Drug Release Of Formulations Research Articles

Physicochemical, Cytotoxic, and Dermal Release Features of a Novel Cationic Liposome Nanocarrier

A novel cationic liposome nanocarrier, having interesting performance in topical drug delivery, is here presented and evaluated for its features. Two penetration enhancers, namely monoolein and lauroylcholine chloride, are combined to rapidly formulate (15 min) a cationic liposome nanostructure endowed of excellent stability (>6 months) and skin penetration ability, along with low short-term cytotoxicity, as evaluated via the MTT test. Cytotoxicity tests and lipid droplet analysis give a strong indication that monoolein and lauroylcholine synergistically endanger long-term cells viability. The physicochemical features, investigated through SAXS, DLS, and cryo-TEM techniques, reveal that the nanostructure is retained after loading with diclofenac in its acid (hydrophobic) form. The drug release performances are studied using intact newborn pig skin. Analysis of the different skin strata proves that the drug mainly accumulates into the viable epidermis with almost no deposition into the derma. Indeed, the flux of the drug across the skin is exceptionally low, with only 1% release after 24 h. These results validate the use of this novel formulation for topical drug release when the delivery to the systemic circulation should be avoided.

FORMULATION & DEVELOPMENT OF PELLETS OF TOLTERODINE TARTRATE: A QUALITATIVE STUDY ON WURSTER BASED FLUIDIZED BED COATING TECHNOLOGY

In recent pharmaceutical applications, multiparticulate dosage forms are gaining much importance over single-unit dosage forms. The purpose of designing multiparticulate dosage form is to develop a reliable formulation that has all the advantages of a single unit formulation and yet devoid of the danger of alteration in drug release profile and formulation behavior due to unit to unit variation. The aim of present work is qualitative study on formulation of multiparticulate modified release pellets of Tolterodine Tartrate, by “Wurster Based Fluidized Bed Coating Process”(layering technique).The main purpose of the present study was to investigate the feasibility of the wurster process for preparing extended release pellets and subsequently comparing the release profile of the pellets so prepared with a marketed reference product in various media. Additionally, the effects of some independent process variables were evaluated. The effect of the various process parameters i.e. inlet air temperature, product temperature, exhaust temperature, atomization speed, spray pump speed, atomization air volume and air flow on the wurster process was studied. The results suggested that the values of process parameters greatly vary with the physical properties of the drug, polymers and solvents used in process for layering of pellets. Key Words: non-pariel-seeds (N.P.S), E.R coating (extended release coating), Wurster technology, process parameters

Application of organogels as oral controlled release formulations of hydrophilic drugs

We previously demonstrated that organogels prepared from soybean oil using 12-hydroxy stearic acid as a gelator can slowly release ibuprofen, a model lipophilic drug. In this study, we investigated the applicability of organogels as controlled release formulations of hydrophilic drugs. The release rates of theophylline and ofloxacin, which are used as model hydrophilic drugs, were significantly slower than those of ibuprofen and antipyrine (model lipophilic drugs). Furthermore, no erosion was noted during drug release from organogels. Lipophilic drug molecules are released after diffusion in organogels because all molecules fully dissolve in the gel. On the other hand, hydrophilic drug molecules need to be dissolved before they diffuse in the organogel, prior to their release from the gel. Therefore, it is speculated that the release rates of hydrophilic drugs are slower than those of lipophilic drugs. To confirm the usefulness of organogels in controlled release formulations in vivo, organogels containing ibuprofen, ofloxacin, theophylline or antipyrine were intraduodenally administered to rats. All drugs used in this study were rapidly absorbed when administered in aqueous suspensions. In contrast, the drug concentrations in plasma after administration in organogels were lower; however, the lower concentrations of drugs sustained for 10 h after administration. With organogel administration, the mean residence time of drugs was longer than that with aqueous suspension administration. In conclusion, organogels are potential candidates for controlled release formulations of not only lipophilic drugs, but also hydrophilic drugs.

Structural evidence of differential forms of nanosponges of beta-cyclodextrin and its effect on solubilization of a model drug

Nanosponges (NS) are a recently developed class of hyper-branched polymers, nano-structured to form three dimensional meshwork; obtained by reacting cyclodextrins with a cross linker like diphenyl carbonate. Herein, we report an anomalous behavior of NS with regards to physical and morphological characteristics and drug encapsulation behavior by minor synthetic modification. Two distinct forms viz. crystalline and para-crystalline of NS were identified and extensively characterized by use of high resolution transmission electron microscopy (HR-TEM), X-ray powder diffraction (XRPD), scanning electron microscope, atomic force microscope, optical microscope and Fourier transform infra-red attenuated total reflectance spectroscopy (FTIR-ATR). Dimension of the crystal lattice was found to be equal to 0.61 nm. Higher magnifications clearly showed a zone axis with a hexagonal symmetry as that of beta-cyclodextrin. XRPD patterns were in concurrence with the HR-TEM results. Solubility studies with a model drug dexamethasone (DEX) showed more than three folds increase in the solubility of the drug in the crystalline NS as compared to the para-crystalline ones. Percent drug association and drug loading for DEX was found to be higher in the crystalline type of NS. An In vitro drug kinetic study evidenced a faster release of DEX from the crystalline type NS. The particle sizes of the formulations were as follows: crystalline NS: 688.6 ± 38.0 nm, para-crystalline NS: 702.2 ± 21.2 nm with polydispersity indices of 0.155 and 0.132; zeta-potential of −26.55 ± 1.7 and −23.42 ± 2.1 respectively. Differential scanning calorimetry and thermogravimetric analysis revealed that both forms encapsulated the drug satisfactorily. FTIR-ATR and Raman spectroscopy showed weak interactions. Crystallinity of NS was thus found to be an important factor in solubilization, in vitro kinetics and encapsulation behavior and can be tuned to give a tailored drug release profile or formulation characteristics.

Formulation of liposomes gels of paeonol for transdermal drug delivery by Box-Behnken statistical design

The aim of this study was to design and optimize a transdermal liposomes gel formulation for paeonol (PAE). A three-factor, three-level Box-Behnken design was used to derive a second-order polynomial equation to construct three-dimensional (3-D) contour plots for prediction of responses. Independent variables studied were the DC-Chol concentration (X1), molar ratio of lipid/drug (X2), and the polymer concentration (X3), and the levels of each factor were low, medium, and high. The dependent variables studied were the encapsulation efficiency (%EE) of PAE (Y1), flux of PAE (Y2), and viscosity of the gels (Y3). Response surface plots were drawn and statistical validity of the polynomials was established to find the compositions of optimized formulation, which was evaluated using the Franz diffusion cell. The %EE of PAE increased proportionally with the molar ratio of lipid/drug, but decreased with polymer concentration, whereas the flux of PAE increased proportionally with polymer concentration and the DC-Chol concentration. The viscosity of gels increased with the polymer concentration. Gels showed a non-Fickian diffusion release mechanism for PAE, and the in vitro release profiles were fit for Higuchi’s order model. The design demonstrated the role of the derived polynomial equation and 3-D contour plots in predicting the values of dependent variables for the preparation and optimization of gel formulation for transdermal drug release.

Modular Hydrogels for Drug Delivery

The development of novel drug delivery systems is an essential step toward controlled site-specific administration of therapeutics within the body. It is desirable for delivery vehicles to be introduced into the body through minimally invasive means and, these vehicles should be capable of releasing drug to their intended location at a controlled rate. Furthermore, it is desirable to develop drug delivery systems that are capable of in vivo to suffer degradation and to deliver the drug completely, avoiding the need to surgically remove the vehicle at the end of its useful lifetime. Hydrogels are of particular interest for drug delivery applications due to their ability to address these needs in addition to their good biocompatibility, tunable network structure to control the diffusion of drugs and, tunable affinity for drugs. However, hydrogels are also limited for drug delivery applications due to the often quick elution of drug from their highly swollen polymer matrices as well as the difficulty inherent in the injection of macroscopic hydrogels into the body. This paper presents an overview to the advances in hydrogels based drug delivery. Different types of hydrogels can be used for drug delivery to specific sites in the gastrointestinal tract ranging from the oral cavity to the colon. These novel systems exhibit a range of several peculiar properties which make them attractive as controlled drug release formulations. Moreover, such materials are biocompatible and can be formulated to give controlled, pulsed, and triggered drug release profiles in a variety of tissues.

Multifunctional Porous Silicon for Therapeutic Drug Delivery and Imaging

Major challenges in drug formulation are the poor solid state stability of drug molecules, poor dissolution/solubility and/or poor pharmacokinetic properties (bioavailability), which may lead to unreliable in vitro-in vivo (IVIV) correlation. To improve current therapeutical strategies, novel means to deliver poorly water soluble active pharmaceutical ingredients, as well as to target them to specific sites or cells in the body are needed. Biomedical applications of porous silicon (PSi) have been actively investigated during the last 10 years, especially in the areas of drug delivery and imaging, due to the biocompatibility and biodegradability of PSi materials, which makes them a potential candidate for controlled drug release. In addition, the unique pore sizes and easily functionalized surface properties of PSi materials allow high drug payloads and controlled kinetics from the drug release formulations. Modification of the PSi surface properties also facilitates biofunctionalization of the surface and the possibility to attach targeting moieties (e.g., antibodies and peptides), thus enabling effective targeting of the payload. In this review, we briefly address the production methodologies of PSi, and we will mainly present and discuss several examples about the biocompatibility of PSi, the most recent in vitro and in vivo applications of PSi as a carrier in drug/protein/peptide delivery and tissue engineering, as well as PSi as a platform for drug targeting and imaging.

Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in adults

Attention Deficit Hyperactivity Disorder (ADHD) is a childhood onset disorder that can persist into adulthood. Amphetamines are used to treat adult ADHD, but uncertainties persist about their efficacy and safety. To examine the efficacy and safety of amphetamines for adults with ADHD, as well as the influence of dose, drug type and release formulation type. We searched CENTRAL, PubMed, EMBASE, CINAHL, PsycINFO, clinicaltrials.gov, UK Clinical Trials Gateway and references obtained from articles and experts in the field. We conducted the electronic searches on 25 February 2010. Randomized controlled trials comparing the efficacy of amphetamine derivatives against placebo or an active intervention. Two authors extracted data from each included study. We used the standardized mean difference (SMD) and the risk ratio (RR) to assess continuous and dichotomous outcomes, respectively. We conducted a stratified analysis to determine the influence of moderating variables. We assessed the trials for risk of bias and drew a funnel plot to investigate the possibility of publication bias. We included seven studies, which enrolled 1091 participants. All studies were placebo-controlled and three included an active comparator: guanfacine, modafinil and paroxetine. Most studies had short-term follow-up, with a mean study length of 8.1 weeks. Amphetamines improved ADHD symptom severity (SMD = -0.72; 95% CI -0.87 to -0.57) but did not improve retention in treatment overall and were associated with increased dropout due to adverse events (RR 3.03; 95% CI 1.52 to 6.05). The three amphetamine derivatives investigated (dextroamphetamine, lisdexamphetamine and mixed amphetamine salts (MAS)) were all efficacious for reducing ADHD symptoms, but MAS also increased retention in treatment. Different doses did not appear associated with differences in efficacy. We investigated immediate and sustained drug release formulations but found no difference between them on any outcome. When amphetamines were compared to other drug interventions, no differences were found. We did not find any study to be at low risk of bias overall, mainly because amphetamines have powerful subjective effects that may reveal the assigned treatment. Amphetamines improved short-term ADHD symptom severity. MAS also increased retention in treatment. Amphetamines were associated with higher attrition due to adverse events. The short study length and the restrictive inclusion criteria limit the external validity of these findings. Furthermore, the possibility that the results of the included studies were biased was high, which could have led to an overestimation of amphetamine efficacy.

Preparation and characterization of bioadhesive systems containing propolis or sildenafil for dental pulp protection

Purpose: Binary polymeric systems containing poloxamer 407 (P407) and Carbopol 934P (C934P) were designed to deliver propolis extract (PE) or sildenafil citrate for the endodontic treatment (pulp protection).Methods: Gelation temperature, rheology (flow), bioadhesion, and in vitro drug release of formulations were determined.Results: Formulations showed thermoresponsive behavior, existing as a liquid at room temperature and gel at 34–37°C. In addition, they exhibited pseudoplastic flow and low degrees of thixotropy or rheopexy. The greatest bioadhesion was noted in the formulation containing 20% P407 (w/w) and 0.10% C934P (w/w). PE release from formulation containing 15% P407 (w/w) and 0.25% C934P (w/w) was controlled by the phenomenon of relaxation of polymer chains. Moreover, sildenafil release from formulation containing 20% P407 (w/w) and 0.10% C934P (w/w) was controlled by Fickian diffusion.Conclusion: The data obtained on these formulations indicate a potentially useful role in the endodontic treatment (pulp protection) and suggest they are worthy of clinical evaluation.

The Design of Analytical Methods for Use in Topical Epidermal Growth Factor Product Development

Data from a reverse phase gradient elution HPLC assay for human epidermal growth factor (EGF) was compared and correlated with data obtained from a competitive heterogeneous radioimmunoassay (RIA). The RIA was established to measure very low concentrations of EGF in formulation drug release and compatibility studies. The HPLC assay, capable of resolving parent and possible modified or fragmented forms of EGF isolated from human urine, was studied as a potential development tool for stability and final product evaluation. As independent analytical methods, the HPLC and the RIA procedures produced correlated results when quantifying freshly prepared and certain degraded samples of EGF. The capacity of the HPLC method to serve as a stability indicating assay was examined. Degradation of EGF was induced by storage in 0.05 M phosphate buffer pH 7.4 at 25, 37 or 50 degrees C. The same three degradation products were detected at each temperature by the HPLC method, one of which was identified as L-isoaspartyl EGF.

MATHEMATICAL TREATMENT OF ORAL SUSTAINED RELEASE DRUG FORMULATIONS.

Abstract A mathematical model is described for an ideal sustained release dosage form in which there is a constant rate of release of drug from the maintenance dose. Kinetic equations related to this model are derived. The implications of these equations in the calculation of the dosage regimen for a sustained release product are considered.

MATHEMATICAL TREATMENT FOR ORAL SUSTAINED RELEASE DRUG FORMULATIONS.

MATHEMATICAL TREATMENT FOR ORAL SUSTAINED RELEASE DRUG FORMULATIONS.

Optimization and Formulation Design of Gels of Diclofenac and Curcumin for Transdermal Drug Delivery by Box-Behnken Statistical Design

The aim of this study was to develop and optimize a transdermal gel formulation for Diclofenac diethylamine (DDEA) and Curcumin (CRM). A 3-factor, 3-level Box-Behnken design was used to derive a second-order polynomial equation to construct contour plots for prediction of responses. Independent variables studied were the polymer concentration (X(1)), ethanol (X(2)) and propylene glycol (X(3)) and the levels of each factor were low, medium, and high. The dependent variables studied were the skin permeation rate of DDEA (Y(1)), skin permeation rate of CRM (Y(2)), and viscosity of the gels (Y(3)). Response surface plots were drawn, statistical validity of the polynomials was established to find the compositions of optimized formulation which was evaluated using the Franz-type diffusion cell. The permeation rate of DDEA increased proportionally with ethanol concentration but decreased with polymer concentration, whereas the permeation rate of CRM increased proportionally with polymer concentration. Gels showed a non-Fickian super case II (typical zero order) and non-Fickian diffusion release mechanism for DDEA and CRM, respectively. The design demonstrated the role of the derived polynomial equation and contour plots in predicting the values of dependent variables for the preparation and optimization of gel formulation for transdermal drug release.

Efficacy of Methylphenidate for Adults with Attention-Deficit Hyperactivity Disorder

The efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder (ADHD) shows wide between-study variability, which yields heterogeneous results in meta-analysis. The reasons for this variability have not been comprehensively investigated. To determine the influence of treatment-related covariates of methylphenidate for adults with ADHD by means of meta-analysis. Clinical and methodological moderators and clinical trial reporting quality were also collected to control for their potential confounding effect. We searched for randomized, placebo-controlled clinical trials investigating the efficacy of methylphenidate for adults with ADHD. The study outcome was the efficacy of methylphenidate for reducing ADHD symptom severity. Treatment-related covariates included dose, type of drug-release formulation (formulations with a continuous drug release vs those with a non-continuous drug release), dose regimen (fixed vs flexible) and treatment length. Clinical (presence of co-morbid substance use disorders [SUD]) and methodological (design and rater) covariates were also collected, in addition to clinical trial reporting quality. The standardized mean difference (SMD) was calculated for each study. The analysis of the influence of methylphenidate effect modifiers was performed by means of random-effects meta-regression. Eighteen studies were included. Dose, type of formulation and SUD appeared to modify the efficacy of methylphenidate in the bivariate analysis. These variables were included in a multivariate meta-regression, which showed that methylphenidate, at an average dose of 57.4 mg/day, delivered by means of non-continuous-release formulations, had a moderate effect on ADHD symptoms compared with placebo (SMD 0.57-0.58). A dose-response relationship was found, indicating that efficacy could be increased by SMD 0.11-0.12 for every 10 mg increment of methylphenidate. Continuous-release formulations and co-morbid SUD appeared to reduce the efficacy of methylphenidate. Nevertheless, the effect of treatment formulation may have been confounded by co-morbid SUD, since all studies using this continuous-release formulation were conducted in dual ADHD-SUD patients. No residual heterogeneity was found. This study shows that methylphenidate improves ADHD symptoms in adults in a dose-dependent fashion. The efficacy of methylphenidate appears to be reduced in patients with co-morbid SUD. It is unclear whether methylphenidate efficacy is influenced by the type of formulation, because the effect of this covariate is confounded by that of co-morbid SUD.

Preformulation characteristics of the opioid growth factor antagonist-naltrexone hydrochloride: stability and lipophilicity studies

In the last twenty years mesoporous materials (e.g., silica, silicon, and to a lesser extent titanium) have been extensively investigated as possible carriers for controlled drug delivery purposes. The great benefits of these materials are their high surface areas and pore volumes with tunable pore sizes and easily functionalized pore surface properties, which allow high drug payloads and from very rapid to slow release kinetics for controlled drug release formulations. The present review focuses on recent research on the exploitation of mesoporous silica and silicon based materials for controlled drug release applications. In particular, fabrication processes of these materials, drug loading and drug release profiles and mechanisms, as well as further functionalization of the porous surface structures of the materials are surveyed. Several examples of drug delivery formulations, together with drug release mechanisms, such as sustained release and stimuli-responsive controlled-release, are also presented herein.

Mesoporous materials as controlled drug delivery formulations

In the last twenty years mesoporous materials (e.g., silica, silicon, and to a lesser extent titanium) have been extensively investigated as possible carriers for controlled drug delivery purposes. The great benefits of these materials are their high surface areas and pore volumes with tunable pore sizes and easily functionalized pore surface properties, which allow high drug payloads and from very rapid to slow release kinetics for controlled drug release formulations. The present review focuses on recent research on the exploitation of mesoporous silica and silicon based materials for controlled drug release applications. In particular, fabrication processes of these materials, drug loading and drug release profiles and mechanisms, as well as further functionalization of the porous surface structures of the materials are surveyed. Several examples of drug delivery formulations, together with drug release mechanisms, such as sustained release and stimuli-responsive controlled-release, are also presented herein.

Thermal degradation of platinum(IV) precursors to antitumor drugs

Organoplatinum antitumor agents are very effective, broad-spectrum drugs used for the treatment of a variety of cancerous conditions. The two most prominent of these, Cisplatin [cis-diamminodichloroplatinum(II)] and Carboplatin [diammino(1,1-cyclobutanedicarboxylato)platinum(II)], are large scale commercial successes. The third, Oxaliplatin [((trans-1,2-diamminocyclohexane)oxalato)platinum(II)], is now commercially available. The administration of all these drugs is accompanied by severe side effects. For Cisplatin, the most debilitating of these is kidney damage and extreme nausea. Several approaches to generate drug-release formulations that might mitigate toxic side effects have been explored. Now, platinum(IV) compounds which are more inert than platinum(II) compounds, and consequently less toxic, but which may be reduced to platinum(II) species within the cell are being evaluated for effectiveness in the treatment of cancer. The thermal stability of several precursors to compounds of this kind has been examined by thermogravimetry. In general, these materials lose ligands sequentially to generate a residue of platinum. This behavior may be generally useful for the characterization of such materials.

Pharmacokinetics of methylphenidate in oral fluid and sweat of a pediatric subject

Methylphenidate (MPH) is a stimulant medication widely used for treating attention-deficit hyperactivity disorder (ADHD) in children and adolescents. Therapeutic monitoring for this drug is essentially lacking and alternative biological matrices, such as oral fluid and sweat, should be investigated for noninvasive assessment of short- and long-term history of drug use. We report the excretion profile of MHP and its metabolite ritalinic acid (RA) in oral fluid and sweat from a 12-year-old boy treated with the extended release drug formulation. Concentrations of MPH and RA in oral fluid, sweat and plasma were measured by liquid chromatography–mass spectrometry. Oral fluid-to-plasma ratio at each time interval was calculated at the start of the treatment and correlated with salivary pH. Excretion of MPH in sweat patches, collected up to 24 h with PharmChek patches was also investigated. MPH and RA were both detected in oral fluid with a pharmacokinetic profile similar to that in plasma. Oral fluid peak concentrations of MPH ranged between 13.5 and 30.9 ng/mL at 3.0 h after drug intake. Oral fluid-to-plasma MPH ratio between 13.1 and 3.2 demonstrated an accumulation of the drug in oral fluid. Conversely, RA was found in oral fluid at peak concentration (23.4–62.9 ng/mL) equivalent to one-tenth of those found in plasma. Concentration profiles of MPH and RA in oral fluid were quite constant during the four weeks of drug administration. In sweat, MPH was detected for the first time at 5 h after drug administration (range: 9.3–11.2 ng/patch) up to 24 h (range: 29.8–38.7 ng/patch). RA was not detected in the sweat patches during the 24 h time of collection. The results suggest that measurement of MPH in oral fluid can be used as a potential alternative to drug monitoring in plasma. Moreover, MPH measurement in sweat patches can be used for noninvasive monitoring of MPH consumption and misuse in situations where detection of recent abuse is of interest.

Electrospinning of Manmade and Biopolymer Nanofibers—Progress in Techniques, Materials, and Applications

AbstractElectrospinning of nanofibers has developed quickly from a laboratory curiosity to a highly versatile method for the preparation of a wide variety of nanofibers, which are of interest from a fundamental as well as a technical point of view. A wide variety of materials has been processed into individual nanofibers or nanofiber mats with very different morphologies. The diverse properties of these nanofibers, based on different physical, chemical, or biological behavior, mean they are of interest for different applications ranging from filtration, antibacterial coatings, drug release formulations, tissue engineering, living membranes, sensors, and so on. A particular advantage of electrospinning is that numerous non‐fiber forming materials can be immobilized by electrospinning in nanofiber nonwovens, even very sensitive biological objects such as virus, bacteria, and cells. The progress made during the last few years in the field of electrospinning is fascinating and is highlighted in this Feature Article, with particular emphasis on results obtained in the authors' research units. Specific areas of importance for the future of electrospinning, and which may open up novel applications, are also highlighted.

Optimization and Development of Swellable Controlled Porosity Osmotic Pump Tablet for Theophylline

Purpose: To develop swellable controlled porosity osmotic pump tablet of theophylline and to define the formulation and process variables responsible for drug release by applying statistical optimizationtechnique.Methods: Formulations were prepared based on Taguchi Orthogonal Array design and Fraction Factorial design for core and coating, respectively. The tablets were prepared by direct compression and wet granulation methods; spray coated with ethyl cellulose solution containing varying amounts ofPEG 400 and plasdone. Drug release from the osmotic drug delivery system was studied using USP Type I paddle type apparatus. The membrane morphology of the delivery system was determined byscanning electron microscopy (SEM).Results: Optimization results indicated that the release rate of theophylline from the swellable controlled porosity osmotic pump tablet is directly proportional to the levels of osmotic agent, solubilizing agent andpore former in the tablet core and the membrane, respectively. SEM showed the formation of pores in the membrane through which drug release occurred. The best formulation showed 98.2 % drug releaseand complied with USP requirements.Conclusion: The results confirmed that the factors responsible for drug release were osmotic agents (core) and pore former (membrane). Also, the preparation of swellable controlled porosity osmotic pumptablet was facilitated by coating the core tablet with pore forming agent, thus eliminating the need for the more expensive laser drilling.