Design and in vitro characterization of buccoadhesive tablets of timolol maleate

Objective: The purpose of this work was to develop and evaluate buccoadhesive tablets of timolol maleate (TM) due to its potential to circumvent the first-pass metabolism and to improve its bioavailability.

Methods: The tablets were prepared by direct compression using two release modifying polymers, Carbopol 974P (Cp-974p) and sodium alginate (SA). A 3² full factorial design was employed to study the effect of independent variables, Cp-974p and SA, in various proportions in percent w/w, which influences the in vitro drug release and bioadhesive strengths. Physicochemical properties of the drug were evaluated by ultraviolet, Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder X-ray diffraction (P-XRD). Tablets were evaluated for hardness, thickness, weight variation, drug content, surface pH, swelling index, bioadhesive force and in vitro drug release.

Results: The FTIR and DSC studies showed no evidence of interactions between drug, polymers and excipients. The P-XRD study revealed that crystallinity of TM remain unchanged in optimized formulation tablet. Formulation F9 achieves an in vitro drug release of 98.967%?±?0.28 at 8?h and a bioadhesive force of 0.088 N?±?0.01211.

Conclusion: We successfully developed buccal tablet formulations of TM and describe a non-Fickian-type anomalous transport as the release mechanism.     

Development of amitriptyline buccoadhesive tablets for management of pain in dental procedures

Administration of lidocaine and nonsteroidal anti-inflammatory drugs (NSAIDs) as a routine procedure for relief of dental pains by and large is restricted due to some side effects. Amitriptyline (AM) has long been known to exert analgesic activity as a result of blocking the Na? channels. The objective of the present investigation was to prepare suitable buccoadhesive tablets using cellulose derivatives in order to obtain new formulations containing AM to provide local analgesic action. The tablets were evaluated in terms of physical characteristics, mucoadhesion performance, drug release, and in vivo assessment of analgesic efficiency. Tablets containing higher amounts of high-viscosity hydroxypropylmethyl cellulose (HPMC-K4M) significantly demonstrated enhanced adhesive performances. On the other hand, presence of sodium carboxymethyl cellulose (NaCMC) in formulations including HPMC of lower-viscosity grade (HPMC-E5LV) provided further adhesiveness by increase in viscosity. Rate of drug release from HPMC-E5LV tablets was significantly higher than the HPMC-K4M tablets. Kinetically, patterns of AM release from the tablets fitted best to Higuchi model. Moreover, in a randomized double-blind trial, analgesic efficiency of the prepared bioadhesive tablets was revealed to be satisfactory. It is suggested that applying the topical AM mucoadhesive tablet containing the low amount of drug is a safe and promising alternative to relief the pain in the buccal region.     

Formulation and evaluation of secnidazole or doxycycline dento-oral gels

Local delivery of antibiotics has been shown to be effective in reducing periodontopathic microorganisms. The purpose of this study is to formulate gels containing secnidazole or doxycycline hydrochloride that could be used in the treatment of periodontitis by direct periodontal intrapocket administration. Different mucoadhesive polymers were used as cellulose derivatives, carbopol and eudragit. The prepared gels were evaluated for their in vitro drug release, rheological behavior, and mucoadhesive force. Increasing the concentration of each polymer increased the viscosity, mucoadhesion, and the time required for 30 and 50% release of the original mass of each drug. Gels with appropriate balance of the above-examined parameters were selected for microbiological evaluation. Microbiological studies on selected gels showed faster release of the two drugs (expressed as inhibition zones) than the commercial products of chlorhexidine gel (Eluge and miconazole nitrate emulgel (Miconaz).     

Development and Characterization of a Buccoadhesive Dosage Form of Oxycodone Hydrochloride

A buccoadhesive system for the delivery of oxycodone hydrochloride to the oral mucosa was prepared from a colloidal solution of gelatin used as a bioadhesive agent. An in vitro method for measuring the adhesion of release system to a substrate was developed by employing a modified balance. The eflects of thickness and of the presence of the drug on swelling and mucoadhesion properties were evaluated. The in vitro release of the buccoadhesive formulation was studied by a USP paddle dissolution apparatus and the results were fitted to an empirical equation. In vivo compliance and permanence time in 10 healthy volunteers were estimated.     

Buccoadhesive films for once-a-day administration of rivastigmine: systematic formulation development and pharmacokinetic evaluation

Context: Rivastigmine, an anti-Alzheimer’s drug, suffers from major predicaments like low oral bioavailability, severe GI adverse effects related to rapid fluctuations in drug plasma levels, and high frequency of dosing.

Objective: The present investigation aims at developing buccoadhesive films capable of delivering the drug in vivo in a sustained manner. Augmentation of drug bioavailability by the avoidance of first-pass effect through the buccal route and reduction in GI side effects would be other key advantages of this system.

Methods: Buccoadhesive films of rivastigmine were systematically designed and evaluated for in vitro drug release, ex vivo buccal permeation and ex vivo buccoadhesive strength. Optimal composition of the polymer blends was rationally chosen using a central composite design and overlay plot. In vivo pharmacokinetic studies were carried out in rabbits, and attempts were made to establish in vitro/ in vivo correlations (IVIVC).

Results: Besides possessing the requisite drug release regulation, the optimized formulation exhibited excellent buccoadhesion, and buccal permeation. Pharmacokinetic studies indicated extension of plasma drug levels and level A of IVIVC was successfully established.

Discussion: Excellent buccal bioadhesion and transmucosal permeation, coupled with drug release control, ratify the potential of the optimized formulation to deliver the drug in a controlled and site-specific manner. Successful establishment of IVIVC substantiated the judicious choice of in vitro dissolution media for simulating the in vivo conditions.

Conclusion: Besides unraveling the polymer synergism, the study helped in developing an optimal once-a-day buccoadhesive drug delivery system exhibiting excellent trans-buccal permeation and buccoadhesive characteristics with improved bioavailability potential.     

Development and Characterization of a Buccoadhesive Dosage Form of Oxycodone Hydrochloride

Abstract

A buccoadhesive system for the delivery of oxycodone hydrochloride to the oral mucosa was prepared from a colloidal solution of gelatin used as a bioadhesive agent. An in vitro method for measuring the adhesion of release system to a substrate was developed by employing a modified balance. The eflects of thickness and of the presence of the drug on swelling and mucoadhesion properties were evaluated. The in vitro release of the buccoadhesive formulation was studied by a USP paddle dissolution apparatus and the results were fitted to an empirical equation. In vivo compliance and permanence time in 10 healthy volunteers were estimated.     

Formulation and Evaluation of Secnidazole or Doxycycline Dento-Oral Gels

Local delivery of antibiotics has been shown to be effective in reducing periodontopathic microorganisms. The purpose of this study is to formulate gels containing secnidazole or doxycycline hydrochloride that could be used in the treatment of periodontitis by direct periodontal intrapocket administration. Different mucoadhesive polymers were used as cellulose derivatives, carbopol and eudragit. The prepared gels were evaluated for their in vitro drug release, rheological behavior, and mucoadhesive force. Increasing the concentration of each polymer increased the viscosity, mucoadhesion, and the time required for 30 and 50% release of the original mass of each drug. Gels with appropriate balance of the above-examined parameters were selected for microbiological evaluation. Microbiological studies on selected gels showed faster release of the two drugs (expressed as inhibition zones) than the commercial products of chlorhexidine gel (Elugel®) and miconazole nitrate emulgel (Miconaz®).     

Preparation, in vitro and in vivo evaluation of liposomal/niosomal gel delivery systems for clotrimazole

Clotrimazole, which is an imidazole derivative antifungal agent, was widely used for the treatment of mycotic infections of the genitourinary tract. To develop alternative formulation for the vaginal administration of clotrimazole to provide sustained and controlled release of appropriate drug for local vaginal therapy, liposomes/niosomes were evaluated as delivery vehicles. To optimize the preparation of liposomes/niosomes with regard to size and entrapment efficiency, multilamellar liposomes/niosomes containing drug were prepared by lipid hydration method. The prepared liposomes/niosomes were incorporated into 2% carbopol gel, and the systems were evaluated for drug stability in phosphate-buffered saline (pH 7.4) and simulated vaginal fluid at 37 +/- 1 degrees C. Further, the vesicle gel system was evaluated by antifungal activity and tolerability on tissue level in rat.     

Strategies to Overcome pH-Dependent Solubility of Weakly Basic Drugs by Using Different Types of Alginates

Weakly basic drugs demonstrate higher solubility at lower pH, thus often leading to faster drug release at lower pH. The objective of this study was to achieve pH-independent release of weakly basic drugs from extended release formulations based on the naturally occurring polymer sodium alginate. Three approaches to overcome the pH-dependent solubility of the weakly basic model drug verapamil hydrochloride were investigated. First, matrix tablets were prepared by direct compression of drug substance with different types of sodium alginate only. Second, pH-modifiers were added to the drug/alginate matrix systems. Third, press-coated tablets consisting of an inner pH-modifier tablet core and an outer drug/sodium alginate coat were prepared. pH-Independent drug release was achieved from matrix tablets consisting of selected alginates and drug substance only. Alginates are better soluble at higher pH. Therefore, they are able to compensate the poor solubility of weakly basic drugs at higher pH as the matrix of the tablets dissolves faster. This approach was successful when using alginates that demonstrated fast hydration and erosion at higher pH. The approach failed for alginates with less-pronounced erosion at higher pH. The addition of fumaric acid to drug/alginate-based matrix systems decreased the microenvironmental pH within the tablets thus increasing the solubility of the weakly basic drug at higher pH. Therefore, pH-independent drug release was achieved irrespective of the type of alginate used. Drug release from press-coated tablets did not provide any further advantages as compound release remained pH-dependent.     

Strategies to overcome pH-dependent solubility of weakly basic drugs by using different types of alginates

Weakly basic drugs demonstrate higher solubility at lower pH, thus often leading to faster drug release at lower pH. The objective of this study was to achieve pH-independent release of weakly basic drugs from extended release formulations based on the naturally occurring polymer sodium alginate. Three approaches to overcome the pH-dependent solubility of the weakly basic model drug verapamil hydrochloride were investigated. First, matrix tablets were prepared by direct compression of drug substance with different types of sodium alginate only. Second, pH-modifiers were added to the drug/alginate matrix systems. Third, press-coated tablets consisting of an inner pH-modifier tablet core and an outer drug/sodium alginate coat were prepared. pH-Independent drug release was achieved from matrix tablets consisting of selected alginates and drug substance only. Alginates are better soluble at higher pH. Therefore, they are able to compensate the poor solubility of weakly basic drugs at higher pH as the matrix of the tablets dissolves faster. This approach was successful when using alginates that demonstrated fast hydration and erosion at higher pH. The approach failed for alginates with less-pronounced erosion at higher pH. The addition of fumaric acid to drug/alginate-based matrix systems decreased the microenvironmental pH within the tablets thus increasing the solubility of the weakly basic drug at higher pH. Therefore, pH-independent drug release was achieved irrespective of the type of alginate used. Drug release from press-coated tablets did not provide any further advantages as compound release remained pH-dependent.     

Buccoadhesive Tablets of Nifedipine: Standardization of A Novel Buccoadhesive-Erodible Carrier

Buccoadhesive tablets of nifedipine were obtained by incorporation of nifedipine in suitable carrier systems standardised based on bioadhesion and dissolution. The carrier systems were formulated using sodium alginate as the bioadhesive. Mannitol, lactose, polyethylene glycol 6000 and polyethylene glycol 4000 were incorporated as solubilisers, singly or in combination. Carrier systems having a diameter of 11 mm and weighing about 200 mg were obtained by standard tabletting techniques using polyvinylpyrolidone as the binder. The systems were evaluated for bioadhesion and dissolution, 'in vitro' and 'in vivo' in seven normal healthy human volunteers. Based on these studies, nifedipine (5 mg) was incorporated in selected carrier systems to obtain buccoadhesive tablets of nifedipine. These tablets exhibited rapid 'in vitro' drug release.     

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.     

Miconazole Chewing Gum as a Drug Delivery System Application of Solid Dispersion Technique and Lecithin

The release of the antifungal drug miconazole from chewing gum was evaluated both in vitro and in vivo. It was proved that the addition of lecithin and the application of a miconazole polyethyleneglycol 6000 solid dispersion increased the release of miconazole from chewing gum. The in vitro results correlated well with the in vivo results. 6 healthy volunteers obtained therapeutically active concentrations of miconazole in saliva when they chewed gum. In the microbiological experiments performed, lecithin did not antagonize the anti-Candida albicans effect of miconazole at pH 7.2.     

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.     

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.     

Controlled release camptothecin tablets based on pluronic and poly(acrylic acid) copolymer. Effect of fabrication technique on drug stability, tablet structure, and release mode

Poly(ethylene oxide)-b-poly(propylene oxide)-b-(polyethylene oxide)-g-poly(acrylic acid), a graft-comb copolymer of Pluronic 127 and poly(acrylic acid) (Pluronic-PAA), was explored as an excipient for tablet dosage form of camptothecin (CPT). The tablets were prepared by either direct compression of the drug-polymer physical blend, suspension in ethanol followed by evaporation, or compression after kneading and characterized with respect to their physical structures, drug stability, and release behavior. Porosity and water uptake rate were strongly dependent on the fabrication procedure, ranking in the order: direct compression of physical blend > compression after suspension/evaporation in ethanol > compression after kneading. Tablets prepared by compression of physical blends swelled in water with a rapid surface gel layer formation that impeded swelling and disintegration of the tablets core. These tablets were able to sustain the CPT release for a period of time longer than those observed with the tablets made by either suspension/evaporation or kneading, which disintegrated within a few minutes. Despite the tablet disintegration, the CPT release was impeded for at least 6 hr, which was attributed to the ability of the Pluronic-PAA copolymers to form micellar aggregates at the hydrated surface of the particles. Physical mixing did not alter the fraction of CPT being in the pharmaceutically active lactone form, whilst the preparation of the tablets by the other two methods caused a significant reduction in the lactone form content. Tablets prepared from the physical blends demonstrated CPT release rates increasing with the pH due to the PAA ionization leading to the increase in the rate and extent of the tablet swelling. The results obtained demonstrate the potential of the Pluronic-PAA copolymers for the oral administration of chemotherapeutic agents.     

Preparation,in Vitro and in Vivo Evaluation of Liposomal/Niosomal Gel Delivery Systems for Clotrimazole

Clotrimazole, which is an imidazole derivative antifungal agent, was widely used for the treatment of mycotic infections of the genitourinary tract. To develop alternative formulation for the vaginal administration of clotrimazole to provide sustained and controlled release of appropriate drug for local vaginal therapy, liposomes/niosomes were evaluated as delivery vehicles. To optimize the preparation of liposomes/niosomes with regard to size and entrapment efficiency, multilamellar liposomes/niosomes containing drug were prepared by lipid hydration method. The prepared liposomes/niosomes were incorporated into 2% carbopol gel, and the systems were evaluated for drug stability in phosphate-buffered saline (pH 7.4) and simulated vaginal fluid at 37 ± 1°C. Further, the vesicle gel system was evaluated by antifungal activity and tolerability on tissue level in rat.     

Wax-matrix tablet for time-dependent colon-specific delivery system of sophora flavescens Aiton: preparation and in vivo evaluation

A wax-matrix time-dependent colon-specific tablet (WM-TDCS) was studied. Wax-matrix tablet core consisting of semi-synthetic glycerides, as a wax polymeric expanding agent, carboxymethyl starch sodium (CMS-Na), and NaCl was prepared, and Sophora flavescens Aiton (ASF, extracts of traditional Chinese medicine) was used as model drug. The wax-matrix ASF tablets core was coated with Eudragit NE 30 D as the inner coating materials and with Opadry OY-P-7171 as the outer coating materials. The in vitro release behaviors of the coated tablets were examined and then in vivo absorption kinetics of the coated tablets in dogs was further investigated. The volume of the tablet core was markedly increased at 37 degrees C because of the expand effect of polymer semi-synthetic glycerides and CMS-Na. The drug release from WM-TDCS was more stable than TDCS in vitro and in vivo. The lag time of ASF release was also controlled by the thickness of the inner coating layer. In vivo evaluation demonstrated that in vivo lag time of absorption was in a good agreement with in vitro lag time of release. ASF wax-matrix tablets coated with Eudragit NE 30 D and Opadry OY-P-7171 using the regular coating technique could be designed to achieve a lag time of 3 h in the small intestinal tract.     

Preparation, in Vitro and in Vivo Evaluation of Liposomal/Niosomal Gel Delivery Systems for Clotrimazole

Clotrimazole, which is an imidazole derivative antifungal agent, was widely used for the treatment of mycotic infections of the genitourinary tract. To develop alternative formulation for the vaginal administration of clotrimazole to provide sustained and controlled release of appropriate drug for local vaginal therapy, liposomes/niosomes were evaluated as delivery vehicles. To optimize the preparation of liposomes/niosomes with regard to size and entrapment efficiency, multilamellar liposomes/niosomes containing drug were prepared by lipid hydration method. The prepared liposomes/niosomes were incorporated into 2% carbopol gel, and the systems were evaluated for drug stability in phosphate-buffered saline (pH 7.4) and simulated vaginal fluid at 37 ± 1°C. Further, the vesicle gel system was evaluated by antifungal activity and tolerability on tissue level in rat.     

Miconazole Chewing Gum as a Drug Delivery System Application of Solid Dispersion Technique and Lecithin

Abstract

The release of the antifungal drug miconazole from chewing gum was evaluated both in vitro and in vivo. It was proved that the addition of lecithin and the application of a miconazole polyethyleneglycol 6000 solid dispersion increased the release of miconazole from chewing gum. The in vitro results correlated well with the in vivo results. 6 healthy volunteers obtained therapeutically active concentrations of miconazole in saliva when they chewed gum. In the microbiological experiments performed, lecithin did not antagonize the anti-Candida albicans effect of miconazole at pH 7.2.