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1.  An Epichlorohydrin-Crosslinked Semi-Interpenetrating GG-PEO Network as a Xerogel Matrix for Sustained Release of Sulpiride 
AAPS PharmSciTech  2014;15(5):1292-1306.
The current study involved the development of a novel sustained release crosslinked semi-IPN xerogel matrix tablet prepared by chemical crosslinking of poly(ethylene) oxide (PEO) and gellan gum (GG) employing epichlorohydrin (EPI) as crosslinker. A Box–Behnken design was employed for the statistical optimization of the matrix system to ascertain the ideal combination of native polymeric and crosslinking agents. Characterization studies were performed by employing standard polymer characterization techniques such as Fourier transform infrared spectrometry, differential scanning calorimetry, and scanning electron microscopy. Formulated matrix tablets displayed zero-order release kinetics, extending over 24 h. The mechanism of drug release was primarily by swelling and surface erosion. Crosslinked semi-IPN xerogel matrix tablets were compared to non-crosslinked polymer blends; results from the study conducted showed that the physiochemical properties of the PEO and GG were sufficiently modified to allow for sustained release of sulpiride with a 100% drug release at 24 h in a controlled manner as compared to non-crosslinked formulations which displayed further release beyond the test period. Crosslinked formulations displayed water uptake between 450 and 500% indicating a controlled rate of swelling and erosion allowing for sustained release. Surface morphology of the crosslinked system depicted a porous structure formed by interpenetrating networks of polymers, allowing for a greater degree of controlled penetration into the system affording it the ability to sustain drug release. Therefore, conclusively, based on the study performed, crosslinked PEO-GG allows for the sustained release of sulpiride from a hydrophilic semi-IPN xerogel matrix system.
doi:10.1208/s12249-014-0153-4
PMCID: PMC4179658  PMID: 24920521
epichlorohydrin; matrix tablet; semi-interpenetrating polymer network; sustained release; sulpiride
2.  Stabilization of hot-melt extrusion formulations containing solid solutions using polymer blends 
AAPS PharmSciTech  2007;8(2):E152-E161.
This study was aimed at enhancing the physical stability of the drug clotrimazole (CT) and the polymer contained within hot-melt extrusion (HME) films using polymer blends of hydroxypropyl cellulose (HPC) and poly(ethylene oxide) (PEO). The HME films were investigated for solid-state characteristics, moisture sorption, bioadhesivity, mechanical properties, glass transition temperature, release characteristics, and physical and chemical stability of the drug and the polymer within the HME films. The solid-state characterization of the drug and the polymer was performed using differential scanning calorimetry, x-ray diffractometry, and dynamic mechanical analysis. A texture analyzer was used to study the bioadhesive and mechanical properties of the HME films. The physical and chemical stability of the films, stored at 25°C/60% relative humidity or in a desiccator, was studied for up to 12 months. CT was found to be in solid solution within all of the formulations extruded. The physical stability of the drug and PEO in the HME films increased with increasing HPC concentration, but the bioadhesivity and flexibility of the PEO films decreased with increasing HPC concentration. Films containing HPC: PEO∶CT in the ratio of 55∶35∶10 demonstrated optimum physical-mechanical, bioadhesive, and release properties. In conclusion, polymer blends of HPC and PEO were used successfully to tailor the drug release, mechanical and bio-adhesive properties, and stability of the HME films.
doi:10.1208/pt0802050
PMCID: PMC2750365  PMID: 17622123
Solid solution; physical stability; hot-melt extrusion; polymers; physicochemical characterization
3.  Effect of Drug Solubility on Polymer Hydration and Drug Dissolution from Polyethylene Oxide (PEO) Matrix Tablets 
AAPS PharmSciTech  2008;9(2):437-443.
The purpose of the study was to investigate the effect of drug solubility on polymer hydration and drug dissolution from modified release matrix tablets of polyethylene oxide (PEO). Different PEO matrix tablets were prepared using acetaminophen (ACE) and ibuprofen (IBU) as study compounds and Polyox® WSR301 (PEO) as primary hydrophilic matrix polymer. Tablet dissolution was tested using the USP Apparatus II, and the hydration of PEO polymer during dissolution was recorded using a texture analyzer. Drug dissolution from the preparations was dependent upon drug solubility, hydrogel formation and polymer proportion in the preparation. Delayed drug release was attributed to the formation of hydrogel layer on the surface of the tablet and the penetration of water into matrix core through drug dissolution and diffusion. A multiple linear regression model could be used to describe the relationship among drug dissolution, polymer ratio, hydrogel formation and drug solubility; the mathematical correlation was also proven to be valid and adaptable to a series of study compounds. The developed methodology would be beneficial to formulation scientists in dosage form design and optimization.
doi:10.1208/s12249-008-9060-x
PMCID: PMC2976924  PMID: 18431663
drug dissolution; modified release; polymer hydration; texture analyzer
4.  Polymeric micelles for the solubilization and delivery of STAT3 inhibitor cucurbitacins in solid tumors 
International journal of pharmaceutics  2007;347(1-2):118-127.
Poly(ethylene oxide)-block-poly(ε-caprolactone) (PEO-b-PCL) and newly developed poly(ethylene oxide)-block-poly(α-benzyl carboxylate ε-caprolactone) (PEO-b-PBCL) micelles were evaluated for the solubilization and delivery of cucurbitacin I and B, poorly water soluble inhibitors of signal transducer and activator of transcription 3 (STAT3). Encapsulation of cucurbitacins in PEO-b-PCL and PEO-b-PBCL by co-solvent evaporation technique resulted in polymeric micelles <90 nm in diameter. The aqueous solubility of both derivatives increased from less than 0.05 mg/mL in the absence of the copolymer to around 0.30–0.44 and 0.65–0.68 mg/mL in the presence of 5000–5000 and 5000–24,000 PEO-b-PCL micelles, respectively. Maximum cucurbitacin solubilization was achieved with PEO-b-PBCL micelles for both derivatives. PEO-b-PCL micelles having longer PCL block were found to be more efficient in sustaining the rate of release for cucurbitacins. The anti-cancer and STAT3 inhibitory activity of polymeric micellar cucurbitacins were comparable with free drugs in B16.F10 melanoma cell line in vitro. Intratumoral injection of 1 mg/kg/day cucurbitacin I resulted in the regression of established B16.F10 mouse melanoma tumors in vivo. In comparison to free cucurbitacin I, PEO-b-PBCL micellar cucurbitacin I was found to provide comparable anti-cancer effects against B16.F10 tumors and limit drug levels in animal serum while maintaining high drug levels in tumor following intratumoral administration. The results indicate the potential of polymeric micelles as suitable vehicles for the delivery of cucurbitacin- I and B.
doi:10.1016/j.ijpharm.2007.06.032
PMCID: PMC2663961  PMID: 17681440
Polymeric micelles; Cucurbitacin; Solubilization; Drug delivery; STAT3
5.  Macroscopic Lateral Heterogeneity Observed in a Laterally-Mobile Immiscible Mixed Polyelectrolyte/Neutral Polymer Brush 
Soft matter  2014;10(21):3771-3782.
We studied mixed poly(ethylene oxide) (PEO) and poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) brushes. The question we attempted to answer was: When the chain grafting points are laterally mobile, how will this lateral mobility influence the structure and phase behavior of the mixed brush? Three different model mixed PEO/PDMAEMA brush systems were prepared: (1) a laterally-mobile mixed brush by spreading onto the air-water interface a mixture of poly(ethylene oxide)-poly(n-butyl acrylate) (PEO-PnBA) and poly(2-(dimethylamino)ethyl methacrylate)-poly(n-butyl acrylate) (PDMAEMA-PnBA) diblock copolymers (the specific diblock copolymers used will be denoted as PEO113-PnBA100 and PDMAEMA118-PnBA100, where the subscripts refer to the number-average degrees of polymerization of the individual blocks), (2) a mobility-restricted (inseparable) version of the above mixed brush prepared using a PEO-PnBA-PDMAEMA triblock copolymer (denoted as PEO113-PnBA89-PDMAEMA120) having respective brush molecular weights matched to those of the diblock copolymers, and (3) a different laterally-mobile mixed PEO and PDMAEMA brush prepared from a PEO113-PnBA100 and PDMAEMA200-PnBA103 diblock copolymer combination, which represents a further more height-mismatched mixed brush situation than described in (1). These three mixed brush systems were investigated by surface pressure-area isotherm and X-ray (XR) reflectivity measurements. These experimental data were analyzed within the theoretical framework of a continuum self-consistent field (SCF) polymer brush model. The combined experimental and theoretical results suggest that the mobile mixed brush derived using the PEO113-PnBA100 and PDMAEMA118-PnBA100 combination (i.e., Mixed Brush System #1) undergoes a lateral macroscopic phase separation at high chain grafting densities, whereas the more height-mismatched system (System #3) is only microscopically phase separated under comparable brush density conditions even though the lateral mobility of the grafted chains is unrestricted. The macroscopic phase separation observed in the laterally-mobile mixed brush system is in contrast to the microphase separation behavior commonly observed in two-dimensional laterally-mobile charged small molecule mixtures. Further study is needed to determine the detailed morphologies of the macro and microphase-separated mixed PEO/PDMAEMA brushes.
doi:10.1039/c4sm00022f
PMCID: PMC4397986  PMID: 24695635
6.  Floating Matrix Tablets of Domperidone Formulation and Optimization Using Simplex Lattice Design 
The purpose of this research was to prepare a floating matrix tablet containing domperidone as a model drug. Polyethylene oxide (PEO) and hydroxypropyl methylcellulose (HPMC) were evaluated for matrix-forming properties. A simplex lattice design was applied to systemically optimize the drug release profile. The amounts of PEO WSR 303, HPMC K15M and sodium bicarbonate were selected as independent variables and floating lag time, time required to release 50% of drug (t50) and 80% of drug (t80), diffusion coefficient (n) and release rate (k) as dependent variables. The amount of PEO and HPMC both had significant influence on the dependent variables. It was found that the content of PEO had dominating role as drug release controlling factor, but using suitable concentration of sodium bicarbonate, one can tailor the desired drug release from hydrophilic matrixes. The linear regression analysis and model fitting showed that all these formulations followed Korsmeyer and Peppas model, which had a higher value of correlation coefficient (r). The tablets of promising formulation were found to be stable for 3 months under accelerated (40°C / 75% RH) stability testing.
PMCID: PMC3813035  PMID: 24250376
Domperidone; Floating matrix tablets; Simplex lattice design; Release kinetics; Polyethylene oxide; Hydroxypropyl methylcellulose; Floating lag time; Total floating time.
7.  Klucel™ EF and ELF polymers for immediate-release oral dosage forms prepared by melt extrusion technology 
AAPS PharmSciTech  2012;13(4):1158-1169.
The objective of this research work was to evaluate Klucel™ hydroxypropylcellulose (HPC) EF and ELF polymers, for solubility enhancement as well as to address some of the disadvantages associated with solid dispersions. Ketoprofen (KPR), a Biopharmaceutics Classification System class II drug with poor solubility, was utilized as a model compound. Preliminary thermal studies were performed to confirm formation of a solid solution/dispersion of KPR in HPC matrix and also to establish processing conditions for hot-melt extrusion. Extrudates pelletized and filled into capsules exhibited a carrier-dependent release with ELF polymer exhibiting a faster release. Tablets compressed from milled extrudates exhibited rapid release owing to the increased surface area of the milled extrudate. Addition of mannitol (MNT) further enhanced the release by forming micro-pores and increasing the porosity of the extrudates. An optimized tablet formulation constituting KPR, MNT, and ELF in a 1:1:1 ratio exhibited 90% release in 15 min similar to a commercial capsule formulation. HPC polymers are non-ionic hydrophilic polymers that undergo polymer-chain-length-dependent solubilization and can be used to enhance solubility or dissolution rate of poorly soluble drugs. Dissolution/release rate could be tailored for rapid-release applications by selecting a suitable HPC polymer and altering the final dosage form. The release obtained from pellets was carrier-dependent and not drug-dependent, and hence, such a system can be effectively utilized to address solubility or precipitation issues with poorly soluble drugs in the gastrointestinal environment.
doi:10.1208/s12249-012-9834-z
PMCID: PMC3513444  PMID: 22961411
hot-melt extrusion; Klucel™ EF/ELF; solid solutions/dispersions; solubility enhancement; thermal miscibility evaluation
8.  Development of Push–Pull Osmotic Tablets Using Chitosan–Poly(Acrylic Acid) Interpolymer Complex as an Osmopolymer 
AAPS PharmSciTech  2010;12(1):132-140.
The objectives of this study were to prepare push–pull osmotic tablets (PPOT) of felodipine using an interpolymer complex of chitosan (CS) and poly(acrylic acid) (PAA) as an osmopolymer, and to study the mechanisms of drug release from these tablets. The interpolymer complexes were prepared with different weight ratios of CS to PAA. Preparation of PPOT involved the fabrication of bilayered tablets with the drug layer, containing felodipine, polyethylene oxide, and the polymeric expansion layer, containing the CS–PAA complex. The effects of polymer ratios, type of plasticizers, and compression forces on release characteristics were investigated. It was found that drug release from PPOT exhibited zero-order kinetics and could be prolonged up to 12 or 24 h depending on the plasticizer used. PPOT using dibutyl sebacate showed a longer lag time and slower drug release than that using polyethylene glycol 400. In the case of polyethylene glycol 400, an increase in the CS proportion resulted in an increase in the drug release rate. The compression force had no effect on drug release from PPOT. Drug release was controlled by two consecutive mechanisms: an osmotic pump effect resulting in the extrusion of the drug layer from the tablet and subsequent erosion and dissolution of the extruded drug layer in the dissolution medium. The mathematical model (zero-order) related to extrusion and erosion rates for describing the mechanism of drug release showed a good correlation between predicted and observed values.
doi:10.1208/s12249-010-9572-z
PMCID: PMC3066366  PMID: 21181509
chitosan; felodipine; interpolymer complex; poly(acrylic acid); push–pull osmotic tablet
9.  Influence of Process and Formulation Parameters on Dissolution and Stability Characteristics of Kollidon® VA 64 Hot-Melt Extrudates 
AAPS PharmSciTech  2014;16(2):444-454.
The objective of the present study was to investigate the effects of processing variables and formulation factors on the characteristics of hot-melt extrudates containing a copolymer (Kollidon® VA 64). Nifedipine was used as a model drug in all of the extrudates. Differential scanning calorimetry (DSC) was utilized on the physical mixtures and melts of varying drug–polymer concentrations to study their miscibility. The drug–polymer binary mixtures were studied for powder flow, drug release, and physical and chemical stabilities. The effects of moisture absorption on the content uniformity of the extrudates were also studied. Processing the materials at lower barrel temperatures (115–135°C) and higher screw speeds (50–100 rpm) exhibited higher post-processing drug content (~99–100%). DSC and X-ray diffraction studies confirmed that melt extrusion of drug–polymer mixtures led to the formation of solid dispersions. Interestingly, the extrusion process also enhanced the powder flow characteristics, which occurred irrespective of the drug load (up to 40% w/w). Moreover, the content uniformity of the extrudates, unlike the physical mixtures, was not sensitive to the amount of moisture absorbed. The extrusion conditions did not influence drug release from the extrudates; however, release was greatly affected by the drug loading. Additionally, the drug release from the physical mixture of nifedipine–Kollidon® VA 64 was significantly different when compared to the corresponding extrudates (f2 = 36.70). The extrudates exhibited both physical and chemical stabilities throughout the period of study. Overall, hot-melt extrusion technology in combination with Kollidon® VA 64 produced extrudates capable of higher drug loading, with enhanced flow characteristics, and excellent stability.
doi:10.1208/s12249-014-0226-4
PMCID: PMC4370970  PMID: 25361900
extrusion; Kollidon® VA 64; moisture absorption; nifedipine; solid dispersion
10.  Use of fine particle ethylcellulose as the diluent in the production of pellets by extrusion-spheronization 
The effect of small ethylcellulose particle size on the manufacture and properties of pellets produced by extrusion-spheronization was investigated. A factorial design revealed the effects of microcrystalline cellulose (MCC), polyethylene oxide (PEO), water, and spheronization speed and time on pellet properties. Response surface modeling allowed optimization of the responses with expansion to a central composite design. Pellet yield, size, shape, friability and drug release profile were studied, along with surface and interior morphology. Pellets were spherical irrespective of the formulation and process variables and exhibited physical and mechanical characteristics appropriate for further processing. Yield in the 12/20 mesh cut was lower with FPEC than observed with coarse particle ethylcellulose (CPEC), but FPEC-containing pellets were more rugged and the PEO to obtain optimal pellets was lower for FPEC compared to CPEC. Immediate release products were obtained and ethylcellulose particle size was of no consequence to drug release. Observed responses for the optimized product agreed with predicted values, demonstrating the success of the optimization procedure. These results suggest that FPEC is a good diluent for extrusion-spheronization.
doi:10.1016/j.jsps.2013.11.001
PMCID: PMC4142371  PMID: 25161381
Ethylcellulose; Extrusion; Microcrystalline cellulose; Pellets; Poly(ethylene oxide); Spheronization
11.  Water Dynamics and Interactions in Water-Polyether Binary Mixtures 
Poly(ethylene) oxide (PEO) is a technologically important polymer with a wide range of applications including ion-exchange membranes, protein crystallization, and medical devices. PEO’s versatility arises from its special interactions with water. Water molecules may form hydrogen bond bridges between the ether oxygens of the backbone. While steady-state measurements and theoretical studies of PEO’s interactions with water abound, experiments measuring dynamic observables are quite sparse. A major question is the nature of the interactions of water with the ether oxygens as opposed to the highly hydrophilic PEO terminal hydroxyls. Here, we examine a wide range of mixtures of water and tetraethylene glycol dimethyl ether (TEGDE), a methyl-terminated derivative of PEO with 4 repeat units (5 ether oxygens) using ultrafast infrared polarization selective pump-probe measurements on water’s hydroxyl stretching mode to determine vibrational relaxation and orientational relaxation dynamics. The experiments focus on the dynamical interactions of water with the ether backbone because TEGDE does not have the PEO terminal hydroxyls. The experiments observe two distinct subensembles of water molecules: those that are hydrogen bonded to other waters and those that are associated with TEGDE molecules. The water orientational relaxation has a fast component of a few ps (water-like) followed by much slower decay of ∼20 ps (TEGDE associated). The two decay times vary only mildly with the water concentration. The two subensembles are evident even in very low water content samples, indicating pooling of water molecules. Structural change as water content is lowered either through conformational changes in the backbone or increasing hydrophobic interactions is discussed.
doi:10.1021/ja809261d
PMCID: PMC2889155  PMID: 19323522
12.  Kaempferol nanoparticles achieve strong and selective inhibition of ovarian cancer cell viability 
Ovarian cancer is one of the leading causes of cancer death for women throughout the Western world. Kaempferol, a natural flavonoid, has shown promise in the chemoprevention of ovarian cancer. A common concern about using dietary supplements for chemoprevention is their bioavailability. Nanoparticles have shown promise in increasing the bioavailability of some chemicals. Here we developed five different types of nanoparticles incorporating kaempferol and tested their efficacy in the inhibition of viability of cancerous and normal ovarian cells. We found that positively charged nanoparticle formulations did not lead to a significant reduction in cancer cell viability, whereas nonionic polymeric nanoparticles resulted in enhanced reduction of cancer cell viability. Among the nonionic polymeric nanoparticles, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) nanoparticles incorporating kaempferol led to significant reduction in cell viability of both cancerous and normal cells. Poly(DL-lactic acid-co-glycolic acid) (PLGA) nanoparticles incorporating kaempferol resulted in enhanced reduction of cancer cell viability together with no significant reduction in cell viability of normal cells compared with kaempferol alone. Therefore, both PEO-PPO-PEO and PLGA nanoparticle formulations were effective in reducing cancer cell viability, while PLGA nanoparticles incorporating kaempferol had selective toxicity against cancer cells and normal cells. A PLGA nanoparticle formulation could be advantageous in the prevention and treatment of ovarian cancers. On the other hand, PEO-PPO-PEO nanoparticles incorporating kaempferol were more effective inhibitors of cancer cells, but they also significantly reduced the viability of normal cells. PEO-PPO-PEO nanoparticles incorporating kaempferol may be suitable as a cancer-targeting strategy, which could limit the effects of the nanoparticles on normal cells while retaining their potency against cancer cells. We have identified two nanoparticle formulations incorporating kaempferol that may lead to breakthroughs in cancer treatment. Both PEO-PPO-PEO and PLGA nanoparticle formulations had superior effects compared with kaempferol alone in reducing cancer cell viability.
doi:10.2147/IJN.S33670
PMCID: PMC3410694  PMID: 22866004
nanochemoprevention; kaempferol; ovarian cancer; nanoparticles; viability; natural compound
13.  Exploring the Potential of A Highly Compressible Microcrystalline Cellulose as Novel Tabletting Excipient in the Compaction of Extended-Release Coated Pellets Containing an Extremely Water-Soluble Model Drug 
AAPS PharmSciTech  2009;10(3):850-857.
Compaction of controlled-release coated pellets into tablets is challenging because of the fusion of pellets and the rupturing of coated film. The difficulty in compaction intensifies with the use of extremely water-soluble drugs. Therefore, the present study was conducted to prepare and compact pellets containing pseudoephedrine hydrochloride as an extremely water-soluble model drug. The pellets were produced using an extrusion–spheronization technique. The drug-loaded pellets were coated to extend the drug release up to 12-h employing various polymers, and then they were compressed into tablets using microcrystalline cellulose Ceolus KG-801 as a novel tabletting excipient. The in vitro drug release studies of coated pellets and tablets were undertaken using the USP basket method in dissolution test apparatus I. The amount of drug released was analyzed at a wavelength of 215 nm. The combined coatings of hydroxypropyl methylcellulose and Kollicoat SR-30D yielded 12-h extended-release pellets with drug release independent of pH of dissolution medium following zero-order kinetics. The drug release from the tablets prepared using inert Celous KG-801 granules as tabletting excipient was found faster than that of coated pellets. However, a modification in drug release rate occurred with the incorporation of inert Ceolus KG-801 pellets. The drug dissolution profile from tablets containing 40% w/w each of coated pellets and inert granules along with 20% w/w inert pellets was found to be closely similar to that of coated pellets. Furthermore, the friability, tensile strength, and disintegration time of the tablets were within the USP specifications.
doi:10.1208/s12249-009-9278-2
PMCID: PMC2802164  PMID: 19554454
ceolus KG-801; compaction of coated pellets; microcrystalline cellulose; pseudoephedrine hydrochloride; tabletting excipients
14.  Poly(ethylene oxide)-block-polyphosphoester-graft-paclitaxel Conjugates with Acid-labile Linkages as a pH-Sensitive and Functional Nanoscopic Platform for Paclitaxel Delivery 
Advanced healthcare materials  2013;3(3):441-448.
There has been an increasing interest to develop new types of stimuli-responsive drug delivery vehicles with high drug loading and controlled release properties for chemotherapeutics. An acid-labile, polyphosphoester-based degradable, polymeric paclitaxel (PTX) conjugate containing ultra-high levels of PTX loading has been improved significantly, in this second generation development, which involves connection of each PTX molecule to the polymer backbone via a pH-sensitive β-thiopropionate linkage. The results for this system indicate that it has great potential as an effective anti-cancer agent. Poly(ethylene oxide)-block-polyphosphoester-graft-PTX drug conjugate (PEO-b-PPE-g-PTX G2) was synthesized by organocatalyst-promoted ring-opening polymerization of 2-(but-3-en-1-yloxy)-1,3,2-dioxaphospholane-2-oxide from a PEO macroinitiator, followed by thermo-promoted thiolene click conjugation of a thiol-functionalized PTX prodrug to the pendant alkene groups of the block copolymer. The PEO-b-PPE-g-PTX G2 formed well-defined nanoparticles in aqueous solution, by direct dissolution into water, with a number-averaged hydrodynamic diameter of 114 ± 31 nm. The conjugate had PTX loading capacity as high as 53 wt%, and a maximum PTX concentration of 0.68 mg/mL in water (vs. 1.7 μg/mL for free PTX). Although the PTX concentration is ca. 10× less than for our first generation material, its accelerated release allowed for similar free PTX concentrations vs. time. The PEO-b-PPE-g-PTX G2 exhibited accelerated drug release under acidic conditions (~50 wt% PTX released in 8 d) compared to neutral conditions (~20 wt% PTX released in 8 d) and compared to the first generation analog that contained ester linkages between PTX and the polymer backbone (<5 wt% PTX released in 4 d), due to their acid-sensitive hydrolytically-labile β-thiopropionate linkages between PTX molecules and the polymer backbone. The positive cell-killing activity of PEO-b-PPE-g-PTX G2 against two cancer cell lines was demonstrated, and the presence of pendant reactive functionality provides a powerful platform for future work to involve conjugation of multiple numbers and/or types of targeting ligands, other drugs and imaging agents to achieve chemotherapy and bioimaging. Compared to our previously reported polyphosphoester-based PTX drug conjugates, PEO-b-PPE-g-PTX G1 without the β-thiopropionate linker, the PEO-b-PPE-g-PTX G2 showed pH-triggered drug release property and 5-to-8-fold enhanced in vitro cytotoxcity against two cancer cell lines.
doi:10.1002/adhm.201300235
PMCID: PMC3938983  PMID: 23997013
Polyphosphoester; pH-triggered release; polymer drug conjugates; paclitaxel; thiol-ene
15.  Gastroretentive Pulsatile Release Tablets of Lercanidipine HCl: Development, Statistical Optimization, and In Vitro and In Vivo Evaluation 
The Scientific World Journal  2014;2014:421931.
The present study was aimed at the development of gastroretentive floating pulsatile release tablets (FPRTs) of lercanidipine HCl to enhance the bioavailability and treat early morning surge in blood pressure. Immediate release core tablets containing lercanidipine HCl were prepared and optimized core tablets were compression-coated using buoyant layer containing polyethylene oxide (PEO) WSR coagulant, sodium bicarbonate, and directly compressible lactose. FPRTs were evaluated for various in vitro physicochemical parameters, drug-excipient compatibility, buoyancy, swelling, and release studies. The optimized FPRTs were tested in vivo in New Zealand white rabbits for buoyancy and pharmacokinetics. DoE optimization of data revealed FPRTs containing PEO (20% w/w) with coat weight 480 mg were promising systems exhibiting good floating behavior and lag time in drug release. Abdominal X-ray imaging of rabbits after oral administration of the tablets, confirmed the floating behavior and lag time. A quadratic model was suggested for release at 7th and 12th h and a linear model was suggested for release lag time. The FPRT formulation improved pharmacokinetic parameters compared to immediate release tablet formulation in terms of extent of absorption in rabbits. As the formulation showed delay in drug release both in vitro and in vivo, nighttime administration could be beneficial to reduce the cardiovascular complications due to early morning surge in blood pressure.
doi:10.1155/2014/421931
PMCID: PMC4261557  PMID: 25525619
16.  Influence of Plasticizers on the Stability and Release of a Prodrug of Δ9-Tetrahydrocannabinol Incorporated in Poly (Ethylene Oxide) Matrices 
The objective of the present research was to stabilize a heat-labile novel prodrug of Δ9-tetrahydrocannabinol (THC), THC-hemiglutarate (THC-HG), in polyethylene oxide (PEO) [PolyOx® WSR N-80 (PEO N-80), MW 200,000 Daltons] polymeric matrix systems produced by hot-melt fabrication for systemic delivery of THC through the oral transmucosal route. For this purpose, the effects of processing conditions (processing temperature and heating duration), plasticizer type and concentration and storage conditions on the stability of the prodrug were investigated. The selected plasticizers studied included vitamin E succinate (VES), acetyltributyl citrate (ATBC), triethyl citrate (TEC), triacetin and polyethylene glycol 8000 (PEG 8000). Furthermore, the influence of plasticizer concentration on drug release was also studied. The stability of THC-HG in PEO matrices was influenced by all of the aforementioned variables. Films processed at 110 °C for 7 min were found to be favorable for hot-melt processing with a post- processing drug content of 95%, while significant degradation of THC-HG (~42%) was observed in those processed at 200 °C for 15 min. The degradation of the prodrug during hot-melt fabrication and also upon storage was considerably reduced in the presence of the plasticizers investigated, VES being the most effective. Modulation of the microenvironmental pH to an acidic range via incorporation of citric acid in PEO-plasticizer matrices significantly improved the stability of the prodrug, with almost 90% of the theoretical drug remaining as opposed to only 15% remaining in PEO-only matrices when stored at 40 °C for up to 3 months. The release of drug from PEO matrices was influenced both by the plasticizer type and concentration. A faster release resulted from water-soluble plasticizers, PEG 8000 and triacetin, and with increasing concentration. However, a slower release was observed with an increase in concentration of water-insoluble plasticizers, VES and ATBC.
doi:10.1016/j.ejpb.2008.06.009
PMCID: PMC2628598  PMID: 18602993
THC; Plasticizers; Stability; Hot-melt; Poly (ethylene oxide); Release; Microenvironmental pH; Prodrug
17.  Development and Evaluation of a Novel Modified-Release Pellet-Based Tablet System for the Delivery of Loratadine and Pseudoephedrine Hydrochloride as Model Drugs 
AAPS PharmSciTech  2010;11(2):910-916.
Modified-release multiple-unit tablets of loratadine and pseudoephedrine hydrochloride with different release profiles were prepared from the immediate-release pellets comprising the above two drugs and prolonged-release pellets containing only pseudoephedrine hydrochloride. The immediate-release pellets containing pseudoephedrine hydrochloride alone or in combination with loratadine were prepared using extrusion–spheronization method. The pellets of pseudoephedrine hydrochloride were coated to prolong the drug release up to 12 h. Both immediate- and prolonged-release pellets were filled into hard gelatin capsule and also compressed into tablets using inert tabletting granules of microcrystalline cellulose Ceolus KG-801. The in vitro drug dissolution study conducted using high-performance liquid chromatography method showed that both multiple-unit capsules and multiple-unit tablets released loratadine completely within a time period of 2 h, whereas the immediate-release portion of pseudoephedrine hydrochloride was liberated completely within the first 10 min of dissolution study. On the other hand, the release of pseudoephedrine hydrochloride from the prolonged release coated pellets was prolonged up to 12 hr and followed zero-order release kinetic. The drug dissolution profiles of multiple-unit tablets and multiple-unit capsules were found to be closely similar, indicating that the integrity of pellets remained unaffected during the compression process. Moreover, the friability, hardness, and disintegration time of multiple-unit tablets were found to be within BP specifications. In conclusion, modified-release pellet-based tablet system for the delivery of loratadine and pseudoephedrine hydrochloride was successfully developed and evaluated.
doi:10.1208/s12249-010-9456-2
PMCID: PMC2902326  PMID: 20496016
extrusion–spheronization; loratadine; modified-release multiple-unit tablet; pseudoephedrine hydrochloride
18.  Synthesis and in vitro characterizations of porous carboxymethyl cellulose-poly(ethylene oxide) hydrogel film 
Biomaterials Research  2015;19:12.
Background
Cellulose and its derivatives such as carboxymethyl cellulose (CMC) have been employed as a biomaterial for their diverse applications such as tissue engineering, drug delivery and other medical materials. Porosity of the scaffolds has advantages in their applications to tissue engineering such as more cell adhesion and migration leading to better tissue regeneration. After synthesis of CMC-poly(ethylene oxide) (PEO) hydrogel by mixing the solutions of both CMC-acrylate and PEO-hexa-thiols, fabrication and evaluation of a CMC-PEO gel and its film in porous form have been made for its possible applications to tissue regeneration. Physicochemical and biological properties of both CMC-PEO hydrogel and porous films have been evaluated by using physicochemical assays by SEM, FTIR and swelling behaviors as well as in vitro assays of MTT, Neutral red, BrdU, gel covering and tissue ingrowth into the pores of the CMC-PEO gel films. Degradation of CMC-PEO hydrogel was also evaluated by treating with esterase over time.
Results
Chemical grafting of acrylate to CMC was verified by analyses of both FTIR and NMR. CMC-PEO hydrogel was obtained by mixing two precursor polymer solutions of CMC-acrylate and PEO-hexa-thiols and by transforming into a porous CMC-PEO gel film by gas forming of ammonium bicarbonate particles. The fabricated hydrogel has swollen in buffer to more than 6 times and degraded by esterase. The results of in vitro assays of live and dead, MTT, BrdU, Neutral red and gel covering on the cells showed excellent cell compatibility of CMC-PEO hydrogel and porous gel films. Furthermore the porous films showed excellent in vitro adhesion and migration of cells into their pore channels as observed by H&E and MT stains.
Conclusions
Both CMC-PEO hydrogel and porous gel films showed excellent biocompatibility and were expected to be a good candidate scaffold for tissue engineering.
doi:10.1186/s40824-015-0033-3
PMCID: PMC4552372  PMID: 26331082
Carboxymethyl cellulose; Poly(ethylene oxide); Gel film; Biocompatibility; Pores
19.  Development and evaluation of natural gum-based extended release matrix tablets of two model drugs of different water solubilities by direct compression 
The study was aimed at developing extended release matrix tablets of poorly water-soluble diclofenac sodium and highly water-soluble metformin hydrochloride by direct compression using cashew gum, xanthan gum and hydroxypropylmethylcellulose (HPMC) as release retardants. The suitability of light grade cashew gum as a direct compression excipient was studied using the SeDeM Diagram Expert System. Thirteen tablet formulations of diclofenac sodium (∼100 mg) and metformin hydrochloride (∼200 mg) were prepared with varying amounts of cashew gum, xanthan gum and HPMC by direct compression. The flow properties of blended powders and the uniformity of weight, crushing strength, friability, swelling index and drug content of compressed tablets were determined. In vitro drug release studies of the matrix tablets were conducted in phosphate buffer (diclofenac: pH 7.4; metformin: pH 6.8) and the kinetics of drug release was determined by fitting the release data to five kinetic models. Cashew gum was found to be suitable for direct compression, having a good compressibility index (ICG) value of 5.173. The diclofenac and metformin matrix tablets produced generally possessed fairly good physical properties. Tablet swelling and drug release in aqueous medium were dependent on the type and amount of release retarding polymer and the solubility of drug used. Extended release of diclofenac (∼24 h) and metformin (∼8–12 h) from the matrix tablets in aqueous medium was achieved using various blends of the polymers. Drug release from diclofenac tablets fitted zero order, first order or Higuchi model while release from metformin tablets followed Higuchi or Hixson-Crowell model. The mechanism of release of the two drugs was mostly through Fickian diffusion and anomalous non-Fickian diffusion. The study has demonstrated the potential of blended hydrophilic polymers in the design and optimization of extended release matrix tablets for soluble and poorly soluble drugs by direct compression.
doi:10.1016/j.jsps.2015.03.005
PMCID: PMC4720012  PMID: 26903772
Cashew gum; Xanthan gum; HPMC; Direct compression; SeDeM Diagram Expert System; Diclofenac sodium; Metformin hydrochloride
20.  Development and Evaluation of Buccoadhesive Controlled Release Tablets of Lercanidipine 
AAPS PharmSciTech  2008;9(1):182-190.
The purpose of this research was to develop and evaluate buccal mucoadhesive controlled release tablets of lercanidipine hydrochloride using polyethylene oxide and different viscosity grades of hydroxypropyl methylcellulose individually and in combination. Effect of polymer type, proportion and combination was studied on the drug release rate, release mechanism and mucoadhesive strength of the prepared formulations. Buccal mucoadhesive tablets were made by direct compression and were characterized for content uniformity, weight variation, friability, surface pH, thickness and mechanism of release. In order to estimate the relative enhancement in bioavailability one optimized formulation was evaluated in rabbits. Further, placebo tablets were also evaluated for acceptability in human subjects. Results indicated acceptable physical characteristics of designed tablets with good content uniformity and minimum weight variation. Drug release and mucoadhesive strength were found to depend upon polymer type, proportion and viscosity. The formulations prepared using poly ethylene oxide gave maximum mucoadhesion. The release mechanism of most formulations was found to be of anomalous non-Fickian type. In vivo studies of selected formulation in rabbits demonstrated significant enhancement in bioavailability of lercanidipine hydrochloride relative to orally administered drug. Moreover, in human acceptability studies of placebo formulations, the designed tablets adhered well to the buccal mucosa for more than 4 h without causing any discomfort. It may be concluded that the designed buccoadhesive controlled release tablets have the potential to overcome the disadvantage of poor and erratic oral bioavailability associated with the presently marketed formulations of lercanidipine hydrochloride.
doi:10.1208/s12249-007-9031-7
PMCID: PMC2976881  PMID: 18446480
buccal; hydroxypropyl methylcellulose; lercanidipine; mucoadhesive; poly ethylene oxide
21.  Formulation of Controlled-Release Capsules of Biopharmaceutical Classification System I Drugs Using Niacin as a Model 
AAPS PharmSciTech  2010;11(4):1650-1661.
Vitamin B3 is made up of niacin (nicotinic acid) and its amide, niacinamide. Both have equivalent vitamin activity, but only niacin (not niacinamide) is effective in lowering elevated low-density lipoprotein cholesterol and triglyceride levels in the blood. Administration of an extended-release (ER) oral tablet would frequently encounter food. If hydrogel is used to formulate the matrix of a biopharmaceutical classification system I drug (high solubility and high permeability), the dosage form absorbs water and swells.. The softened outer layer may be slashed off by food present in the stomach, thus, exposing the core tablet more readily for water absorption and speeding up drug release from its original designed rate. This project aimed to formulate niacin CR pellets made of hydrophobic inert matrix. After niacin was melted with excipients and cooled, the mass was extruded and spheronized into pellets. Size distribution and flowability were determined before pellets were filled into hard gelatin capsule. The USP dissolution study revealed that a candidate formulation of 250 mg in strength released similar amount of niacin as its commercial reference, niacin controlled-release 500 mg tablet, in 6 h (223.9 ± 23.8 mg, n = 4 versus 259.4 ± 2.6 mg, n = 3). The differential scanning calorimetry study of the pellets in capsules stored in 40°C for 4 weeks, and the content assay of capsules in 40°C up to 6 months suggested that niacin was stable within the innovative formulation. In vitro release from this innovative ER capsules stored at 40°C up to 4 weeks were also investigated.
doi:10.1208/s12249-010-9543-4
PMCID: PMC3011082  PMID: 21107774
controlled-release; flowability; innovative formulation; in vitro release; niacin; particle size analysis; pellets; Raman image
22.  The Influence of Sodium Carboxymethylcellulose on Drug Release from Polyethylene Oxide Extended Release Matrices 
AAPS PharmSciTech  2011;12(3):862-871.
Anionic polymer sodium carboxymethylcellulose (CELLOGEN® HP-HS and/or HP-12HS) was investigated for its ability to influence the release of three model drugs propranolol hydrochloride, theophylline and ibuprofen from polyethylene oxide (POLYOX™ WSR 1105 and/or Coagulant) hydrophilic matrices. For anionic ibuprofen and non-ionic theophylline, no unusual/unexpected release profiles were obtained from tablets containing a mixture of two polymers. However, for cationic propranolol HCl, a combination of polyethylene oxide (PEO) with sodium carboxymethylcellulose (NaCMC) produced a significantly slower drug release compared to the matrices with single polymers. The potential use of this synergistic interaction can be a design of new extended release pharmaceutical dosage forms with a more prolonged release (beyond 12 h) using lower polymer amount, which could be particularly beneficial for freely water-soluble drugs, preferably for once daily oral administration. In order to explain changes in the obtained drug release profiles, Fourier transform infrared absorption spectroscopy was performed. A possible explanation for the more prolonged propranolol HCl release from matrices based on both PEO and NaCMC may be due to a chemical bond (i.e. ionic/electrostatic intermolecular interaction) between amine group of the cationic drug and carboxyl group of the anionic polymer, leading to a formation of a new type/form of the active (i.e. salt) with sustained release pattern.
doi:10.1208/s12249-011-9648-4
PMCID: PMC3167260  PMID: 21710334
extended release; FT-IR; ibuprofen; matrix tablet; polyethylene oxide; polymer combination; propranolol hydrochloride; sodium carboxymethylcellulose; theophylline
23.  Development of a Melting Tablet Containing Promethazine HCl Against Motion Sickness 
AAPS PharmSciTech  2008;9(3):1006-1015.
The purpose of this study was to design a ‘Traveller Friendly Drug Delivery System’ for PM-HCl. Conventional promethazine (PM-HCl) tablets are bitter, need to be taken 1 h before symptoms and water is also needed. Taste-masked granules were produced with Eudragit® E100 by extrusion, and analyzed with FTIR, DSC, and XRD. Tablets formulated from granules by direct compression using Ac-Di-Sol, Polyplasdone®-XL, Primojel® and ion-exchanger Tulsion®339 and evaluated for mass uniformity, friability, tensile strength, drug content uniformity, water absorption ratio, in-vitro and in-vivo disintegration time and in-vitro dissolution studies. The observed drug-polymer interactions and reduced crystallinity may be reasons for increased dissolution rates. The formulated tablets were disintegrated within 15 s. Tablets (25 mg PM-HCl) with Ac-Di-Sol (4%) showed complete release within 1 min, while marketed conventional tablets (Phenergan®; Rhone-Poulec) release 25% during the same period. A preliminary stability studies for the prepared tablets carried at 30 ± 2°C/60 ± 5% RH, and 40 ± 2°C/75 ± 5%RH for 3 months showed no significant changes in the tablets quality at 30 ± 2°C/60 ± 5% RH. However, at 40 ± 2°C/75 ± 5%RH marked increase in in-vitro disintegration time, tensile strength and decrease in friability and water absorption ratio was found. The present studies indicate the abilities of Eudragit® E 100 for taste masking and improving the dissolution profile of PM-HCl after complexation. In addition, by employing cost effective direct compression method, fast-dissolving tablets of 400 mg total weight with an acceptable quality could be prepared.
doi:10.1208/s12249-008-9133-x
PMCID: PMC2977014  PMID: 18770049
Eudragit® E 100; Eudragit® RD 100; promethazine hydrochloride; rapidly disintegrating tablet; stability study; superdisintegrants
24.  Comparative evaluation of tableting compression behaviors by methods of internal and external lubricant addition: Inhibition of enzymatic activity of trypsin preparation by using external lubricant addition during the tableting compression process 
AAPS PharmSci  2001;3(3):32-42.
This study evaluated tableting compression by using internal and external lubricant addition. The effect of lubricant addition on the enzymatic activity of trypsin, which was used as a model drug during the tableting compression process, was also investigated. The powder mixture (2% crystalline trypsin, 58% crystalline lactose, and 40% microcrystalline cellulose) was kneaded with 5% hydroxypropyl cellulose aqueous solution and then granulated using an extruding granulator equipped with a 0.5-mm mesh screen at 20 rpm. After drying, the sample granules were passed through a 10-mesh screen (1680 μm). A 200-mg sample was compressed by using 8-mm punches and dies at 49, 98, 196, or 388 MPa (Mega Pascal) at a speed of 25 mm/min. The external lubricant compression was performed using granules without lubricant in the punches and dies. The granules were already dry coated by the lubricant. In contrast, the internal lubricant compression was performed using sample granules (without dry coating) containing 0.5% lubricant. At 98 MPa, for example, the compression level using the external lubricant addition method was about 13% higher than that for internal addition. The significantly higher compressing energy was also observed at other MPas. By comparison, the friction energy for the external addition method calculated based on upper and lower compression forces was only slightly larger. The hardness of tablets prepared using the internal addition method was 34% to 48% lower than that for the external addition method. The total pore volume of the tablet prepared using the external addition method was significantly higher. The maximum ejection pressure using the no-addition method (ie, the tablet was prepared using neither dry-coated granules nor added lubricant) was significantly higher than that of other addition methods. The order was as follows: no addition, external addition, and then internal addition. The ejection energy (EE) for internal addition was the lowest; for no addition, EE was the highest. In the dissolution test, the tablets obtained using external addition immediately disintegrated and showed faster drug release than those prepared using internal addition. This result occurred because the water penetration rate of the tablet using the external addition was much higher. The trypsin activity in tablets prepared using the external addition method was significantly higher than that produced using the internal addition method at the same pressure. All these results suggest that the external addition method might produce a fast-dissolution tablet. Because the drug will be compressed using low pressure only, an unstable bulk drug may be tableted without losing potency.
doi:10.1208/ps030320
PMCID: PMC2751015  PMID: 11741271
Tableting; Trypsin; Preparation; Compression; Dissolution
25.  Agarose Hydrogels Embedded with pH-Responsive Diblock Copolymer Micelles for Triggered Release of Substances 
Biomacromolecules  2013;14(8):2713-2723.
Hybrid agarose hydrogels embedded with pH-responsive diblock copolymers micelles were developed to achieve functional hydrogels capable of stimulus-triggered drug release. Specifically, a well-defined poly(ethylene oxide) (PEO)-based diblock copolymer, PEO-bpoly(2-(N,N-diisopropylamino)ethyl methacrylate) (PEO113-b-PDPAEMA31, where the subscripts represent the degrees of polymerization of two blocks), was synthesized by atom transfer radical polymerization. PDPAEMA is a pH-responsive polymer with a pKa value of 6.3. The PEO113-b-PDPAEMA31 micelles were formed by a solvent-switching method, and their pH-dependent dissociation behavior was investigated by dynamic light scattering and fluorescence spectroscopy. Both studies indicated that the micelles were completely disassembled at pH = 6.40.
The biocompatibility of PEO113-b-PDPAEMA31 micelles was demonstrated by in vitro primary cortical neural culture. Hybrid agarose hydrogels were made by cooling agarose solutions that contained various amounts of PEO113-b-PDPAEMA31 micelles at either 2 or 4 °C. Rheological measurements showed that the mechanical properties of gels were not significantly adversely affected by the incorporation of diblock copolymer micelles with a concentration as high as 5.0 mg/g. Using Nile Red as a model hydrophobic drug, its incorporation into the core of diblock copolymer micelles was demonstrated. Characterized by fluorescent spectroscopy, the release of Nile Red from the hybrid hydrogel was shown to be controllable by pH due to the responsiveness of the block copolymer micelles. Based on the prominent use of agarose gels as scaffolds for cell transplantation for neural repair, the hybrid hydrogels embedded with stimuli-responsive block copolymer micelles could allow the controlled delivery of hydrophobic neuroprotective agents to improve survival of transplanted cells in tune with signals from the surrounding pathological environment.
doi:10.1021/bm4005639
PMCID: PMC3773184  PMID: 23815070
hydrogels; agarose; block copolymers; pH responsive; micelles; neurons

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