Oral sustained-release bioadhesive tablet formulation of didanosine

The objective of this study was to formulate a hydrogel-forming bioadhesive drug delivery system for oral administration of didanosine (ddI). The aim of this tablet dosage form is to improve the oral absorption of ddI by delivering it in small doses over an extended period and localizing it in the intestine by bioadhesion. Compressed tablets of ddI using Polyox® WSRN-303, Carbopol® 974P-NF, and Methocel® K4M as the bioadhesive release rate-controlling polymers were prepared. The effect of polymer concentration on the release profile and in vitro bioadhesion of the matrix tablets was studied. Tablet formulations with Polyox WSRN-303 (10%) and Methocel K4M (30%) showed 93 and 90% drug release, respectively, after 12 h. The drug release was found to be linear when fitted in the Higuchi equation (square-root time equation), suggesting zero-order release. Carbopol 974-P-NF was found to inhibit the complete release of ddI because of drug-polymer interaction; hence, is not suitable for formulation of ddI. Drug diffusion and swelling of the polymer (anomalous Fickian release) was found dominant in ddI release. In general, in vitro bioadhesion increased with an increase in polymer concentration. Tablets containing a single polymer can be designed to form hydrogels serving the dual purpose of bioadhesion and sustained release.     

Mucoadhesive delivery systems. II. Formulation and in-vitro/in-vivo evaluation of buccal mucoadhesive tablets containing water-soluble drugs

From the previous work (Part I), mucoadhesive formulae containing 5% CP/65% HPMC/30% lactose and 2% PC/68% HPMC/30% mannitol as well as formulae based on sodium carboxymethyl cellulose (SCMC) were selected. Medicated tablets were prepared using diltiazem hydrochloride (DZ) and metclopramide hydrochloride (MP) in two different doses (30 and 60 mg). The effect of drug and dose on the mucoadhesive properties and in-vitro drug release was evaluated. All formulae produced extended drug release (over 8 to 12 h). Polyacrylic acid based matrices (PAA) showed Fickian's diffusion release pattern for both drugs. SCMC ensured zero-order release for DZ, which deviated to anomalous behavior in case of MP. Doubling the dose significantly reduced the bioadhesion strength (p<0.05) with a slight improvement in drug release rate. The formulation of bilayer tablets containing drug-free layer and medicated layer enhanced the drug release without affecting the bioadhesive performance. The bilayer tablet formulated with 2% PC/68% HPMC/30% mannitol (PC2) was selected for studying the in-vivo metoclopramide release in four healthy volunteers. The tablet ensured controlled drug release for 12 h, in addition, good correlation (r=0.9398) was observed between in-vitro and in-vivo data. The effect of ageing on selected formulae containing DZ and MP, respectively, was studied. Storage at 40 degrees C and 75% relative humidity for 6 months didn't influence the mucoadhesive performance, however, an enhanced released rate was observed.     

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 nanoliposomal formulation for vaginal delivery of an antifungal

Context: Ciclopirox olamine (CPO) is indicated in the treatment of vaginal fungal infections. The frequent and large dosing of available vaginal CPO creams gives rise to poor compliance amongst females. In such a situation a delivery system capable of providing sustained release of CPO is warranted and can be realized through incorporation of its liposomal formulation into a mucoadhesive gel base. The liposomal formulation would offer sustained release whereas mucoadhesive gel would prolong the contact with vaginal wall; thus avoiding frequent and large dosing.

Objective: The present study aimed at investigating mucoadhesive liposomal CPO gel for vaginal use.

Method: The study embarked on evaluating liposomal CPO and its Carbopol 974^®P gel for stability at vaginal pH, release profile, rheological characteristics, mucoadhesive behavior and finally antifungal activity.

Results: The results revealed that CPO liposomes were stable at vaginal pH; its Carbopol gel released 58.75?±?6.4% of CPO at the end of 24?h which suggested sustained release. Rheology via viscometric, oscillatory stress sweep and oscillatory frequency sweep testing of the gel, studied at different temperatures and under different dilutions with vaginal fluid simulant testified pseudoplastic behavior of the gel. It also pointed towards the predominance of elastic behavior of the gel at all the dilutions. The gel exhibited good mucoadhesivity to sheep vaginal tissue. Furthermore, CPO entrapped in liposome too displayed antifungal activity.

Conclusion: The study undertaken recommended Carbopol 974^®P gel loaded with CPO liposomes as a potential delivery system for treatment of fungal vaginal infections.     

Evaluation of the methylene blue addition in binary polymeric systems composed by poloxamer 407 and Carbopol 934P using quality by design: rheological,textural, and mucoadhesive analysis

This study describes the investigation about the physicochemical behavior of methylene blue (Mb) addition to systems containing poloxamer 407 (Polox), Carbopol 934P (Carb), intended to be locally used by photodynamic therapy. A factorial design 2³ (plus center point) was used to analyze the rheological, mucoadhesive and textural properties of the preparations. Systems containing the lower concentrations of Polox (15 and 17.5%, w/w) exhibited pseudoplastic flow and low degrees of rheopexy. On the other hand, at higher Polox concentration (20%, w/w) the systems display plastic flow and thixotropy. Carb and Mb exhibited a negative influence for the consistency and flow behavior index, due to the interaction between them. For most of the formulations, the increase of Polox and Mb content significantly increased storage modulus, loss modulus and dynamic viscosity. The systems display a sol–gel transition temperature, existing as a liquid at room temperature and gel at 29–37?°C. Increasing the temperature and the polymer concentration, the compressional properties of systems significantly increased. The mucoadhesion was noted to all formulations, except to systems composed by 15% (w/w) of Polox. The analyses enabled to understand and predict the performance of formulations and the polymer–Mb interactions, tailoring to the suit systems (Polox/Carb/Mb): 17.5/0.50/0.20 and 20/0.15/0.25.     

A critical review about methodologies for the analysis of mucoadhesive properties of drug delivery systems

Mucoadhesion is a useful strategy for drug delivery systems, such as tablets, patches, gels, liposomes, micro/nanoparticles, nanosuspensions, microemulsions and colloidal dispersions. Moreover, it has contributed to many benefits like increased residence time at application sites, drug protection, increased drug permeation and improved drug availability. In this context, investigation into the mucoadhesive properties of pharmaceutical dosage forms is fundamental, in order to characterize, understand and simulate the in vivo interaction between the formulation and the biological substrate, contributing to the development of new mucoadhesive systems with effectiveness, safety and quality. There are a lot of in vivo, in vitro and ex vivo methods for the evaluation of the mucoadhesive properties of drug delivery systems. However, there also is a lack of standardization of these techniques, which makes comparison between the results difficult. Therefore, this work aims to show an overview of the most commonly employed methods for mucoadhesion evaluation, relating them to different proposed systems and using artificial or natural mucosa from humans and animals.     

Design,characterization and ex vivo evaluation of chitosan film integrating of insulin nanoparticles composed of thiolated chitosan derivative for buccal delivery of insulin

The purpose of this study is to optimize and characterize of chitosan buccal film for delivery of insulin nanoparticles that were prepared from thiolated dimethyl ethyl chitosan (DMEC-Cys). Insulin nanoparticles composed of chitosan and dimethyl ethyl chitosan (DMEC) were also prepared as control groups. The release of insulin from nanoparticles was studied in vitro in phosphate buffer solution (PBS) pH 7.4. Optimization of chitosan buccal films has been carried out by central composite design (CCD) response surface methodology. Independent variables were different amounts of chitosan and glycerol as mucoadhesive polymer and plasticizer, respectively. Tensile strength and bioadhesion force were considered as dependent variables. Ex vivo study was performed on excised rabbit buccal mucosa. Optimized insulin nanoparticles were obtained with acceptable physicochemical properties. In vitro release profile of insulin nanoparticles revealed that the highest solubility of nanoparticles in aqueous media is related to DMEC-Cys nanoparticles. CCD showed that optimized buccal film containing 4% chitosan and 10% glycerol has 5.81?kg/mm² tensile strength and 2.47?N bioadhesion forces. Results of ex vivo study demonstrated that permeation of insulin nanoparticles through rabbit buccal mucosa is 17.1, 67.89 and 97.18% for chitosan, DMEC and DMEC-Cys nanoparticles, respectively. Thus, this study suggests that DMEC-Cys can act as a potential enhancer for buccal delivery of insulin.     

Evaluation of monolithic osmotic tablet system for nifedipine delivery in vitro and in vivo

The aim of this study was to evaluate the monolithic osmotic tablet system (MOTS) containing a solid dispersion with the practically water-insoluble drug nifedipine in vitro and in vivo. In the drug release study in vitro, the release profiles of this system had almost zero-order kinetics. The influences of tablet formulation variables, sizes of the delivery orifice, membrane variables, and values of pH in the dissolution medium on nifedipine release from MOTS have been investigated. The results provided evidence that the tablet core played an important role in MOTS. While orifice sizes and membrane variables affected the nifedipine release rate, MOTS was independent of the dissolution medium. The appropriate orifice size was found to be in the range of 0.5-1.0 mm. The coating membrane incorporating hydrophilic polyethylene glycol (PEG) formed a porous structure. The human pharmacokinetics and relative bioavailability of MOTS containing nifedipine were compared with a commercial Adalat® osmotic tablet system containing an equivalent dose of nifedipine following an oral single dose of 30 mg given to each of 11 healthy volunteers in an open, randomized crossover study in vivo. The relative bioavailability for MOTS was 112%. There was no statistically significant difference in the pharmacokinetic parameters between two dosage forms. It is concluded that the monolithic osmotic tablet controlled release system is feasible for a long-acting preparation as a once-daily treatment.     

Evaluation of intratympanic formulations for inner ear delivery: methodology and sustained release formulation testing

A convenient and efficient in vitro diffusion cell method to evaluate formulations for inner ear delivery via the intratympanic route is currently not available. The existing in vitro diffusion cell systems commonly used to evaluate drug formulations do not resemble the physical dimensions of the middle ear and round window membrane. The objectives of this study were to examine a modified in vitro diffusion cell system of a small diffusion area for studying sustained release formulations in inner ear drug delivery and to identify a formulation for sustained drug delivery to the inner ear. Four formulations and a control were examined in this study using cidofovir as the model drug. Drug release from the formulations in the modified diffusion cell system was slower than that in the conventional diffusion cell system due to the decrease in the diffusion surface area of the modified diffusion cell system. The modified diffusion cell system was able to show different drug release behaviors among the formulations and allowed formulation evaluation better than the conventional diffusion cell system. Among the formulations investigated, poly(lactic-co-glycolic acid)–poly(ethylene glycol)–poly(lactic-co-glycolic acid) triblock copolymer systems provided the longest sustained drug delivery, probably due to their rigid gel structures and/or polymer-to-cidofovir interactions.     

A finite strain framework for the simulation of polymer curing. Part I: elasticity

A phenomenologically motivated small strain model to simulate the curing of thermosets has been developed and discussed in a recently published paper (Hossain et al. in Comput Mech 43(6):769–779, 2009). Inspired by the concepts used there, this follow-up contribution presents an extension towards the finite strain regime. The thermodynamically consistent framework proposed here for the simulation of curing polymers particularly is independent of the choice of the free energy density, i.e. any phenomenological or micromechanical approach can be utilised. Both the governing equations for the curing simulation framework and the necessary details for the numerical implementation within the finite element method are derived. The curing of polymers is a very complex process involving a series of chemical reactions typically resulting in a conversion of low molecular weight monomer solutions into more or less cross-linked solid macromolecular structures. A material undergoing such a transition can be modelled by using an appropriate constitutive relation that is distinguished by prescribed temporal evolutions of its governing material parameters, which have to be determined experimentally. Part I of this work will deal with the elastic framework whereas the following Part II will focus on viscoelastic behaviour and shrinkage effects. Some numerical examples demonstrate the capability of our approach to correctly reproduce the behaviour of curing materials.     

A thermodynamic property formulation for air. I. Single-phase equation of state from 60 to 873 K at pressures to 70 MPa

A revised interim formulation for the thermodynamic properties of air has been developed for calculating properties of the vapor and estimating properties for the liquid at temperatures as low as 60 K. The formulation incorporates separate equations for the calculation of bubble-point and dew-point pressures and densities and for the ideal-gas heat capacity. A new fundamental equation of state is given for vapor and liquid states of air based upon available experimental data and predicted values of isochoric heat capacity for the liquid using corresponding states methods. Procedures for predicting C _v are discussed. The fundamental equation for air is explicit in nondimensional Helmholtz energy. The terms of the fundamental equation were selected from a larger set of 75 proposed terms using a least-squares fitting procedure. Representative graphical comparisons of calculated property values to experimental measurements are given. The estimated accuracy of calculated densities is generally ± 0.2% except near the dew and bubble lines. Calculated heat capacities for the liquid must be considered only as estimates until substantiated by experimental measurements.Paper presented at the Tenth Symposium on Thermophysical Properties, June 20–23, 1988, Gaithersburg, Maryland, U.S.A.Formerly National Bureau of Standards     

Use of a Novel Modified TSI for the Evaluation of Controlled-Release Aerosol Formulations. I

When considering the development of potential controlled-release pulmonary drug delivery systems, there is at present no standard method available for the assessment of in vitro drug release profiles necessary to understand how the drug might release following deposition in the lungs. For this purpose, the twin-stage impinger (TSI), apparatus A of the BP, has been redesigned and tested. This modified TSI was found capable of discriminating between drug release rates from conventional and different dry powder formulations consisting of model controlled-release excipients, providing information related to (a) drug diffusion properties of controlled-release dry powder blends with different excipient components and (b) the effect of varying drug concentration within a given formulation.     

Feasibility of obtaining in situ nanocapsules through modified self-microemulsifying drug delivery systems. A new manufacturing approach for oral route administration

Nanocapsules (NCs) are submicron-sized core shell systems which present important advantages such as improvement of drug efficacy and bioavailability, prevention of drug degradation, and provision of controlled-release delivery. The available methods for NC production require expensive recovery and purification steps which compromised the morphology of NCs. Industrial applications of NCs have been avoided due to the aforementioned issues. In this study, we developed a new method based on a modified self-microemulsifying drug delivery system (SMEDDS) for in situ NCs production within the gastrointestinal tract. This new methodology does not require purification and recovery steps and can preserve the morphology and the functionality of NCs. The in situ formed NCs of Eudragit^® RL PO were compared with nanospheres (NEs) in order to obtain evidence of their core-shell structure. NCs presented a spherical morphology with a size of 126.2?±?13.1?nm, an ibuprofen encapsulation efficiency of 31.3% and a zeta-potential of 37.4?mV. Additionally, NC density and release profile (zero order) showed physical evidence of the feasibility of NCs in situ creation.     

Fictitious notch rounding concept applied to sharp V-notches: Evaluation of the microstructural support factor for different failure hypotheses. Part I: Basic stress equations

With the aim to perform a comprehensive and accurate evaluation of the microstructural support factor of sharp V-notches (Neuber’s notch rounding concept), in Part I of this contribution, the indispensable theoretical tools, especially the basic stress equations, are reconsidered and amended in respect of accuracy of results. First, the analytical solution derived by Neuber [Neuber H. Kerbspannungslehre. 2nd ed. Berlin: Springer-Verlag; 1958] for sharp rounded V-notches with an arbitrary flank angle under tension loading is considered. The equation of the normal stress has been obtained with the restriction to the notch bisector. Using the Airy stress function suggested by Neuber, this solution is extended to the region outside the notch bisector, and the complete stress field is derived in this manner. A comparison between Neuber’s solution, a more recent solution due to Filippi et al. [Filippi S, Lazzarin P, Tovo R. Developments of some explicit formulas useful to describe elastic stress fields ahead of notches in plates. Int J Solids Struct 2002;39:4543-65] and highly accurate FE results is performed. Filippi’s equations which include Williams’ solution [Williams ML. Stress singularities resulting from various boundary conditions in angular corners on plates in tension. J Appl Mech 1952;19:526-8] for pointed V-notches, are shown to be superior.