Studies on pectins as potential hydrogel matrices for controlled-release drug delivery

Polymeric hydrogels are widely used as controlled-release matrix tablets. In the present study, we investigated high-methoxy pectins for their potential value in controlled-release matrix formulations. The effects of compression force, ratio of drug to pectin, and type of pectin on drug release from matrix tablets were also investigated. The results of the in vitro release studies show that the drug release from compressed matrix tablets prepared from pectin can be modified by changing the amount and the type of pectin in the matrix tablets. However, compression force did not significantly affect the drug release. The mechanisms controlling release rate were discussed with respect to drug diffusion through the polymer matrices, but may be more complex.     

Ketoprofen Suppository Dosage Forms: In Vitro Release and in Vivo Absorption Studies in Rabbits

In vitro release of ketoprofen from suppository bases and in vivo absorption in rabbits were studied. Suppositories containing 50 mg of ketoprofen were prepared using theobroma oil, esterified (c₁₀–c₁₈) fatty acids, and polyethylene glycol 1000 bases. The displacement values of the drug were determined and found to be of the order of theobroma oil > esterified (c₁₀–c₁₈) fatty acids and polyethylene glycol 1000 bases. The suppository hardness data revealed that the theobroma oil base produced relatively brittle suppositories. Using the USP dissolution method, the release of ketoprofen was observed to be greatest from polyethylene glycol 1000 suppositories. With the dialysis technique, the maximum release of drug was obtained from theobroma oil suppository containing polysorbate 40 at a 6% level. Selected suppository formulations were evaluated for rectal absorption studies in rabbits. The in vivo data showed that the optimum drug absorption took place from the polyethylene glycol 1000 base and theobroma oil formulation containing 6% polysorbate 40.     

In Situ Gelling Pectin Formulations for Oral Sustained Delivery of Paracetamol

The purpose of this study was to evaluate the potential of a pectin formulation with in situ gelling properties for the oral sustained delivery of paracetamol (acetaminophen). The formulations consisted of dilute aqueous solutions (1% to 2% w/v) of low methoxy pectin containing calcium ions in complexed form, which on release in the acidic environment of the stomach caused gelation of the pectin. In vitro studies demonstrated diffusion‐controlled release of paracetamol from the gels over a period of 6 h. A bioavailability of approximately 96% of that of a paracetamol solution could be achieved from gels containing an identical dose of drug formed in situ in the stomachs of rats, with appreciably lower peak plasma levels and a sustained release of drug over a period of at least 6 h.     

Development of a Multiple Unit Pellet Formulation for a Weakly Basic Drug

ABSTRACT

SAG/ZK [3-(5-Chloro-2-{2-[(2R)-4-(4-fluorobenzyl)-2-methylpiperazin-1-yl]-2-oxoethoxy}phenyl)uronium hydrogen sulfate], a potent candidate for the oral treatment of inflammatory diseases, demonstrated pH-dependent solubility. Drug release from conventional pellet formulations decreased with increasing pH values of the dissolution medium. The aim of this study was to overcome this problem and to achieve pH-independent drug release. Extended release pellets were prepared by extrusion/spheronization followed by film coating with an aqueous polyvinylacetate/polyvinylpyrrolidone dispersion. To overcome the problem of pH-dependent drug release organic acids such as fumaric, tartaric, and adipic acid were incorporated into the core pellets. X-ray diffraction studies were done in order to investigate potential recrystallization and formation of different salts of SAG/ZK. The addition of fumaric acid was found to lower the pH values within the core pellets during the release of SAG/ZK in phosphate buffer pH 6.8. Therefore, increased release rates at higher pH values were observed thus leading to pH-independent drug release. In contrast, drug release remained pH-dependent for pellets containing tartaric and adipic acid, which can be explained with the lower acidic strength and higher aqueous solubility of these acids. X-ray diffraction studies showed no recrystallization and formation of salts of active ingredient and organic acid.     

Controlled Drug Delivery Systems Based on Thiolated Chitosan Microspheres

The aim of the present study was to verify the potential of chitosan-thio-butyl-amidine (TBA) microspheres as carrier systems for controlled drug delivery. In this study microspheres were prepared utilizing water in oil (w/o) emulsification solvent evaporation technique. A concentration of 0.5% of chitosan-TBA conjugate displaying 100 µM thiol groups per gram polymer was used in the aqueous phase of the emulsion in order to prepare microspheres. The obtained non-aggregated free-flowing microspheres were examined with conventional light microscope as well as scanning electron microscopy (SEM). The microscopic images indicated that the prepared chitosan-TBA microspheres were of spherical shape and smooth surface while microparticles obtained from the unmodified chitosan were of porous structure and non-spherical shape. Particle size distribution was determined to be in the range from 1 to 59 µm. The free thiol group content of chitosan-TBA microspheres prepared with an aqueous phase of pH 2, 5, and 6.5 were determined to be 71.4, 49.4, and 8.2 µM/g polymer, respectively. Furthermore, results attained from in vitro release studies with fluorescein isothiocyanate labelled dextran (FITC-dextran) loaded chitosan-TBA microspheres showed a controlled release rate for more than three hours while the control reached the maximum peak level of release already within an hour. According to these results, chitosan-TBA microspheres seem to be a promising tool in transmucosal drug delivery for poorly absorbed therapeutic agents.     

Optimization of Biodegradable Sponges as Controlled Release Drug Matrices. I. Effect of Moisture Level on Chitosan Sponge Mechanical Properties

Cross‐linked chitosan sponges as controlled release drug carrier systems were developed. Tramadol hydrochloride, a centrally acting analgesic, was used as a model drug. The sponges were prepared by freeze‐drying 1.25% and 2.5% (w/w) high and low M.wt. chitosan solutions, respectively, using glutaraldehyde as a cross‐linking agent. The hardness of the prepared sponges was a function of glutaraldehyde concentration and volume where the optimum concentration that offered accepted sponge consistency was 5%. Below or above 5%, very soft or very hard and brittle sponges were obtained, respectively. The determined drug content in the prepared sponges was uniform and did not deviate markedly from the calculated amount. Scanning electron microscopy (SEM) was used to characterize the internal structures of the sponges. The SEM photos revealed that cross‐linked high M.wt. chitosan sponges have larger size surface pores that form connections (channels) with the interior of the sponge than cross‐linked low M.wt. ones. Moreover, crystals of the incorporated Tramadol hydrochloride were detected on the lamellae and within pores in both chitosan sponges. Differences in pore size and dissolution medium uptake capacity were crucial factors for the more delayed drug release from cross‐linked low M.wt. chitosan sponges over high M.wt. ones at pH 7.4. Kinetic analysis of the release data using linear regression followed the Higuchi diffusion model over 12 hours. Setting storage conditions at room temperature under 80–92% relative humidity resulted in soft, elastic, and compressible sponges.     

An In Vitro Evaluation of Fenugreek Mucilage as a Potential Excipient for Oral Controlled-Release Matrix Tablet

A polysaccharide mucilage derived from the seeds of fenugreek, Trigonella foenum-graceum L (family Fabaceae) was investigated for use in matrix formulations containing propranolol hydrochloride. Methocel® hypomellose K4M was used as a standard controlled release polymer for comparison purposes. In this study the effect of lactose on the release behaviour of propranolol hydrochloride from matrices formulated to contain the fenugreek mucilage also was investigated. An increase in concentration of the mucilage in matrices resulted in a reduction in the release rate of propranolol hydrochloride comparable to that observed with hypomellose matrices. The rate of release of propranolol hydrochloride from fenugreek mucilage matrices was mainly controlled by the drug:mucilage ratio. However, the mechanism of release from matrices containing drug:mucilage ratios of 1:1, 1:1.25, 1:1.5, and 1:2 remained the same. The kinetics of release, utilising the release exponent n, showed that the values of n were between 0.46–0.57 indicating that the release from fenugreek mucilage matrices was predominantly by diffusion. The presence of lactose in matrices containing mucilage increased the release rate of propranolol hydrochloride. This is due to a reduction in tortuoisity and increased pore size of channels caused by lactose through which propranolol diffuses and therefore diffusion of water into the tablet is facilitated.     

The influence of diluent on the release of theophylline from hydrophilic matrix tablets

The role of β-cyclodextrin (β-CD) on the apparent solubility of theophylline was investigated by the solubility method. Binary systems of theophylline and β-CD were prepared using the dry co-grinding method. Their characterization was performed by differential scanning calorimetry (DSC). The dissolution rate of theophylline and theophylline/β-CD and dissolution studies of matrix tablets prepared from mixtures containing theophylline and ground theophylline were carried out. It can be concluded that β-CD is related to an increase in the apparent solubility and dissolution rate of the drug, promoting improvement on the release of theophylline from matrices manufactured with hydroxypropylmethylcellulose (HPMC). This can be attributed to the amorphous state and the increased wettability of the drug.     

片状水凝胶药物载体释药机理的研究

解释了包埋5-氟尿嘧啶药物的片状水凝胶载体在模拟体液中的释药机理,通过分析药物在凝胶中扩散所遵循的数学规律得出结论:当药物的释放过程为水凝胶的松弛控制,以溶剂的移动为主要影响因素时,药物将从水凝胶载体中匀速释放.并以实验验证所得结论,实验结果与由数学分析得出的结论相符.     

D-Optimal Mixture Design: Optimization of Ternary Matrix Blends for Controlled Zero-Order Drug Release From Oral Dosage Forms

ABSTRACT

The objective of the present study was to develop a tablet formulation with a zero-order drug release profile based on a balanced blend of three matrix ingredients. To accomplish this goal, a 17-run, three-factor, two-level D-Optimal mixture design was employed to evaluate the effect of Polyox? (X₁), Carbopol® (X₂), and lactose (X₃) concentrations on the release rate of theophylline from the matrices. Tablets were prepared by direct compression and were subjected to an in vitro dissolution study in phosphate buffer at pH 7.2. Polynomial models were generated for the responses Y₄ (percent released in 8 h) and Y₆ (similarity factor or f₂). Fitted models were used to predict the composition of a formulation that would have a similar dissolution profile to an ideal zero-order release at a rate of 8.33% per hour. When tested, dissolution profile of the optimized formulation was comparable to the reference profile (f₂ was 74.2, and n [release exponent] was 0.9). This study demonstrated that a balanced blend of matrix ingredients could be used to attain a zero-order release profile. Optimization was feasible by the application of response surface methodology, which proved efficient in designing controlled-release dosage forms.     

Synthesis of Hydroxypropyl Methacrylate/Polysaccharide Graft Copolymers as Matrices for Controlled Release Tablets

ABSTRACT

Hydrophilic matrices are an interesting option when developing drug delivery systems. With this aim, hydroxypropyl methacrylate was grafted onto hydroxypropyl starch and hydroxypropyl cellulose substrates by following the Ce(IV) redox initiation method. Different amounts of ethyleneglycol dimethacrylate, 7 and 34 mol%, as the crosslinking monomer, were also added. The drying of grafted products was carried out by lyophilization, obtaining white powders. Reaction yields (percent grafting, grafting efficiency, etc.) and some physical characteristics of the powders (particle size, moisture uptake, density, morphology, etc.) were determined. These parameters indicate how useful these products may be as potential matrices for direct compressed tablets. In this light, the powder flowability and the binding properties of each copolymer were determined. The graft copolymers can be considered of great interest as direct compression excipients. Due to their different chemical structure and composition, they showed differences in viscoelastic properties that revealed an interesting range of possibilities for use in drug delivery formulations. Tablets formulated with conventional excipients were also tested. Dissolution tests of various tablets were carried out. In 12 hr, 60–80% of the model drugs was released.     

Tableting of Eudragit RS and Propranolol Hydrochloride Solid Dispersion: Effect of Particle Size,Compaction Force,and Plasticizer Addition on Drug Release

The application of a solid dispersion (SD) system of propranolol HCl and Eudragit RS was evaluated in the preparation of prolonged release tablets. The effects of SD size fraction, compaction force, and inclusion of plasticizers [namely diethylphtalate (DEP) and triethylcitrate (TEC)] on crushing strengths of matrices and release profile of drug were also investigated. The results showed that when compressed as a tablet, the SD system was more efficient in prolonging drug release than physical mixture. This effect was due to formation of much harder tablets of the SD system (crushing strength 8.5 kg) compared with those of physical mixtures (crushing strength 2.7 kg). All matrices of the SD system showed release rate patterns that were best described by the Higuchi equation. It was also shown that the rate of drug release decreased from 19.8% to 9.13% min^??1/2 as the SD size fraction decreased from 300–350 to 125–250 µm. However, further reduction of size fraction did not significantly affect tablet crushing strength and drug release rate. Increase in compaction force from 5 to 30 kN increased the crushing strength of matrices from 2.9 to 13.6 kg. However, the rate of drug release remained nearly unchanged beyond compaction pressure of 10 kN, indicating that crushing strength of matrices in the range of 8.5–13.6 kg did not affect drug release rate. The addition of 5% or 10% of either plasticizer (DEP or TEC) led to an increase in crushing strength of matrices and more retardation of drug release. This effect was more pronounced for higher concentrations of plasticizers. This effect was probably due to more plastic deformation of matrices under the compaction force, which helped matrices to retain their shape throughout the dissolution test.     

Gold Nanorods Coated with Mesoporous Silica Shell as Drug Delivery System for Remote Near Infrared Light‐Activated Release and Potential Phototherapy

In this study, we report the synthesis of a nanoscaled drug delivery system, which is composed of a gold nanorod‐like core and a mesoporous silica shell (GNR@MSNP) and partially uploaded with phase‐changing molecules (1‐tetradecanol, TD, T_m 39 °C) as gatekeepers, as well as its ability to regulate the release of doxorubicin (DOX). Indeed, a nearly zero premature release is evidenced at physiological temperature (37 °C), whereas the DOX release is efficiently achieved at higher temperature not only upon external heating, but also via internal heating generated by the GNR core under near infrared irradiation. When tagged with folate moieties, GNR@MSNPs target specifically to KB cells, which are known to overexpress the folate receptors. Such a precise control over drug release, combining with the photothermal effect of GNR cores, provides promising opportunity for localized synergistic photothermal ablation and chemotherapy. Moreover, the performance in killing the targeted cancer cells is more efficient compared with the single phototherapeutic modality of GNR@MSNPs. This versatile combination of local heating, phototherapeutics, chemotherapeutics and gating components opens up the possibilities for designing multifunctional drug delivery systems.     

Nifedipine Molecular Dispersion in Microparticles of Ammonio Methacrylate Copolymer and Ethylcellulose Binary Blends for Controlled Drug Delivery: Effect of Matrix Composition

ABSTRACT

The objective of this study is to explore matrix-type microparticles, comprising a solid dispersion of drug with an ammonio methacrylate copolymer and ethylcellulose binary blend, for use in the controlled release of a poorly water-soluble drug, nifedipine. Microparticles consisting of an ethylcellulose N7 (N7) and Eudragit RL® (RL) binary blend at different ratios were prepared using phase-separation methodology. The effects of matrix composition on microparticle properties were evaluated by polarized light microscopy, differential scanning calorimetry (DSC), FT-infrared and UV-visible spectroscopy, stability, and drug release studies. Study results indicate that the particle size distribution, particle morphology, and drug release rate from the microparticles were influenced by the ratio of RL to N7. Discrete spherical microparticles with a narrow size distribution and a controlled release profile were obtained when the ratio of RL to N7 was in the range from 1:1 to 2:1 w/w. Solid-state characterization and release kinetic studies on these microparticles confirmed that the nifedipine release from the microparticles followed the Baker and Lonsdale's matrix diffusion model (1974) for microspheres containing dissolved drug, and the nifedipine diffusion in the microparticle matrix was the rate-limiting step. As the ratio of RL to N7 was changed from 0:1 to 4:1 w/w, the effective drug diffusion coefficient in the micro-matrix increased from 5.8?×?10^?10 to 8.6?×?10^?9 (cm²/h). In addition, probably due to formation of a stable molecular dispersion promoted by hydrogen bonding between nifedipine and the polymers, no significant changes in the nifedipine physical form or release kinetics were observed after 1-year storage at ambient room temperature followed by 3-month accelerated stability at 40°C/75% RH in a closed container.     

Xenon Difluoride Dry Etching for the Microfabrication of Solid Microneedles as a Potential Strategy in Transdermal Drug Delivery

Although hypodermic needles are a “gold standard” for transdermal drug delivery (TDD), microneedle (MN)-mediated TDD denotes an unconventional approach in which drug compounds are delivered via micron-size needles. Herein, an isotropic XeF₂ dry etching process is explored to fabricate silicon-based solid MNs. A photolithographic process, including mask writing, UV exposure, and dry etching with XeF₂ is employed, and the MN fabrication is successfully customized by modifying the CAD designs, photolithographic process, and etching conditions. This study enables fabrication of a very dense MNs (up to 1452 MNs cm⁻²) with height varying between 80 and 300 µm. Geometrical features are also assessed using scanning electron microscopy (SEM) and 3D laser scanning microscope. Roughness of the MNs are improved from 0.71 to 0.35 µm after titanium and chromium coating. Mechanical failure test is conducted using dynamic mechanical analyzer to determine displacement and stress/strain values. The coated MNs are subjected to less displacement (≈15 µm) upon the applied force. COMSOL Multiphysics analysis indicates that MNs are safe to use in real-life applications with no fracture. This technique also enables the production of MNs with distinct shape and dimensions. The optimized process provides a wide range of solid MN types to be utilized for epidermis targeting.