Controlled release from zein matrices: Interplay of drug hydrophobicity and pH

Purpose: In earlier studies, the corn protein zein is found to be suitable as a sustained release agent, yet the range of drugs for which zein has been studied remains small. Here, zein is used as a sole excipient for drugs differing in hydrophobicity and isoelectric point: indomethacin, paracetamol and ranitidine. Methods: Caplets were prepared by hot-melt extrusion (HME) and injection moulding (IM). Each of the three model drugs were tested on two drug loadings in various dissolution media. The physical state of the drug, microstructure and hydration behaviour were investigated to build up understanding for the release behaviour from zein based matrix for drug delivery. Results: Drug crystallinity of the caplets increases with drug hydrophobicity. For ranitidine and indomethacin, swelling rates, swelling capacity and release rates were pH dependent as a consequence of the presence of charged groups on the drug molecules. Both hydration rates and release rates could be approached by existing models. Conclusion: Both the drug state as pH dependant electrostatic interactions are hypothesised to influence release kinetics. Both factors can potentially be used factors influencing release kinetics release, thereby broadening the horizon for zein as a tuneable release agent

Mechanisms of burst release from pH-responsive polymeric microparticles.

Microencapsulation of drugs into preformed polymers is commonly achieved through solvent evaporation techniques or spray drying. We compared these encapsulation methods in terms of controlled drug release properties of the prepared microparticles and investigated the underlying mechanisms responsible for the “burst release” effect. Using two different pH-responsive polymers with a dissolution threshold of pH 6 (Eudragit L100 and AQOAT AS-MG), hydrocortisone, a model hydrophobic drug, was incorporated into microparticles below and above its solubility within the polymer matrix. Although, spray drying is an attractive approach due to rapid particle production and relatively low solvent waste, the oil-in-oil microencapsulation method is superior in terms of controlled drug release properties from the microparticles. Slow solvent evaporation during the oil-in-oil emulsification process allows adequate time for drug and polymer redistribution in the microparticles and reduces uncontrolled drug burst release. Electron microscopy showed that this slower manufacturing procedure generated non-porous particles whereas thermal analysis and X-ray diffractometry showed that drug loading above the solubility limit of the drug in the polymer generated excess crystalline drug on the surface of the particles. Raman spectral mapping illustrated that drug was homogeneously distributed as a solid solution in the particles when loaded below saturation in the polymer with consequently minimal burst release

Controlled Drug Release Asymptotics

The solution of Higushi's model for controlled release of drugs is examined when the solubility of the drug in the polymer matrix is a prescribed function of time. A time-dependent solubility results either from an external control or from a change in pH due to the activation of pH immobilized enzymes. The model is described as a one-phase moving boundary problem which cannot be solved exactly. We consider two limits of our problem. The first limit considers a solubility much smaller than the initial loading of the drug. This limit leads to a pseudo-steady-state approximation of the diffusion equation and has been widely used when the solubility is constant. The second limit considers a solubility close to the initial loading of the drug. It requires a boundary layer analysis and has never been explored before. We obtain simple analytical expressions for the release rate which exhibits the effect of the time-dependent solubility

Adriamycin loading and release characteristics of albumin-heparin conjugate microspheres

Biodegradable ion-exchange microspheres, prepared from a prefabricated conjugate of albumin and heparin were investigated as carriers for adriamycin. The ion-exchange microspheres could be loaded with adriamycin giving payloads up to 33% w/w, depending on the heparin content of the conjugate. In vitro adriamycin release depended on the ionic strength of the release medium. In ion containing media, for instance saline, 90% of the drug was released within 45 min, whereas in non-ionic media, such as distilled water, only 30% was released. Drug release profiles could be modelled by combining ion-exchange kinetics and diffusion controlled drug release models

Influence of excipients on spray-dried powders for inhalation

Two areas attracting considerable attention when developing effective pulmonary drug delivery systems include the improvement of aerosolisation efficiency of the inhaled formulation and the controlled release of drug from the formulation following deposition within the lung. In this study, four saccharides were employed as excipients in the preparation of spray-dried powder formulations for the pulmonary drug delivery. Beta-cyclodextrin-, starch-, and sodium carboxymethylcellulose (NaCMC)-based spray-dried powders showed a significant (one-way ANOVA, Duncan's test, p < 0.05) increase in lower stage drug deposition in the Next Generation Impactor (NGI) when compared to lactose-based spray-dried powders. Furthermore, NaCMC-based spray-dried powder formulations exhibited a sustained drug release profile in dissolution testing; approximately 80% of salbutamol sulphate was released after an hour, whereas drug from the lactose-based spray-dried powder formulation was released within 5 min. Our results clearly demonstrate that the inclusion of NaCMC in spray-dried powder formulations increases the aerosolisation efficiency of the powder and also offers the potential for sustained drug release, which may be of benefit in the treatment of local and systemic conditions

Mathematical Modelling of Variable Porosity Coatings for Dual Drug Delivery

In this paper we describe a theoretical mathematical model of dual drug delivery from a durable polymer coated medical device. We demonstrate how the release rate of each drug may in principle be controlled by altering the initial loading configuration of the two drugs. By varying the underlying microstructure of polymer coating, further control may be obtained, providing the opportunity to tailor the release profile of each drug for the given application

Formulation and evaluation of floating mucoadhesive alginate beads for targetingHelicobacter pylori

Objectives: There are various obstacles in the eradication of Helicobacter.pylori (H. pylori) infections, including low antibiotic levels and poor accessibility of the drug at the site of the infection. This study describes the preparation and characterisation of novel floating-mucoadhesive alginate beads loaded with clarithromycin (CMN) for delivery to the gastric mucosa to improve the eradication of this micro-organism. Methods: Calcium alginate beads were prepared by ionotropic gelation. The formulation was modified through addition of oil and coating with chitosan in order to improve floating, mucoadhesion and modify drug release. Key findings: SEM confirmed the sphericity of the beads with X-ray microtomography (XμMT) showing the 3D structure of the beads with the layered internal structure of the bead and the even distribution of the drug within the bead. This formulation combined two gastro-retentive strategies and these formulations produced excellent in vitro floating, mucoadhesive and drug release characteristics. Enhanced stability of the beads in phosphate buffer raises a potential for the modified formulations to be targeted to regions of higher pH within the gastrointestinal tract with a higher pH. Drug release from these beads was sustained through an unstirred mucin layer simulating in vivo conditions under which the H. pylori resides in the gastric mucosa. Conclusions: This novel formulation will ensure retention for a longer period in the stomach than conventional formulations and control drug release, ensuring high local drug concentrations, leading to improved eradication of the bacteria

Validation of Smart Nanoparticles as Controlled Drug Delivery Systems: Loading and pH-Dependent Release of Pilocarpine

Micelles are good devices for use as controlled drug delivery systems because they exhibit the ability to protect the encapsulated substance from the routes of degradation until they reach the site of action. The present work assesses loading kinetics of a hydrophobic drug, pilocarpine, in polymeric micellar nanoparticles (NPs) and its pH-dependent release in hydrophilic environments. The trigger pH stimulus, pH 5.5, was the value encountered in damaged tissues in solid tumors. The new nanoparticles were prepared from an amphiphilic block copolymer, [(HEMA19%- DMA31%)-(FMA5%-DEA45%)]. For the present research, three systems were validated, two of them with cross-linked cores and the other without chemical stabilization. A comparison of their loading kinetics and release profiles is discussed, with the support of additional data obtained by scanning electron microscopy and dynamic light scattering. The drug was loaded into the NPs within the first minutes; the load was dependent on the degree of cross-linking. All of the systems experienced a boost in drug release at acidic pH, ranging from 50 to 80% within the first 48 h. NPs with the highest degree (20%) of core cross-linking delivered the highest percentage of drug at fixed times. The studied systems exhibited fine-tuned sustained release features, which may provide a continuous delivery of the drug at specific acidic locations, thereby diminishing side effects and increasing therapeutic rates. Hence, the studied NPs proved to behave as smart controlled drug delivery systems capable of responding to changes in pH.Ministerio de Economía y Competitividad de España-MAT2016-77345-C3-2-PJunta de Andalucía-P12-FQM-155

Formulation and Drug Release of Isoxsuprine HCL Enteric Coated Tablets

The aim of the study is to formulate and evaluate enteric coated tablets using Isoxsuprine Hydrochloride as a model drug. Different core tablets and enteric coated tablets were prepared and drug release was studied. Isoxsuprine Hydrochloride core tablets were prepared by wet granulation method, using polymers, by changing drug ratios. The granules are evaluated for physical properties and the in-vitro drug release studies. Enteric coating was carried out using different sub coating materials. Enteric coating was performed in a mini coating pan at 107 rpm using low-pressure air atomized liquid spray technique. By changing the coating material, were done single coated, Double coated tablets are evaluated for uniformity hardness, friability, invitro disintegration and dissolution studies. The in-vitro drug release data was fitted into various kinetic models. All the formulations showed the values within the prescribed limit. It was observed that the higher rate and drug release was observed for the double coated tablets, this is because second layer having high viscosity

Validation of smart nanoparticles as controlled drug delivery systems: loading and pH-dependent release of pilocarpine

Micelles are good devices for use as controlled drug delivery systems because they exhibit the ability to protect the encapsulated substance from the routes of degradation until they reach the site of action. The present work assesses loading kinetics of a hydrophobic drug, pilocarpine, in polymeric micellar nanoparticles (NPs) and its pH-dependent release in hydrophilic environments. The trigger pH stimulus, pH 5.5, was the value encountered in damaged tissues in solid tumors. The new nanoparticles were prepared from an amphiphilic block copolymer, [(HEMA19%-DMA31%)-(FMA5%-DEA45%)]. For the present research, three systems were validated, two of them with cross-linked cores and the other without chemical stabilization. A comparison of their loading kinetics and release profiles is discussed, with the support of additional data obtained by scanning electron microscopy and dynamic light scattering. The drug was loaded into the NPs within the first minutes; the load was dependent on the degree of cross-linking. All of the systems experienced a boost in drug release at acidic pH, ranging from 50 to 80% within the first 48 h. NPs with the highest degree (20%) of core cross-linking delivered the highest percentage of drug at fixed times. The studied systems exhibited fine-tuned sustained release features, which may provide a continuous delivery of the drug at specific acidic locations, thereby diminishing side effects and increasing therapeutic rates. Hence, the studied NPs proved to behave as smart controlled drug delivery systems capable of responding to changes in pH.Peer ReviewedPostprint (published version