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1.  Effect of oppositely charged polymer and dissolution medium on swelling, erosion, and drug release from chitosan matrices 
AAPS PharmSciTech  2007;8(2):E110-E118.
The purpose of this research was to investigate the potential use of anionick-carrageenan and nonionic hydroxypropyl-methylcellulose (HPMC, K4) to improve the matrix integrity of directly compressed chitosan tablets containing naproxen sodium, an anionic drug. The influence of buffer pH and drug:polymer ratio on the water uptake, matrix erosion, and drug release were studied. The rapid release of naproxen sodium was seen from matrices containing 100% chitosan due to loss in the matrix cohesiveness; whereas, it was relatively slow for matrices containing optimum concentration ofk-carrageenan. In-situ interaction between oppositely charged moieties resulted in the formation of polyelectrolyte complexes with stoichiometric charge ratios of unity. Fourier transform in frared (FTIR) spectroscopy and powder x-ray diffraction (PXRD) data confirmed the importance of ionic bonds in polyelectrolyte complexation. The ionic interactions between polymers were absent in matrices containing HPMC and the integrity of tablets was improved owing to the presence of viscous gel barrier.
The reasons for retarded release of naproxen sodium from the chitosan matrices at different pH include poor aqueous solubility of drug, the formation of a rate-limiting polymer gel barrier along the periphery of matrices, the interaction of naproxen sodium with protonated amino, groups of chitosan, and the interaction of ionized amino groups of chitosan with ionized sulfate groups ofk-carrageenan.
doi:10.1208/pt0802044
PMCID: PMC2750359  PMID: 17622119
Charged polymers; naproxen sodium; insitu complexation; sustained release matrices; chitosan; k-carrageenan
2.  Effect of Oppositely Charged Polymer and Dissolution Media on Rheology of Spray-Dried Ionic Complexes 
AAPS PharmSciTech  2010;11(1):226-232.
The purpose of this research was to address the utility of rheological study in understanding the influence of oppositely charged polymers on release of naproxen sodium encapsulated in chitosan particles. The interaction between oppositely charged κ-carrageenan (κ-Ca) and chitosan leads to relatively higher gel strength, which is proportional to the ability to retard the drug release at acidic pH. The oscillatory tests within the linear viscoelastic range where the stress is proportional to the applied strain were performed on the hydrated sample matrices containing chitosan-naproxen sodium spray-dried complexes and k-Ca or hydroxypropyl methylcellulose (HPMC) in various ratios. It was observed that the effect of pH change on the dynamic moduli in spray-dried complexes containing κ-Ca was much stronger than that with HPMC reflecting presence of strong ionic interaction between κ-Ca and chitosan. The combination of oppositely charged polymers in different ratios proved to be useful in modulating the rheological properties of the hydrated formulations and their release-retarding properties. Dynamic moduli can be used to measure gel strength and are significant for the interpretation of oral sustained release spray-dried complexes.
doi:10.1208/s12249-010-9379-y
PMCID: PMC2850499  PMID: 20131020
gel strength; ionic complexes; rheology
3.  Terminalia Gum as a Directly Compressible Excipient for Controlled Drug Delivery 
AAPS PharmSciTech  2011;13(1):16-23.
ABSTRACT
The exudates from the incised trunk of Terminalia randii has been evaluated as controlled release excipient in comparison with xanthan gum and hydroxypropylmethylcellulose (HPMC) using carvedilol (water insoluble) and theophylline (water soluble) as model drugs. Matrix tablets were prepared by direct compression and the effects of polymer concentration and excipients—spray dried lactose, microcrystalline cellulose and dicalcium phosphate dihydrate on the mechanical (crushing strength (CS) friability (F) and crushing strength–friability ratio (CSFR)) and drug release properties of the matrix tablets were evaluated. The drug release data were fitted into different release kinetics equations to determine the drug release mechanism(s) from the matrix tablets. The results showed that the CS and CSFR increased with increase in polymer concentration while F decreased. The ranking of CS and CSFR was HPMC > terminalia > xanthan while the ranking was reverse for F. The ranking for t25 (i.e. time for 25% drug release) at a polymer concentration of 60% was xanthan > terminalia = HPMC. The dissolution time, t25, of theophylline matrices was significantly lower (p < 0.001) than those of carvedilol matrix tablets. Drug release from the matrices was by swelling, diffusion and erosion. The mechanical and drug release properties of the tablets were significantly (p < 0.05) dependent on the type and concentration of polymer and excipients used with the release mechanisms varying from Fickian to anomalous. Terminalia gum compared favourably with standard polymers when used in controlled release matrices and could serve as a suitable alternative to the standard polymers in drug delivery.
doi:10.1208/s12249-011-9712-0
PMCID: PMC3299455  PMID: 22068290
excipients; hydroxypropylmethylcellulose; matrix tablets; terminalia gum; xanthan gum
4.  Preparation of Chlorpheniramine Maleate-loaded Alginate/Chitosan Particulate Systems by the Ionic Gelation Method for Taste Masking 
Background:
Chlorpheniramine maleate (CM) is widely used as an antihistaminic drug but it is very bitter and as yet no mouth dissolving/disintegrating taste-masked preparation that might be useful for pediatric and geriatric patients is available in the market.
Objectives:
The purpose of this research was to mask the bitter taste of CM by formulating microspheres of the taste-masked drug.
Materials and Methods:
This work was done to develop alginate/chitosan particles prepared by ionic gelation (Ca2+ and Al3+) for the CM release. The effect of different chitosan and Ca2+ concentrations on taste masking and the characteristics of the microspheres were investigated. Ca2+ and Al3+ alginates microspheres of CM were prepared using cross-linked insoluble complexes that precipitate, incorporating the drug. Formulations were characterized for particle size and shape, entrapment efficiency, fourier transform spectroscopy (FTIR), x-ray diffraction (XRD), and differential scanning calorimetry (DSC), bitter taste threshold and in vitro drug release in simulated gastrointestinal fluids.
Results:
FTIR, XRD and DSC demonstrated unstable characters of CM in the drug-loaded microspheres and revealed an amorphous form. Also, the peak of alginate microparticles (Ca2+ and Al3+ ions) in all formulations remained the same, with low intensity of spectrum. The results of DSC, X-ray diffraction and FTIR showed the presence of several CM chemical interactions with alginate and ions (Ca2+ and Al3+). The microsphere formulations showed desirable drug entrapment efficiencies (62.2-94.2%). Calcium/aluminum alginate retarded the release of CM at low pH = 1.2 and released the drug from microspheres slowly at pH = 6.8, simulating intestine pH. The drug release duration and the release kinetics were dependent on the nature of the polymers, the cation concentrations, and valences (Ca2+ and Al3+). The drug release rate was decreased by an increase in chitosan and cation concentrations.
Conclusions:
The results of the present study indicated that oral preparation of CM with an acceptable taste is feasible.
PMCID: PMC3957142  PMID: 24644438
Chlorpheniramine; Calcium; Aluminium; Taste
5.  Effects of Spray Drying on Physicochemical Properties of Chitosan Acid Salts 
AAPS PharmSciTech  2011;12(2):637-649.
The effects of spray-drying process and acidic solvent system on physicochemical properties of chitosan salts were investigated. Chitosan used in spray dryings was obtained by deacetylation of chitin from lobster (Panulirus argus) origin. The chitosan acid salts were prepared in a laboratory-scale spray drier, and organic acetic acid, lactic acid, and citric acid were used as solvents in the process. The physicochemical properties of chitosan salts were investigated by means of solid-state CP-MAS 13C nuclear magnetic resonance (NMR), X-ray powder diffraction (XRPD), differential scanning calorimetry, and Fourier transform infrared spectrometry (FTIR) and near-infrared spectroscopy. The morphology of spray-dried chitosan acid salts showed tendency toward higher sphericity when higher temperatures in a spray-drying process were applied. Analysis by XRPD indicated that all chitosan acid salts studied were amorphous solids. Solid-state 13C NMR spectra revealed the evidence of the partial conversion of chitosan acetate to chitin and also conversion to acetyl amide form which appears to be dependent on the spray-drying process. The FTIR spectra suggested that the organic acids applied in spray drying may interact with chitosan at the position of amino groups to form chitosan salts. With all three chitosan acid salts, the FTIR bands at 1,597 and 1,615 cm−1 were diminished suggesting that –NH groups are protonated. The FTIR spectra of all chitosan acid salts exhibited ammonium and carboxylate bands at 1,630 and 1,556 cm−1, respectively. In conclusion, spray drying is a potential method of preparing acid salts from chitosan obtained by deacetylation of chitin from lobster (P. argus) origin.
doi:10.1208/s12249-011-9620-3
PMCID: PMC3134675  PMID: 21560022
chitin; chitosan salt; lobster (Panulirus argus); physicochemical properties; spray drying
6.  Effects of spray drying conditions on the physicochemical properties of the Tramadol-Hcl microparticles containing Eudragit® RS and RL 
Journal of Pharmacy & Bioallied Sciences  2012;4(Suppl 1):S50-S53.
The preparation of Tramadol-HCL spray-dried microspheres can be affected by the long drug recrystallization time. Polymer type and drug–polymer ratio as well as manufacturing parameters affect the preparation. The purpose of this work was to evaluate the possibility to obtain tramadol spray-dried microspheres using the Eudragit® RS and RL; the influence of the spray-drying parameters on morphology, dimension, and physical stability of microspheres was studied. The effects of matrix composition on microparticle properties were characterized by Laser Light scattering, differential scanning calorimetry (DSC), X-ray diffraction study, FT-infrared and UV-visible spectroscopy. The spray-dried microparticles were evaluated in terms of shape (SEM), size distribution (Laser light scattering method), production yield, drug content, initial drug loding and encapsulation efficiency. The results of X-ray diffraction and thermal analysis reveals the conversion of crystalline drug to amorphous. FTIR analysis confirmed the absence of any drug polymer interaction. The results indicated that the entrapment efficiency (EE), and product yield were depended on polymeric composition and polymeric ratios of the microspheres prepared. Tramadol microspheres based on Eudragit® blend can be prepared by spray-drying and the nebulization parameters do not influence significantly on particle properties.
doi:10.4103/0975-7406.94134
PMCID: PMC3467858  PMID: 23066205
Tramadol; spray-drying parameters; microspheres; Eudragit®
7.  Effect of a Pharmaceutical Cationic Exchange Resin on the Properties of Controlled Release Diphenhydramine Hydrochloride Matrices Using Methocel K4M or Ethocel 7cP as Matrix Formers 
AAPS PharmSciTech  2008;9(3):899-908.
This work was aimed at evaluating the effect of a pharmaceutical cationic exchange resin (Amberlite IRP-69) on the properties of controlled release matrices using Methocel K4M (HPMC) or Ethocel 7cP (EC) as matrix formers. Diphenhydramine hydrochloride (DPH), which was cationic and water soluble, was chosen as a model drug. HPMC- and EC-based matrices with varying amounts (0–40%w/w) of resin incorporation were prepared by a direct compression. Matrix properties including diameter, thickness, hardness, friability, surface morphology and drug release were evaluated. The obtained matrices were comparable in diameter and thickness regardless of the amount of resin incorporation. Increasing the incorporated resin decreased the hardness of HPMC- and EC-based matrices, correlating with the degree of rupturing on the matrix surfaces. The friability of HPMC-based matrices increased with increasing the incorporated resin, corresponding to their decreased hardness. In contrast, the EC-based matrices showed no significant change in friability in spite of decreasing hardness. The incorporated resin differently influenced DPH release from HPMC- and EC-based matrices in deionized water. The resin further retarded DPH release from HPMC-based matrices due to the gelling property of HPMC and the ion exchange property of the resin. In contrast, the release from EC-based matrices initially increased because of the disintegrating property of the resin, but thereafter declined due to the complex formation between released drug and dispersed resin via the ion exchange process. The release in ionic solutions was also described. In conclusion, the incorporated resin could alter the release and physical properties of matrices.
doi:10.1208/s12249-008-9129-6
PMCID: PMC2977024  PMID: 18668370
diphenhydramine hydrochloride; ethylcellulose; hydroxypropylmethylcellulose; ion exchange resin; matrix properties
8.  Reduced Ulcerogenic Potential and Antiarthritic Effect of Chitosan–Naproxen Sodium Complexes 
AAPS PharmSciTech  2012;13(3):896-902.
The purpose of this research was to address the utility of naproxen sodium–chitosan spray-dried complexes for antiulcer and antiarthritic activities. The cold stress technique was used to examine the ulcerogenic potential of naproxen sodium (NPX) and spray-dried formulations in the different doses. The ulcerations reduced with the dose of spray-dried complexes of naproxen sodium and chitosan. The conspicuous hemorrhagic lesions were visible in the morphological features of the animal treated with naproxen 50 mg/kg (p.o.). Thus, the results suggest that the spray-dried naproxen sodium–chitosan complex (NPXF) was not corrosive to the gastric mucosa at high doses of 50, 100, and 200 mg/kg (p.o.) under stressful conditions. It is evident from the present investigation that NPXF does not possess any ulcerogenic potential in comparison to naproxen which, under stressful conditions, led to the hypersecretion of HCl, culminating to petichial hemorrhages in the gastric mucosa of the animals. The biphasic pattern was observed in the various arthritic parameters. The rise in paw volume, joint diameter, WBC count, arthritis score, and fall in body weight was significantly ameliorated in the animals treated with NPXF (5, 10, and 20 mg/kg, p.o). At the end of the study, slight erythema was visible in the naproxen-treated animals. However, no erythema, redness, or ulcers were visible in the animals treated with NPXF. Thus, the direct compression properties and reduced ulcerogenic activity, combined with the demonstrated solubilizing power and analgesic effect enhancer ability toward the drug, make naproxen sodium–chitosan spray-dried complexes particularly suitable for developing a reduced-dose, fast-release, solid oral dosage form of naproxen.
doi:10.1208/s12249-012-9779-2
PMCID: PMC3429684  PMID: 22711255
antiarthritic; chitosan complexes; ulcer
9.  Spray-dried mucoadhesive microspheres: Preparation and transport through nasal cell monolayer 
AAPS PharmSciTech  2006;7(1):E79-E88.
The purpose of this research was to prepare spray-dried mucoadhesive microspheres for nasal delivery. Microspheres composed of hydroxypropyl methylcellulose (H), chitosan (CS), carbopol 934P (CP) and various combinations of these mucoadhesive polymers, and maltodextrin (M), colloidal silicon dioxide (A), and propylene glycol (P) as filler and shaper, were prepared by spray-drying technique. Using propranolol HCl as a model drug, microspheres were prepared at loadings exceedings 80% and yields between 24% and 74%. Bulky, free flowing microspheres that had median particle size between 15 and 23 μm were obtained. Their zeta potential was according to the charge of polymer. Adhesion time of mucoadhesive microspheres on isolated pig intestine was ranked, CS>CP: H>CP>H, while the rank order of swelling was CP>CS>H. Increasing the amount of CP in CP∶H formulations increased the percentage of swelling. Infrared (IR) spectra showed no interaction between excipients used except CS with acetic acid. The release of drug from CP and CP∶H microspheres was slower than the release from H and CS microspheres, correlated to their viscosity and swelling. Long lag time from the CP microspheres could be shortened when combined with H. The permeation of drug through nasal cell monolayer corresponded to their release profiles. These microspheres affected the integrity of tight junctions, relative to their swelling and charge of polymer. Cell viability was not affected except from CS microspheres, but recovery could be obtained. In conclusion, spray-dried microspheres of H, CS, CP, and CP∶H could be prepared to deliver drug through nasal cell monolayer via the opening of tight junction without cell damaging.
doi:10.1208/pt070112
PMCID: PMC2750719  PMID: 16584142
mucoadhesive polymers; spray-dried microspheres; nasal cell monolayer; permeation; cell viability
10.  Lyophilized Chitosan/xanthan Polyelectrolyte Complex Based Mucoadhesive Inserts for Nasal Delivery of Promethazine Hydrochloride  
The objective of this investigation was the development of chitosan/xanthan polyelectrolyte complex based mucoadhesive nasal insert of promethazine hydrochloride a drug used in the treatment of motion sickness. A 32 factorial design was applied for preparing chitosan/xanthan polyelectrolyte complex and to study the effect of independent variables i.e. concentration of xanthan [X1] and concentration of chitosan [X2] on various responses i.e. viscosity of polyelectrolyte complex solution, water uptake of nasal inserts (at pH 2, 5.5, 7.4), bioadhesion potential of nasal inserts and in-vitro drug release at Q6h through nasal inserts. FTIR and DSC analysis were carried out to confirm complex formation and on loaded and unloaded nasal insert to investigate any drug excipient interaction. The nasal inserts were also characterized by powder X-ray diffractometry (PXRD) and Scanning electron microscopy (SEM) and for ex-vivo permeation studies. The results show that higher amount of xanthan in polyelectrolyte complexes with respect to higher amount of chitosan retarded in-vitro drug release. The water uptake behaviour of nasal insert was strongly influenced by pH of the medium and by polycation/ polyanion concentration. The investigation verifies the formation of polyelectrolyte complexes formation between chitosan and xanthan at pH values in the vicinity of pKa intervals of the two polymers and confirms their potential for the nasal delivery of promethazine hydrochloride.
PMCID: PMC4177638  PMID: 25276178
Promethazine hydrochloride; Polyelectrolyte complexes; Lyophilized mucoadhesive inserts; In-vitro drug release; Ex-vivo permeation
11.  Development of Press-Coated, Floating-Pulsatile Drug Delivery of Lisinopril 
Scientia Pharmaceutica  2014;82(2):423-440.
Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor, primarily used for the treatment of hypertension, congestive heart failure, and heart attack. It belongs to BCS class III having a half-life of 12 hrs and 25% bioavailability. The purpose of the present work was to develop a press-coated, floating-pulsatile drug delivery system. The core tablet was formulated using the super-disintegrants crosprovidone and croscarmellose sodium. A press-coated tablet (barrier layer) contained the polymer carrageenan, xanthan gum, HPMC K4M, and HPMC K15M. The buoyant layer was optimized with HPMC K100M, sodium bicarbonate, and citric acid. The tablets were evaluated for physical characteristics, floating lag time, swelling index, FTIR, DSC, and in vitro and in vivo behavior. The 5% superdisintgrant showed good results. The FTIR and DSC study predicted no chemical interactions between the drug and excipients. The formulation containing xanthan gum showed drug retaining abilities, but failed to float. The tablet containing HPMC K15M showed a high swelling index. The lag time for the tablet coated with 200 mg carrageenan was 3±0.1 hrs with 99.99±1.5% drug release; with 140 mg HPMC K4M, the lag time was 3±0.1 hrs with 99.71±1.2% drug release; and with 120 mg HPMC K15M, the lag time was 3±0.2 hrs with 99.98±1.7% drug release. The release mechanism of the tablet followed the Korsmeyer-Peppas equation and a first-order release pattern. Floating and lag time behavior have shown good in vitro and in vivo correlations.
doi:10.3797/scipharm.1301-27
PMCID: PMC4065132  PMID: 24959410
Floating; Press-coated; Carrageenan; Xanthan; Pulsatile; Delivery
12.  Effect of microenvironment pH of swellable and erodable buffered matrices on the release characteristics of diclofenac sodium 
AAPS PharmSciTech  2003;4(3):110-115.
The aim of this work is to design pH-dependent swellable and erodable-buffered matrices and to study the effect of the microenvironment pH on the release pattern of diclofenac sodium. Buffered matrix tablets containing diclofenac sodium, physically mixed with hydrophilic polymer (hydroxypropyl methylcellulose [HPMC]) and pH-dependent solubility polymer (Eudragit L100-55) were prepared with different microenvironment pHs. The release of diclofenac sodium from the buffer matrices was studied in phosphate buffer solutions of pH 5.9 and 7.4. The swelling and erosion matrices containing only HPMC and Eudragit L100-55 were studied in phosphate buffer solution of pH similar to the microenvironment pHs of the matrices. Drug release from matrices was found to be linear as a function of time. Amount of drug released was found to be higher in the medium of pH 7.4 than that of pH 5.9. The rate of drug release increased with the increase of the microenvironment pH of the matrices as determined from the slope. The pattern of drug release did not change with the change of microenvironment pH. The swelling and erosion occurred simultaneously from matrices made up of HPMC and Eudragit L100-55. Both extent of swelling and erosion increased with increase of the medium pH. It was concluded from this study that changing the pH within the matrix influenced the rate of release of the drug without affecting the release pattern.
doi:10.1208/pt040343
PMCID: PMC2750636  PMID: 14621975
controlled release; buffered matrix; swelling; erosion; sustained release
13.  A Novel Multilayered Multidisk Oral Tablet for Chronotherapeutic Drug Delivery 
BioMed Research International  2013;2013:569470.
A Multilayered Multidisk Tablet (MLMDT) comprising two drug-loaded disks enveloped by three drug-free barrier layers was developed for use in chronotherapeutic disorders, employing two model drugs, theophylline and diltiazem HCl. The MLMDT was designed to achieve two pulses of drug release separated by a lag phase. The polymer disk comprised hydroxyethylcellulose (HEC) and ethylcellulose (EC) granulated using an aqueous dispersion of EC. The polymeric barrier layers constituted a combination of pectin/Avicel (PBL) (1st barrier layer) and hydroxypropylmethylcellulose (HPMC) (HBL1 and HBL2) as the 2nd and 3rd barrier layers, respectively. Sodium bicarbonate was incorporated into the diltiazem-containing formulation for delayed drug release. Erosion and swelling studies confirmed the manner in which the drug was released with theophylline formulations exhibiting a maximum swelling of 97% and diltiazem containing formulations with a maximum swelling of 119%. FTIR spectra displayed no interactions between drugs and polymers. Molecular mechanics simulations were undertaken to predict the possible orientation of the polymer morphologies most likely affecting the MLMDT performance. The MLMDT provided two pulses of drug release, separated by a lag phase, and additionally it displayed desirable friability, hardness, and uniformity of mass indicating a stable formulation that may be a desirable candidate for chronotherapeutic drug delivery.
doi:10.1155/2013/569470
PMCID: PMC3762207  PMID: 24024200
14.  Guar Gum, Xanthan Gum, and HPMC Can Define Release Mechanisms and Sustain Release of Propranolol Hydrochloride 
AAPS PharmSciTech  2010;12(1):77-87.
The objectives were to characterize propranolol hydrochloride-loaded matrix tablets using guar gum, xanthan gum, and hydroxypropylmethylcellulose (HPMC) as rate-retarding polymers. Tablets were prepared by wet granulation using these polymers alone and in combination, and physical properties of the granules and tablets were studied. Drug release was evaluated in simulated gastric and intestinal media. Rugged tablets with appropriate physical properties were obtained. Empirical and semi-empirical models were fit to release data to elucidate release mechanisms. Guar gum alone was unable to control drug release until a 1:3 drug/gum ratio, where the release pattern matched a Higuchi profile. Matrix tablets incorporating HPMC provided near zero-order release over 12 h and erosion was a contributing mechanism. Combinations of HPMC with guar or xanthan gum resulted in a Higuchi release profile, revealing the dominance of the high viscosity gel formed by HPMC. As the single rate-retarding polymer, xanthan gum retarded release over 24 h and the Higuchi model best fit the data. When mixed with guar gum, at 10% or 20% xanthan levels, xanthan gum was unable to control release. However, tablets containing 30% guar gum and 30% xanthan gum behaved as if xanthan gum was the sole rate-retarding gum and drug was released by Fickian diffusion. Release profiles from certain tablets match 12-h literature profiles and the 24-h profile of Inderal® LA. The results confirm that guar gum, xanthan gum, and HPMC can be used for the successful preparation of sustained release oral propranolol hydrochoride tablets.
doi:10.1208/s12249-010-9570-1
PMCID: PMC3066369  PMID: 21174179
guar gum; hydropropylmethylcellulose; propranolol; sustained release; xanthan gum
15.  Use of hydrophilic natural gums in formulation of sustained-release matrix tablets of tramadol hydrochloride 
AAPS PharmSciTech  2006;7(1):E168-E174.
The objective of this work was to develop matrix sustained-release tablets of highly water-soluble tramadol HCl using natural gums (xanthan [X gum] and guar [G gum]) as cost-effective, nontoxic, easily available, and suitable hydrophilic matrix systems compared with the extensively investigated hydrophilic matrices (ie, hydroxypropyl methylcellulose [HPMC]/carboxymethyl cellulose [CMC] with respect to in vitro drug release rate) and hydration rate of the polymers. Matrix tablets of tramadol (dose 100 mg) were produced by direct compression method. Different ratios, of 100∶0, 80∶20, 60∶40, 20∶80, 0∶100 of G gum (or X):HPMC, X gum:G gum, and triple mixture of these polymers (G gum, X gum, HPMC) were applied. After evaluation of physical characteristics of tablets, the dissolution test was, performed in the phosphate buffer media (pH 7.4) up to 8 hours. Tablets with only X had the highest mean dissolution time (MDT), the least dissolution efficiency (DE8%), and released the drug following a zero-order model via swelling, diffusion, and erosion mechanisms. Guar gum alone could not efficiently control the drug release, while X and all combinations of natural gums with HPMC could retard tramadol HCl release. However, according to the similarity factor (f2), pure HPMC and H8G2 were the most similar formulations to Topalgic-LP as the reference standard.
doi:10.1208/pt070124
PMCID: PMC2750731
natural gums; xanthan; guar gum; tramadol; sustained-release
16.  A Composite Polyelectrolytic Matrix for Controlled Oral Drug Delivery 
AAPS PharmSciTech  2011;12(1):227-238.
The purpose of this study was to formulate drug-loaded polyelectrolyte matrices constituting blends of pectin, chitosan (CHT) and hydrolyzed polyacrylamide (HPAAm) for controlling the premature solvation of the polymers and modulating drug release. The model drug employed was the highly water-soluble antihistamine, diphenhydramine HCl (DPH). Polyelectrolyte complex formation was validated by infrared spectroscopy. Matrices were characterized by textural profiling, porositometry and SEM. Drug release studies were performed under simulated gastrointestinal conditions using USP apparatus 3. FTIR spectra revealed distinctive peaks indicating the presence of –COO− symmetrical stretching (1,425–1,390 cm−1) and -NH3+ deformation (1,535 cm−1) with evidence of electrostatic interaction between the cationic CHT and anionic HPAAm corroborated by molecular mechanics simulations of the complexes. Pectin–HPAAm matrices showed electrostatic attraction due to residual –NH2 and –COO− groups of HPAAm and pectin, respectively. Textural profiling demonstrated that CHT-HPAAm matrices were most resilient at 6.1% and pectin–CHT–HPAAm matrices were the least (3.9%). Matrix hardness and deformation energy followed similar behavior. Pectin–CHT–HPAAm and CHT–HPAAm matrices produced type IV isotherms with H3 hysteresis and mesopores (22.46 nm) while pectin–HPAAm matrices were atypical with hysteresis at a low P/P0 and pore sizes of 5.15 nm and a large surface area. At t2 h, no DPH was released from CHT–HPAAm matrices, whereas 28.2% and 82.2% was released from pectin–HPAAm and pectin–CHT–HPAAm matrices, respectively. At t4 h, complete DPH release was achieved from pectin–CHT–HPAAm matrices in contrast to only 35% from CHT–HPAAm matrices. This revealed the release-modulating capability of each matrix signifying their applicability in controlled oral drug delivery applications.
doi:10.1208/s12249-010-9576-8
PMCID: PMC3066358  PMID: 21225384
composite polyelectrolytes; controlled oral drug delivery; hydrolyzed polyacylamide; matrix characterization; polysaccharides
17.  Design and Characterization of a Silk-Fibroin-Based Drug Delivery Platform Using Naproxen as a Model Drug 
Journal of Drug Delivery  2012;2012:490514.
The objective of this proof-of-concept study was to develop a platform for controlled drug delivery based on silk fibroin (SF) and to explore the feasibility of using SF in oral drug delivery. The SF-containing matrixes were prepared via spray-drying and film casting, and the release profile of the model drug naproxen sodium was evaluated. Attenuated total reflectance Fourier transform infrared spectroscopy (FTIR) has been used to observe conformational changes in SF- and drug-containing compositions. SF-based films, spray-dried microparticles, and matrixes loaded with naproxen were prepared. Both FTIR spectra and in vitro dissolution data demonstrated that SF β-sheet conformation regulates the release profile of naproxen. The controlled release characteristics of the SF-containing compositions were evaluated as a function of SF concentration, temperature, and exposure to dehydrating solvents. The results suggest that SF may be an attractive polymer for use in controlled drug delivery systems.
doi:10.1155/2012/490514
PMCID: PMC3312329  PMID: 22506122
18.  Development and evaluation of aceclofenac-loaded mucoadhesive microcapsules 
Microencapsulation is an accepted process used to achieve controlled release and drug targeting for many years. Mucoadhesion has been a topic of interest in the design of drug delivery systems to prolong its intestinal residence time. Mucoadhesion facilitates the intimate contact of the dosage form with the underlying absorption surface for improved bioavailability of drugs. Aceclofenac is a newer nonsteroidal anti-inflammatory drug (NSAID) having short biological half-life of 4–4.3 h, and therefore a sustained release medication is required to get prolonged effect and to reduce fluctuations in drug plasma concentration levels. Aceclofenac microcapsules were prepared employing sodium alginate as the coat material in combination with some mucoadhesive polymers such as (hydroxypropyl methyl cellulose) HPMC, (sodium carboxymethyl cellulose) Sod. CMC, Carbopol and methyl cellulose (MC) (drug:SA:polymer at ratios 2:2:1, 2:3:1 and 2:4:1), following orifice-ionic gelation technique. Infrared (IR) spectroscopy, differential scanning calorimetry and X-ray diffraction studies proved the compositions were compatible, without any interaction between the drug and excipients. The prepared microcapsules were evaluated for various physical and release parameters. The resulted microcapsules were found to be discrete and spherical in scanning electron microscopy studies and free flowing in rheological studies. The size of microcapsules was found to be around 757.44 ± 5.201 μm to 814.46 ± 6.586 μm. The microencapsulation efficiency was found to be higher in HPMC than in Carbopol > MC > Sod. CMC containing formulations, but the swelling index was found to be higher in Sod. CMC formulations. The microcapsules with HPMC exhibited good mucoadhesive property in the in vitro wash-off test. In vitro drug release studies of aceclofenac microcapsules were carried out up to 24 h and they followed zero-order release kinetics with Super Case II mechanism. The drug release from the microcapsules was sustained over a prolonged period with greater retardation in drug:SA:HPMC (2:4:1) containing microcapsules and this proved to be the best formulation.
doi:10.4103/2231-4040.90881
PMCID: PMC3255352  PMID: 22247892
Aceclofenac; controlled release; ionic-orifice gelation; microencapsulation; mucoadhesion
19.  Design and In Vitro/In Vivo Evaluation of Novel Mucoadhesive Buccal Discs of an Antifungal Drug: Relationship Between Swelling, Erosion, and Drug Release 
AAPS PharmSciTech  2008;9(4):1207-1217.
Two groups of fluconazole mucoadhesive buccal discs were prepared: (a) Fluconazole buccal discs prepared by direct compression containing bioadhesive polymers, namely, Carbopol 974p (Cp), sodium carboxymethyl cellulose (SCMC), or sodium alginate (SALG) in combination with hydroxypropyl methylcellulose (HPMC) or hydroxyethyl cellulose (HEC). (b) Fluconazole buccal discs prepared by freeze drying containing different polymer combinations (SCMC/HPMC, Cp/HPMC, SALG/HPMC, and chitosan/SALG). The prepared discs were evaluated by investigating their release pattern, swelling capacity, mucoadhesion properties, and in vitro adhesion time. In vivo evaluation of the buccal disc and in vivo residence times were also performed. Fluconazole salivary concentration after application of fluconazole buccal systems to four healthy volunteers was determined using microbiological assay and high-performance liquid chromatography. SCMC/HPMC buccal disc prepared by direct compression could be considered comparatively superior mucoadhesive disc regarding its in vitro adhesion time, in vivo residence time, and in vitro/in vivo release rates of the drug. Determination of the amount of drug released in saliva after application of the selected fluconazole disc confirmed the ability of the disc to deliver the drug over a period of approximately 5 h and to reduce side effects and possibility of drug interaction encountered during systemic therapy of fluconazole, which would be beneficial in the case of oral candidiasis.
doi:10.1208/s12249-008-9166-1
PMCID: PMC2628258  PMID: 19082739
buccal; fluconazole; mucoadhesive disc; oral candidiasis; residence time
20.  Development and evaluation of chitosan based oral controlled matrix tablets of losartan potassium 
Aim and Background:
The novelty of the present study was to control the release profile of matrix tablets of losartan potassium prepared by using different concentrations of chitosan and trisodium citrate as cross-linking agent with combination of various release retardant polymers.
Materials and Methods:
Twelve formulations were prepared using HPMC K100M, carbopol 934P, and xanthan gum as polymers. Matrix tablets were prepared by wet granulation technique. The granules were subjected to precompression parameters such as angle of repose, loose bulk density, tapped bulk density, compressibility index. Tablets were evaluated for weight variation, hardness, drug content, in-vitro dissolution, stability studies, respectively. Drug -polymer compatibility studies were determined by FTIR spectroscopy. Further stability studies were carried out for 3months in accelerated conditions at 40°C and 75%RH. The granules of all formulations exhibited good flow and compressibility. In-vitro dissolution studies were carried out for 24 h using 0.1 N HCl for the first 2 h and pH 6.8 phosphate buffers for the remaining 22h.
Results:
It was found that among the 12 formulations F11 and F12 showed good dissolution profile to control the drug release. The release data was fitted to various mathematical models such as, Higuchi, Korsmeyer, first-order, and zero-order to evaluate the kinetics and the drug release. The drug release follows zero-order kinetics and the mechanism was found to be diffusion controlled and Case II transport. FT-IR spectroscopic studies revealed no interaction between drug and polymer. The stability studies indicated that F11 and F12 formulations were stable for 3months.
Conclusion:
The above results concluded that by combining different classes of polymers an acceptable release profile can be obtained in the fluctuating in vivo environment.
doi:10.4103/2230-973X.104399
PMCID: PMC3555011  PMID: 23373007
Chitosan; controlled release matrix tablets; losartan potassium; trisodium citrate
21.  Superporous hybrid hydrogels based on polyacrylamide and chitosan: Characterization and in vitro drug release 
Objective:
Current research was aimed at the development of the drug delivery systems based on the superporous hydrogels (SPH) with the desired swelling and the mechanical properties.
Materials and Methods:
Superporous hydrogel composites (SPHCs) and superporous hybrid hydrogels (SPHHs) based on the chitosan and the polyacrylamide were synthesized using the gas blowing technique. The prepared hydrogels were evaluated for swelling studies, mechanical strength and scanning electron microscopy. The selected hydrogels were loaded with the drug (verapamil hydrochloride) by aqueous loading method. Drug integrity with in polymeric network was evaluated via fourier transform infrared spectroscopy (FTIR), X-ray diffraction (X-RD), differential scanning calorimetry (DSC), proton nuclear magnetic resonance (1HNMR) studies. In vitro drug release studies were carried out using the united state pharmacopoeial (USP) dissolution apparatus (type II).
Results and Discussion:
The mechanical strength was observed to be higher in SPH hybrids in comparison to that in SPHCs while no significant difference was observed in swelling behavior. In situ crosslinking of chitosan with glutaraldehyde (GA) may be responsible for high mechanical strength. The equilibrium swelling time was slight higher in SPHH than in SPHCs. The integrity of pores was maintained in ethanol treated hydrogels as observed in scanning electron micrographs. Whereas, freeze dried SPH samples showed non-uniform pores. No drug polymer interaction was observed as indicated by DSC, FTIR, X-RD and NMR studies. However, the crosslinking of chitosan with GA was clearly indicated by these studies. The in vitro drug release studies from SPH hybrids indicated initial fast release (65%) with in first 2 h and then sustained release at the end of 24 h (95%). The addition of hydroxypropyl methyl cellulose with drug; however, leads to a significant decrease in drug release (56% at the end of 24 h).
Conclusion:
Superporous hybrid hydrogels can be promising devices for the sustained delivery of drug candidates to the gastrointestinal region.
doi:10.4103/2230-973X.114906
PMCID: PMC3757904  PMID: 24015380
Equilibrium swelling; in situ crosslinking; integrity; mechanical strength; porous network
22.  Controlled Release Pulmonary Administration of Curcumin Using Swellable Biocompatible Microparticles 
Molecular Pharmaceutics  2011;9(2):269-280.
This study involves a promising approach to achieve sustained pulmonary drug delivery. Dry powder particulate carriers were engineered to allow simultaneous aerosol lung delivery, evasion of macrophage uptake, and sustained drug release through a controlled polymeric architecture. Chitosan grafted with PEG was synthesized and characterized (FTIR, EA, DSC and 2D-XRD). Then, a series of respirable amphiphilic hydrogel microparticles were developed via spray drying of curcumin-loaded PLGA nanoparticles with chitosan-grafted-PEG or chitosan. The nano and microparticles were fully characterized using an array of physicochemical analytical methods including particle size, surface morphology, dynamic swelling, density, moisture content and biodegradation rates. The PLGA nanoparticles and the hydrogel microspheres encapsulating the curcumin-loaded PLGA nanoparticles showed average size of (221-243 nm) and (3.1-3.9 μm), respectively. The developed carriers attained high swelling within a few minutes, showed low moisture content as dry powders (0.9-1.8%), desirable biodegradation rates, high drug loading (up to 97%), and good sustained release. An aerosolization study was conducted using a next generation impactor and promising aerosolization characteristics were shown. In vitro macrophage uptake studies, cytotoxicity and in-vitro TNF-α assays were performed for the investigated particles. These assays revealed promising bio-interactions for the respirable/swellable nano-micro particles developed in this study as potential carriers for sustained pulmonary drug delivery.
doi:10.1021/mp200351y
PMCID: PMC3276370  PMID: 22136259
Nanoparticles; microspheres; PLGA; chitosan; PEG; curcumin; pulmonary; sustained; lung; drug delivery
23.  Evaluation of Ionotropic Cross-Linked Chitosan/Gelatin B Microspheres of Tramadol Hydrochloride 
AAPS PharmSciTech  2010;12(1):28-34.
Microspheres of tramadol hydrochloride (TM) for oral delivery were prepared by complex coacervation method without the use of chemical cross-linking agents such as glutaraldehyde to avoid the toxic reactions and other undesirable effects of the chemical cross-linking agents. Alternatively, ionotropic gelation was employed by using sodium-tripolyphosphate as cross-linking agent. Chitosan and gelatin B were used as polymer and copolymer, respectively. All the prepared microspheres were subjected to various physicochemical studies, such as drug–polymer compatibility by thin layer chromatography (TLC) and Fourier transform infrared (FTIR) spectroscopy, surface morphology by scanning electron microscopy, frequency distribution, drug entrapment efficiency, in vitro drug release characteristics and release kinetics. The physical state of drug in the microspheres was determined by differential scanning calorimetry (DSC) and X-ray diffractometry (XRD). TLC and FTIR studies indicated no drug–polymer incompatibility. All the microspheres showed initial burst release followed by a fickian diffusion mechanism. DSC and XRD analysis indicated that the TM trapped in the microspheres existed in an amorphous or disordered-crystalline status in the polymer matrix. From the preliminary trials, it was observed that it may be possible to formulate TM microspheres by using biodegradable natural polymers such as chitosan and gelatin B to overcome the drawbacks of TM and to increase the patient compliance.
Electronic supplementary material
The online version of this article (doi:10.1208/s12249-010-9537-2) contains supplementary material, which is available to authorized users.
doi:10.1208/s12249-010-9537-2
PMCID: PMC3066349  PMID: 21161459
chitosan; complex coacervation; gelatin B; microspheres; tramadol hydrochloride
24.  An approach for lacidipine loaded gastroretentive formulation prepared by different methods for gastroparesis in diabetic patients 
The present work deals with various attempts to prepare a gastroretentive formulation of lacidipine for treating gastroparesis. High density sucrose beads were modified by coating with certain polymers, but unfortunately sustained release could not be achieved. Granules were prepared by wet granulation technology using different combinations of polymers and a release of the drug was observed. The method failed to release the drug as per desired specifications. Polymeric coating followed by wet granulation was thought to be a better process to sustain the dissolution rate. The release rate can be modified by the incorporation of different polymeric coatings, but the mucoadhesive potential of granules was only 4.23% which might be due to its large size and the presence of other ingredients. Further, the lacidipine loaded microparticles were prepared by different methods such as compression, ionic gelation with TPP, ionic gelation with TPP and glutaraldehyde, spray drying and coacervation techniques. The formulations were evaluated for average particle size, surface morphology, entrapment efficiency, % yield and mucoadhesive potential. The microparticles prepared by compression method using HPMC K4M and SCMC as mucoadhesive polymers and BaSO4 as high density diluent showed poor bioadhesion (8.3%) and poor release characteristics (100% in 120 min). Ionic gelation with tripolyphosphate yielded microspheres with poor mechanical strength. In order to improve its mechanical strength, TPP ionic gelation was combined with step-wise cross-linking with glutaraldehyde. The additional solidification step to improve mechanical strength left this procedure tedious, time consuming and cytotoxic. Spray drying method gave a very low yield with 46.67% bioadhesion. The method using CaCl2 for ionotropic gelation showed the best results with regard to physical characteristics (well formed discrete, spherical surface microcapsule), particle size (88.57 ± 0.51), in vitro bioadhesion (67.33%), yield (>85%) and loading (>70%).
doi:10.1016/j.jsps.2013.03.005
PMCID: PMC3745044  PMID: 23960846
Lacidipine; Bioadhesion; Ionotropic gelation; Gastroparesis
25.  Polymer Percolation Threshold in Multi-Component HPMC Matrices Tablets 
Introduction:The percolation theory studies the critical points or percolation thresholds of the system, where one component of the system undergoes a geometrical phase transition, starting to connect the whole system.The application of this theory to study the release rate of hydrophilic matrices allows to explain the changes in release kinetics of swellable matrix type system and results in a clear improvement of the design of controlled release dosage forms. Methods: In this study, the percolation theory has been applied to multi-component hydroxypropylmethylcellulose (HPMC) hydrophilic matrices. Matrix tablets have been prepared using phenobarbital as drug, magnesium stearate as a lubricant employing different amount of lactose and HPMC K4M as a filler and matrix forming material, respectively. Ethylcelullose (EC) as a polymeric excipient was also examined. Dissolution studies were carried out using the paddle method.In order to estimate the percolation threshold, the behaviour of the kinetic parameters with respect to thevolumetric fraction of HPMC at time zero, was studied. Results: In both HPMC/lactose and HPMC/EC/lactose matrices, from the point of view of the percolation theory, the optimum concentration for HPMC, to obtain a hydrophilic matrix system for the controlled release of phenobarbital is higher than 18.1% (v/v) HPMC. Above 18.1% (v/v) HPMC, an infinite cluster of HPMC would be formed maintaining integrity of the system and controlling the drug release from the matrices. According to results, EC had no significant influence on the HPMC percolation threshold. Conclusion: This may be related to broad functionality of the swelling hydrophilic matrices.
doi:10.5681/apb.2011.004
PMCID: PMC3850001  PMID: 24312753
Percolation theory; HPMC; Phenobarbital; Percolation threshold

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