model. Patches were designed in two fashions, bi-layer (BLP; LDHCL, carbopol, glycerin, pentration enhancer, and Tween 20 as the first layer; and EVA as the second layer) and triple layer (TLP; LDHCL, carbopol and glycerin as the first layer; carbopol, glycerin, pentration enhancer and pluronic F-127 as the middle layer; and EVA as the third layer) patches, respectively. Presence of oleic acid as PE in the formulation significantly enhanced the in vitro permeability of LDHCL (p<0.05), while propylene glycol monolaurate as PE suppressed it (p<0.05). The in vivo evaluation in rabbits showed that TLP had significantly higher Cmax and AUC0-8 (p<0.05) than BLP. Furthermore, TLP showed a well-controlled drug plasma concentration over 6 hr which was significantly longer than BLP (p<0.05). Patches were well adhered to buccal mucosa of the rabbits over the 8-hr study period. It was postulated that the hypothetical release mechanism of the drug and oleic acid from TLP was controlled by their diffusion through the swollen polymer network and micelled gel.     

High-energy ball milling of saquinavir increases permeability across the buccal mucosa

Saquinavir (SQV), a candidate for buccal drug delivery, is limited by poor solubility. This study identified the effects of high-energy ball milling on the buccal permeability of SQV and compared it to the effects of chemical enhancers, i.e. ethylenediaminetetraacetic acid (EDTA), sodium lauryl sulfate (SLS), polyethylene glycol (PEG) and beta cyclodextrin (β-cyclodextrin). SQV was ball milled using a high energy planetary mill (1, 3, 15 and 30?h) and permeation studies across porcine buccal mucosa were performed using franz diffusion cells. Drug was quantified by UV spectrophotometry. Both unmilled and milled SQV samples were able to permeate the buccal mucosa. Milled samples of 15?h displayed the greatest flux of 10.40?±?1.24?µg/cm^2?h and an enhancement ratio of 2.61. All enhancers were able to increase the buccal permeability of unmilled SQV, with SLS achieving the greatest flux (6.99?±?0.7?µg/cm²) and an enhancement ratio of 1.75. However, all the milled SQV samples displayed greater permeability than SLS, the best chemical enhancer for unmilled SQV. Enhanced permeability by ball milling was attributed to reduction in particle size, formation of solid dispersions and an increase in solubility of milled samples. Microscopical evaluation revealed no significant loss in mucosal cellular integrity treated with either unmilled or milled SQV. Histological studies suggest that SQV uses both the paracellular and transcellular route of transport across the mucosa, with drug treatment having no permanent affects. High-energy ball milling was superior to the chemical enhancers studied for enhancement of SQV buccal permeation.     

Oral Bioadhesive Drug Delivery Systems

The oral mucosal cavity is a feasible, safe, and very attractive site for drug delivery with good acceptance by users. The mucosa is relatively permeable and robust, shows short recovery times after stress or damage, is tolerant to potential allergens, and has a rich blood supply. Moreover, oral mucosal drug delivery bypasses the first-pass effect and avoids presystemic elimination in the gastrointestinal tract. Bioadhesive systems provide intimate contact between a dosage form and the absorbing tissue, which may result in high concentration in a local area and hence high drug flux through the absorbing tissue. The efficacy of oral bioadhesive drug delivery systems is affected by the biological environment and the properties of the polymer and the drug. In the present paper, we review systematically some relevant citations regarding the environment, strategies for oral drug delivery and evaluation, and utilization of the main polymers.     

Oral bioadhesive drug delivery systems

The oral mucosal cavity is a feasible, safe, and very attractive site for drug delivery with good acceptance by users. The mucosa is relatively permeable and robust, shows short recovery times after stress or damage, is tolerant to potential allergens, and has a rich blood supply. Moreover, oral mucosal drug delivery bypasses the first-pass effect and avoids presystemic elimination in the gastrointestinal tract. Bioadhesive systems provide intimate contact between a dosage form and the absorbing tissue, which may result in high concentration in a local area and hence high drug flux through the absorbing tissue. The efficacy of oral bioadhesive drug delivery systems is affected by the biological environment and the properties of the polymer and the drug. In the present paper, we review systematically some relevant citations regarding the environment, strategies for oral drug delivery and evaluation, and utilization of the main polymers.     

In‐Vitro Permeability of Neutral Polystyrene Particles via Buccal Mucosa

Drugs can be absorbed well in the oral cavity, which eliminates problems related to intestinal and hepatic first‐pass metabolism. Although it is well‐established that nanoparticles are small enough to penetrate/permeate epithelial barriers, there is no clear understanding of how they interact with the buccal mucosa. This work provides useful information regarding particle properties with regard to mucosal uptake and can be used for the rational design of nanocarriers. In the buccal mucosa, the uptake of neutral polystyrene nanoparticles (PP) is size‐dependent. Compared to 25 and 50 nm particles, 200 nm PP particles penetrate into deeper regions of the mucosa. This is attributed to the structure of the buccal mucosa, i.e., mucus layer and microplicae. The particles permeate the mucus layer and deposit in ridge‐like folds of superficial buccal cells. Thus, the effects of thermodynamic driving forces and/or interparticle electrostatic repulsion are enhanced and cellular uptake might be reduced for smaller particle sizes.     

Delivery of Renin Inhibitor Through Mouth Mucosa

The aim of this work was to investigate the efficiency of transporting the orally inactive renin inhibitor A-64662 through oral mucosa-floor of mouth, cheek, or gum-using the dog as an animal model. It has been demonstrated that A-64662, can be effectively delivered to the bloodstream through mouth mucosa with various dosage forms. Compared to buccal adsorption, a relatively fast onset was observed after sublingual administration of an aqueous solution. A slightly higher bioavailability but lower C_max and extended plasma drug levels were observed after sublingual administration of a slow-release gel formulation. This work has also shown that mucoadhesive patch application can provide sustained and controlled release of A-64662 by either buccal or gum administration. The absorption through the gum is slower than the cheek.     

Preparation and in-vivo evaluation of dimenhydrinate buccal mucoadhesive films with enhanced bioavailability

Abstract

Dimenhydrinate (DMH)-loaded buccal bioadhesive films for the prevention and treatment of motion sickness were prepared and optimized. This study examines the rate of drug release from the films for prolonged periods of time to reduce or limit the frequency of DMH administration. Based on preliminary studies using various polymers and concentrations, hydroxyethylcellulose (2.5, 3.0, and 3.2%), and xanthan gum (2.8%) were chosen as matrix polymers. The films were analyzed with respect to their mechanical, physicochemical, bioadhesive, swelling, and in-vitro release properties. In in-vivo pharmacokinetic studies, xanthan gum-based DMH buccal film was associated with significantly increased DMH plasma levels between 1 h and 5 h after DMH dosing when compared with an oral drug solution. The area under the curve AUC_{0–7 h} value of the mucoadhesive buccal film was two-fold higher than the oral DMH solution. Histological analysis revealed that DMH films cause mild morphological and inflammatory changes in rabbit buccal mucosa. The DMH buccal film is effective for approximately 7 h, thus representing an option for single-dose antiemetic therapy. This dosage regimen could be particularly beneficial for chain travelers who travel for long periods of time.     

Physicochemical Characterization and Evaluation of Buccal Adhesive Tablets Containing Omeprazole

The objective of this study was to develop an effective omeprazole buccal adhesive tablet with excellent bioadhesive force and good drug stability in human saliva. The omeprazole buccal adhesive tablets were prepared with various bioadhesive polymers, alkali materials, and croscarmellose sodium. Their physicochemical properties, such as bioadhesive force and drug stability in human saliva, were investigated. The release and bioavailability of omeprazole delivered by the buccal adhesive tablets were studied. As bioadhesive additives for the omeprazole tablet, a mixture of sodium alginate and hydroxypropylmethylcellulose (HPMC) was selected. The omeprazole tablets prepared with bioadhesive polymers alone had bioadhesive forces suitable for a buccal adhesive tablet, but the stability of omeprazole in human saliva was not satisfactory. Among alkali materials, only magnesium oxide could be an alkali stabilizer for omeprazole buccal adhesive tablets due to its strong waterproofing effect. Croscarmellose sodium enhanced the release of omeprazole from the tablets; however, it decreased the bioadhesive forces and stability of omeprazole tablets in human saliva. The tablet composed of omeprazole/sodium alginate/HPMC/magnesium oxide/croscarmellose sodium (20/24/6/50/10 mg) could be attached on the human cheek without disintegration, and it enhanced the stability of omeprazole in human saliva for at least 4 h and gave fast release of omeprazole. The plasma concentration of omeprazole in hamsters increased to a maximum of 370 ng/ml at 45 min after buccal administration and continuously maintained a high level of 146-366 ng/ml until 6 h. The buccal bioavailability of omeprazole in hamsters was 13.7% ± 3.2%. These results demonstrate that the omeprazole buccal adhesive tablet would be useful for delivery of an omeprazole that degrades very rapidly in acidic aqueous medium and undergoes hepatic first-pass metabolism after oral administration.