Drug Release from Novel Rubbery Coatings

This paper reviews the development of coronary stents from a polymer scientist's view point, and presents the first results of an interdisciplinary team assembled for the development of new stent systems. Poly(styrene-b-isobutylene-b-styrene) block copolymer (SIBS), a nanostructured thermoplastic elastomer, is used in clinical practice as the drug-eluting polymeric coating on the Taxus coronary stent (trademark of Boston Scientific Co.). Our group has been developing new architectures comprising of arborescent (dendritic) polyisobutylene cores (D_SIBS), which were shown to be as biocompatible as SIBS. ElectroNanospray (Nanocopoeia Inc.) was used to coat test coupons and coronary stents with selected D(S)IBS polymers loaded with dexamethasone, a model drug. The surface topology varied from smooth to nanosized particulate coating. This paper will demonstrate how drug release profiles were influenced by both the molecular weight of the polyisobutylene core and spraying conditions of the polymer-drug mixture.

Qualitative evaluation of the mechanism of release of matrix sustained release dosage forms by measurement of polymer release

Gastro-retentive dosage form offer many advantages having absorption from upper gastrointestinal tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new gastro-retentive floating drug delivery system was developed for ciprofloxacin preferably once daily. The design of the delivery system was based on the sustained release formulation with floating and swelling features in order to prolong the gastric retention time of the drug delivery system. Final formulations were prepared and optimized by Box-Behnken design by using HPMC K100M and Carbopol 934 as a polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. The prepared formulations were evaluated for hardness, weight variations, thickness, swelling index, in-vitro buoyancy, drug content and drug release study. The effect of polymer (HPMC K100M and Carbopol 934) concentration on drug release profile and swelling index was evaluated. The in-vitro dissolution study showed that the drug release profile could be sustained by increasing the concentration of polymers (HPMC K100M and Carbopol 934). Result of swelling index showed that increasing the concentration of polymers, increases the swelling index of tablet. The optimized formulations containing 12.36 % of HPMC K100M, 7.47 % of Carbopol 934 and 18.66% of Sodium bicarbonate with citric acid in the ratio of 2:1 sustained the drug release upto 12 hours, following Higuchi model of drug release and drug release mechanism was non-fickian diffusion. This study proves that using HPMC K100M and Carbopol 934 as a matrix polymer in combination with Sodium Bicarbonate as a gas generating agent can be used to develop sustained release floating tablets of Ciprofloxacin.

Slowly degradable copolymers of L-lactide and ε-caprolactone can provide long-term delivery and may be interesting as alternative release systems of cyclosporine A (CyA) and rapamycin (sirolimus), in which available dosage forms cause a lot of side effects. The aim of this study was to obtain slowly degradable matrices containing immunosuppressive drug from PLACL initiated by nontoxic Zr[Acac]4. Three kinds of poly(L-lactide-co-ε-caprolactone) (PLACL) matrices with different copolymer chain microstructure were used to compare the release process of cyclosporine A and rapamycine. The influence of copolymer chain microstructure on drug release rate and profile was also analyzed. The determined parameters could be used to tailor drug release by synthesis of demanded polymeric drug carrier. The studied copolymers were characterized at the beginning and during the degradation process of the polymeric matrices by NMR spectroscopy, GPC (gel permeation chromatography), and DSC (differential scanning calorimetry). Different drug release profiles have been observed from each kind of copolymer. The correlation between drug release process and changes of copolymer microstructure during degradation process was noticed. It was determined that different copolymer composition (e.g., lower amount of caprolactone units) does not have to influence the drug release, but even small changes in copolymer randomness affect this process.

Mechanistic modelling of drug release from a polymer matrix using magnetic resonance microimaging

A new dual stimuli responsive hydrogel: Modeling approaches for the prediction of drug loading and release profile

Sustained delivery by leucine-modified chitosan spray-dried respirable powders

Calcium-induced alginate gel bead (Alg-Ca) coated with an alginate hydrolysate (Alg), e.g. the guluronic acid block (GB) was prepared and the model drug, hydrocortisone release profiles were investigated under simulated gastrointestinal conditions. Their molecular weights were one sixth or one tenth that of Alg and the diffraction patterns of the hydrolysates resembled that of Alg. The drug release rate from Alg-Ca coated with GB apparently lowered than that of Alg-Ca (coating-free) in the gastric juice (pH1.2). And the coating did not resist the disintegration of Alg-Ca in the intestinal juice (pH 6.8) and the gel erosion accelerated the drug release. On the other hand, for the coated Alg-Ca containing chitosan, the drug release showed zero-order kinetics without rapid erosion of Alg-Ca. The drug release rate from Alg-Ca was able to be controlled by the coating and modifying the composition of the gel matrix.

Polyisobutylene (PIB)-based block copolymers have attracted significant interest as biomaterials. Poly(styrene-b-isobutylene-b-styrene) (SIBS) has been shown to be vascularly compatible and, when loaded with paclitaxel (PTx) and coated on a coronary stent, has the ability to deliver the drug directly to arterial walls. Modulation of drug release from this polymer has been achieved by varying the drug/polymer ratio, by blending SIBS with other polymers, and by derivatizing the styrene end blocks to vary the hydrophilicity of the copolymer. In this paper, results are reported on the synthesis, physical properties, and drug elution profile of PIB-based block copolymers containing methacrylate end blocks. The preparation of PIB-poly(alkyl methacrylate) block copolymers has been accomplished by a new synthetic methodology using living cationic and anionic polymerization techniques. 1,1-Diphenylethylene end-functionalized PIB was prepared from the reaction of living PIB and 1,4-bis(1-phenylethenyl)benzene, followed by the methylation of the resulting diphenyl carbenium ion with dimethylzinc (Zn(CH(3))(2)). PIB-DPE was quantitatively metalated with n-butyllithium in tetrahydrofuran, and the resulting macroinitiator could initiate the polymerization of methacrylate monomers, yielding block copolymers with high blocking efficiency. Poly(methyl methacrylate-b-isobutylene-b-methyl methacrylate) (PMMA-b-PIB-b-PMMA) and poly(hydroxyethyl methacrylate-b-isobutylene-b-hydroxyethyl methacrylate) (PHEMA-b-PIB-b-PHEMA) triblock copolymers were synthesized and used as drug delivery matrixes for coatings on coronary stents. The PMMA-b-PIB-b-PMMA/PTx system displayed zero-order drug release, while stents coated with PHEMA-b-PIB-b-PHEMA/PTx formulations exhibited a significant initial burst release of PTx. Physical characterization using atomic force microscopy and differential scanning calorimetry of the formulated PMMA-b-PIB-b-PMMA coating matrix indicated the partial miscibility of PTx with the PMMA microphase of the matrix.

Several studies have revealed that the fruit mucilage of different species of Cordia is found to be an excellent binder in tablet manufacturing. However, the binding ability of the mucilage of Cordia Africana (CM) is not yet established. Therefore, this study aimed to evaluate the tablet-binding ability of the CM using paracetamol as a model drug. The fruit of Cordia Africana was extracted with the maceration technique and characterized for different properties, such as its compatibility with the model drug (paracetamol) using the Fourier transform infrared spectroscopy (FTIR) and its crystallinity nature with X-ray Diffractometer (XRD). Granules were prepared using the wet granulation method and compressed into tablets. The prepared tablets were evaluated for their hardness, disintegration time, friability, and drug release profile. The effect of these independent variables was further studied and optimized using the central composite design (CCD). The yield of extracted CM powder was 29%. The FTIR study revealed that the CM is compatible with the model drug. The loss in drying and moisture sorption studies was 6 ± 0.02% and 1.3–6.7%, respectively. The granules exhibited good flowability (angle of repose < 30 °) and compressibility properties with Carr’s and Hausner ratios of < 10 and < 1.11, respectively. All the prepared tablets have shown a hardness value of less than 100 N and a disintegration time in the range of 0.55 to 10.27 min. The ANOVA analysis for model adequacy testing confirmed the adequacy of the optimization model. Accordingly, the model provided an optimum formulation at 5.32% of CM concentration, 5% of disintegrant (Starch), and 76.71 N of compression force (CF). Under this condition, the software predicted 83.3% drug release at 30 min and 0.63 of friability. The validity of this optimum formulation was confirmed experimentally. The CM can be used as an alternative binder for tablets, and the optimization model was proven to be effective in identifying the optimum concentration of the CM along with CF and ST.

Smart drug delivery: Capping strategies for mesoporous silica nanoparticles

ABSTRACTA series of drug‐loaded pectin hydrogels were prepared by mixing method in two ion types, Ca+2 or Zn+2, for wound dressing applications and their drug release performances were investigated at pH 6.4 in four different calcium ion concentrations of external solution. Pectin hydrogels were synthesized in three different concentrations of initial pectin solution and theophylline was used as a model drug. Fourier transform infrared spectroscopy, scanning electron microscopy, and atomic force microscopy were used for hydrogel characterization. Additionally, fluid handling capacity, swelling behavior, dehydration rate, dispersion characteristic, dressing pH determination, water vapor permeability, oxygen permeability, surface contact angle, flexibility, mass per unit area, and thickness were determined for selected hydrogels. One of the most valuable contributions of our study is that the concentration of initial pectin solution and calcium ion concentration of external solution are very important parameters to obtain an effective drug release. After evaluating all data, we have shown that flexible and transparent pectin‐based wound dressings can be synthesized as a controlled drug release system. Zinc‐containing hydrogel was antibacterial against Staphylococcus aureus and Escherichia coli but not suitable for cell migration. On the other hand, calcium‐based hydrogel was nontoxic on the fibroblast cells and it had no negative effect on cell migration. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 48155.

Polymer micelles with a tunable drug release would be suitable for the concept of drug delivery system. We constructed photo-responsive polymer micelles from amphiphilic block copolymers. The polymer micelles were synthesized by mechanochemical solid-state copolymerization of poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) and 4,5-dimethoxy-2-nitrobenzyl methacrylate as a photosensitive moiety. The above mechanochemical solid-state copolymerization was performed by vibratory-ball milling at 30 Hz in a nitrogen atmosphere with the use of an agate vessel and an agate ball to yield amphiphilic block copolymers (PHPMA-b-PDNMA). Spherical polymer micelles were formed by the self-assembly of PHPMA-b-PDNMA. The diameter of the PHPMA-b-PDNMA micelles was in the range of 130-200 nm. The PHPMA-b-PDNMA micelles loaded with the antitumor drug 5-fluorouracil (5-FU) showed photo irradiation induced time-dependent release of 5-FU with an associated decrease of micellar size. The drug release profile of the PHPMA-b-PDNMA micelles followed a clear sigmoid curve. Our approach provides a controlled drug release system through the use of photo-responsive polymer micelles, accompanied by the gradual decrease of micellar size. Polymer micelles with a tunable drug release are promising carriers for drug delivery system. It is very important to clarify the correlation between micellar dissociation kinetics and drug release profile on a stimuli-induced deformation of polymer micelles. In this study, photo-cleavable o-nitrobenzyl ester-based amphiphilic block copolymer was successfully designed and prepared by mechanochemical solid-state copolymerization without any solvents and initiators. The self-assembled block copolymer micelles containing anticancer drugs showed sigmoidal decrease of micellar size and released the corresponding drugs depending on the photo-irradiation time.

PLGA/PLA polymeric nanoparticles could potentially enhance the effectiveness of convective delivery of drugs, such as carboplatin, to the brain, by enabling a more sustained dosage over a longer time than otherwise possible. However, the link between the controlled release nanoparticle synthesis route, and the subsequent drug release profile obtained, is not well-understood, which hinders design of synthesis routes and availability of suitable nanoparticles. In particular, despite pore structure evolution often forming a key aspect of past theories of the physical mechanism by which a particular drug release profile is obtained, these theories have not been independently tested and validated against pore structural information. Such validation is required for intelligent synthesis design, and NMR cryoporometry can supply the requisite information. Unlike conventional pore characterisation techniques, NMR cryoporometry permits the investigation of porous particles in the wet state. NMR cryoporometry has thus enabled the detailed study of the evolving, nanoscale structure of nanoparticles during drug release, and thus related pore structure to drug release profile in a way not done previously for nanoparticles. Nanoparticles with different types of carboplatin drug release profiles were compared, including burst release, and various forms of delayed release. ESEM and TEM images of these nanoparticles also provided supporting data showing the rapid initial evolution of some nanoparticles. Different stages, within a complex, varying drug release profile, were found to be associated with particular types of changes in the nanostructure which could be distinguished by NMR. For a core-coat nanoparticle formulation, the development of smaller nanopores, following an extended induction period with no structural change, was associated with the onset of substantial drug release. This information could be used to independently validate the rationale for a particular synthesis method. Hence, the specific reasons for the effectiveness of the synthesis route, for obtaining core-coat nanoparticles with delayed release, have been elucidated.

Fused deposition modeling (FDM), known as a highly effective 3D printing technique, holds promise as an alternative approach to tablet manufacturing. While commonly employing thermoplastic polymers as starting materials, the integration of established pharmaceutical excipients remains unexplored. Polyvinyl pyrrolidone (PVP) is a frequently used excipient known for its potential to confer immediate-release properties to drugs. However, its suitability for extrusion is hindered by its thermal and melt-rheological properties. In contrast, polylactic acid (PLA), which has robust mechanical strength and thermal plasticity, was expected to overcome PVP’s limitations. This study aims to obtain drug-loaded filaments using the combination of PVP and PLA through a hot-melt extrusion process, aiming for favorable mechanical properties and immediate-release behavior. Utilizing a twin-screw extruder, and theophylline was used as the model drug, three formulations were optimized –FP1, FP2, and FP3– containing 0%, 10%, and 20% theophylline, respectively. Subsequent evaluation including filament morphology, mechanical properties, drug content, and drug release profile, were performed to each filament. FP2 emerged as the most promising formulation, with 10.35% (w/w) drug load and over 95% drug released in an hour. All formulations exhibited slightly rough filament surfaces with diameters averaging 1.4-1.6 mm. Notably, an increase in the theophylline content correlates with the diminished filament strength, evident in reduced hardness and a rise in brittleness. This study emphasized the potential of PVP-PLA-based filaments for future pharmaceutical 3D printing formulations, providing immediate drug release characteristics.