Delivery Matrix Research Articles

Crosslinked Networks Based on Polysaccharides and Collagen for Pilocarpine Sustained Release

The paper presents the experimental studies regarding synthesis and characterization of hydrogels based on gellan (Gel)/chitosan (CS) and collagen (Col), obtained by crosslinking with glutaraldehyde (GLA). The influence of the polysaccharide content and GLA ratio on the final composition and swelling characteristics was evaluated. Hydrogels swelling analysis, in distilled water and phosphate buffer (PBS, pH 7.2) has shown higher swelling degrees at increased concentration of polysaccharide into hydrogels. In vitro release of pilocarpine has demonstrated the possibility to use gellan-collagen and chitosan-collagen hydrogels as ophthalmic drug delivery matrix.

Migration of marrow stromal cells in response to sustained release of stromal-derived factor-1α from poly(lactide ethylene oxide fumarate) hydrogels

Stromal derived factor-1α (SDF-1α) is an important chemokine in stem cell trafficking and plays a critical role in the homing of bone marrow stromal (BMS) cells. However, its use in tissue regeneration is limited by its relatively short half-life and the time-dependent nature of cell homing to the site of injury. The objective of this work was to investigate the release characteristics of SDF-1α from degradable poly(lactide ethylene oxide fumarate) (PLEOF) hydrogels and to determine the effect of sustained release of SDF-1α on migration of BMS cells. Three PLEOF hydrogels with poly( l-lactide) (PLA) fractions of 6%, 9%, and 24% by weight were synthesized. After the addition of chemokine, the polymerizing mixture was crosslinked to produce SDF-1α loaded PLEOF hydrogels. The hydrogels were characterized with respect to sol fraction, water uptake, degradation, SDF-1α loading efficiency and release kinetics, and migration rate of bone marrow stromal (BMS) cells. The more hydrophilic hydrogels with 6% and 9% PLA fraction had a pronounced burst release followed by a period of sustained release by diffusion for 21 days. The more hydrophobic hydrogel with 24% PLA fraction had a less pronounced burst release and displayed a slow but constant release by diffusion between days 1 and 9 followed by a fast release by diffusion-degradation from days 9 to 18. The fraction of active SDF-1α released from 6%, 9%, and 24% hydrogels after 21 days was 34.3%, 32.3%, and 35.8%, respectively. The migration of BMS cells in response to time-released SDF-1α closely followed the protein release kinetics from the hydrogels. The biodegradable PLEOF hydrogel may potentially be useful as a delivery matrix for sustained release of SDF-1α in the proliferative phase of healing for recruitment of progenitor cells in tissue engineering applications.

Prevention of in vivo lung tumor growth by prolonged local delivery of hydroxycamptothecin using poly(ester-carbonate)-collagen composites

Local tumor recurrence has a major impact on long-term patient survival following the surgical treatment of most cancers, and this is especially true with lung cancer. Consequently, methods to deliver chemotherapeutics locally at a lung tumor resection margin would be beneficial since: 1) systemic treatment approaches are ineffective or highly toxic; 2) the incidence of local recurrence does not warrant universal treatment of all patients with a highly morbid systemic therapy; and 3) surgical resection of recurrent disease is not an option and alternative rescue therapies are generally unsuccessful. To begin to meet this clinical need, we have prepared poly(glycerol monostearate-co-ε-caprolactone) films as a controlled, prolonged, and low dose delivery matrix for the potent anticancer agent 10-hydroxycamptothecin (HCPT). These drug-loaded films were applied to a collagen-based scaffold clinically indicated for the mechanical buttressing of lung tissue following surgical resection, resulting in a flexible composite that can be secured to the tissue that releases HCPT over seven weeks and thereby prevents the local growth and establishment of Lewis lung carcinoma tumors in vivo (a freedom of local tumor growth of 86%). In comparison, all animals treated with a larger intravenous dose of HCPT or unloaded composites developed rapid local tumors.

Construction and in vitro characterization of an optimized porosity-enabled amalgamated matrix for sustained transbuccal drug delivery

This research focused on constructing and characterizing an optimized porosity-enabled amalgamated matrix (P-EAM) for sustained transbuccal drug delivery. An interphase, co-particulate, co-solvent, homogenization technique and lyophilization guided through a Box–Behnken experimental design was employed in the fabrication, characterization and optimization of 15 P-EAMs. The effects of varying factor levels on the characteristic in vitro physicochemical performances of the P-EAMs were explored. Formulations had an average weight of 128.44 ± 3.48 mg with a dimensional size of 8 mm by 5 mm. Surface morphology showed varieties of pore structures, widespread distributions and uneven interconnectors. Satisfactory drug-loading was achieved (53.14 ± 2.19–99.02 ± 0.74%). Overall amount of drug released in 8 h was measured by the MDT 50% value which ranged between 22.50 and 225.00 min. Formulation demonstrated significant levels of ex vivo bioadhesive strength measured as detachment force ( F det = 0.964 ± 0.015 to 1.042 ± 0.025 N) and work of adhesion ( ω adh = 0.0014 ± 0.00005 to 0.0028 ± 0.00008 J). The potential of the P-EAMs to initiate and sustain ex vivo transbuccal permeation of drug was shown and measured as a cumulative value of between 25.02 ± 0.85 and 82.21 ± 0.57% in 8 h. Formulations were mesoporous in nature with pore sizes ranging from 40 to 100 Å characterized by the presence of interconnectors. Statistical constraints were simultaneously set to obtain levels of independent variables that optimized the P-EAM formulation.

Fibrin-mediated lentivirus gene transfer: Implications for lentivirus microarrays

We employed fibrin hydrogel as a bioactive matrix for lentivirus mediated gene transfer. Fibrin-mediated gene transfer was highly efficient and exhibited strong dependence on fibrinogen concentration. Efficient gene transfer was achieved with fibrinogen concentration between 3.75 and 7.5 mg/ml. Lower fibrinogen concentrations resulted in diffusion of virus out of the gel while higher concentrations led to ineffective fibrin degradation by target cells. Addition of fibrinolytic inhibitors decreased gene transfer in a dose-dependent manner suggesting that fibrin degradation by target cells may be necessary for successful gene delivery. Under these conditions transduction may be limited only to cells interacting with the matrix thereby providing a method for spatially-localized gene delivery. Indeed, when lentivirus-containing fibrin microgels were spotted in an array format gene transfer was confined to virus-containing fibrin spots with minimal cross-contamination between neighboring sites. Collectively, our data suggest that fibrin may provide an effective matrix for spatially-localized gene delivery with potential applications in high-throughput lentiviral microarrays and in regenerative medicine.

Sucrose esters with various hydrophilic–lipophilic properties: Novel controlled release agents for oral drug delivery matrix tablets prepared by direct compaction

Sucrose esters (SE) are esters of sucrose and fatty acids with various hydrophilic–lipophilic properties which have attracted interest from being used in pharmaceutical applications. This study aimed to gain insight into the use of SE as controlled release agents for direct compacted matrix tablets. The study focused on the effect of hydrophilic–lipophilic properties on tableting properties and drug release. Sucrose stearate with hydrophilic–lipophilic balance (HLB) values ranging from 0 to 16 was systematically tested. Tablet formulations contained SE, metoprolol tartrate as a highly soluble model drug and dibasic calcium phosphate dihydrate as a tablet formulation filler in the ratio 1:1:2. The compaction behaviour of matrix tablets was compared with the compacts of individual starting materials as reference. SE incorporation improved the plasticity, compressibility and lubricating property of powder mixtures. The hydrophilic–lipophilic properties of SE affected tableting properties, drug release rate and release mechanism. Increasing hydrophilicity corresponding to the increased monoesters in SE composition increased the relative porosity, elastic recovery and tensile strength of the tablets due to the increased hydrogen bonding between the monoesters. This also facilitated the swelling behaviour of SE, which sustained the drug release rate. A sustained release effect prevailed in tablets containing SE with HLB values of 3–16. The ability to improve the tableting properties as well as sustain the drug release rate of the highly soluble model drug via gelation of SE highlights SE as promising controlled release regulators for direct compacted matrix tablets comprising drugs with various solubilities according to the Biopharmaceutics Classification System.

Microfluidic characterization of sustained solute release from porous supraparticles

We present a novel microfluidic technique for precise characterization of controlled release of solute from porous latex supraparticles in a laminar flow environment. Dye-infused supraparticles are fabricated via dry self-assembly method using droplet templates dispensed on superhydrophobic substrates. A water-soluble dye is used as a model compound, the release rate of which is measured colorimetrically. The sustained release rates of dye from supraparticles and dye pellets are quantified and compared to common diffusion/dissolution mass transfer models. The results illustrate the potential of microfluidics as a tool in monitoring controlled release process and the role of the uniformly porous supraparticle matrix for the prolonged continuous solute delivery.

Enzymatic Antioxidants: Next Phase of Pharmacological Effort to Fight Oxidative Stress?

The focus in the research of antioxidants is notably displaced in favour of research of enzyme derivatives. Extracellular superoxide dismutase (EC-SOD) is of the particular interest, as it demonstrates in vivo the protective action against development of atherosclerosis, hypertension, heart failure, diabetes mellitus. The reliable association of coronary artery disease with the decreased level of heparin-released EC-SOD was established in clinical researches. To base and develop antioxidant therapy, various SOD isozymes, catalase (CAT), the methods of experimental gene therapy, combined application of SOD- and CAT-activities are used. Covalent bienzyme SOD - CHS - CAT conjugate (where CHS - chondroitin sulphate) showed in the experimental trials its high efficacy as the antithrombotic agent. Pre-clinical research data approve the reliable option to gain for it the status of drug candidate. The trend to use the components of glycocalyx and extracellular matrix for target delivery of medical substances is evident. Development of new enzyme antioxidants for therapeutical destination is closely connected with becoming and progress of medical biotechnology, pharmaceutical industry, bioeconomy.

A Processing Approach to Tuning the Drug Delivery Characteristics of Calcium Polyphosphate Matrices

Amorphous calcium polyphosphate (CPP) has potential as an implantable drug delivery matrix by virtue of a low temperature gelling protocol that has been shown to eliminate burst release and extend drug release time from the matrix. However, a greater understanding of this material’s interaction with aqueous environments is needed to more fully exploit this application. Variations in aqueous exposure were assessed using as-made amorphous CPP as well as CPP processed using established low temperature protocols. Solid-state 31P-NMR along with thermal and X-ray diffraction analyses were used to track resulting structural changes. Exposure to aqueous environments caused a reduction in CPP chain length that was dependant on gel time and mode of exposure. Significantly, increased gel times or water availability further resulted in crystallization events upon drying, except in the presence of a buffered solution. In general, drug elution studies showed an increase in the burst release of vancomycin from CPP disks gelled for extended periods, with matrix-water interactions appearing to be most influential during the drug loading stage. Overall, this study shows that CPP drug delivery matrices can be produced with tailored properties by closely controlling CPP-water interactions during processing.

Microstructure and properties of nano-fibrous PCL-b-PLLA scaffolds for cartilage tissue engineering

Nano-fibrous scaffolds which could potentially mimic the architecture of extracellular matrix (ECM) have been considered a good candidate matrix for cell delivery in tissue engineering applications. In the present study, a semicrystalline diblock copolymer, poly(epsilon-caprolactone)-block-poly(L-lactide) (PCL-b-PLLA), was synthesized and utilized to fabricate nano-fibrous scaffolds via a thermally induced phase separation process. Uniform nano-fibrous networks were created by quenching a PCL-b-PLLA/THF homogenous solution to -20 degrees C or below, followed by further gelation for 2 hours due to the presence of PLLA and PCL microcrystals. However, knot-like structures as well as continuously smooth pellicles appeared among the nano-fibrous network with increasing gelation temperature. DSC analysis indicated that the crystallization of PCL segments was interrupted by rigid PLLA segments, resulting in an amorphous phase at high gelation temperatures. Combining TIPS (thermally induced phase separation) with salt-leaching methods, nano-fibrous architecture and interconnected pore structures (144+/-36 mm in diameter) with a high porosity were created for in vitro culture of chondrocytes. Specific surface area and protein adsorption on the surface of the nano-fibrous scaffold were three times higher than on the surface of the solid-walled scaffold. Chondrocytes cultured on the nano-fibrous scaffold exhibited a spherical condrocyte-like phenotype and secreted more cartilage-like extracellular matrix (ECM) than those cultured on the solid-walled scaffold. Moreover, the protein and DNA contents of cells cultured on the nano-fibrous scaffold were 1.2-1.4 times higher than those on the solid-walled scaffold. Higher expression levels of collagen II and aggrecan mRNA were induced on the nano-fibrous scaffold compared to on the solid-walled scaffold. These findings demonstrated that scaffolds with a nano-fibrous architecture could serve as superior scaffolds for cartilage tissue engineering.

Polyisoprene matrix for progesterone release: In vitro and in vivo studies

Latex, a polyisoprene (PI) hydrophobic elastomer, was evaluated in vitro and in vivo as a matrix for intravaginal steroid hormone delivery. Matrices containing hormone were prepared by swelling latex in chloroform that contained soluble progesterone (P4). In vitro studies demonstrate that P4 release from PI follows a zero order model during at least 100 h and depends on initial load up to 10 mg cm −2. The release of P4 from a PI matrix was found to be two times faster than from a polydimethylsiloxane (PDMS) matrix. FT-IR and X-ray powder diffraction analysis of P4 polymorphs show that when nucleated in PDMS, the hormone crystallizes only in α-form while in latex, crystallizes as a mixture of α- and β-form. In vivo studies show that devices with a PI matrix containing 0.5 g of P4 are effective to reach plasma levels above 1 ng ml −1 that are needed to synchronize estrous in cattle. Altogether, the results show that PI, a vulcanized polymer with a carbon–carbon backbone, can be used as a new matrix for the intravaginal administration of progesterone with improved release profile than silicone and that the matrix can influence the crystalline state of the hormone.

Design and in vitro evaluation of formulations with pH and transit time controlled sigmoidal release profile for colon-specific delivery

The primary objective of the study was to develop a pH and transit time controlled sigmoidal release polymeric matrix for colon-specific delivery of indomethacin. Tablet matrices were prepared using a combination of hydrophilic polymers (polycarbophil or carbopol) having pH-sensitive swelling properties with hydrophobic polymer ethyl cellulose. The prepared matrices were characterized for physical properties and in vitro release kinetics. The presence of ethyl cellulose in a hydrophilic polymer matrix resulted in a sigmoidal in vitro drug release pattern with negligible-to-very low drug release in the initial phase (0–6 h) followed by controlled release for 14–16 h. The retardation in initial release can be attributed to the presence of ethyl cellulose that reduced swelling of hydrophilic polymer(s), while in the later portion, polymer relaxation at alkaline pH due to the ionization of acrylic acid units on carbopol and polycarbophil resulted in enhanced drug release. Thus, a sigmoidal release pattern was obtained that could be ideal for colonic delivery of indomethacin in the potential treatment of colon cancer.

Starch–acrylics graft copolymers and blends: Synthesis, characterization, and applications as matrix for drug delivery

AbstractA series of acrylic monomers–starch graft copolymers were prepared by ceric ion initiation method by varying the amount of monomers. These graft copolymers were characterized by IR and 13C‐NMR spectroscopy. It was seen that as the concentration of monomer [acrylic acid (AA), methacrylic acid (MA), and methyl methacrylate (MMA)] increased the percent add‐on increased in all the graft copolymers, whereas grafting efficiency increased initially but showed a slight decrease with further increase in the monomer concentration (except for MMA). The release rate of paracetamol as a model drug from graft copolymers as well as their blends was studied at two different pH, 1.2 and 7.4, spectrophotometrically. The release of paracetamol in phosphate buffer solution at pH 1.2 was insignificant in the first 3 h for St‐g‐PAA‐ and St‐g‐PMA‐graft copolymers, which was attributed to the matrix compaction and stabilization through hydrogen bonding at lower pH. At pH 7.4, the release rate was seen to decrease with increase in add‐on. The tablet containing poly(methyl methacrylate) (PMMA) did not disintegrate at the end of 30–32 h, which may be attributed to the hydrophobic nature of PMMA. These results indicate that the graft copolymers may be useful to overcome the harsh environment of the stomach and can be used as excipients in colon‐targeting matrices. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009

Drug release kinetics and transport mechanisms from semi-interpenetrating networks of gelatin and poly(ethylene glycol) diacrylate.

To elucidate the key parameters affecting solute transport from semi-interpenetrating networks (sIPNs) comprised of poly(ethylene glycol) diacrylate (PEGdA) and gelatin that are partially crosslinked, water-swellable and biodegradable. Effects of material compositions, solute size, solubility, and loading density have been investigated. sIPNs of following gelatin/PEGdA weight-to-weight ratios were prepared: 10:15, 10:20, 10:30, 15:15, 20:15. Five model solutes of different physicochemical properties were selected, i.e. silver sulfadiazine (AgSD), bupivacaine hydrochloride (Bup), sulfadiazine sodium (NaSD), keratinocyte growth factor (KGF), and bovine serum albumin conjugated with fluorescein isothiocyanate (BSA-FITC). Release studies were performed and the results were analyzed using three hydrogel based common theories (free volume, hydrodynamic and obstruction). The release kinetics of model solutes was influenced by each factor under investigation. Specifically, the initial release rates and intra-gel diffusivity decreased with increasing PEGdA content or increasing solute molecular weight. However, the initial release rate and intra-gel diffusivity increased with increasing gelatin content or increasing solute water solubility, which contradicted with the classical hydrogel based solute transport theories, i.e. increasing polymer volume leads to decreased solute diffusivity within the gel. This analysis provides structure-functional information of the sIPN as a potential therapeutic delivery matrix.

Chitosan–glycolic acid: a possible matrix for progesterone delivery into skin

Background: Chitosan-EDTA is an interesting matrix for dermal delivery; however, the adhesiveness is too small. Therefore, the purpose of this study was to investigate chitosan-glycolic acid as possible dermal matrix for progesterone in comparison to chitosan-EDTA and carrageenan. Method: After preparation of the chitosan-glycolic acid salt and characterization by NMR and FTIR, tensile studies using porcine skin and rheology measurements as well as standard diffusion experiments using dermatomed porcine skin were performed. Results: Results showed an improved skin adhesiveness of chitosan-glycolic acid and increased viscosity. Skin diffusion studies indicated the highest cumulative permeation of progesterone after 48 hours from chitosan-glycolic acid followed by carrageenan and chitosan-EDTA. A possible explanation might be a longer residence time on skin caused by the higher adhesiveness and with it higher progesterone skin permeation. Conclusion: Chitosan-glycolic acid can be recommended as a suitable polymer for hydrogels and an adhesive matrix for a transdermal application of progesterone exhibiting excellent skin adhesiveness and permeation properties.

An alginate hydrogel matrix for the localised delivery of a fibroblast/keratinocyte co‐culture

There is significant interest in the development of tissue-engineered skin analogues, which replace both the dermal and the epidermal layer, without the use of animal or human derived products such as collagen or de-epidermalised dermis. In this study, we proposed that alginate hydrogel could be used to encapsulate fibroblasts and that keratinocytes could be cultured on the surface to form a bilayered structure, which could be used to deliver the co-culture to a wound bed, initially providing wound closure and eventually expediting the healing process. Encapsulation of fibroblasts in 2 and 5% w/v alginate hydrogel effectively inhibited their proliferation, whilst maintaining cell viability allowing keratinocytes to grow uninhibited by fibroblast overgrowth to produce a stratified epidermal layer. It was shown that the alginate degradation process was not influenced by the presence of fibroblasts within the hydrogel and that lowering the alginate concentration from 5 to 2% w/v increased the rate of degradation. Fibroblasts released from the scaffold were able to secrete extracellular matrix (ECM) and thus should replace the degrading scaffold with normal ECM following application to the wound site. These findings demonstrate that alginate hydrogel may be an effective delivery vehicle and scaffold for the healing of full-thickness skin wounds.

Macromolecular conjugate based particulates: Preparation, characterisation and evaluation of controlled release properties

A new particulate delivery matrix based on macromolecular conjugate, chitosan–whey protein isolate ([Ch–WPI]) was found to exhibit controlled release properties. Fourier-Transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) demonstrated the formation of the conjugate. Particle formation of the conjugate was carried out by the ionic crosslinking technique using sodium tripolyphospate (STP). Catechin entrapped particles were prepared by varying the weight ratios of STP to conjugate [Ch–WPI]. Both the placebo and catechin-entrapped particles were found to be positively charged below pH 7.2, indicating their stability to aggregation and their suitability for bioadhesion in the gastrointestinal tract (GIT). The entrapment efficiencies of the particles ranged between 29% and 42% for particles prepared using different weight ratios of the conjugate to STP. There was 34–56% of catechin release in simulated GIT conditions depending on the entrapment efficiencies and the degree of crosslinking of the particles.

Design and in vitro evaluation of formulations with pH and transit time controlled sigmoidal release profile for colon-specific delivery

The primary objective of the study was to develop a pH and transit time controlled sigmoidal release polymeric matrix for colon-specific delivery of indomethacin. Tablet matrices were prepared using a combination of hydrophilic polymers (polycarbophil or carbopol) having pH sensitive swelling properties with hydrophobic polymer ethyl cellulose. The prepared matrices were characterized for physical properties and in vitro release kinetics. The presence of ethyl cellulose in a hydrophilic polymer matrix resulted in a sigmoidal in vitro drug release pattern with negligible to very low drug release in the initial phase (0–6 h) followed by controlled release for 14–16 h. The retardation in initial release can be attributed to the presence of ethyl cellulose that reduced swelling of hydrophilic polymer(s) while in the later portion, polymer relaxation at alkaline pH due to the ionization of acrylic acid units on carbopol and polycarbophil resulted in enhanced drug release. Thus, a sigmoidal release pattern was obtained that could be ideal for colonic delivery of indomethacin in the potential treatment of colon cancer.

Synthesis and characterization of new copolymers of ethyl methacrylate grafted on tapioca starch as novel excipients for direct compression matrix tablets

In last years, the introduction of new materials for drug delivery matrix tablets has become more important. This paper evaluates the physicochemical and mechanical properties of new graft copolymers of ethyl methacrylate (EMA) on tapioca starch (TS) and hydroxypropylstarch (THS), synthesized by free radical polymerization and dried in a vacuum oven (OD) or freeze–dried (FD). Infrared and 13C NMR spectroscopies confirm the change of chemical structure of the copolymers and X-ray diffraction shows up the higher amorphization of copolymers respect to the carbohydrates. Particle size analysis and SEM indicate that graft copolymerization leads to an increase of particle size and a more irregular shape. Graft copolymerization implies decrease of density and moisture content values. Heckel equation shows that copolymers have less densification by particle rearrangement and fragmentation than carbohydrates. Concerning the drying methods, FD products have larger plasticity and lower elasticity than OD copolymers. Graft copolymerization produces a decrease of the applied pressure necessary to obtain tablets, ejection force and friction work. Furthermore, graft copolymers show longer disintegration time than tablets from raw starches. These qualities suggest that these copolymers could be used as excipients in matrix tablets obtained by direct compression, and with a potential use in controlled release.

Bone healing induced by local delivery of an engineered parathyroid hormone prodrug

Regenerative medicine requires innovative therapeutic designs to accommodate high morphogen concentrations in local depots, provide their sustained presence, and enhance cellular invasion and directed differentiation. Here we present an example for inducing local bone regeneration with a matrix-bound engineered active fragment of human parathyroid hormone (PTH 1–34), linked to a transglutaminase substrate for binding to fibrin as a delivery and cell-invasion matrix with an intervening plasmin-sensitive link (TGplPTH 1–34). The precursor form displays very little activity and signaling to osteoblasts, whereas the plasmin cleavage product, as it would be induced under the enzymatic influence of cells remodeling the matrix, was highly active. In vivo animal bone-defect experiments showed dose-dependent bone formation using the PTH–fibrin matrix, with evidence of both osteoconductive and osteoinductive bone-healing mechanisms. Results showed that this PTH-derivatized matrix may have potential utility in humans as a replacement for bone grafts or to repair bone defects.