Ampholytic starch excipients for high loaded drug formulations: Mechanistic insights

Ampholytic starch derivatives are proposed as a new class of excipients carrying simultaneously anionic carboxymethyl (CM) and cationic aminoethyl (AE) groups on starch (St) polymeric chains. Three different types of derivatives were obtained by using the same reagents and varying only the order of their addition in the reaction medium: in one step method (OS) the two reactants were added simultaneously, whereas in two steps method (TS) either CMSt or AESt were prepared separately in the first step, followed by subsequent addition of the second reactant. It was found that all ampholytic derivatives were able to generate monolithic tablets by direct compression and allowed 60% loading of acidic (Acetylsalicylic acid), basic (Metformin), zwitterion (Mesalamine) or neutral (Acetaminophen) as drug models. The in vitro dissolution tests followed for 2?h in SGF and then in SIF, showed that the mentioned starch derivatives were stabilized by self-assembling and generated matrices able to control the release of drugs for about 24?h. The addition order of reagents has an impact on ampholytic starch properties offering thus a high versatility of this new class of starch excipients that can be tailored for challenging formulations with high dosages of several drugs.     

Chitosan-based hydrogels for controlled, localized drug delivery

Hydrogels are high-water content materials prepared from cross-linked polymers that are able to provide sustained, local delivery of a variety of therapeutic agents. Use of the natural polymer, chitosan, as the scaffold material in hydrogels has been highly pursued thanks to the polymer's biocompatibility, low toxicity, and biodegradability. The advanced development of chitosan hydrogels has led to new drug delivery systems that release their payloads under varying environmental stimuli. In addition, thermosensitive hydrogel variants have been developed to form a chitosan hydrogel in situ, precluding the need for surgical implantation. The development of these intelligent drug delivery devices requires a foundation in the chemical and physical characteristics of chitosan-based hydrogels, as well as the therapeutics to be delivered. In this review, we investigate the newest developments in chitosan hydrogel preparation and define the design parameters in the development of physically and chemically cross-linked hydrogels.     

Hydrogel-based matrices for controlled drug delivery of etamsylate: Prediction of in-vivo plasma profiles

ObjectivesTo design oral controlled release (CR) hydrogel matrix tablets of etamsylate using various hydrophilic polymers. Additionally, to predict plasma concentration-time profiles of etamsylate released from different CR matrices.MethodsCharacterization of the in-vitro release rate was performed by various model dependent and model independent approaches. A simple numerical convolution strategy was adopted to predict the in-vivo performance of all matrices from their in-vitro percent released data. The statistical analysis was conducted utilizing a student t-test and ANOVA.ResultsThe release of etamsylate from all matrices showed a deviation from Fickian transport mechanism except; F2 followed Case II release whereas, F9 and F11 obeyed Fickian diffusion. CR hydrogel based-matrices (F4 and F11) demonstrated the maximum drug retardation and satisfied the USP release limits. Concentration–time profiles of etamsylate were predicted successfully from the in-vitro release data of all prepared matrices. Pharmacokinetic parameters of etamsylate CR hydrogel matrices were significantly changed with comparison to reference product except F1.ConclusionThe designed (F2-F11) matrices had the capability to extend the plasma level of etamsylate for an adequate time. However, F4 and F11 were considered the most ideal formulations for once daily application of etamsylate. The prediction of in-vivo pharmacokinetics of etamsylate was very useful to assess the rationality of the designed matrices for the practical application in humans.     

Diisocyanate mediated polyether modified gelatin drug carrier for controlled release

Gelatin is an extensively studied biopolymer hydrogel drug carrier due to its biocompatibility, biodegradability and non-toxicity of its biodegraded products formed in vivo. But with the pristine gelatin it is difficult to achieve a controlled and desirable drug release characteristics due to its structural and thermal lability and high solubility in aqueous biofluids. Hence it is necessary to modify its solubility and structural stability in biofluids to achieve controlled release features with improved drug efficacy and broader carrier applications. In the present explorations an effort is made in this direction by cross linking gelatin to different extents using hitherto not studied isocyanate terminated poly(ether) as a macrocrosslinker prepared from poly(ethylene glycol) and isophorone diisocyanate in dimethyl sulfoxide. The crosslinked samples were analyzed for structure by Fourier transform-infrared spectroscopy, thermal behavior through thermogravimetric analysis and differential scanning calorimetry. The cross linked gelatins were biodegradable, insoluble and swellable in biofluids. They were evaluated as a carrier for in vitro drug delivery taking theophylline as a model drug used in asthma therapy. The crosslinking of gelatin decreased the drug release rate by 10–20% depending upon the extent of crosslinking. The modeled drug release characteristics revealed an anomalous transport mechanism. The release rates for ampicillin sodium, 5-fluorouracil and theophylline drugs in a typical crosslinked gelatin carrier were found to depend on the solubility and hydrophobicity of the drugs, and the pH of the fluid. The observed results indicated that this material can prove its mettle as a viable carrier matrix in drug delivery applications.     

Novel Natrosol/Pectin-co-poly (acrylate) based pH-responsive polymeric carrier system for controlled delivery of Tapentadol Hydrochloride

Background & ObjectivesThis study aimed to create a controlled delivery system for Tapentadol Hydrochloride by developing interpenetrating networks (IPNs) of Natrosol-Pectin copolymerized with Acrylic Acid and Methylene bisacrylamide, and to analyze the effects of various ingredients on the physical and chemical characteristics of the IPNs.MethodsNovel Tapentadol Hydrochloride-loaded Natrosol-Pectin based IPNs were formulated by using the free radical polymerization technique. Co-polymerization of Acrylic Acid (AA) with Natrosol and Pectin was performed by using Methylene bisacrylamide (MBA). Ammonium persulfate (APS) was used as the initiator of crosslinking process. The impact of ingredients i.e. Natrosol, Pectin, MBA, and Acrylic Acid on the gel fraction, porosity, swelling (%), drug loading, and drug release was investigated. FTIR, DSC, TGA, SEM and EDX studies were conducted to confirm the grafting of polymers and to evaluate the thermal stability and surface morphology of the developed IPNs.ResultsSwelling studies exhibited an increase in swelling percentage from 84.27 to 91.17% upon increasing polymer (Natrosol and Pectin) contents. An increase in MBA contents resulted in a decrease in swelling from 85 to 67.63%. Moreover, the swelling was also observed to increase with higher AA contents. Significant drug release was noted at higher pH instead of gastric pH value. Oral toxicological studies revealed the nontoxic and biocompatible nature of Natrosol-Pectin IPNs.Interpretation & ConclusionThe developed IPNs were found to be an excellent system for the controlled delivery of Tapentadol Hydrochloride.     

Mesoporous silica nanoparticles as controlled release drug delivery and gene transfection carriers

In this review, we highlight the recent research developments of a series of surface-functionalized mesoporous silica nanoparticle (MSN) materials as efficient drug delivery carriers. The synthesis of this type of MSN materials is described along with the current methods for controlling the structural properties and chemical functionalization for biotechnological and biomedical applications. We summarized the advantages of using MSN for several drug delivery applications. The recent investigations of the biocompatibility of MSN in vitro are discussed. We also describe the exciting progress on using MSN to penetrate various cell membranes in animal and plant cells. The novel concept of gatekeeping is introduced and applied to the design of a variety of stimuli-responsive nanodevices. We envision that these MSN-based systems have a great potential for a variety of drug delivery applications, such as the site-specific delivery and intracellular controlled release of drugs, genes, and other therapeutic agents.     

Characterization and evaluation of dialdehyde starch as an erodible medical polymer and a drug carrier

The characteristics of dialdehyde starch as a polymer, particularly molecular weight distribution, dissolution and degradation behavior were investigated. The effects of salts, pH and temperature on dissolution and degradation were studied. Moreover, the usefulness of dialdehyde starch as a drug carrier was evaluated in vitro using its conjugate with isoniazid.     

Mathematical modeling of drug delivery

Due to the significant advances in information technology mathematical modeling of drug delivery is a field of steadily increasing academic and industrial importance with an enormous future potential. The in silico optimization of novel drug delivery systems can be expected to significantly increase in accuracy and easiness of application. Analogous to other scientific disciplines, computer simulations are likely to become an integral part of future research and development in pharmaceutical technology. Mathematical programs can be expected to be routinely used to help optimizing the design of novel dosage forms. Good estimates for the required composition, geometry, dimensions and preparation procedure of various types of delivery systems will be available, taking into account the desired administration route, drug dose and release profile. Thus, the number of required experimental studies during product development can be significantly reduced, saving time and reducing costs. In addition, the quantitative analysis of the physical, chemical and potentially biological phenomena, which are involved in the control of drug release, offers another fundamental advantage: The underlying drug release mechanisms can be elucidated, which is not only of academic interest, but a pre-requisite for an efficient improvement of the safety of the pharmaco-treatments and for effective trouble-shooting during production. This article gives an overview on the current state of the art of mathematical modeling of drug delivery, including empirical/semi-empirical and mechanistic realistic models. Analytical as well as numerical solutions are described and various practical examples are given. One of the major challenges to be addressed in the future is the combination of mechanistic theories describing drug release out of the delivery systems with mathematical models quantifying the subsequent drug transport within the human body in a realistic way. Ideally, the effects of the design parameters of the dosage form on the resulting drug concentration time profiles at the site of action and the pharmacodynamic effects will become predictable.     

Glass encapsulation of flavours with chemically modified starch blends

Carrier compositions based on blends of various octenylsuccinic acid anhydride (OSAN)-modified starches were utilized in the glass encapsulation of flavours by means of melt extrusion and spray drying. Dextrinized, acid and enzymatically hydrolysed OSAN starches were used in various combinations. Processing parameters were optimized for desirable physical chemical and functional properties of the encapsulating compositions. One key property in the optimization of the extrusion process was setting rate of the exiting melt into a glass. Glassy states of identical spray-dried and extruded compositions were characterized by MDSC for glass transition temperature(s), heat capacity change and enthalpy relaxation. Flavour retention, surface flavour, moisture, particle density and flavour particle size distribution were also measured and compared for the extruded and spray-dried compositions. In addition, elastic recovery and caking were evaluated for extruded compositions. The glass transition parameters were correlated directly or indirectly with most of the physical properties of encapsulating compositions, especially flavour retention, surface flavour and caking. In extruded compositions, two phases were revealed by the presence of two glass transitions, whereas spray-dried compositions showed only one broad glass transition.     

In vitro evaluation of sol-gel processed spray dried silica gel microspheres as carrier in controlled drug delivery

The objective of this study was to evaluate sol–gel-derived spray dried silica gel microspheres as carrier material for dexmedetomidine HCl and toremifene citrate. The drug was dissolved in sol–gel processed silica sol before spray drying with Büchi laboratory scale equipment. Microspheres with a low specific surface area were spherical by shape with a smooth surface without pores on the external surface. The particle size distribution was quite narrow. The in vitro release of toremifene citrate and dexmedetomidine HCl showed a dose-dependent burst followed by a slower release phase, that was proportional to the drug concentration in the concentration range between 3.9 and 15.4 wt.%. The release period for toremifene citrate was approximately 10 days and for dexmedetomidine HCl between 7 and 50 days depending on drug concentration. Spray drying is a promising way to produce spherical silica gel particles with a narrow particle size range for controlled delivery of toremifene citrate and dexmedetomidine HCl.     

Engineered polymers for advanced drug delivery

Engineered polymers have been utilized for developing advanced drug delivery systems. The development of such polymers has caused advances in polymer chemistry, which, in turn, has resulted in smart polymers that can respond to changes in environmental condition such as temperature, pH, and biomolecules. The responses vary widely from swelling/deswelling to degradation. Drug-polymer conjugates and drug-containing nano/micro-particles have been used for drug targeting. Engineered polymers and polymeric systems have also been used in new areas, such as molecular imaging as well as in nanotechnology. This review examines the engineered polymers that have been used as traditional drug delivery systems and as more recent applications in nanotechnology.     

Carboxymethyl xanthan microparticles as a carrier for protein delivery

Xanthan gum (XG) was derivatized to sodium carboxymethyl xanthan gum (SCMXG) and then cross-linked with aluminium ions (Al⁺³) to prepare BSA-loaded microparticles (MPs) from a completely aqueous environment. The derivatized gum was characterized by various physical methods. Discrete and spherical BSA-loaded MPs were obtained from SCMXG solution, the pH of which was adjusted to 6 and 7 and the BSA entrapment efficiency was found to reach as high as 82%. The protein release in acidic dissolution medium was faster than that in alkaline dissolution medium and was accounted for the higher swelling ratio of the MPs in acidic environment. Moreover, the pH of the gum solution used to prepare the MPs also influenced the swelling and consequently protein release considerably.     

A biopharmaceutic approach in designing a controlled release tablet of sodium monofluorophosphate: 1. in vitro and in vivo studies in beagle dogs

The purpose of this study was to develop a controlled release tablet (CRT) of sodium monofluorophosphate (NaMFP) based on biopharmaceutic and pharmacokinetic principles. NaMFP was introduced in the early eighties to treat osteoporosis. The required dose size (200 mg of NaMFP) and time of drug delivery (8.3 h) were theoretically determined based on the pharmacokinetic parameters of fluoride (F^?). A CRT was formulated with ethyl cellulose (EC) by the direct compression method. The ratio of drug to polymer was adjusted 1:1, after studying the in vitro release profiles. The release mechanism from the developed dosage form followed the square root of time relationship. This dosage form was evaluated for its in vivo performance in dogs. The pharmacokinetics of F^?, after the IV and PO administration of NaMFP, was determined to standardize the animal model. F^? followed a two-compartment model and no significant differences were found between the two routes of administration. The bioavailability in dogs was only 60%. The reason for this poor bioavailability was postulated to be the delivery of drug extended beyond the principal sites of absorption of the gastrointestinal tract. Hence, we decided to characterize the absorption sites of NaMFP and to modify the CRT.     

New amphiphilic and pH-sensitive hydrogel for controlled release of a model poorly water-soluble drug

This paper presents the development of new pH-sensitive, amphiphilic and biocompatible hydrogels based on alginate-g-PCL, cross-linked with calcium ions to form beads, prepared for controlled delivery of poorly water-soluble drug. We have focused our study on the effect of the length of PCL chains (530 and 1250 g mol⁻¹). Swelling profiles obtained clearly indicated that these hydrogels swell slightly (10-14%) in a simulated gastric fluid (pH 1.2), and strongly (700-1300% before disintegration) in a simulated intestinal fluid (pH 6.8). In both media, rates of swelling were lower for beads based on amphiphilic derivatives than for alginate/Ca²⁺ ones due to the hydrophobic PCL grafts, and decreased when hydrophobic character increased. A model drug, theophylline, was entrapped into these hydrogels and release studies were carried out. The drug was protected in acidic fluid (only 14-20% of release for alginate-g-PCL hydrogel against 35% of release for alginate hydrogel during 350 min). The drug is released completely in neutral fluid due to ion exchanges and disintegration of the hydrogel. PCL leads to decrease in the release kinetics in SIF (2 h for alginate-g-PCL/Ca²⁺ beads against 1 h for alginate/Ca²⁺ beads). It was demonstrated that the establishment of clusters inside beads by intramolecular interactions between PCL grafts of 530 g mol⁻¹ in salt media allowed to retain the drug and to slow down its release considerably.     

Niosomes as a propitious carrier for topical drug delivery

Introduction: Topical delivery is defined as drug targeting to the pathologic sites of skin with the least systemic absorption. Drug localization in this case is a crucial issue. For these purposes vesicular drug delivery systems including niosomes, proniosomes, liposomes and transferosomes have been developed.

Areas covered: This review first highlights the role of niosome in dermatology focusing on localized skin delivery and then reviews the most recent literatures regarding specific applications of niosomal drug delivery systems in clinics.

Expert opinion: Niosomes are becoming popular in the field of topical drug delivery due to their outstanding characteristics like enhancing the penetration of drugs, providing a sustained pattern of drug release, increasing drug stability and ability to carry both hydrophilic and lipophilic drugs.     

Synthesis and evaluation of the structural and physicochemical properties of carboxymethyl pregelatinized starch as a pharmaceutical excipient

A pregelatinized starch (PGS) was derivatized with sodium chloroacetate (SCA) in alcoholic medium under alkaline condition to produce carboxymethyl pregelatinized starch (CMPGS) with various degrees of substitution (DS). Influence of the molar ratio of SCA to the glucopyranose units (SCA/GU), reaction time, temperature and the amount of sodium hydroxide on the degree of substitution (DS) and the reaction efficiency (RE) was studied. An optimal concentration of 30% of NaOH, for a reaction time of 1 h at 50 °C and molar ratio (SCA/GU) equal to 1.0, yielded an optimal DS of 0.55 and a RE of 55%. SEM micrographs revealed that the carboxymethylation assigned the structural arrangement of CMPGS and caused the granular disintegration. Wide angle diffraction X-ray (XRD) showed that the crystallinity of starch was obviously varied after carboxymethylation. New bands in FTIR spectra at 1417 and 1603 cm⁻¹ indicated the presence of carboxymethyl groups. The solubility and viscosity of CMPGS increased with an increase in the degree of modification. In order to investigate the influence of DS on physical and drug release properties, CMPGS obtained with DS in the range of 0.12–0.55 was evaluated as tablet excipient for sustained drug release. Dissolution tests performed in phosphate buffer (pH 6.8), with Ibuprofen as drug model (25% loading) showed that CMPGS seems suitable to be used as sustained release excipient since the drug release was driven over a period up to 8 h. The in vitro release kinetics studies revealed that all formulations fit well with Korsmeyer-Peppas model and the mechanism of drug release is non-Fickian diffusion.     

缓释型肺吸入制剂的研究进展

近年来,肺吸入制剂因为直接将药物递送至患病部位、无首过效应、患者依从性大等优点,成为研究热点。但肺吸入制剂仍然存在许多问题如药物消除迅速、给药次数频繁、存在临床用药安全性隐患。本文将从肺部主要的消除机制入手,对目前缓释肺吸入制剂进行综述,为今后肺吸入的临床应用提供思路。     

Preparation of glutinous rice starch/polyvinyl alcohol copolymer electrospun fibers for using as a drug delivery carrier

Glutinous rice starch (GRS) is commonly produced in the Northeast of Thailand. GRS is a biopolymer which is widely used in the food industry but not yet commonly applied within the pharmaceutical industry as an alternative resource. GRS exhibits a branch chain structure which is not feasible to fabricate as nanofiber. Therefore, combining GRS with polyvinyl alcohol (PVA) in hybrid form can be a potential platform to produce GRS-PVA nanofibers. Smooth nanofibers of 2% (w/v) GRS combined with 8% (w/v) PVA were fabricated by an electrospinning process. A scanning electron microscope (SEM) revealed an average diameter size of the GRS-PVA nanofibers equal to 191 ± 25 nm. A highly water soluble model drug, Chlorpheniramine maleate (CPM), was incorporated into the GRS-PVA electrospun fibers to prove a drug delivery carrier concept and drug release control of the nanofibers. The GRS-PVA nanofibers exhibited a biphasic CPM release in which approximately 60% of the drug immediately released in 10 min, and it reached 90% drug release in 120 min. This study demonstrated a potential application of GRS combining with PVA as an oral drug delivery carrier. Therefore, it can be a promised step that expands the application GRS in pharmaceuticals and related areas.     

Amphiphilic gels as a potential carrier for topical drug delivery

This study involves development of amphiphilic gels consisting solely of nonionic surfactants bearing cyclosporine and characterized for microstructure, gelation temperature, and in vitro drug release into dermis. The formulation is nonirritant and suitable for topical application. Gels consisting of cyclosporine were prepared using different methods by mixing the solid gelator (sorbitan or glyceryl fatty acid esters) and the liquid phase (liquid sorbitan esters or polysorbates) and heating them at 60°C to form a clear isotropic sol phase, and cooling this sol phase to form an opaque semisolid at room temperature. Gel microstructure was examined by phase contrast microscopy while gelation temperatures were measured by melting point apparatus and differential scanning calorimetry. These amphiphilic gels were evaluated in vitro for topical as well as transdermal delivery using rat skin mounted in a Franz diffusion cell. Gel microstructures consisted mainly of clusters of tubules of gelator molecules that had aggregated upon cooling of the sol phase, forming a 3D network throughout the continuous phase. The gels demonstrated thermoreversibility with robust gel network. At temperatures near the skin surface temperature, the gels softened considerably and moreover, it facilitated the drug to accumulate in dermis, thus making an ideal delivery vehicle of cyclosporine topically that can be used in treatment of psoriasis. Thus amphiphilic gels were demonstrated as the ideal vehicle for topical use of cyclosporine.