Design of meloxicam and lornoxicam transdermal patches: Preparation, physical characterization, ex vivo and in vivo studies

Transdermal patches of meloxicam (MX) and lornoxicam (LX) were aimed to be prepared in order to overcome their side effects by oral application. The strategy was formulation of optimized films to prepare transdermal patches by determination of physical properties and investigation of drug-excipient compatibility. As the next step, in vitro drug release, assesment of anti-inflammatory effect on Wistar Albino rats, ex vivo skin penetration and investigation of factors on drug release from transdermal patches were studied. Hydroxypropyl methylcellulose (HPMC) was concluded to be suitable polymer for formulation of MX and LX transdermal films indicating pharmaceutical quality required. MX and LX transdermal patches gave satisfactory results regarding to the edema inhibition in the assessment of anti-inflammatory effect. MX was found out to be more effective compared to LX on relieving of edema and swelling. These results were supported by data obtained from ex vivo penetration experiments of drug through rat skin. Indicative parameters like log P, molecular weight and solubility constraint on penetration rate of drugs also indicated good skin penetration. Transdermal patches of MX and LX can be suggested to be used especially for the immediate treatment of inflammated area since it displays anti-inflammatory effect, soon.     

Preparation of hydroxypropylmethyl cellulose-based porous matrix for gastroretentive delivery of gabapentin using the freeze-drying method

The aims of the present study were to prepare hydroxypropylmethyl cellulose (HPMC)-based porous matrix tablets for gastroretentive drug delivery and to characterize their physicochemical properties. Gabapentin (GBP) was used as a model drug. Paste containing GBP, HPMC and water was molded and freeze-dried to prepare freeze-dried gastroretentive matrix tablet (FD-GRT). In vitro drug release and erosion studies were also performed. Although FD-GRT exhibited porous structure, they had good tablet strength and friability. Density of FD-GRT ranged from 0.402 to 0.509 g/cm³ and thus they could float on the medium surface without any lag time. FD-GRT was remained floated until the entire matrix erosion or end of drug release during in vitro release test. Release behavior of GBP could be modulated by the amount and the viscosity grade of HPMC. However, large amount and high viscosity of HPMC caused trouble in molding prior to freeze-drying. Addition of ethylcellulose could retard the release rate of GBP, with relatively low increase in viscosity of paste. Since pores generated by freeze drying imparted buoyancy for gastric retention to FD-GRT, additional materials for buoyancy was not necessary and FD-GRT had no lag time for buoyancy due to low density. Therefore it could be a promising tool for gastroretentive drug delivery.     

Effect of Membrane Preparation Methods on the Release of Theophylline through CA Membranes at In-Vitro Conditions

In this study the effect of the membrane preparation methods on the release of theophylline through cellulose acetate (CA) membranes was studied at in vitro conditions. CA/acetone binary and CA/acetone/water ternary systems were used as casting solutions and poly(ethylene glycol) (PEG) was used as the pore forming, plasticizing agent in the study. Membranes were characterized by FTIR, SEM, and DSC analysis. It was determined that pH, temperature and drug concentration affected the release of theophylline. A decrease in pH, increase in temperature and drug concentration increased the permeated amount of theophylline through the membranes. In addition, receiver solution circulation at a capillary blood rate increased the permeation of theophylline. As a result of the study, it was concluded that the release of theophylline could be controlled for a prolonged period of time and modified CA membranes prepared in the study could be as an advisable membrane material for potential release of theophylline at transdermal conditions.     

Effect of the morphology of hydrophilic polymeric matrices on the diffusion and release of water soluble drugs

Drug release mechanisms from, and diffusion processes in, hydrophilic crosslinked polymeric systems were investigated in two macromolecular states: in the glassy and rubbery states during the early part of countercurrent water diffusion, and in the rubbery state after thermodynamic equilibrium between the network and the surrounding dissolution medium (water) was attained. Dilute, aqueous poly(vinyl alcohol) (PVA) solutions containing theophylline were crosslinked with glutaraldehyde. The crosslinking ratio, X, varied between 0.01 and 0.20 moles glutaraldehyde per mole of PVA repeating unit. Theophylline release from these rubbery matrices was followed as a function of time. It was determined that, within the range of crosslinking ratios studied, the crosslinked macromolecular structure affected the solute diffusion process. Theophylline release from crosslinked PVA slabs, which were originally dehydrated at 30°C, was also measured. The drug release process was significantly impeded in these systems, especially for samples with crosslinking ratio X ≥ 0.10. This behavior was explained in terms of relaxation of the macromolecular chains and possible existence of ordered chain structures. Glass-to-rubber transitions, a result of the countercurrent diffusion of water into the originally dried (glassy) polymer, shifted the fractional release of theophylline from a f(t^1/2) to a f(tⁿ) time dependence, with n taking values between 0.50 and 0.76. This type of release behavior indicates anomalous diffusion mechanisms. These results may be helpful in the development of swelling controlled drug delivery systems.     

Acrylate terpolymer in fabrication of medicated skin patches

An acrylate based pressure sensitive adhesive (PSA) was synthesized to design a drug‐in‐adhesive (DIA) type transdermal therapeutic system (TTS) for nitroglycerin used in the treatment of angina pectoris. 2‐Ethylhexyl acrylate (EHA), methyl methacrylate (MMA) and acrylic acid (AA) were used to synthesize the PSA by free radical solution polymerization. The effects of reaction time, reaction temperature, initiator concentration and solvent on polymerization were studied. The synthesized terpolymer was characterized by ¹H‐NMR, FT‐IR, differential scanning calorimetry (DSC) and gel permeation chromatography (GPC) and also evaluated for intrinsic viscosity, refractive index, peel strength, moisture uptake and skin irritation potential. The PSA was used to develop DIA type patches of nitroglycerin. The patches were cast using solvent evaporation technique and dried at controlled temperature. The patches were evaluated for thickness uniformity, weight variation, peel strength and moisture pick‐up. The percent drug content and in vitro drug release was determined by high pressure liquid chromatography (HPLC) method. On the basis of in vitro release profile, patches were selected for in vitro skin permeation studies. The developed formulation TP‐1 (K = 24.892 mcg/cm²/hr) followed zero‐order rate kinetics and showed better skin permeation rate in comparison to the marketed TTS (MTTS) (K = 17.413 mcg/cm²/hr). TP‐1 was subjected to stability testing for a period of 1 year according to ICH guidelines. The patches were found to be stable and an expiry date of 2 years was predicted with storage at 25 °C or below. Copyright © 2001 John Wiley & Sons, Ltd.     

Sodium alginate/HPMC/liquid paraffin emulsified (o/w) gel beads,by factorial design approach; and in vitro analysis

The present study involved development of a novel sodium alginate (SA)/HPMC/light liquid paraffin emulsified (o/w) gel beads containing Diclofenac sodium (DS) as an active pharmaceutical ingredient and its site specific delivery by using hard gelatin capsule fabricated by enteric coated Eudragit L-100 polymer. Emulsified gel beads were formulated by 3-level factorial design, ionic gelatin method. The obtained beads were characterized by Fourier transform infrared, X-ray diffraction and Field emission scanning electron microscope analysis. The variables such as SA (X₁), HPMC (X₂), were optimized for drug loading and in vitro drug release with the help of response surface methodology (RSM). The RSM analysis predicted that SA was significant for both drug loading (p = 0.0005) and drug release (p = 0.0041). HPMC was only significant for drug release (p = 0.0154). The cross-product contribution (2FI) and quadratic model were found to be adequate and statistically accurate with correlation value (R²) of 0.9054 and 0.9450 to predict the drug loading and drug release respectively. An increase in concentration of HPMC and SA decreases the drug loading as well as the drug release. The obtained optimum values of drug loading and DS released were 7.43 % and 85.54 % respectively, which were well in agreement with the predicted value by RSM.     

Thermosensitive and control release behavior of poly (N‐isopropylacrylamide‐co‐acrylic acid) latex particles

In this work, poly(N‐isopropylacrylamide‐co‐acrylic acid) (poly(NIPAAm‐AA)) copolymer latex particles (microgels) were synthesized by the method of soapless emulsion polymerization. Poly(NIPAAm‐AA) copolymer microgels have the property of being thermosensitive. The concentration of acrylic acid (AA) and crosslinking agent N,N′‐methylenebisacrylamide were important factors to influence the lower critical solution temperature (LCST) of poly(NIPAAm‐AA) microgels. The effects of AA and crosslinking agent on the swelling behavior of poly(NIPAAm‐AA) microgels were also studied. The poly(NIPAAm‐AA) copolymer microgels were then used as a thermosensitive drug carrier to load caffeine. The effects of concentration of AA and crosslinking agent on the control release of caffeine were investigated. How the AA content and crosslinking agent influenced the morphology and LCST of the microgels was discussed in detail. The relationship of morphology, swelling, and control release behavior of these thermosensitive microgels was established. A new scheme was proposed to interpret the control release of the microgels with different morphological structures. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 5734–5741, 2008     

Chondroitin/polypyrrole nanocomposite hydrogels for the accurate release of 5-fluorouracil by electrical stimulation

The development of electro-stimulated drug release devices is an innovative approach to attain the drug delivery in accurate doses at target sites in a programmed manner. In this work, novel electroactive nanocomposite hydrogels were prepared by encapsulating green-synthesized polypyrrole (PPy) colloids within chondroitin sulfate (CS) networks during the self-crosslinking of CS via N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide chemistry. The structural and morphological properties of CS/PPy hydrogels were studied by Fourier-transformed infrared spectroscopy, scanning electron microscopy, and swelling kinetic measurements. The chemotherapeutic agent 5-fluorouracil (5-FU) was loaded into CS/PPy samples by hydrogel swelling method, or alternatively, by pre-incubating the drug in polymer mixture before crosslinking. Different electrical stimulations can be used to switch ON and accurately tune the 5-FU delivery from GG/PPy hydrogels. A single pulse potential of 5 V switched on the drug delivery up to 90% from nanocomposite hydrogel, in contrast to the low 5-FU amount released in a passive form (< 20%). PPy electroactive behavior played a determining role as the main driving force in 5-FU release activation. Cytotoxicity of hydrogels with and without 5-FU was examined in normal and cancer cells. Considering the high cytotoxicity of 5-FU, the ON/OFF 5-FU release patterns evidenced the potential of CS/PPy hydrogels for electrically controlled drug delivery in implantable or transdermal drug release devices.     

Thermal analysis applied in the osmotic tablets pre-formulation studies

Osmotically controlled and oral drug delivery systems utilize osmotic pressure for controlled delivery of active agent(s). Drug delivery from these systems, to a large extent, is independent of the physiological factors of the gastrointestinal tract and these systems can be utilized for systemic as well as targeted delivery of drugs. We apply the thermal methods and IR spectroscopy to study compatibility between atenolol and several excipients usually found in the osmotic systems formulations (Polyethylene oxide, MW 3350, 100000, 200000 and 5000000; HPMC K4000, magnesium stearate and cellulose acetate. Cellulose acetate, HPMC K4000 and magnesium stearate have essentially no interaction with atenolol otherwise all Polyethylene oxide excipients modifies significantly the drug melting point indicating some extend of interaction.     

Hydroxypropyl methylcellulose based cephalexin extended release tablets: influence of tablet formulation,hardness and storage on in vitro release kinetics

The object of this study was to develop hydroxypropyl methylcellulose (HPMC) based cephalexin extended release tablet, which can release the drug for six hours in predetermined rate. Twenty-one batches of cephalexin tablets were prepared by changing various physical and chemical parameters, in order to get required theoretical release profile. The influences of HPMC, microcrystalline cellulose powder (MCCP), granulation technique, wetting agent and tablet hardness on cephalexin release from HPMC based extended release tablets were studied. The formulated tablets were also characterized by physical and chemical parameters. The dissolution results showed that a higher amount of HPMC in tablet composition resulted in reduced drug release. Addition of MCCP resulted in faster drug release. Tablets prepared by dry granulation was released the drug slowly than the same prepared with a wet granulation technique. Addition of wetting agent in the tablets prepared with dry granulation technique showed slower release. An increase in tablet hardness resulted in faster drug release. Tablets prepared with a wet granulation technique and having a composition of 9.3% w/w HPMC with a hardness of 10-12 kg/cm(2) gave predicted release for 6 h. The in vitro release data was well fit in to Higuchi and Korsmeyer-Peppas model. Physical and chemical parameters of all formulated tablets were within acceptable limits. One batch among formulated twenty-one batches was successful and showed required theoretical release. The effect of storage on in vitro release and physicochemical parameters of successful batch was studied and was found to be in acceptable limits.     

Modulation of Tenoxicam release from hydrophilic matrix: modulator membrane versus rate-controlling membrane

This paper describes the preparation of two layered device comprising of tenoxicam containing layer and a drug free membrane layer based on Geomatrix Technology. Our device based on bilaminated films which produced by a casting/solvent evaporation technique. The drug-hydroxypropyl methylcellulose (HPMC) layer was covered by drug free membrane layer composed of a mixture of different ratios of HPMC and ethyl cellulose (EC). The prepared devices were evaluated for thickness, weight, drug content uniformity, water absorption capacity and in-vitro drug release. The films were also evaluated for appearance, smoothness and transparency. The influence of drug free membrane layer composition and thickness on the drug release pattern was studied on 12 devices (D1 to D12). The results indicate that, the release of drug from HPMC matrixes without the drug free membrane layer was fast and follows diffusion controlled mechanism. The release of drug from the devices D1, D4, D9 and D12 follow the same mechanism, while the release of drug from other devices become linear with time (zero order) and extended for long time especially when thickness and the ratio of EC was increased in the drug free membrane layer. From this study it is concluded that, changing the geometry of drug layer by addition of drug free membrane layer and changing its composition and thickness plays an important role in determining whether the drug free membrane layer is rate-controlling or modulator membrane. Hence it can facilitate the development of different pharmaceutical products with different release pattern.     

Chemical Modification of A Vinyl Ester Resin by Acid Anhydrides and Characterization of the Products by l3C NMR

A vinyl ester resin was modified into half ester-acids by reaction with phthalic, maleic, and succinic anhydrides, using pyridine as catalyst. GPC analysis indicated that the reaction proceeds without crosslinking or polymerization. ¹³C-NMR analysis showed that the β-isomer of the vinyl ester resin containing a primary hydroxyl group reacts much more rapidly than the α-isomer with a secondary hydroxyl group.     

Reducible polyethylenimine hydrogels with disulfide crosslinkers prepared by michael addition chemistry as drug delivery carriers: Synthesis,properties, and in vitro release

Degradable hydrogels crosslinked with disulfide bonds were prepared by Michael addition between amine groups of branched polyethylenimine and carbon–carbon double bonds of N,N′‐bis(acryloyl)cystamine. The influences of the chemical composition of the resulted hydrogels on their properties were examined in terms of morphology, surface area, swelling kinetics, and degradation. The hydrogels were uniformly crosslinked and degraded into water‐soluble polymers in the presence of the reducing agent of dithiothreitol, which improved the control over the release of encapsulated drug. The degradation of hydrogels can trigger the release of encapsulated molecules, as well as facilitate the removal of empty vehicles. Results obtained from in vitro drug release suggested that the disulfide crosslinked hydrogels exhibited an accelerated release of encapsulated drug in dithiothreitol‐containing PBS buffer solution. Moreover, the drug release rate decreased gradually with increasing crosslinking density. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 4074–4082, 2009     

Development of a sustained-release matrix tablet formulation of DHEA as ternary complex with α-cyclodextrin and glycine

Sustained-release matrix-tablets of dehydroepiandrosterone (DHEA) as ternary complex with α-cyclodextrin and glycine (c-DHEA) were prepared by direct compression with suitable excipients. The influence of the swelling properties of hydroxypropylmethylcellulose (HPMC) and the disintegrating power of Explotab^® used in combination, as well as the effect of the presence, type and amount of suitable channelling agents (Emcocel^® and spray-dried lactose, alone or in combination) on drug release behaviour from matrix-tablets has been evaluated. The best performances in terms of drug release was obtained from formulations containing a 75:25 w/w spray-dried lactose:Emcocel^® combination in the presence of HPMC as matrix-forming polymer, leading to a more than 65% DHEA released at the end of the test, a value which was, respectively, 1.9 and 2.7 times higher than those achieved with the corresponding formulations containing spray-dried lactose or Emcocel^® alone. The drug release profile from the most effective matrix-tablet formulation of c-DHEA allowed achievement of a more than 6-fold increase in the drug amount released within 24 h in comparison with the same formulation containing the simple physical mixtures of DHEA, α-cyclodextrin and glycine. Therefore the advantage of using DHEA as ternary complex, prepared by mechano-chemical treatment, was clearly demonstrated, thus allowing the development of an effective sustained-release formulation of the drug.     

Effect of method of preparation and process variables on controlled release of insoluble drug from chitosan microspheres

An inexpensive and simple method was adopted for the preparation of chitosan microspheres, crosslinked with glutaraldehyde (GA), for the controlled release of an insoluble drug‐ibuprofen, which is a commonly used NSAID (non‐steroidal anti‐inflammatory drug). The chitosan microspheres were prepared by different methods and varying the process conditions such as rate of stirring, concentration of crosslinking agent, and drug:polymer ratio in order to optimize these process variables on microsphere size, size distribution, degree of swelling, drug entrapment efficiency, and release rates. The absence of any chemical interaction between drug, polymer, and the crosslinking agent was confirmed by Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and thermogravimetric analyses (TGA) techniques. The microspheres were characterized by optical microscopy, which indicated that the particles were in the size range of 30–200 µm and scanning electron microscopy (SEM) studies revealed a smooth surface and spherical shape of microspheres. The microsphere size/size distributions were increased with the decreased stirring rates as well as GA concentration in the suspension medium. Decreasing the concentration of crosslinker increased the swelling ratio whereas extended crosslinking exhibited lowered entrapment efficiency. The in vitro drug release was controlled and extended up to 10 hr. Copyright © 2007 John Wiley & Sons, Ltd.     

Influence of hydration and crosslinking in transdermal delivery of nicotine from chitosan-based gels by thermal analysis

Chitosan is a biopolymer that forms hydrogels after swell in acid medium. The environment of the three-dimensional network of the chitosan-based hydrogels can be modified by its degree of swelling and crosslinking. In this way, nicotine was incorporated in the hydrogel formulations, with or without crosslinking with glutaraldehyde (0.01%), in different swollen states. Transdermal delivery of nicotine by chitosan-based hydrogels was studied in order to achieve the prolonged administration of the drug. Thermal analysis indicated a preliminary stability of these formulations, and the mechanism of drug release from hydrogels was dependent of the swelling degree and crosslinking. These formulations were able to control the transdermal flux of nicotine for up to 48 h following zero-order kinetics. The hydrogels with higher amounts of water or the partially dried crosslinked hydrogels reduced the partition of nicotine into the skin, leading to a minor transdermal flux of the drug (<3.4 µg cm⁻² h⁻¹). On the other hand, the partially dried non-crosslinked hydrogels lead to a major transdermal flux of the drug (20.19 µg cm⁻² h⁻¹) due to modifications of the environment into the hydrogel. In this way, these transdermal formulations were promising vehicles for prolonged administration of nicotine.

     

Novel Carboxymethyl Chitosan Microspheres for Controlled Delivery of Chelerythrine

Novel carboxymethyl chitosan (O-CMCS) microspheres containing an anti-tumor drug chelerythrine (CHE) have been successfully prepared by an emulsion crosslinking method using glutaraldehyde. The optimized microsphere formulation was characterized for particle size, shape, morphology, crystallinity and in vitro drug release. Results for mean particle size, drug loading content, entrapment efficiency and in vitro drug release of chelerythrine loaded microspheres were found to be 12.18 μm, 4.08%, 54.78% and 35.30% at pH 7.4 in 20 h, respectively. The optimized microspheres had an imperfect crystalline lattice and a spherical, rough morphology and the CHE release from O-CMCS microspheres followed the Higuchi matrix model. All these results suggested that O-CMCS microspheres are a promising carrier system for controlled drug delivery.     

Physicochemical characterisation and cyclodextrin complexation of erlotinib

Erlotinib (ERL), the anticancer drug of poor bioavailability, was quantified in terms of bio-relevant physicochemical parameters, such as acid–base properties, lipophilicity and solubility, and a comprehensive study on its inclusion complexation was carried out. The protonation constant of ERL (log K = 5.32) indicates that it exists mainly in deprotonated form at the pH of blood plasma. The high lipophilicity (log p = 2.75) explains its good permeability, while the very low solubility (S₀ = 12.46 μM) causes its low bioavailability and renders injection formulation a difficult job. This problem could be alleviated by enhancing ERL solubility through cyclodextrin (CD) inclusion complexation. Therefore, ERL–CD interactions were studied by a number of analytical techniques. The apparent stability constants of ERL with seven different CDs were determined using affinity capillary electrophoresis. Results indicated that the seven-membered β-CD and its derivatives were the most suitable hosts. Using UV Job plot titration 1:1 stoichiometry was determined, confirmed by electrospray ionisation-mass spectrometry experiments. The geometry of the inclusion complex was investigated by 2D ROESY NMR techniques, revealing that the ethynylphenyl ring enters the β-CD cavity. Phase-solubility analysis shows greatly enhanced solution concentration by CD complexation. The determined equilibrium and structural information offer molecular basis to elaborate improved drug formulation with enhanced bioavailability.     

Acrylate-based pressure sensitive adhesive in fabrication of transdermal therapeutic system

An acrylate-based pressure sensitive adhesive (PSA) was synthesized to incorporate in a design of a drug-in-adhesive (DIA) type transdermal therapeutic system (TTS) for nitrendipine and nicorandil in treatment of hypertension and angina pectoris, respectively. Solutions of 2-ethylhexyl acrylate (EHA; 85% w/w), methyl methacrylate (MMA; 10% w/w), acrylic acid (AA; 3% w/w) and vinyl acetate (VA; 2% w/w) in either ethyl acetate, acetone or methanol were polymerized under free radical conditions to synthesize the PSA. The effects of solvent, reaction time, initiator concentration and reaction temperature on polymerization were studied. The resultant copolymers were characterized by ¹H-NMR, IR, differential scanning calorimetry (DSC) and gel permeation chromatography (GPC) and the intrinsic viscosities, refractive index, peel strength, moisture uptake and skin irritation potential were determined. The PSA was used to develop DIA type patches for delivery of nitrendipine and nicorandil. The TTS were evaluated for thickness, weight, peel strength, moisture uptake, in vitro release and in vitro skin permeation through guinea-pig skin. The copolymer found to effectively control the rate of drug release and the corresponding TTSs could be successfully employed in transdermal delivery of nitrendipine and nicorandil. Copyright © 2003 John Wiley & Sons, Ltd.     

Electron beam processed transdermal delivery system for administration of an anti-anginal agent

Electron beam irradiation was used to synthesize a matrix type transdermal system of isosorbide dinitrate, an effective anti-anginal agent. The drug was dissolved in two monomeric systems, 2-ethylhexyl acrylate (EHA) and 2-ethylhexyl acrylate : methyl methacrylate (9 : 1). The solutions were then directly irradiated on a backing membrane (Scotchpak^®1006) at different doses to get transdermal patches. The developed systems were evaluated for residual monomer content, equilibrium weight swelling ratio, weight uniformity, thickness uniformity, drug content, peel strength, in vitro release and skin permeation kinetics. They possessed excellent tack and adhesive properties. In the case of isosorbide dinitrate–EHA systems, an increase in the peel strength values with respect to the skin was observed with increasing radiation doses. The systems exhibited promising skin permeation kinetics favorable for transdermal drug delivery. The radiation stability of the drug in the pure solid state form was also assessed.