Cross-linked High Amylose Starch Research Articles

Blends of cross-linked high amylose starch/pectin loaded with diclofenac

Polymers blends represent an important approach to obtain materials with modulated properties to reach different and desired properties in designing drug delivery systems in order to fulfill therapeutic needs. The aim of this work was to evaluate the influence of drug loading and polymer ratio on the physicochemical properties of microparticles of cross-linked high amylose starch–pectin blends loaded with diclofenac for further application in controlled drug delivery systems. Thermal analysis and X-ray diffractograms evidenced the occurrence of drug–polymer interactions and the former pointed also to an increase in thermal stability due to drug loading. The rheological properties demonstrated that drug loading resulted in formation of weaker gels while the increase of pectin ratio contributes to origin stronger structures.

NMR imaging of chitosan and carboxymethyl starch tablets: Swelling and hydration of the polyelectrolyte complex

The hydration and swelling properties of the tablets made of chitosan, carboxymethyl starch, and a polyelectrolyte complex of these two polysaccharides have been studied by NMR imaging. We studied the effect of pH and ionic strength on the swelling of the tablets and on the diffusion of fluid into the tablets in water and simulated physiological fluids. The pH value of the fluids exerts a more significant effect than their ionic strengths on the swelling of the tablets. The tablets are compared also with those made of cross-linked high amylose starch. The formation of complex helps to keep the integrity of the tablets in various media and render a slow and restricted swelling similar to that of the tablets of the cross-linked high amylase starch, which is significantly lower than the swelling of chitosan and of carboxymethyl starch. The capacities to modulate the release rate of drugs in different media are discussed by comparing the matrices and evaluating the preparation process of the complex. A sustained release of less soluble drugs such as aspirin in gastrointestinal fluids can be provided by the complex, due to the ionic interaction and hydrogen bonding between the drug and the biopolymer complex.

NMR imaging study of cross-linked high-amylose starch tablets — The effect of drug loading

NMR imaging techniques were used to study the effect of drug loading in cross-linked high-amylose starch tablets. The tablets contained acetaminophen with loading levels from 10 to 40 wt%. The absolute amount of the drug released increased with a larger amount of drug loading, but the percentages of drug released had only minor differences for the different tablets, probably due to the rapid formation of a gel layer for all the tablets, which slowed down drug release significantly. The release of drugs from the tablets in all cases is dominated by a diffusion mechanism before the disappearance of the dry core of the tablets. Radial and axial swelling and water uptake were found to increase with the amount of drug loading. The diffusion rates of water were comparable at the initial stage for all the tablets with different loadings, but became faster later for the tablets with higher amounts of drug loading as water diffusion may be facilitated by the hydrophilicity of the drug.

Membrane Formation and Drug Loading Effects in High Amylose Starch Tablets Studied by NMR Imaging

Cross-linked high amylose starch is used as an excipient in the preparation of pharmaceutical tablets for the sustained release of drugs. NMR imaging with contrast enhanced by proton density and by self-diffusion coefficient was used to follow the water uptake and swelling, two critical parameters controlling the drug release of the cross-linked starch tablets containing 10 wt % of ciprofloxacin and of acetaminophen, respectively. The drug-loaded tablets were studied in a H2O/D2O mixture at 37 degrees C in comparison to the tablets without any drug loading. The diffusion of water in the tablets all showed a Fickian behavior, but the kinetics of water uptake was faster in the case of the drug-loaded tablets. The formation of a membrane at the water/tablet interface was observed.

Study of hydration of cross-linked high amylose starch by solid state 13C NMR spectroscopy

Starch is subjected to chemical treatments such as cross-linking or hydroxypropylation to meet the material requirements for food uses or controlled release in the pharmaceutical industries. In this work, two types of cross-linking formulations have been employed for the preparation of high amylose starch for use as an excipient for sustained drug release. The structural differences and chain dynamics of the modified starches in the dry and hydrated states have been compared by the use of variable contact time cross polarization-magic angle spinning solid state 13C NMR spectroscopy.

Mucoadhesive properties of cross-linked high amylose starch derivatives

Acetate (Ac-), aminoethyl (AE-) and carboxymethyl (CM-)derivatives of cross-linked high amylose starch (HASCL-6) were previously shown to control, over more than 20 h, the release of drugs from highly loaded (up to 60% drug) monolithic tablets. It was now of interest to evaluate their mucoadhesive characteristics in view of further utilization in buccal or vaginal transmucosal delivery. The present study shows that ionic AE-HASCL-6 and CM-HASCL-6 derivatives exhibit higher mucoadhesive properties than neutral HASCL-6 and Ac-HASCL-6, suggesting that the ionic groups introduced on cross-linked starch chains play a role in the bioadhesion process. The adhesiveness seemed related to capillary attraction forces. Surface adhesion parameters were calculated for slabs based on the mentioned polymers and corroborated with their swelling behavior at various pH changes. The positively charged AE-derivatives presented a higher adhesion at acidic pH, being thus recommended for vaginal delivery, whereas the negatively charged derivatives (CM-HASCL-6) exhibited a better adhesion at neutral pH, being thus more appropriate for buccal delivery.

Optimization of cross-linked high amylose starch microspheres containing 5-fluorouracil

The objective of the present investigation was the preparation of microspheres consisting of high amylose starch cross-linked in situ by means of sodium trimetaphosphate. 5-fluorouracil was chosen as a model drug. Since this preparation entailed several process and formulation variables, a preliminary screening design was applied to identify the most important factors and thereby simplify the system under study. This was performed with regard to the spherical shape and the capacity of drug encapsulation of the obtainable microparticles. An eight-factor 12-run Plackett-Burman design enabled the factor number to be reduced so that a three-factor face-centered central composite design could subsequently be applied in order to optimize the formulation by response surface methodology. The factors involved in the optimization process were the concentrations of the following components: 5-fluorouracil, starch and cross-linker. The responses evaluated were the morphology of the microspheres (a qualitative response) and the drug encapsulation efficiency. An optimal formulation yielded microparticles that were spherical in shape, with a volume diameter of 25.5±0.6pm and a narrow particle size distribution. Particle yield ranged from 85 to 98%, the encapsulation efficiency reached about 30% and the drug loading was in the range of 0.8-1.5%. Due to polymer swelling properties, 5-fluorouracil was released in vitro in a sustained manner by an anomalous release mechanism. Microparticles also showed good mucoadhesion properties that would make them suitable for peroral drug administration.

Imaging of High-Amylose Starch Tablets. 3. Initial Diffusion and Temperature Effects

The penetration of water into cross-linked high amylose starch tablets was studied at different temperatures by nuclear magnetic resonance (NMR) imaging, which follows the changes occurring at the surface and inside the starch tablets during swelling. It was found that the swelling was anisotropic, whereas water diffusion was almost isotropic. The water proton image profiles at the initial stage of water penetration were used to calculate the initial diffusion coefficient. The swelling and water concentration gradients in this controlled release system show significant temperature dependence. Diffusion behavior changed from Fickian to Case II diffusion with increasing temperature. The observed phenomena are attributed to the gelatinization of starch and the pseudo-cross-linking effect of double helix formation.

Cross-linked high amylose starch derivatives for drug release: III. Diffusion properties

Acetate (Ac-), aminoethyl (AE-) and carboxymethyl (CM-) derivatives of cross-linked high amylose starch (HASCL-6) 1 1 Cross-linking degree (conventionally expressed in grams of bifunctional agent used to cross-link 100 g of polymer). were previously shown to control the release of drugs over 20 h from highly loaded (up to 60% drug) monolithic tablets. This report presents a diffusion analysis, aimed to facilitate a better understanding of the mechanisms involved in the control of the drug release from these hydrogels. The diffusion was found to depend on the molecular weight of the diffusant, whereas the partition coefficient depended on the affinities of the diffusant for the polymers and for the dissolution media via attractive or repulsive ionic interactions. The diffusion was also affected by the swelling of CM-HASCL-6, which, unexpectedly, increased with the decrease of the ionic strength. This diffusion analysis completes the swelling studies of HASCL-6 and of its derivatives, allowing the prediction of release kinetics of various active agents.

Prevention and treatment of experimental osteomyelitis in dogs with ciprofloxacin-loaded crosslinked high amylose starch implants

Crosslinked high amylose starch (CLHAS) matrix was used as a biodegradable drug delivery implant for the prevention and treatment of osteomyelitis. Thirty-two dogs underwent the femoral insertion of a screw inoculated with Staphylococcus aureus and were then randomly assigned to four groups: (A) prevention with ciprofloxacin-CLHAS implants, (B) surgical debridement (positive control), (C) surgical debridement and oral ciprofloxacin treatment and (D) surgical debridement and treatment with ciprofloxacin-CLHAS implants. At week 4 the osteomyelitis was confirmed, the infected site debrided and respective treatments initiated for groups B, C and D. Radiographs, macroscopic evaluations, bacterial cultures and histopathological examinations were used to evaluate the femora at week 10. Femora from preventive group A were almost normal. Dogs of both ciprofloxacin treatment groups C and D showed better bone healing, less periosteal reaction and less screw mobility than dogs from group B. Eradication of infection was observed at proximal/distal sites in B: 25%/12%, C: 37%/62% and D: 62%/75%. Both ciprofloxacin treated groups improved radiographically from week 4 to week 10. Periosteal and marrow neutrophilic and lymphoplasmocytic infiltrations were less severe in groups C and D versus group B. These data suggest that biodegradable ciprofloxacin-CLHAS implants are a safe and efficient modality for the prevention and treatment of osteomyelitis.

Cross-linked high amylose starch derivatives for drug release: II. Swelling properties and mechanistic study

Acetate (Ac-), aminoethyl (AE-), and carboxymethyl (CM-) high amylose starch cross-linked 6 (HASCL-6) derivatives were previously shown to control the release of drugs over 20 h from monolithic tablets highly loaded (up to 60% drug). This report describes the swelling characteristics, which allow a better understanding of the mechanisms involved in the control of the drug release from the said polymeric matrices. The tablet swelling of HASCL-6, Ac-HASCL-6, and AE-HASCL-6 was found to not be affected by the ionic strength and by the pH between 1.2 (gastric) and 7 (intestinal), whereas the swelling of CM-HASCL-6 was shown to depend on both ionic strength and pH of the release medium. For all the studied polymers the drug loading did not change the equilibrium swelling ratio but affected the initial swelling velocity, seemingly due to the competition between drug and polymer for water uptake, a phenomenon probably influenced by the loading and the drug solubility. It was also shown that the increase of ionic strength would slightly increase the drug release time probably by decreasing the amount of free water still available to solubilize the drug present into the matrix.

Cross-linked high amylose starch derivatives for drug releaseII. Swelling properties and mechanistic study

Acetate (Ac-), aminoethyl (AE-), and carboxymethyl (CM-) high amylose starch cross-linked 6 (HASCL-6) derivatives were previously shown to control the release of drugs over 20 h from monolithic tablets highly loaded (up to 60% drug). This report describes the swelling characteristics, which allow a better understanding of the mechanisms involved in the control of the drug release from the said polymeric matrices. The tablet swelling of HASCL-6, Ac-HASCL-6, and AE-HASCL-6 was found to not be affected by the ionic strength and by the pH between 1.2 (gastric) and 7 (intestinal), whereas the swelling of CM-HASCL-6 was shown to depend on both ionic strength and pH of the release medium. For all the studied polymers the drug loading did not change the equilibrium swelling ratio but affected the initial swelling velocity, seemingly due to the competition between drug and polymer for water uptake, a phenomenon probably influenced by the loading and the drug solubility. It was also shown that the increase of ionic strength would slightly increase the drug release time probably by decreasing the amount of free water still available to solubilize the drug present into the matrix.

Characterization of crosslinked high amylose starch matrix implants: 1. In vitro release of ciprofloxacin

The objective of this study was to characterize in vitro the potential of crosslinked high amylose starch (CLHAS) as an implant matrix for the delivery of ciprofloxacin (CFX). Direct compression of dry blends of four different matrices: control CLHAS; CLHAS with 1% hydrogenated vegetable oil (HVO); and CLHAS with 10 or 20% hydroxypropylmethylcellulose (HPMC), each of them with three CFX loadings (2.5, 5.0 and 7.5%) was performed to prepare twelve implant formulations. All CLHAS implants were used for 24-h dissolution tests to evaluate swelling, erosion, water uptake and CFX release. Additionally, 1%-HVO– CLHAS implants were used for an extended dissolution test. The presence of HPMC in the matrix increased CFX release rate, swelling, erosion and water uptake in a concentration-dependent manner whereas HVO had no effect. With increasing drug loading, a decrease of cumulative CFX percent release was observed in both 24-h and extended dissolution tests. Of the different formulations tested, CLHAS implants with 1% HVO and 7.5% CFX provided the longest period of drug delivery without any initial burst effect.

Characterization of crosslinked high amylose starch matrix implants: 2. In vivo release of ciprofloxacin

The purpose of this study was to develop a crosslinked high amylose starch (CLHAS) matrix implant as a sustained antimicrobial delivery system for local prevention and/or treatment of osteomyelitis. Implants (200 mg) of CLHAS containing 2.5% (5 mg), 7.5% (15 mg), 15.0% (30 mg) and 20.0% (40 mg) of ciprofloxacin (CFX), were prepared by direct compression of dry blends. Rabbits were administered six 2.5, two 7.5, one 15.0 or one 20.0%-CFX implants along the femur between the quadriceps and biceps femoris muscles to determine systemic (serum) versus local (muscle and bone) CFX concentrations over 1 month. Blood samples were taken throughout the study for CFX assay. Muscle and femur were collected at 3, 7, 14, 21 and 28 days after implantation for host response evaluation and CFX assay. Residual polymer was explanted to determine the remaining dose of CFX. All animals remained healthy during the study. Local tissue reaction was mild and limited to the implantation site. Serum CFX concentrations remained low regardless of implant loading. Increased drug loading resulted in a higher and longer release of CFX in muscle and in bone. Local CFX concentrations were detected largely in excess of the MIC over 28 days with 20.0%-CFX implants. More residual CFX in polymer was detected over a longer period of time at high loading. These results strongly support the development of CLHAS implants for local antibacterial therapy.

Structure–properties relationship in cross-linked high amylose starch cast films

Cross-linked high amylose starch cast films were prepared to study the effect of cross-linking degree on various properties in normal environmental conditions. Mechanical tensile properties (Young's modulus, elongation at break, tensile strength), water vapour transmission rate (WVTR) and oxygen permeability coefficients of cast films were determined as a function of cross-linking degree and percentage of free humidity. Cross-linking degree and degree of crystallinity are closely related and seem to have non-negligible opposite effect on the properties of interest. By using increased amounts of cross-linking agents, the effect of cross-linking degree tends to reduce the degree of crystallinity modulating thus mechanical properties, water vapour permeability and oxygen permeability coefficients. Yield strength, tensile strength at break, WVTR versus cross-linking degree showed a non-monotonous behaviour. Maximal values for these properties were reached for moderate cross-linking degree. Optimal crystalline/amorphous ratio in the films may induce interactions and balanced effects, which would be responsible for the non-linear behaviour of some of the investigated properties. By cross-linking with epichlorohydrin in the range 1–10g crosslinker/100g polymer, the mechanical properties of films are still related to water content and water vapour permeability remains high compared to some synthetic polymeric materials.

Influence of physical parameters and lubricants on the compaction properties of granulated and non-granulated cross-linked high amylose starch.

Cross-linked high amylose starch (CLA) is a pharmaceutical excipient used in direct compression for the preparation of controlled release tablets and implants. In this work the compression properties of CLA in bulk and granulated forms (without binder) were evaluated for the first time. Tablets were prepared on an instrumented single punch machine. The flow properties and the compression characteristics (compressibility, densification behavior, work of compression) of the materials as well as the mechanical strength of the finished compacts (compactibility) were systematically examined. Wet granulation was found to improve the flowability and the compressibility of CLA but concomitantly reduced its compactibility. It was demonstrated that CLA was a plastically deforming material with a plasticity index and a yield pressure value comparable to those of pregelatinized starch. The compactibility of granulated CLA was independent of particle size in the range of 75 to 500 microm, but slightly decreased when the percentage of the fine particles (<75 microm) in the bulk powder was increased. Water and colloidal silicone dioxide facilitated the consolidation of CLA, while magnesium stearate had an opposite effect on the tablet crushing force.

Tissue reaction and biodegradation of implanted cross-linked high amylose starch in rats.

The biocompatibility and degradation characteristics of cross-linked high amylose starch (Contramid were investigated in rats over 4 months. Contramid pellets (3-mm diameter and thickness) obtained by direct compression, were implanted subcutaneously and intramuscularly. On sequential time points, macroscopic observations of implantation sites were performed and tissue samples were removed, fixed, and histologically evaluated. No macroscopic inflammatory reaction was observed with Contramid.. Upon histologic examination, inflammatory reaction produced by Contramid was moderate and restricted to implantation sites. The sequence of inflammatory events with Contramid was similar regardless of implantation site. Degradation of Contramid pellets was characterized by fragmentation with formation of fibrovascular septa and phagocytosis by macrophages. Finally Contramid was mostly absorbed by the end of the 4-month period and substituted by adipocytes. It has been demonstrated that Contramid is a biocompatible and absorbable material.

Characterization of subcutaneous Contramid® implantation: host response and delivery of a potent analog of the growth hormone-releasing factor

Cross-linked high amylose starch (Contramid®) was investigated as a solid implant for evaluation of host response in mice and as a possible delivery system for a human growth hormone-releasing factor analog (Hex-hGRF) release profile in pigs. Seventy mice were administered subcutaneously one 3 mm diameter Contramid® pellet and host reaction was evaluated over 6 months. Thirty pigs were divided into four groups. All animals of the three implanted groups were administered subcutaneously 15 mg Hex-hGRF, (1) one pure Hex-hGRF implant; (2) four 30/70 w/w Hex-hGRF/Contramid® implants; or (3) eight 15/85 w/w Hex-hGRF/Contramid® implants. The fourth group ( n=6) was injected subcutaneously twice daily with 10 μg/kg of Hex-hGRF over 5 consecutive days. Serum insulin-like growth factor-I (IGF-I) was monitored over 1 month. In mice, no adverse reaction occurred after implantation. Macroscopic and microscopic inflammatory reactions were always localized. Polymorphonuclear cells (PMNs) and macrophages predominated within and around the pellets, respectively. Thin fibrovascular septas eventually subdivided Contramid® pellets which were progressively phagocytosed by macrophages. In pigs, serum IGF-I concentrations were increased over a 10 day period in all implanted groups. The initial IGF-I peak observed in the daily injected group was avoided in both Contramid® implant groups but not in the pure Hex-hGRF implant group. These encouraging results warrant the development of Contramid® implants as a sustained delivery system for peptidic drugs.

Mechanical properties and structure of swollen crosslinked high amylose starch tablets

Crosslinked high amylose starch (CLHAS) has been introduced as an excipient for controlled oral drug delivery. The kinetics of delivery is governed by the diffusion of the medication through a hydrogel matrix, which forms as water penetrates the CLHAS tablet. The formation of the gel from the compressed spray-dried starch powder comes from pseudo-crosslinking of particles by the self-assembly of amylose and amylopectin segments into double helices. Tablets reach equilibrium swelling after more than 24 h and contain about 200% water. They demonstrated nearly reversible non-linear viscoelastic properties. Under compression, water flows out and vice-versa for decompression suggesting a sponge-like behaviour. A series of tablets fabricated under increasing compression force in the dry state showed a decrease of wet equilibrium stiffness with increasing fabrication pressure. Scanning electron microscopy on freeze-dried tablets reveals a fine porous texture at the surface of the tablets, which forms, in the first minutes of water penetration. On the other hand the internal texture which develops over longer periods has much larger pores which account for the high equilibrium water content and the observed sponge-like behaviour.

Cross-linked high amylose starch derivatives as matrices for controlled release of high drug loadings

Selection of hydrogels as excipients in controlled drug release systems depends on the characteristics of the gel and of the drug. Three types of derivatives were synthesized from cross-linked high amylose starch (HASCL-6) by substitution of hydroxylic groups with cationic (carboxymethyl: CM), anionic (aminoethyl: AE) and acetate (Ac) groups. These new polymeric excipients are able to control the release over 20 h from monolithic tablets loaded with 20 to 60% drug. Three drugs were used as model tracer: acetaminophen (uncharged), acetylsalicylic acid (having an acidic group) and metformin (having a basic group). It was found that the release of ionic drugs from CM-HASCL-6 and AE-HASCL-6 matrices can be partially controlled by ionic interaction between pendant groups of polymer and drugs. The substitution degree of HASCL-6 derivatives can also be varied to modulate the drug’s release time. These derivatives represent a novel generation of pharmaceutical excipients, recommended for high loading dosage formulations.