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.     

Optimization of piribedil mucoadhesive tablets for efficient therapy of Parkinson’s disease: physical characterization and ex vivo drug permeation through buccal mucosa

Objective: The aim of this study was optimization of buccal piribedil (PR) mucoadhesive tablets to improve its low bioavailability and provide controlled release for the treatment of Parkinson’s disease.

Methods: Buccal tablets were prepared by direct compression method using carbomer (CP), carboxymethyl cellulose (CMC), and hydroxypropyl methylcellulose (HPMC) as mucoadhesive polymers. Physical properties of powder mixtures and buccal tablets were evaluated. Physicochemical compatibility between ingredients was investigated with infrared spectroscopy and differential scanning calorimetry analysis. In vitro dissolution profiles and drug release kinetics of buccal tablets were investigated. Mucoadhesion and ex vivo permeation studies were performed using sheep buccal mucosa.

Results: Powder mixtures demonstrated sufficient flow properties and physical characteristics of all tablet formulations were within compendia limits. Tablet ingredients were absent of any chemical interactions. CP tablets displayed slower drug release compared to HPMC tablets with zero order release, while CMC tablets lost their integrity and released entire drug after 6?h following Higuchi model. All formulations displayed adequate mucoadhesion and steady state flux of PR through buccal mucosa were higher with HPMC compared to CP-containing tablets.

Conclusion: Overall, HPMC was found to combine desired controlled release and mucoadhesion characteristics with sufficient pharmaceutical quality for optimization of buccal tablets. Piribedil mucoadhesive buccal tablets designed for the first time may introduce a new alternative for the treatment of Parkinson’s disease.     

Evaluation of polyvinyl alcohols as mucoadhesive polymers for mucoadhesive buccal tablets prepared by direct compression

The purpose of the present work was to evaluate polyvinyl alcohols (PVAs) as a mucoadhesive polymer for mucoadhesive buccal tablets prepared by direct compression. Various polymerization degree and particle diameter PVAs were investigated for their usability. The tensile strength, in vitro adhesive force, and water absorption properties of the tablets were determined to compare the various PVAs. The highest values of the tensile strength and the in vitro adhesive force were observed for PVAs with a medium viscosity and small particle size. The optimal PVA was identified by a factorial design analysis. Mucoadhesive tablets containing the optimal PVA were compared with carboxyvinyl polymer and hydroxypropyl cellulose formulations. The optimal PVA gives a high adhesive force, has a low viscosity, and resulted in relatively rapid drug release. Formulations containing carboxyvinyl polymer had high tensile strengths but short disintegration times. Higher hydroxypropyl cellulose concentration formulations had good adhesion forces and very long disintegration times. We identified the optimal characteristics of PVA, and the usefulness of mucoadhesive buccal tablets containing this PVA was suggested from their formulation properties.     

Mucoadhesive tablets for the vaginal delivery of progesterone: in vitro evaluation and pharmacokinetics/pharmacodynamics in female rabbits

Objective: To develop mucoadhesive tablets for the vaginal delivery of progesterone (P4) to overcome its low oral bioavailability resulting from drug hydrophobicity and extensive hepatic metabolism.

Methods: The tablets were prepared using mixtures of P4/Pluronic^® F-127 solid dispersion and different mucoadhesive polymers. The tablets physical properties, swelling index, mucoadhesion and drug release kinetics were evaluated. P4 pharmacokinetic and pharmacodynamic properties were evaluated in female rabbits and compared with vaginal micronized P4 tablets and intramuscular (IM) P4 injection, respectively.

Results: The tablets had satisfactory physical properties and their swelling, in vitro mucoadhesion force and ex vivo mucoadhesion time were dependent on tablet composition. Highest swelling index and mucoadhesion time were detected for tablets containing 20% chitosan-10% alginate mixture. Most tablets exhibited burst release (～25%) during the first 2?h but sustained the drug release for ～48?h. In vivo study showed that chitosan-alginate mucoadhesive tablets had ～2-fold higher P4 mean residence time (MRT) in the blood and 5-fold higher bioavailability compared with oral P4. Further, same tablets showed 2-fold higher myometrium thickness in rabbit uterus compared with IM P4 injection.

Conclusion: These results confirm the potential of these mucoadhesive vaginal tablets to enhance P4 efficacy and avoid the side effects associated with IM injection.     

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.     

Formulation and evaluation of matrix type mucoadhesive tablets aimed at treating oral aphtha

Context: Nonsteroidal anti-inflammatory drugs (NSAIDs) are administered for pain relief from oral mucositis. However, the systemic administration of NSAIDs is limited due to the side effects of thrombocytopenia.

Objective: To avoid systemic side effects, a matrix type mucoadhesive tablet as a topical application preparation to treat oral aphtha was developed.

Methods: A mixture of hard fat with a low irritant property and mucoadhesive polymers was used as the matrix base, and indomethacin was used as a model drug.

Results: Among the water-soluble polymers, carbopol and xanthan gum increased the adhesive force of tablets prepared by the suspending method, but the tensile strength was not increased. Tablets containing ethylcellulose 10 or 45 (EC10, EC45) from a water-insoluble polymer increased the adhesive force and tensile strength. Tablets prepared by the dissolve-drying method containing EC45 showed a 1.8-fold increase of adhesiveness to the eggshell membrane compared with hard fat tablets, and showed a sustained release of the drug (17%) over an 8?h period. The drug release was increased to 28% by a modification to the dissolve-drying method using EC10.

Conclusions: Since this matrix type tablet has long-acting properties, adhesiveness and low irritating properties, its potential as a newly designed preparation to treat oral aphtha is suggested.     

Evaluation of selected polysaccharide excipients in buccoadhesive tablets for sustained release of nicotine

Some naturally occurring biocompatible materials were evaluated as mucoadhesive controlled release excipients for buccal drug delivery. A range of tablets were prepared containing 0-50% w/w xanthan gum, karaya gum, guar gum, and glycol chitosan and were tested for swelling, drug release, and mucoadhesion. Guar gum was a poor mucoadhesive and lacked sufficient physical integrity for buccal delivery. Karaya gum demonstrated superior adhesion to guar gum and was able to provide zero-order drug release, but concentrations greater than 50% w/w may be required to provide suitable sustained release. Xanthan gum showed strong adhesion to the mucosal membrane and the 50% w/w formulation produced zero-order drug release over 4 hours, about the normal time interval between daily meals. Glycol chitosan produced the strongest adhesion, but concentrations greater than 50% w/w are required to produce a nonerodible matrix that can control drug release for over 4 hours. Swelling properties of the tablets were found to be a valuable indicator of the ability of the material to produce sustained release. Swelling studies also gave an indication of the adhesion values of the gum material where adhesion was solely dependent upon penetration of the polymer chains into the mucus layer.     

Oxycellulose as mucoadhesive polymer in buccal tablets

Background: Oxycellulose (OC) is biodegradable and bioabsorbable cellulose derivative used in medicine to support hemostasis and tissue healing. Recently, its antimicrobial and immunomodulating properties, as well as its potential in modern therapeutic systems as release modifying excipient, drug carrier, and/or mucoadhesive polymer, are widely discussed. Method: To study its last-mentioned characteristics, directly compressed tablets containing 5 mg of cetylpyridinium chloride (CPC) as a model drug and 90 mg of mucoadhesive polymer [oxycellulose sodium (NaOC) alone or in a combination with one of five widely used mucoadhesive polymers] were prepared to ensure 8 hours prolonged release of CPC. Physicochemical and mucoadhesive properties of prepared tablets were evaluated. Results: Based on obtained results, tablets containing OC in combination with hydroxypropylmethylcellulose (Methocel® K100LV) or carboxymethylcellulose sodium showed the best quality parameters (friability < 0.04%, tablet thickness < 2.17 mm, tablet hardness > 85 N, residence time > 256 minutes, mucoadhesive strength > 3.45 mN/mm) and dissolution profiles (more than 81% of CPC released within 8 hours). Conclusion: NaOC embodies excellent compressing, mechanical, and mucoadhesive properties; however, formulation with higher content of NaOC only showed shorter adhesion time (107 ± 7 minutes) and faster drug release (93.66% of CPC released within 2 hours), because of its good solubility in aqueous media.     

Combining strategies to optimize a gel formulation containing miconazole: the influence of modified cyclodextrin on textural properties and drug release

Background: Miconazol, an antimycotic drug, is commonly formulated into semisolid formulations designed to be applied in the oral cavity to treat oral candidiasis. However, given its limited aqueous solubility, permeation through the biological membranes is low and therefore its activity is also limited. Cyclodextrins (CDs) have been widely used to increase the solubility and stability of poorly water-soluble drugs. Aim: The aim of this study is to formulate a gel containing an inclusion complex between a modified CD, methyl-β-cyclodextrin (MβCD), and miconazole (MCZ). The influence of the CD on the textural properties of the prepared gel and the drug release from formulation were evaluated. Methods: The gels were prepared using two polymers, Carbopol 71G and Pluronic F127, which were selected taking into account their bioadhesiveness and thermal-sensitive gelling properties, respectively. Texture profile analyses were performed at two different temperatures to ascertain the influence of the temperature on the gel texture properties. The in vitro MCZ release profiles from the prepared gel and the commercial gel formulations were evaluated and compared using modified Franz diffusion cells. Results: The addition of MβCD to the gel resulted in a decrease of the gel adhesiveness and firmness, and the MCZ release profile through f1 and f2 proved to be similar to the commercial product. Conclusions: A gel comprising miconazol in the form of an inclusion complex with MβCD showed suitable textural properties to be applied to the buccal mucosa. The MβCD enhanced the solubility of the MCZ in the gel formulation resulting in adequate in vitro drug release profiles.     

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.     

Mucoadhesive elementary osmotic pump tablets of trimetazidine for controlled drug delivery and reduced variability in oral bioavailability

The objectives of this work was preparation and evaluation of the mucoadhesive elementary osmotic pump tablets of trimetazidine hydrochloride to achieve desired controlled release action and augmentation of oral drug absorption. The drug-loaded core tablets were prepared employing the suitable tableting excipients and coated with polymeric blend of ethyl cellulose and hydroxypropyl methylethylcellulose E5 (4:1). The prepared tablets were characterized for various quality control tests and in vitro drug release. Evaluation of drug release kinetics through model fitting suggested the Fickian mechanism of drug release, which was regulated by osmosis and diffusion as the predominant mechanism. Evaluation of mucoadhesion property using texture analyzer suggested good mucoadhesion potential of the developed osmotic systems. Solid state characterization using Fourier-transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffraction spectroscopy confirmed the absence of any physiochemical incompatibilities between drug and excipients. Scanning electron microscopy analysis showed the smooth surface appearance of the coated tablets with intact polymeric membrane without any fracture. In vivo pharmacokinetic studies in rabbits revealed 3.01-fold enhancement in the oral bioavailability vis-à-vis the marketed formulation (Vastarel MR®). These studies successfully demonstrate the bioavailability enhancement potential of the mucoadhesive elementary osmotic pumps as novel therapeutic systems for other drugs too.     

Development and evaluation of buccoadhesive tablet for selegiline hydrochloride based on thiolated polycarbophil

Selegiline hydrochloride (SHCl), a monoamine oxidase B inhibitor, is used as an adjunct in the therapy of Parkinson’s disease. This study is concerned with the preparation and evaluation of mucoadhesive buccal tablet for controlled systemic delivery of SHCl. Buccal absorption of selegiline can bypass its first-pass metabolism and improve bioavailability accompanied by greatly reduced metabolite formation, which is potentially of enhanced therapeutic value in patients with Parkinson’s disease. Polycarbophil–cysteine (PCP–cys) conjugate, which is a thiolated derivative of the mucoadhesive polymer polycarbophil, was synthesized by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-mediated amide bond coupling. Tablets of SHCl based on native and thiolated polycarbophil were prepared. The prepared tablets were evaluated for drug content, swelling behavior, mucoadhesive strength, in vitro drug release, ex vivo permeation and in vitro cytotoxicity. PCP–cys tablets showed enhanced mucoadhesion and retarded drug release compared to polycarbophil tablets. Permeation data of SHCl from matrices prepared using the PCP–cys polymer revealed a significantly higher value of apparent permeability in comparison to polycarbophil, which supported the information in literature that thiolation imparts permeation enhancing properties to mucoadhesive polymers. In vitro cytotoxicity studies on PCP–cys using L-929 mouse fibroblast cell line indicated that conjugation with cysteine does not impart any apparent toxicity to polycarbophil. The results from the study indicate that the buccal delivery of SHCl using thiolated polycarbophil tablet could provide a way for improved therapy of Parkinson’s disease.     

Development of chitosan/gelatin/keratin composite containing hydrocortisone sodium succinate as a buccal mucoadhesive patch to treat desquamative gingivitis

The aim of this research was to develop chitosan/gelatin/keratin composite containing hydrocortisone sodium succinate as a buccal mucoadhesive patch to treat desquamative gingivitis, which was fabricated through an environmental friendly process. Mucoadhesive films increase the advantage of higher efficiency and drug localization in the affected region. In this research, mucoadhesive films, for the release of hydrocortisone sodium succinate, were prepared using different ratios of chitosan, gelatin and keratin. In the first step, chitosan and gelatin proportions were optimized after evaluating the mechanical properties, swelling capacity, water uptake, stability, and biodegradation of the films. Then, keratin was added at different percentages to the optimum composite of chitosan and gelatin together with the drug. The results of surface pH showed that none of the samples were harmful to the buccal cavity. FTIR analysis confirmed the influence of keratin on the structure of the composite. The presence of a higher amount of keratin in the composite films resulted in high mechanical, mucoadhesive properties and stability, low water uptake and biodegradation in phosphate buffer saline (pH?=?7.4) containing 10⁴?U/ml lysozyme. The release profile of the films ascertained that keratin is a rate controller in the release of the hydrocortisone sodium succinate. Finally, chitosan/gelatin/keratin composite containing hydrocortisone sodium succinate can be employed in dental applications.     

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.     

Development and characterization of a mucoadhesive sublingual formulation for pain control: extemporaneous oxycodone films in personalized therapy

Objective: The aim of this work was the development of mucoadhesive sublingual films, prepared using a casting method, for the administration of oxycodone.

Materials and methods: A solvent casting method was employed to prepare the mucoadhesive films. A calibrated pipette was used to deposit single aliquots of different polymeric solutions on a polystyrene plate lid. Among the various tested polymers, hydroxypropylcellulose at low and medium molecular weight (HPC) and pectin at two different degrees of esterification (PC) were chosen for preparing solutions with good casting properties, capable of producing films suitable for mucosal application.

Results and discussion: The obtained films showed excellent drug content uniformity and stability and rapid drug release, which, at 8?min, ranged from 60% to 80%. All films presented satisfactory mucoadhesive and mechanical properties, also confirmed by a test on healthy volunteers, who did not experience irritation or mucosa damages. Pectin films based on pectin at lower degrees of esterification have been further evaluated to study the influence of two different amounts of drug on the physicochemical properties of the formulation. A slight reduction in elasticity has been observed in films containing a higher drug dose; nevertheless, the formulation maintained satisfactory flexibility and resistance to elongation.

Conclusions: HPC and PC sublingual films, obtained by a simple casting method, could be proposed to realize personalized hospital pharmacy preparations on a small scale.     

Buccal delivery systems

The oral cavity is an attractive site for drug delivery due to ease of administration and avoidance of possible drug degradation in gastrointestinal tract and first-pass metabolism. Buccal drug delivery specifically refers to the delivery of drugs within/through buccal mucosa to affect local/systemic pharmacological actions. This review briefly describes advantages and limitations of buccal drug delivery, anatomical structure of oral mucosa, and methodology in evaluating buccal drug delivery system, focusing on physiology, pharmacology, pathology, and formulation design in line with recent developments in buccal delivery systems.     

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.     

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.     

Mucoadhesive delivery systems. I. Evaluation of mucoadhesive polymers for buccal tablet formulation

Different types of mucoadhesive polymers, intended for buccal tablet formulation, were investigated for their comparative mucoadhesive force, swelling behavior, residence time and surface pH. The selected polymers were carbopols (CP934, and CP940), polycarbophil (PC), sodium carboxymethyl cellulose (SCMC) and pectin representing the anionic type, while chitosan (Ch) as cationic polymer and hydroxypropylmethyl cellulose (HPMC) as a non-ionic polymer. Results revealed that polyacrylic acid derivatives (PAA) showed the highest bioadhesion force, prolonged residence time and high surface acidity. SCMC and chitosan ensured promising bioadhesive characteristics, whilst HPMC and pectin exhibited weaker bioadhesion. Different polymer combinations as well as formulations were evaluated to improve the mucoadhesive performance of the tablets. Bioadhesive tablet formulations containing either 5% CP934, 65% HPMC and 30% spray-dried lactose or 2% PC, 68% HPMC and 30% mannitol showed optimum mucoadhesion and suitable residence time. SCMC, when formulated individually, exhibited promising bioadhesion, acceptable swelling, convenient residence time and surface pH. In-vivo trials of these formulations proved non-irritative and prolonged residence of the mucoadhesive tablets on human buccal mucosa for 8 to 13 h.     

In Vitro Drug Release from Matrix Tablets Containing a Silicone Elastomer Latex

Abstract

A silicone elastomer latex was evaluated as a wet-granulating agent in preparing controlled release matrix tablets containing a water soluble active ingredient. A one-half fractional factorial statistical design was used to investigate the effect of five different formulation and non-formulation variables on the in vitro release characteristics of the drug from the matrix tablets. Tablets containing a high percent of fumed colloidal silica exhibited a faster drug release rate. A high drug to polymer ratio in the tablets was also shown to result in a faster release of the drug. Granules dried at a higher temperature (80°C vs. 60°C) produced tablets with a slower drug release rate. The release of the drug was shown to be pH dependent. A higher drug release rate was obtained in a dissolution medium with a lower pH (1.2 vs. 6.8).