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The objective of this study was to modify the release of two drugs having different solubility in a combined matrix tablet as a fixed-dose combination for extended release. Propranolol HCl (freely soluble) and carbamazepine (very slightly soluble) were used as model drugs, water-soluble hydroxypropyl methylcellulose (HPMC) and water-insoluble ethylcellulose (EC) were used as matrix-forming polymers. Tablets were prepared by direct compression of powder blends, or propranolol HCl was first granulated with one of the matrix-forming polymers (1:1) followed by compression with carbamazepine and matrix former. Propranolol HCl release from directly compressed tablets was faster than carbamazepine because of its higher solubility. The release of both drugs was fast when HPMC-propranolol HCl granules were compressed with carbamazepine into EC matrix tablet. Conversely, the release of both drugs was decreased when HPMC-propranolol HCl granules and carbamazepine were compressed into HPMC matrices. The desired release of both drugs was approached when EC-propranolol HCl granules were compressed with carbamazepine into HPMC matrix. Erosion of the HPMC matrix and, therefore, drug release were adjusted by varying the molecular weight of HPMC. A burst release of propranolol HCl decreased when it was granulated with EC in a fluidized bed coater followed by compression with carbamazepine into HPMC matrix.

The objective of this study was to investigate the fundamental properties of propranolol hydrochloride osmotic pump tablets coated by aqueous polymer dispersion, simultaneously exploring the in vitro and in vivo correlation of the tablet. The physicochemical properties and parameters of aqueous polymer dispersion membranes (SEM, water uptake, and water vapor transmission coefficient) were investigated. In addition, the release behavior and the in vitro release and in vivo absorption profiles of the tablets coated by aqueous polymer dispersion were investigated by comparing with propranolol hydrochloride osmotic pump tablets coated by an organic solvent. Results showed that the similarity factor (f 2 ) between cellulose acetate-coated tablet and Eudragit-coated tablet was 78.1, and f 2 between cellulose acetate-coated tablet and Kollicoat-coated tablet was 77.6. The linear IVIVC of Eudragit-coated and Kollicoat-coated osmotic pump tablets was determined, which confirmed excellent correlation between the absorption in vivo and the drug release in vitro. Consequently, the membrane coated by aqueous polymer dispersion or organic solvent has similar in vitro release rates of controlled release. Also, compared with organic solvent coating, aqueous polymer dispersion has numerous advantages, such as reduced toxicity and no environmental damage. Therefore, the aqueous polymer dispersion technology has enormous potential as a replacement of organic solvent coating.

The objective of this study was to design a time-controlled pulsatile release (TCPR) system containing propranolol (PNH) as an active pharmaceutical ingredient. Here, the developed dosage forms were coated with hydroxypropyl-methylcellulose (HPMC) and other excipients as barrier layer using dry-coated technology. The influence of HPMC, microcrystalline cellulose (MCC), and lactose in the outer coating and the coating weight on drug release were investigated. Then, a three-factor, five-level central composite design (CCD) and response surface method were used to optimize the formula of the coating. After data processing, the optimal prescription was found to be as follows: HPMC E50(X 1 ) 86.2 mg, MCC(X 2 ) 43.8 mg, and lactose (X 3 ) 21.3 mg in the coating. Moreover, the in vitro tests showed that the optimized formulation of TCPR had a lag time of 4 h followed by a 4-h drug release. Also, determination of the extent of erosion of the TCPR tablets revealed that the lag time is related to the coating erosion speed. The in vivo test in beagle dogs and comparison of the parameters for the TCPR tablets and reference preparations showed significant differences for T max (7.83 ± 0.408 and 2 ± 0.00) and C max (185.45 ± 28.561 and 587 ± 45.27 ng/ml) but no significant differences in the AUC 0-∞ (1757.876 ± 208.832 and 1779.69 ± 229.02 ng h/ml). These results demonstrated that the TCPR tablets successfully prolonged the lag time and controlled the release of propranolol.

Double-layered matrix tablets prepared from shellac wax-lutrol were fabricated using a molding technique, and the release of hydrochlorothiazide and propranolol HCl from the inner tablet or outer layer was studied. The simultaneous determination of dual drug release was measured with first derivative UV spectrophotometry. The tablet containing shellac wax as the outer tablet and lutrol as the inner tablet showed more appropriate drug release and the size of the inner layer influenced the rate of drug release. In addition, the aqueous solubility of the drug and the components of the inner tablet or outer layer affected the drug release behavior. Most of the double-layered tablets exhibited the drug-release pattern which fitted well with zero-order kinetic due to the restriction of the release surface. Biphasic drug release pattern was found in the tablet of which the outer layer rapidly eroded. The drug dissolution data from drug-loaded-outer layer could predict the dissolution time for the outer layer of drug-loaded inner part of double-layered matrix tablet. Incorporation of lutrol increased the drug release from shellac wax matrix, and the zero-order release was attained by fabricating it into a double-layered tablet.

Self-emulsifying pellets were prepared using microcrystalline cellulose, emulsions of caprylic/capric triglyceride, and three Cremophors (ELP, RH40, and RH60) at 1.5 and 2.3 weight ratios, and two drugs (furosemide and propranolol) of different lipophilicity. Droplet size, zeta potential (ζ) and viscosity of emulsions, and pellet size, shape, friability, tensile strength, disintegration, and drug migration in pellets were determined. Evaluation of reconstituted emulsions was based on droplet size and ζ. Factorial design and 3-way ANOVA was applied to estimate the significance of the effects of the drug, surfactant and oil/surfactant ratio. It was found that droplet size, viscosity and ζ of emulsions, and size, shape, and friability of pellets were affected by the studied factors and were significant interactions between their effects on pellet size and friability. Migration of drug towards the pellet surface was higher for the less lipophilic furosemide and higher oil content. Linear relationships were found between the emulsion viscosity and the shape parameters of the pellets (for the aspect ratio R (2) = 0.796 for furosemide and R (2) = 0.885 for propranolol and for the shape factor, e R R (2) = 0.740 and R (2) = 0.960, respectively). For all the formulations examined, an exponential relationship was found between migration (M%) and the product of viscosity (η) and solubility of drug in oil/surfactant mixture (S) (M% = 98.1e-0.016 [η•S], R (2) = 0.856), which may be useful in formulation work.

Propranolol (PPL) imprinted microspheres (MIP) were successfully prepared via oil/water polymerization using a methyl methacrylate (MMA) monomer, PLL template, and divinylbenzene (DVB) cross-linker and favorably incorporated in a Eudragit-RS100 nanofiber membrane. A non-PPL imprinted polymer (NIP), without a template, was used as a control. The morphology and particle size of the beads were investigated using scanning electron microscopy. The results revealed that both MIP and NIP had a spherical shape with a micron size of approximately 50-100 μm depending on the amounts of DVB and PPL used. NIP2 (MMA/DVB, 75:2.5) and MIP8 (PPL/MMA/DVB, 0.8:75:2.5) were selected for reloading of PPL, and the result indicated that increasing the ratio of PPL to polymer beads resulted in increase PPL reloading (>80%). A total of 10-50% NIP2 or MIP8 was incorporated into a 40% (w/v) Eudragit-RS100 fiber membrane using an electrospinning technique. PPL could be bound to the 50% MIP8 composite fiber membrane with a higher extent and at a higher rate than the control (NIP2). Furthermore, the MIP8 composite fiber membrane showed higher selectivity to PPL than the other β-blockers (atenolol, metoprolol, and timolol). Thus, the MIP8 composite fiber membrane can be further developed for various applications in pharmaceutical and other affinity separation fields.

The main objective of the present study is the physicochemical characterization of naturally available Terminalia catappa gum (Badam gum [BG]) as a novel pharmaceutical excipient and its suitability in the development of gastroretentive floating drug delivery systems (GRFDDS) to retard the drug for 12 h when the dosage form is exposed to gastrointestinal fluids in the gastric environment. As BG was being explored for the first time for its pharmaceutical application, physicochemical, microbiological, rheological, and stability studies were carried out on this gum. In the present investigation, the physicochemical properties, such as micromeritic, rheological, melting point, moisture content, pH, swelling index, water absorption, and volatile acidity, were evaluated. The gum was characterized by scanning electron microscopy, differential scanning calorimetry (DSC), powder X-ray diffraction studies (PXRD), and Fourier transform infrared spectroscopy (FTIR). Gastroretentive floating tablets of BG were prepared with the model drug propranolol HCl by direct compression methods. The prepared tablets were evaluated for all their physicochemical properties, in vitro buoyancy, in vitro drug release, and rate order kinetics. PBG 04 was selected as an optimized formulation based on its 12-h drug release and good buoyancy characteristics. The optimized formulation was characterized with FTIR, DSC, and PXRD studies, and no interaction between the drug and BG was found. Thus, the study confirmed that BG might be used in the gastroretentive drug delivery system as a release-retarding polymer.

The objective of this study was to investigate the release behaviour of propranolol hydrochloride from psyllium matrices in the presence hydrophilic polymers. The dissolution test was carried out at pH 1.2 and pH 6.8. Binary mixtures of psyllium and hydroxypropyl methylcellulose (HPMC) used showed that an increase in the percentage of HPMC in the binary mixtures caused a significant decrease in the release rate of propranolol. Psyllium-alginate matrices produced lower drug release as compared to when the alginate was the matrix former alone. When sodium carboxy methyl cellulose (NaCMC) was incorporated into the psyllium, the results showed that matrices containing the ratio of psyllium-NaCMC in the 1:1 ratio are able to slow down the drug release significantly as compared to matrices made from only psyllium or NaCMC as retardant agent suggesting that there could be a synergistic effect between psyllium and NaCMC. The double-layered tablets showed that the psyllium and HPMC in the outer shell of an inner formulation of psyllium alone had the greatest effect of protecting the inner core and thus producing the lowest drug release (DE = 38%, MDT = 93 min). A significant decrease in the value of n in Q = kt(n) from 0.70 to 0.51 as the psyllium content was increased from 50 to 150 mg suggests that the presence of psyllium in HPMC matrices affected the release mechanism. Psyllium powder had the ability in the combination with other hydrophilic polymers to produce controlled release profiles. Care and consideration should as such be taken when formulating hydrophilic matrices in different combinations.

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.

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., (© 2010 American Association of Pharmaceutical Scientists)

The purpose of this study was to prepare and evaluate layered matrix tablets of propranolol HCl containing HPMC and phytowax as matrix component using direct compression technique. Layering with this polymeric matrix could prolong the release of drug and shift the release pattern approach to zero order as described from the least square curve fitting. Increasing the amount of coating layer could apparently prolong the drug release. The longer lag time of drug release from one planar apparently when the amount of coating layer was increased. HPMC concentration and compression force did not affect the drug release from this three-layer tablet. The drug release from this three-layer tablet was influenced by hydrodynamic force. An increase in stirring rate was a corresponding increasing in the release rate. From photoimage and SEM, gel mass of HPMC was increased with time during dissolution and covered the core surface, therefore dissolved drug molecules were allowed to diffuse out from the core through the polymer network of gel layer containing the porous structure. This suggested that HPMC and phytowax could be fabricated into the layered matrix tablet exhibiting sustained drug release.

The release of propranolol hydrochloride from matrix tablets with hydroxy propyl methyl cellulose (HPMC K15M) or KollidonSR at different concentrations was investigated with a view to developing twice daily sustained release dosage form. A hydrophilic matrix-based tablet using different concentrations of HPMC K15M or KollidonSR was developed using direct compression technique to contain 80 mg of propranolol hydrochloride. The resulting matrix tablets prepared with HPMC K15M or KollidonSR fulfilled all the official requirements of tablet dosage forms. Formulations were evaluated for the release of propranolol hydrochloride over a period of 12 h in pH 6.8 phosphate buffer using USP type II dissolution apparatus. Propranolol hydrochloride and pure KollidonSR or HPMC K15M compatibility interactions was investigated by using Fourier-transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC). FTIR spectroscopic and DSC studies revealed that there was no well defined chemical interaction between propranolol hydrochloride with KollidonSR or HPMC K15M. Tablets were exposed to 40 degrees C/75% of RH in open disc for stability. The in vitro drug release study revealed that HPMC K15 at a concentration of 40% of the dosage form weight was able to control the release of propranolol hydrochloride for 12 h, exhibit non-Fickian diffusion with first-order release kinetics where as at 40% KollidonSR same dosage forms show zero-order release kinetics. In conclusion, the in vitro release profile and the mathematical models indicate that release of propranolol hydrochloride can be effectively controlled from a single tablet using HPMC K15M or KollidonSR matrix system.

The purpose of this research was to study mucoadhesive bilayer buccal tablets of propranolol hydrochloride using the bioadhesive polymers sodium alginate (Na-alginate) and Carbopol 934P (CP) along with ethyl cellulose as an impermeable backing layer. The tablets were evaluated for weight variation, thickness, hardness, friability, surface pH, mucoadhesive strength, swelling index, in vitro drug release, ex vivo drug permeation, ex vivo mucoadhesion, and in vivo pharmacodynamics in rabbits. Tablets containing Na-alginate and CP in the ratio of 5:1 (F2) had the maximum percentage of in vitro drug release without disintegration in 12 hours. The swelling index was proportional to Na-alginate content and inversely proportional to CP content. The surface pH of all tablets was found to be satisfactory (7.0 +/- 1.5), close to neutral pH; hence, buccal cavity irritation should not occur with these tablets. The mechanism of drug release was found to be non-Fickian diffusion and followed zero-order kinetics. The formulation F4 was optimized based on good bioadhesive strength (28.9 +/- 0.99 g) and sustained in vitro drug permeation (68.65% +/- 3.69% for 12 hours). The behavior of formulation F4 was examined in human saliva, and both the drug and the buccal tablet were found to be stable. The formulation F4 was applied to rabbit oral mucosa for in vivo studies. The formulation inhibited isoprenaline-induced tachycardia. The studies conducted in rabbits confirmed the sustained release as compared with intravenous administration.

The purpose of this study was to develop formulations and systematically evaluate in vitro performances of buccoadhesive patches of propranolol hydrochloride using the hydrophobic polymer Eudragit L-100 as the base matrix. The hydrophilic polymers Carbopol 934 and polyvinyl pyrrolidone (PVP) K30 were incorporated into the Eudragit patches, to provide the patches with bioadhesive properties and to modify the rate of drug release. The patches, which were prepared by the solvent casting method, were smooth and elegant in appearance; were uniform in thickness, weight, and drug content; showed no visible cracks; and showed good folding endurance. A 3(2) full factorial design was employed to study the effect of independent variables like hydrophilic polymers Carbopol 934 and PVP K30, which significantly influenced characteristics like swelling index, ex vivo mucoadhesive strength, in vitro drug release, and ex vivo residence time. A stability study of optimized Eudragit patches was done in natural human saliva; it was found that both drug and buccal patches were stable in human saliva. It can be concluded that the present buccal formulation can be an ideal system to improve the bioavailability of the drug by avoiding hepatic first-pass metabolism.

The purpose of this research work was to establish mucoadhesive buccal devices of propranolol hydrochloride (PRH) in the forms of bilayered and multilayered tablets. The tablets were prepared using sodium carboxymethylcellulose (SCMC) and Carbopol-934 (CP) as bioadhesive polymers to impart mucoadhesion and ethyl cellulose (EC) to act as an impermeable backing layer. Buccal devices were evaluated by different parameters such as weight uniformity, content uniformity, thickness, hardness, surface pH, swelling index, ex vivo mucoadhesive strength, ex vivo mucoadhesion time, in vitro drug release, and in vitro drug permeation. As compared with bilayered tablets, multilayered tablets showed slow release rate of drug with improved ex vivo bioadhesive strength and enhanced ex vivo mucoadhesion time. The mechanism of drug release was found to be non-Fickian diffusion (value of n between 0.5 and 1.0) for both the buccal devices. The stability of drug in both the optimized buccal devices was tested for 6 hours in natural human saliva; both the buccal devices were found to be stable in natural human saliva. The present study concludes that mucoadhesive buccal devices of PRH can be a good way to bypass the extensive hepatic first-pass metabolism and to improve the bioavailability of PRH.

The purpose of this research was to evaluate in vitro transnasal sustained-release ability of sorbitan monostearate (SMS) organogels in isopropyl myristate (IM). Organogels were prepared containing SMS (2.5%-20%) and water (5%-25%) in IM and analyzed microscopically for phase behavior. The effect of Tween surfactants on gel strength and in vitro nasal diffusion of propranolol is reported. The in vitro nasal release retardant effect of SMS and Tween 20 was investigated using factorial design. The microscopic changes in structure of organogel during in vitro nasal diffusion were studied. The water-holding capacity of SMS organogels in IM increased with SMS concentration. The release retardant effect with incorporation of cosurfactant was of the order of Tween 80 > Tween 60 > Tween 20. Gel strengthening and increased viscosity were evident with increased concentration of SMS and Tween 20. The 3-dimensional network of SMS molecules controls the diffusional drug release. The organogel system on nasal mucosa during diffusion is dynamic in nature and changes continuously with the time of diffusion. The water penetration in the organogel network results in percolation and emulsification of organogel, thus affecting the release. Organogels provided an effective barrier for diffusion of propranolol. The surface epithelium lining and the granular cellular structure of treated nasal mucosa were intact.