A. A. Hincal

Chitosan films and hydrogels of chlorhexidine gluconate for oral mucosal delivery

Topical delivery of antimicrobial agents is the most widely accepted approach aimed at prolonging active drug concentrations in the oral cavity. As most antifungals do not posses inherent ability to bind to the oral mucosa, this is best achieved through improved formulations. Chitosan, a partially deacetylated chitin, which is a biologically safe biopolymer, prolongs the adhesion time of oral gels and drug release from them. Chitosan also inhibits the adhesion of Candida albicans to human buccal cells and has antifungal activity. The antifungal agent, chlorhexidine gluconate (Chx), also reduces C. albicans adhesion to oral mucosal cells. The aim of this study was to design a formulation containing chitosan for local delivery of Chx to the oral cavity. Gels (at 1 or 2% concentration) or film forms of chitosan were prepared containing 0.1 or 0.2% Chx and their in vitro release properties were studied. The antifungal activity of chitosan itself as well as the various formulations containing Chx was also examined. Release of Chx from gels was maintained for 3 h. A prolonged release was observed with film formulations. No lag-time was observed in release of Chx from either gels or films. The highest antifungal activity was obtained with 2% chitosan gel containing 0.1% Chx.

Drug permeation enhancement via buccal route: possibilities and limitations.

Over the last decade, there has been a particular interest in delivering drugs, especially peptides and proteins via the buccal route. It provides direct entry into the systemic circulation thus avoiding the hepatic first-pass effect and degradation in the gastrointestinal tract, ease of administration, and the ability to terminate delivery when required. However membrane permeation can be a limiting factor for many drugs administered via the buccal route, and the epithelium that lines the oral mucosa is a very effective barrier to the absorption of drugs. In order to deliver broader classes of drugs across the buccal mucosa, reversible methods of reducing the barrier potential of this tissue must be employed. This requisite has fostered the study of penetration enhancers that will safely alter the permeability restrictions of the buccal mucosa. It has been shown that buccal penetration can be improved by using various classes of transmucosal and transdermal penetration enhancers such as bile salts, surfactants, fatty acids and derivatives, chelators, cyclodextrins and chitosan. Among these chemicals used for the drug permeation enhancement, bile salts are most common. The first part of this paper focuses on work related to the elucidation of mechanisms of action of bile salts in buccal permeation enhancement of various drugs and mucosal irritation. In the second part, results showing the enhancing effect of chitosan on buccal permeation of hydrocortisone, a commonly used topical oral anti-inflammatory agent, and transforming growth factor beta (TGF-beta), which is a bioactive peptide to which the oral mucosa is relatively impermeable is presented.

Diclofenac sodium incorporated PLGA (50:50) microspheres: formulation considerations and in vitro/in vivo evaluation.

Recently, considerable interest has been focused on the use of biodegradable polymers for specialized applications such as controlled release of drug formulations; meanwhile, microsphere drug-delivery systems using various kinds of biodegradable polymers have been studied extensively during the past two decades. Poly (lactide-co-glycolide) (PLGA) polymers have been proven to be excellent drug carriers for microparticulate systems due to their advantages, e.g. biocompatibility and regulatory approval. The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) into the intra-articular cavity in patients with chronic inflammatory disease is complicated due to the short duration of effect. In the present study, controlled-release parenteral formulations of diclofenac sodium (DS), a commonly used NSAID, were prepared for intra-articular administration, and evaluated in vitro for particle size, yield, drug loading, surface morphology and release characteristics. For in vivo studies, Technetium-99m labelled polyclonal human immunogammaglobulin (99m Tc-HIG) was used as the radiopharmaceutical to demonstrate arthritic lesions by gamma scintigraphy. Evaluation of arthritic lesions post-therapy in rabbits showed no significant difference in the group treated with PLGA (50:50) (mw 34000) DS microspheres compared to control groups.

Optimization of Spray-Dried and -Congealed Lipid Micropellets and Characterization of Their Surface Morphology by Scanning Electron Microscopy

Lipid micropellets prepared from glycerides and phospholipids may be a physiological drug carrier system for improving the intestinal absorption of lipophilic drugs. They can be prepared by spray-drying and spray-congealing processes. In this study, formulation and optimization parameters of spray-dried and -congealed lipid pellets in the micro- and nanometer size were investigated. The rapid evaporation of solvents from the droplets, which in turn causes a rapid solidification, influenced the crystalline structures of spray-dried glycerides. Moreover, solvents, the chain length, and the type of lipids and drugs used in the formulations of spray-dried micropellets affected the surface morphology of the micropellets. In contrast to the variations of the surface structure of spray-dried micropellets, formulated spray-congealed micropellets possessed smooth surface properties. The surface morphology and microstructure of both types of micropellets were characterized by SEM.

Mucoadhesive, Thermosensitive, Prolonged-Release Vaginal Gel for Clotrimazole:β-Cyclodextrin Complex

The purpose of this study was to achieve a better therapeutic efficacy and patient compliance in the treatment for vaginitis. Clotrimazole (1%) has been formulated in a vaginal gel using the thermosensitive polymer Pluronic F127 (20%) together with mucoadhesive polymers such as Carbopol 934 and hydroxypropylmethylcellulose (0.2% for both). To increase its aqueous solubility., clotrimazole was incorporated as its inclusion complex with 1∶1 molar ratio with β-cyclodextrin. The inclusion complex was thoroughly characterized using various techniques, including 1H NMR spectroscopy, FT IR spectrophotometry, differential scanning calorimetry, scanning electron microscopy, phase solubility studies, and determination of stability constant (k1∶1). The gelation temperature and rheological behavior of different formulations at varying temperatures were measured. In vitro release profiles of the gels were determined in pH 5.5 citrate buffer. It was observed that complexation with cyclodextrin slowed down the release of clotrimazole considerably. Carbopol 934, on the other hand, was found to interact with β-cyclodextrin, inducing precipitation. As far as rheological properties are concerned, thermosensitive in situ gelling was obtained with formulations containing drug: cyclodextrin complex rather than with free drug. Thus, the optimum formulation for a controlled-release thermosensitive and mucoadhesive vaginal gel was determined to be clotrimazole: β-cyclodextrin 1% with 0.2% hydroxypropylmethylcellulose in Pluronic F127 gel (20%) providing continuous and prolonged release of active material above MIC values.

Design and evaluation of sustained-release and buccal adhesive propranolol hydrochloride tablets

Abstract The release of propranolol hydrochloride incorporated into sustained-release and buccal adhesive tablets was studied in vitro. The formulation containing 20% hydroxypropyl methylcellulose (HPMC) yielded good sustained-release matrix tablets. Buccal adhesive controlled-release tablets were prepared by compression of HPMC with polycarbophil (PAA), which served as the bioactive adhesive compound. The release behaviour of buccal adhesive tablets was found to be non-Fickian. The adhesion force was significantly affected by the mixing ratio of HPMC and PAA in the tablet and the weakest adhesion force was observed at the ratio of 1:1 (HPMC:PAA). Interpolymer complex formation was confirmed between HPMC and PAA in acidic medium by turbidity, viscosity and FT-IR measurements. The kinetics of sustained-release and buccal adhesive tablets of propranolol were examined in nine healthy volunteers. Conventional propranolol (Dideral®) was also studied for comparison purposes. As compared to conventional propranolol (40 mg), a single dose of 20% HPMC (160 mg) produced a smoother plasma level profile, with lower and delayed peak times. Dose corrected AUC0–8 values were greater after Dideral® than after 20% HPMC (168.7 ± 80.3 vs 97.3 ± 36.1 ng h ml−1 p 0.05) in the AUC0–4 values between 20% HPMC and buccal adhesive tablets.

Direct Formation of Nanospheres from Amphiphilic β-Cyclodextrin Inclusion Complexes

AbstractPurpose. The aim of this work was to develop and characterize a highly loaded nanoparticulate system based on amphiphilic β-cyclodextrins (CDs) to facilitate the parenteral administration of poorly soluble antifungal model drugs bifonazole and clotrimazole. Methods. Inclusion complexes were characterized with spectroscopic techniques. Particle size distribution of nanospheres were determined by photon correlation spectroscopy (PCS). Nanospheres were assessed for hemolytic activity. Entrapped and released drug quantities were determined and minimum inhibitory concentration (MIC) values of drugs, amphiphilic β-CDs, and drug loaded nanospheres were evaluated. Results. 1:1 inclusion complexes of model drugs with amphiphilic β-CDs gave nanospheres <300 nm (polydispersity index < 0.15) by nanoprecipitation technique without using surfactants. By direct preparation from preformed inclusion complexes, loading was increased 2- to 8-fold depending on CD type and loading technique. Conventionally loaded CD nanospheres displayed immediate release whereas preloaded and highly loaded nanospheres liberated model drugs over a period of 1 h reducing the initial burst effect. MIC values of bifonazole and clotrimazole were lowered significantly when associated to amphiphilic β-CD nanospheres. Conclusion. Amphiphilic β-CDs form nonsurfactant, highly loaded nanospheres with lower hemolytic activity than that of natural CDs directly from inclusion complexes. They enhanced solubility and subsequently therapeutic efficacy of the model drugs.

In vitro and in vivo evaluation of diclofenac sodium loaded albumin microspheres

The use of polymeric carriers in formulations of therapeutic drug delivery systems has gained widespread application, due to their advantage of being biodegradable and biocompatible. Among the microparticulate systems, microspheres have a special importance since it is possible to target drugs and provide controlled release. Diclofenac sodium (DS), is a potent drug in the NSAID group having non-steroidal, anti-inflammatory properties, and is widely used in the treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. In this present study, it was aimed to prepare microsphere formulations of DS using a natural biodegradable polymer as a carrier for intraarticular administration to extend the duration period of the dosage form in the knee joint. Microsphere formulations of DS which were prepared were evaluated in vitro for particle size, yield value, encapsulation efficiency, surface morphology, and in vitro drug release. Two appropriate formulations were selected for in vivo trials. For the in vivo studies, Technetium-99m labelled polyclonal human immunogammaglobulin (99mTc-HIG) was used as the radiopharmaceutical to demonstrate arthritic lesions by gamma scintigraphy. After the induction of arthritis in knee joints of rabbits, the radio-labelled microspheres loaded with DS were injected directly into the articular cavity and at specific time points gamma scintigrams were obtained to find the residence time of the microspheres in knee joints in order to determine the most suitable formulation.The use of polymeric carriers in formulations of therapeutic drug delivery systems has gained widespread application, due to their advantage of being biodegradable and biocompatible. Among the microparticulate systems, microspheres have a special importance since it is possible to target drugs and provide controlled release. Diclofenac sodium (DS), is a potent drug in the NSAID group having non-steroidal, anti-inflammatory properties, and is widely used in the treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. In this present study, it was aimed to prepare microsphere formulations of DS using a natural biodegradable polymer as a carrier for intraarticular administration to extend the duration period of the dosage form in the knee joint. Microsphere formulations of DS which were prepared were evaluated in vitro for particle size, yield value, encapsulation efficiency, surface morphology, and in vitro drug release. Two appropriate formulations were selected for in vivo trials. For the in vivo studies, Technetium-99m labelled polyclonal human immunogammaglobulin (99mTc-HIG) was used as the radiopharmaceutical to demonstrate arthritic lesions by gamma scintigraphy. After the induction of arthritis in knee joints of rabbits, the radio-labelled microspheres loaded with DS were injected directly into the articular cavity and at specific time points gamma scintigrams were obtained to find the residence time of the microspheres in knee joints in order to determine the most suitable formulation.

Formulation and in vitro-in vivo evaluation of buccoadhesive morphine sulfate tablets

Buccoadhesive controlled-release systems for the delivery of morphine sulfate were prepared by compression of hydroxypropyl methylcellulose (HPMC) with carbomer (CP), which served as the bioactive adhesive compound. The release behavior of systems containing 30 mg of morphine sulfate and various amounts of the two polymers was found to be non-Fickian. The adhesion force was significantly affected by the mixing ratio of HPMC and CP in the tablet, and the weakest adhesion force was observed at a ratio of 1:1 (HPMC:CP). Interpolymer complex formation was confirmed between HPMC and CP in acidic medium by turbidity, viscosity, and FT-IR measurements. The amount absorbed (percentage of the drug loaded) of the controlled-release buccoadhesive tablets in six healthy volunteers and was 30 ± 5%.

Preparation, characterization and in vivo distribution of terbutaline sulfate loaded albumin microspheres

Terbutaline sulfate is widely used as a bronchodilator for the treatment of bronchial asthma, chronic bronchitis and emphysema. As it has a short biological half-life, a long acting terbutaline sulfate formulation is desirable to improve patient compliance. Bovine serum albumin microspheres were prepared by an emulsion polymerization method using glutaraldehyde as the crosslinking agent. All microspheres were spherical and smooth with the mean particle size in the range of 22-30 microm. Drug release from the BSA microspheres displayed a biphasic pattern characterized by an initial fast release, followed by a slower release. The released amount was decreased with an increase in the glutaraldehyde concentration. In the absence of trypsin, the time required for complete degradation of microspheres was increased from 144 to 264 h when the glutaraldehyde concentration increased from 0.1 to 0.7 ml. In the presence of trypsin, a linear relationship was obtained between the degradation rates and trypsin concentrations, indicating that saturation was not reached under the experimental conditions. Biodistribution studies indicated that the degree of uptake by the lungs was higher than that of the other organs. All these results demonstrated that terbutaline sulfate loaded microspheres can be used for passive lung targeting.