Fickian Release Research Articles

Formulation development of physiological environment responsive periodontal drug delivery system for local delviery of metronidazole benzoate

The objective of the present investigation was to develop and evaluate physiological environment responsive periodontal drug delivery system (PERPDDS) for local delivery of metronidazole benzoate. Poly-ϵ-caprolactone an in situ precipitating polymer was used in combination with, carbopol 934P, a pH simulative polymer to develop PERPDDS. The prepared PERPDDS was evaluated for various parameters such as in vitro gelling capacity, viscosity, rheology, compatibility study, and in vitro diffusion study. A 32 full factorial design was used to investigate the influence of formulation variables. Drug release data from all formulations were fitted to different kinetic models and the korsemeyer-peppas model was found the best fit model. The value of diffusional exponent (n) was in between 0.3283 and 0.3979 indicating purely fickian diffusion release mechanism. Increasing the concentration of each polymeric component increases viscosity, and time for 50% and 90% drug release was observed and graphically represented by the surface response and contour plots.

Ethyl Cellulose Microparticles Containing Metformin HCl by Emulsification-Solvent Evaporation Technique: Effect of Formulation Variables

The work investigates the effect of various formulation variables like drug-polymer ratio, stirring speed, and surfactant (Span 80) concentration on the properties of ethyl cellulose microparticles containing metformin HCl, prepared by emulsification solvent evaporation technique. The drug entrapment efficiency, particle size, and drug release behaviour of these microparticles were influenced by these formulation variables. The sustained release characteristic of these microparticles was more prominent in pH 6.8 than pH 1.2. The drug release from ethyl cellulose microparticles was found to follow the Fickian (diffusion-controlled) release mechanism. The drug-polymer interaction and surface topography of these microparticles were analyzed by FTIR spectroscopy and SEM, respectively.

Formulation design space analysis for drug release from swelling polymer tablets

Abstract A model is presented which can be used to simulate polymer swelling and drug release from tablets using a combination of the Discrete Element Method (DEM) and solving mass transfer over an unstructured grid formed by the DEM elements. This work extends a recently developed single-component swelling and dissolution model by incorporating an extra component (drug) that can be either homogeneously or heterogeneously dispersed within the tablet. Parametric studies were conducted on some of the key parameters which affect drug release, namely the drug distribution, maximum swelling ratio of the polymer and the drug–polymer diffusivity dependence. The drug heterogeneity study showed that burst release (i.e. dose-dumping) increased as drug loading increased since the polymer could not form a gel layer to surround the tablet but the time taken for 99% drug release was not significantly different when compared to the homogeneous case. The maximum swelling ratio study showed that drug release could be limited either by its diffusion through the dense polymer network or the thickness of the gel layer. It was shown that a minimum release time exists where the drug diffusivity and gel layer thickness would give fast drug release. The drug–polymer diffusivity study showed that drug release could become closer to zero-order the more dependent it was on polymer concentration (as the drug would diffuse very slowly until the polymer was very dilute) compared to more Fickian release if the drug's diffusion coefficient was not as dependent on polymer concentration. Simulated drug release was compared against experiments where tablets containing 10% or 60% w/w nicotinamide and HPMC k100LV were dissolved and imaged using a combination of Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) spectroscopic imaging and downstream monochromatic UV/Visible detection. The FTIR images and extracted concentration profiles showed that water ingress and drug release were faster for the 60% nicotinamide tablet and that the model could predict drug release using only pure component parameters and the respective mass fractions of drug.

Development and evaluation of a gastro-retentive delivery system for improved antiulcer activity of ginger extract (Zingiber officinale)

Aim was to develop and optimize multiunit gastro-retentive floating beads (FBs) intended for localized and prolonged release of ginger for treating gastric ulcers. Protective effect of ginger extract (GE) against ulcer is well documented, but therapeutic use is compromised due to poor bioavailability and physicochemical properties. GE was only slightly soluble (3.19 ± 0.38 mg/ml) in simulated gastric fluid (SGF; pH 1.2). The solubility decreased in water to 0.69 ± 0.03 mg/ml and further by 26% in the presence of calcium carbonate (0.5% w/v). We prepared FBs of GE using calcium carbonate and sodium alginate in different proportions. Beads were evaluated for diameter, buoyancy, entrapment, and porosity. In vitro dissolution showed a Fickian release with a cumulative release of >80% at 24 h. Preclinical evaluation was done in cold-restraint stress induced gastric ulcers, in albino rats, in terms of (i) ulcer index, hemorrhagic streaks (l), mucus content, (ii) oxido-nitrosative stress, and (iii) histopathology. GE loaded FBs (200 mg/kg) were significantly better than free GE and better/equivalent to cimetidine (10 mg/kg). The system was evaluated for therapeutic effect (curative), i.e. after the induction of ulcers. Most of the natural phytochemical or antioxidants show pretreatment effectiveness. We, however, developed and established GE FBs for sustained curative effect.

Evaluation of Hydroxypropyl Methylcellulose Matrix Systems as Swellable Gastro-Retentive Drug Delivery Systems (GRDDS)

Utilizing gastro-retentive drug delivery systems (GRDDS) to increase absorption of weakly basic drugs by extending their transit time is a promising approach. Swellable systems were evaluated for this purpose. Such systems demonstrate dual mechanism of release-diffusion and erosion. GRDDS requires maintaining its dimensions, which demands diffusion as a predominant mechanism of release (Fickian). In this work, dypyridamole, a weakly basic drug, together with various grades of hydroxypropyl methylcellulose and different excipients were evaluated for release and swelling properties. Dissolution data were analyzed by curve fitting to various models to estimate predominant release mechanism. It was found that matrices containing a swellable diluent like microcrystalline cellulose demonstrated predominantly Fickian mechanism of release, whereas soluble diluents (lactose and mannitol) contributed to a mixed mechanism of release. Addition of copovidone increased the swelling and survivability, whereas sodium chloride altered the erosion behavior. A correlation between matrix weight loss and drug release was obtained, which further consolidated the analysis. Correlation for the soluble excipients was linear, whereas that for the swellable excipient was nonlinear, implying predominance of Fickian release mechanism for the latter. Hence, the selection of excipients can influence matrix survivability and release kinetics, which can be used for developing GRDDS.

Controlled drug release from contact lenses: a comprehensive review from 1965-present

This review covers the progress within the field of drug releasing contact lenses since 1965. It highlights the enormous potential of controlled release mechanisms and offers a comprehensive, comparative review of lenses, drugs, methods, drug loading, drug delivery rate, and release duration. Methods have included molecular imprinting as well various forms of mediated release via carriers, surfactants, inclusion complexes, and molecular barriers. Drug-soaked lens were the earliest releasing lenses, but they offer very little control over the release profile with low drug loading, are characterized by decaying, Fickian release rates, and typically reach completion in a very short amount of time. Molecular imprinting is consistently one of the most promising and versatile methods of enhanced drug loading and extended release with tailorable control over release rate when factors are balanced such as lens thickness, material, and release media and conditions.

Fabrication of plant protein microspheres for encapsulation, stabilization and in vitro release of multiple anti-tuberculosis drugs

An attempt has been made to encapsulate anti-tuberculosis drugs in microspheres. For the present studies Zein has been chosen for the preparation of microspheres. The effect of various constituents on the microspheres fabrication has also been investigated. Various parameters and methodologies such as percentage yield, encapsulation efficiency, optical microscopy, SEM, FTIR and in vitro release have been utilized for characterization of microspheres. Stability studies as reviewed from turbidity results show that increase in the relative turbidity is indicative of agglomeration in different pH mediums. Dissolution of drugs from different formulations (single, binary, ternary mixture) has been analyzed using ratio derivative and double divisor ratio derivative methods. The kinetics of drug release and its release mechanism have been analyzed using different mathematical models. Rifampicin gives non-Fickian release from the single drug formulation and Fickian release in the presence of other drugs (binary, ternary mixtures). The results for isoniazid and pyrazinamide in all the formulations indicate a Fickian release mechanism.

Activepackaging for topical cosmetic/drug products: A hot-melt extruded preservative delivery device

A delivery device intended for the prolonged release of antimicrobial agents, able to enhance the stability profile of liquid/semi-solid cosmetic/pharmaceutical products for topical application, was proposed in the present study. With the aid of a simulation program based on compartment models, the relevant kinetic and formulation parameters were defined using dehydroacetic acid sodium salt (DHA.Na, Prevan®) as the model preservative. Indeed, the overall DHA.Na degradation rate is increased in the presence of formaldehyde releasers that are often employed as co-preservatives. Inert matrices (3 g weight and 18 mm diameter) based on high-density polyethylene (HDPE), possibly consistent with the design of an active packaging meant for preservative delivery, were prepared by hot-melt extrusion. Units with satisfactory physical-technological properties could be obtained up to 50% w/w loads of antimicrobial agent. In an attempt to modify the relevant Fickian release profiles by varying the area exposed to the medium, matrix systems coated with an impermeable film except for one base (CMs) or for the inner surface of a central drilled hole (PCMs) were investigated. On the basis of the n exponent of power equation and the outcome of linear fitting, PCMs were proven able to yield the zero-order release behaviour needed to ensure constant DHA.Na levels over a predetermined time period, as indicated by the simulation process.

Preparation and characterization of nanoparticulate poly(N‐isopropylacryl‐ amide) hydrogel for the controlled release of anti‐tumour drugs

AbstractBACKGROUND: Poly(N‐isopropylacrylamide) (PNIPA) nanohydrogels were synthesized by inverse microemulsion to be used for the controlled release of anti‐tumour drugs. Different methods were used to obtain drug‐loaded xerogels, and their effect on drug release was studied, and evaluated using mathematical modelling.RESULTS: Nanoparticulate hydrogels, with a z‐average diameter of 170 nm, were loaded with 5‐fluorouracil (5‐FU), methotrexate (MTX) or mitomycin C (MMC) by using spray drying (SD) and freeze drying (FD). Xerogels obtained by SD consisted of individual and independent particles, whereas particles established interactions in xerogels obtained by FD. Total drug release took place at 6 and 7 h from 5‐FU‐loaded and MMC‐loaded xerogels prepared by SD, whereas MTX was expelled from the xerogels formed using the SD process. Drug release was slower from xerogels prepared by FD: 5‐FU at 32 h, MMC at 120 h and MTX at 240 h. The Higuchi model most aptly fits the dissolution data. Non‐Fickian and Fickian release behaviour can be attributed to SD and FD formulations, respectively.CONCLUSION: The amount of drug loaded, the morphology of xerogels as well as the drug release characteristics not only depend on the drug but also mainly on the process used to obtain the drug‐loaded PNIPA xerogels. Copyright © 2008 Society of Chemical Industry

A simple model framework for the prediction of controlled release from bulk eroding polymer matrices

A broadly applicable model for predicting controlled release could eliminate the need for exploratory, in vitro experiments during the design of new biodegradable matrix-based therapeutics. We have developed a simple mathematical model that can predict the release of many different types of agents from bulk eroding polymer matrices without regression. New methods for deterministically calculating the magnitude of the initial burst and the duration of the lag phase (time before Fickian release) were developed to enable the model's broad applicability. To complete the model's development, such that predictions can be made from easily measured or commonly known parameters, two correlations were developed by fitting the fundamental equations to published controlled release data. To test the model, predictions were made for several different biodegradable matrix systems. In addition, varying the readily attainable parameters over rational bounds shows that the model predicts a wide range of therapeutically relevant release behaviors.

Development and characterization of 5-FU bearing ferritin appended solid lipid nanoparticles for tumour targeting

Ferritin coupled solid lipid nanoparticles were investigated for tumour targeting. Solid lipid nanoparticles were prepared using HSPC, cholesterol, DSPE and triolien. The SLNs without ferritin which has similar lipid composition were used for comparison. SLNs preparations were characterized for shape, size and percentage entrapment. The average size of SLNs was found to be in the range 110–152 nm and maximum drug entrapment was found to be 34.6–39.1%. In vitro drug release from the formulations is obeying fickian release kinetics. Cellular uptake and IC50 values of the formulation were determined in vitro in MDA-MB-468 breast cancer cells. In vitro cell binding of Fr-SLN exhibits 7.7-folds higher binding to MDA-MB-468 breast cancer cells in comparison to plain SLNs. Ex-vivo cytotoxicity assay on targeted nanoparticles gave IC50 of 1.28 µM and non-targeted nanoparticles gave IC50 of 3.56 µM. In therapeutic experiments, 5-FU, SLNs and Fr-SLNs were administered at the dose of 10 mg 5-FU/kg body weight to MDA-MB-468 tumour bearing Balb/c mice. Administration of Fr-SLNs formulation results in effective reduction in tumour growth as compared with free 5-FU and plain SLNs. The result demonstrates that this delivery system possessed an enhanced anti-tumour activity. The results warrant further evaluation of this delivery system.

Structural stability and release profiles of proteins from core‐shell poly (DL‐lactide) ultrafine fibers prepared by emulsion electrospinning

This study was aimed at assessing the potential use of emulsion electrospinning to prepare core-shell structured ultrafine fibers as carriers for therapeutic proteins. It focused on the effect of fiber structure on the release profiles and structural stability of encapsulated proteins. In the case of bovine serum albumin (BSA) which was selected as a model protein, poly-DL-lactide ultrafine fibers prepared by emulsion electrospinning using a lower volume ratio of aqueous to organic phase, showed higher structural integrity of core-shell fiber as assessed by laser confocal scanning microscope (LCSM). This structural property can reduce the initial drug burst and improved the ability of the device to provide sustained therapeutic action. Fickian release was observed for the initial 60% of protein release. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and size exclusion chromatography (SEC) were used to assess the primary structure of BSA. These studies indicated that ultra-sonication caused denaturation of protein molecules, while the core-shell structured electrospun fibers protected the structural integrity of encapsulated protein during incubation in the medium. Fourier transform infrared (FTIR) analyses showed that the electrospinning process had much less effect on the secondary structure of protein than ultra-sonication. In vitro degradation study showed that the protein release from fibers led to more significant mass loss, higher molecular weight reduction and larger molecular weight distribution of the matrix residues, compared with fibers without protein inoculation. These data suggest that emulsion electrospinning can provide a useful core-sheath structure, which may serve as a promising scaffold for sustainable, controllable, and effective release of bioactive proteins in tissue engineering and other applications.

Zero-order therapeutic release from imprinted hydrogel contact lenses within in vitro physiological ocular tear flow

Zero-order or concentration independent release kinetics are highly desirable from drug delivery devices. In this paper we demonstrate experimentally, for the first time, zero-order release of a small molecular weight therapeutic, ketotifen fumarate (MW = 425), from molecularly imprinted hydrogels used as therapeutic contact lenses. We performed dynamic, in vitro drug release studies from imprinted hydrogel contact lenses within a novel microfluidic device that simulates the volumetric flow rates, tear volume and tear composition of the eye. Imprinted gels with multiple functional monomers and complexation points to the drug demonstrated a significantly delayed release of drug compared to less functionalized systems. There were no statistical differences in experimentally determined equilibrium swollen polymer volume fractions, which correlate with molecular weight between crosslinks and mesh size of the gel. Under infinite sink conditions, imprinted contact lenses demonstrated Fickian (concentration dependent) release kinetics with diffusion coefficients ranging from 4.04 × 10 − 9 to 5.57 × 10 − 10 cm 2/s. The highest functionalized gel exhibited a diffusion coefficient averaging ten times smaller than less functionalized gels and released drug for over 5 days with 3 distinct rates of release. Under physiological volumetric flow rates, the release rate was constant for a duration of 3.5 days delivering a therapeutically relevant dosage and was fit to a power law model indicating zero-order release characteristics with n = 0.981 ± 0.006 ( r 2 = 0.997). This work demonstrates the potential of micro/nanofluidic devices to determine physiological release rates and stresses the importance of matching local conditions to adequately characterize drug delivery devices. It also demonstrates the enormous potential for molecular imprinting to further tailor therapeutic release kinetics via the imprinting process.

Effects of calcination temperature on the drug delivery behaviour of Ibuprofen from hydroxyapatite powders

The effects of heat treatment time and temperature on the delivery behaviour of Ibuprofen from hydroxyapatite particles were investigated in this study. The drug release was seen to follow Fickian diffusion for the initial period of release for all heat treatment conditions. The gradient of Fickian release increased with (1) increasing crystallite size, attributed to the decreasing amount of boundary area, and (2) with decreasing surface area, due to the reduction in porosity and hence tortuosity within the apatite particles. This study has shown that altering the heat treatment conditions used to calcine hydroxyapatite may alter its drug delivery abilities, whereby calcination temperature was noted to influence the drug release behaviour to a greater extent than calcination time.

Preparation of a novel freeze thawed poly(vinyl alcohol) composite hydrogel for drug delivery applications

We describe a drug delivery system based on a physically cross-linked poly(vinyl alcohol) (PVA) hydrogel for the release of Theophylline (TH). A composite was created by freezing an aqueous solution of PVA/NaOH onto a PVA/poly(acrylic acid) substrate. This formed a strong interface and demonstrated greater physical strength than the hydrogel alone. Such systems have potential for a variety of localised controlled drug delivery applications, for example, as coatings for implantable devices. Importantly, the results suggest that a versatile synthetic platform is possible that may provide different functional materials or combination of such. The resultant samples were characterised using optical microscopy, modulated differential scanning calorimetry (MDSC) and dissolution testing. The microstructure of the gels was examined using micro-thermal analysis (μTA) which is a combination of atomic force microscopy and thermal analysis. TH was found to have an effect on the crystalline structure and dissolution showed a Fickian release, suggesting that swelling and crystallinity were the controlling mechanisms.

Microparticles prepared with poly(hydroxybutyrate-co-hydroxyvalerate) and poly(ε-caprolactone) blends to control the release of a drug model

The objective of this work was to verify the influence of the poly(ϵ-caprolactone) PCL concentration in poly(hydroxybutyrate-co-hydroxyvalerate) P(HBHV)/PCL microparticles, prepared by an emulsion/solvent evaporation process, on the release behavior of a drug. Differential Scanning Calorimetry analyses demonstrated that the preparation process increased the crystallite heterogeneity for the P(HBHV) in the particles. The drug caused an increase in the glass transition of the P(HBHV) in the microparticles. Dexamethasone acetate-loaded microparticles demonstrated drug sustained releases (up to 250 h), which profiles fit the biexponential model. The release of dexamethasone acetate caused an increase in the surface area of the microparticles. The kinetic constants of the sustained phase increased with the augmentation of the PCL content in the blend. The drug release mechanism was dependent on the presence of PCL in the microparticles. A Fickian release was determined for the microparticles prepared exclusively with P(HBHV), while non-Fickian release behaviors were found for the P(HBHV)/PCL microparticles.

Controlled release of an anti-malarial drug from a pH-sensitive poly(methacrylamide-co-methacrylic acid) hydrogel system

Novel pH-sensitive hydrogels, synthesized by free radical aqueous co-polymerization of methacrylic acid and methacrylamide, were investigated for oral delivery of the anti-malarial drug methylene blue under physiological conditions. The gels demonstrated nearly 97–98% entrapment efficiency. The release in simulating gastric fluid (SGF, pH 1.2) and in simulating intestinal fluid (SIF, pH 7.4) was found to be nearly 29 and 75%, respectively. The release rate was found to depend upon the diameter of the cylindrical gels, geometry of the device and gastric transit time. The pH-dependent release was co-related with the structural changes observed within the polymer network resulting from change in pH of the release medium. The values of the release exponent n suggested a non-Fickian release mechanism in phosphate buffer (pH 7.4), while a Fickian release was observed in SGF (pH 1.2). The first-order kinetic model was found to fit best to the experimental release data, which was also confirmed by a novel curve area measurement approach.

Design and development of folate appended liposomes for enhanced delivery of 5-FU to tumor cells

Folate appended sterically-stabilized liposomes (FA–SL) were investigated for tumor targeting. Liposomes were prepared using HSPC, cholesterol and FA–polyethylene glycol (PEG)–SA. The liposomes with polyethylene glycol (PEG) without folic acid which has similar lipid composition were used for comparison. Liposomal preparations were characterized for shape, size and percent entrapment. The average size of liposomes was found to be in range 124–163 nm and maximum drug entrapment was found to be 34.2–40.3%. In vitro drug release from the formulations is obeying fickian release kinetics. Cellular uptake and IC50 values of the FR-targeted formulation were determined in vitro in FR (+) B16F10 melanoma cells. In vitro cell binding of FA–SL exhibits 11-folds higher binding to B16F10 melanoma cells in comparison to SL. In vivo cytotoxicy assay on FR targeted liposomes gave IC50 of 1.87 μM and non-targeted liposomes gave IC50 of 4.02 μM. In therapeutic experiments 5-fluorouracil (5-FU), SL and FA–SL were administered at the dose of 10 mg 5-FU/kg body weight to B16F10 tumor bearing Balb/c mice. Administration of FA–SL formulation results in effective reduction in tumor growth as compared with free 5-FU and SL. Results indicate that folic acid appended SL bearing 5-FU are significantly (P < 0.01) active against primary tumor and metastasis than non-targeted sterically-SL. Thus, it could be concluded that folate coupled liposomal formulations enhanced drug uptake by tumor cells.

Development and &lt;i&gt;In vitro&lt;/i&gt; Evaluation of Oral Controlled Release Formulations of Celecoxib Using Optimization Techniques

The objective of this study was to develop controlled release matrix embedded formulations of celecoxib (CCX) as candidate drug using hydroxy propyl methyl cellulose (HPMC) and ethyl cellulose (EC), either alone or in combination, using optimization techniques like polynomial method and composite design. This would enable development of controlled release formulations with predictable and better release characteristics in lesser number of trials. Controlled release matrix tablets of CCX were prepared by wet granulation method. The in vitro release rate studies were carried out in USP dissolution apparatus (paddle method) in 900 ml of sodium phosphate buffer (pH 7.4) with 1% v/v tween-80. The in vitro drug release data was suitably transformed and used to develop mathematical models using first order polynomial equation and composite design techniques of optimization. In the formulations prepared using HPMC alone, the release rate decreased as the polymer proportion in the matrix base was increased. Whereas in case of formulations prepared using EC alone, only marginal difference was observed in the release rate upon increasing the polymer proportion. In case of formulations containing combination of HPMC and EC, the release of the drug was found to be dependent on the relative proportions of HPMC and EC used in the tablet matrix. The release of the drug from these formulations was extended up to 21 h indicating they can serve as once daily controlled release formulations for CCX. Mathematical analysis of the release kinetics indicates a near approximate Fickian release character for most of the designed formulations. Mathematical equation developed by transforming the in vitro release data using composite design model showed better correlation between observed and predicted t(50%) (time required for 50% of the drug release) when compared to first order polynomial equation model. The equation thus developed can be used to predict the release characteristics of the drug from matrix embedded formulations depending upon the proportion of HPMC and EC used in the formulation.

Optimization of bilayer floating tablet containing metoprolol tartrate as a model drug for gastric retention

The purpose of the present study was to develop an optimized gastric floating drug delivery system (GFDDS) containing metoprolol tartrate (MT) as a model drug by the optimization technique. A 2(3) factorial design was employed in formulating the GFDDS with total polymer content-to-drug ratio (X1), polymer-to-polymer ratio (X2), and different viscosity grades of hydroxypropyl methyl cellulose (HPMC) (X3) as independent variables. Four dependent variables were considered: percentage of MT release at 8 hours, T50%, diffusion coefficient, and floating time. The main effect and interaction terms were quantitatively evaluated using a mathematical model. The results indicate that X1 and X2 significantly affected the floating time and release properties, but the effect of different viscosity grades of HPMC (K4M and K10M) was nonsignificant. Regression analysis and numerical optimization were performed to identify the best formulation. Fickian release transport was confirmed as the release mechanism from the optimized formulation. The predicted values agreed well with the experimental values, and the results demonstrate the feasibility of the model in the development of GFDDS.