Development of Tablet Formulation of Amorphous Solid Dispersions Prepared by Hot Melt Extrusion Using Quality by Design Approach

The objective of the study was to identify the extragranular component requirements (level and type of excipients) to develop an immediate release tablet of solid dispersions prepared by hot melt extrusion (HME) process using commonly used HME polymers. Solid dispersions of compound X were prepared using polyvinyl pyrrolidone co-vinyl acetate 64 (PVP VA64), Soluplus, and hypromellose acetate succinate (HPMCAS-LF) polymers in 1:2 ratio by HME through 18 mm extruder. A mixture design was employed to study effect of type of polymer, filler (microcrystalline cellulose (MCC), lactose, and dicalcium phosphate anhydrous (DCPA)), and disintegrant (Crospovidone, croscarmellose sodium, and sodium starch glycolate (SSG)) as well as level of extrudates, filler, and disintegrant on tablet properties such as disintegration time (DT), tensile strength (TS), compactibility, and dissolution. Higher extrudate level resulted in longer DT and lower TS so 60–70% was the maximum amount of acceptable extrudate level in tablets. Fast disintegration was achieved with HPMCAS-containing tablets, whereas Soluplus- and PVP VA64-containing tablets had higher TS. Crospovidone and croscarmellose sodium were more suitable disintegrant than SSG to achieve short DT, and MCC was a suitable filler to prepare tablets with acceptable TS for each studied HME polymer. The influence of extragranular components on dissolution from tablets should be carefully evaluated while finalizing tablet composition, as it varies for each HME polymer. The developed statistical models identified suitable level of fillers and disintegrants for each studied HME polymer to achieve tablets with rapid DT (<15 min) and acceptable TS (≥1 MPa at 10–15% tablet porosity), and their predictivity was confirmed by conducting internal and external validation studies.     

Investigation of Thermal and Viscoelastic Properties of Polymers Relevant to Hot Melt Extrusion,IV: Affinisol™ HPMC HME Polymers

Most cellulosic polymers cannot be used as carriers for preparing solid dispersion of drugs by hot melt extrusion (HME) due to their high melt viscosity and thermal degradation at high processing temperatures. Three HME-grade hydroxypropyl methylcelluloses, namely Affinisol™ HPMC HME 15 cP, Affinisol™ HPMC HME 100 cP, and Affinisol™ HPMC HME 4 M, have recently been introduced by The Dow Chemical Co. to enable the preparation of solid dispersion at lower and more acceptable processing temperatures. In the present investigation, physicochemical properties of the new polymers relevant to HME were determined and compared with that of Kollidon^® VA 64. Powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), thermogravimetric analysis (TGA), moisture sorption, rheology, and torque analysis by melt extrusion were applied. PXRD and mDSC showed that the Affinisol™ polymers were amorphous in nature. According to TGA, the onset of degradation for all polymers was >220°C. The Affinisol™ polymers exhibited less hygroscopicity than Kollidon^® VA 64 and another HPMC polymer, Methocel™ K100LV. The complex viscosity profiles of the Affinisol™ polymers as a function of temperature were similar. The viscosity of the Affinisol™ polymers was highly sensitive to the shear rate applied, and unlike Kollidon^® VA 64, the viscosity decreased drastically when the angular frequency was increased. Because of the very high shear rate encountered during melt extrusion, Affinisol™ polymers showed capability of being extruded at larger windows of processing temperatures as compared to that of Kollidon^® VA 64.KEY WORDS: Affinisol™ HPMC HME, hot melt extrusion, hydroxypropyl methylcellulose, solid dispersion, thermal analysis, viscosity     

Thermal Processing of PVP- and HPMC-Based Amorphous Solid Dispersions

Thermal processing technologies continue to gain interest in pharmaceutical manufacturing. However, the types and grades of polymers that can be utilized in common thermal processing technologies, such as hot-melt extrusion (HME), are often limited by thermal or rheological factors. The objectives of the present study were to compare and contrast two thermal processing methods, HME and KinetiSol® Dispersing (KSD), and investigate the influence of polymer type, polymer molecular weight, and drug loading on the ability to produce amorphous solid dispersions (ASDs) containing the model compound griseofulvin (GRIS). Dispersions were analyzed by a variety of imaging, solid-state, thermal, and solution-state techniques. Dispersions were prepared by both HME and KSD using polyvinylpyrrolidone (PVP) K17 or hydroxypropyl methylcellulose (HPMC) E5. Dispersions were only prepared by KSD using higher molecular weight grades of HPMC and PVP, as these could not be extruded under the conditions selected. Powder X-ray diffraction (PXRD) analysis showed that dispersions prepared by HME were amorphous at 10% and 20% drug load; however, it showed significant crystallinity at 40% drug load. PXRD analysis of KSD samples showed all formulations and drug loads to be amorphous with the exception of trace crystallinity seen in PVP K17 and PVP K30 samples at 40% drug load. These results were further supported by other analytical techniques. KSD produced amorphous dispersions at higher drug loads than could be prepared by HME, as well as with higher molecular weight polymers that were not processable by HME, due to its higher rate of shear and torque output.     

A New Extrudable Form of Hypromellose: AFFINISOL™ HPMC HME

Hypromellose is a hydrophilic polymer widely used in immediate- and modified-release oral pharmaceutical dosage forms. However, currently available grades of hypromellose are difficult, if not impossible, to process by hot melt extrusion (HME) because of their high glass transition temperature, high melt viscosity, and low degradation temperature. To overcome these challenges, a modified grade of hypromellose, AFFINISOL? HPMC HME, was recently introduced. It has a significantly lower glass transition temperature and melt viscosity as compared to other available grades of hypromellose. The objective of this paper is to assess the extrudability and performance of AFFINISOL? HPMC HME (100LV and 4M) as compared to other widely used polymers in HME, including HPMC 2910 100cP (the currently available hypromellose), Soluplus®, Kollidon® VA 64, and EUDRAGIT® E PO. Formulations containing polymer and carbamazepine (CBZ) were extruded on a co-rotating 16-mm twin-screw extruder, and the effect of temperature, screw speed, and feed rate was investigated. The performance of the solid dispersions was evaluated based on Flory–Huggins modeling and characterized by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD), Raman spectroscopy, Fourier-transform infrared (FTIR) spectroscopy, and dissolution. All formulations extruded well except for HPMC 2910 100cP, which resulted in over-torqueing the extruder (machine overloading because the motor cannot provide efficient energy to rotate the shaft). Among the HME extrudates, only the EUDRAGIT® E PO formulation was crystalline as confirmed by DSC, XRD, and Raman, which agreed with predictions from Flory–Huggins modeling. Dissolution testing was conducted under both sink and non-sink conditions. Sink dissolution testing in neutral media revealed that amorphous CBZ in the HME extrudates completely dissolved within 15 min, which was much more rapid than the time for complete dissolution of bulk CBZ (60 min) and EUDRAGIT® E PO solid dispersion (more than 6 h). Non-sink dissolution in acidic media testing revealed that only CBZ contained in the AFFINISOL? HPMC HME, and EUDRAGIT® E PO solid dispersions rapidly supersaturated after 15 min, reaching a twofold drug concentration compared to the CBZ equilibrium solubility. In summary, AFFINISOL? HPMC HME 100LV and AFFINISOL? HPMC HME 4M are useful in the pharmaceutical HME process to increase wetting and dissolution properties of poorly water-soluble drugs like CBZ.     

Fusion Method for Solubility and Dissolution Rate Enhancement of Ibuprofen Using Block Copolymer Poloxamer 407

Aim of current research was to prepare ibuprofen-poloxamer 407 binary mixtures using fusion method and characterize them for their physicochemical and performance properties. Binary mixtures of ibuprofen and poloxamer were prepared in three different ratios (1:0.25, 1:0.5, and 1:0.75, respectively) using a water-jacketed high shear mixer. In vitro dissolution and saturation solubility studies were carried out for the drug, physical mixtures, and formulations for all ratios in de-ionized water, 0.1 N HCl (pH?=?1.2), and phosphate buffer (pH?=?7.2). Thermal and physical characterization of samples was done using modulated differential scanning calorimetry (mDSC), X-ray powder diffraction (XRD), and infrared spectroscopy (FTIR). Flow properties were evaluated using a powder rheometer. Maximum solubility enhancement was seen in acidic media for fused formulations where the ratio 1:0.75 had 18-fold increase. In vitro dissolution studies showed dissolution rate enhancement for physical mixtures and the formulations in all three media. The most pronounced effect was seen for formulation (1:0.75) in acidic media where the cumulative drug release was 58.27% while for drug, it was 3.67%. Model independent statistical methods and ANOVA based methods were used to check the significance of difference in the dissolution profiles. Thermograms from mDSC showed a characteristic peak for all formulations with T_peak of around 45°C which suggested formation of a eutectic mixture. XRD data displayed that crystalline nature of ibuprofen was intact in the formulations. This work shows the effect of eutectic formation and micellar solubilization between ibuprofen and poloxamer at the given ratios on its solubility and dissolution rate enhancement.     

Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation

Hot-melt extrusion (HME) is a promising technology for the production of new chemical entities in the developmental pipeline and for improving products already on the market. In drug discovery and development, industry estimates that more than 50% of active pharmaceutical ingredients currently used belong to the biopharmaceutical classification system II (BCS class II), which are characterized as poorly water-soluble compounds and result in formulations with low bioavailability. Therefore, there is a critical need for the pharmaceutical industry to develop formulations that will enhance the solubility and ultimately the bioavailability of these compounds. HME technology also offers an opportunity to earn intellectual property, which is evident from an increasing number of patents and publications that have included it as a novel pharmaceutical formulation technology over the past decades. This review had a threefold objective. First, it sought to provide an overview of HME principles and present detailed engineered extrusion equipment designs. Second, it included a number of published reports on the application of HME techniques that covered the fields of solid dispersions, microencapsulation, taste masking, targeted drug delivery systems, sustained release, films, nanotechnology, floating drug delivery systems, implants, and continuous manufacturing using the wet granulation process. Lastly, this review discussed the importance of using the quality by design approach in drug development, evaluated the process analytical technology used in pharmaceutical HME monitoring and control, discussed techniques used in HME, and emphasized the potential for monitoring and controlling hot-melt technology.     

Application of Carrier and Plasticizer to Improve the Dissolution and Bioavailability of Poorly Water-Soluble Baicalein by Hot Melt Extrusion

The objective of this study was to develop a suitable formulation for baicalein (a poorly water-soluble drug exhibiting high melting point) to prepare solid dispersions using hot melt extrusion (HME). Proper carriers and plasticizers were selected by calculating the Hansen solubility parameters, evaluating melting processing condition, and measuring the solubility of obtained melts. The characteristic of solid dispersions prepared by HME was evaluated. The dissolution performance of the extrudates was compared to the pure drug and the physical mixtures. Physicochemical properties of the extrudates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Relative bioavailability after oral administration in beagle dogs was assessed. As a result, Kollidon VA64 and Eudragit EPO were selected as two carriers; Cremophor RH was used as the plasticizer. The dissolution of all the extrudates was significantly improved. DSC and PXRD results suggested that baicalein in the extrudates was amorphous. FTIR spectroscopy revealed the interaction between drug and polymers. After oral administration, the relative bioavailability of solid dispersions with VA64 and EPO was comparative, about 2.4- and 2.9-fold greater compared to the pure drug, respectively.

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Open in a separate windowᅟKEY WORDS: baicalein, carrier, high melting point, hot melt extrusion, plasticizer, solid dispersion     

Physicochemical and Pharmacokinetic Characterization of Amorphous Solid Dispersion of Meloxicam with Enhanced Dissolution Property and Storage Stability

The aim of the present study was to develop amorphous solid dispersion (ASD) of meloxicam (MEL) for providing rapid onset of action. ASDs of MEL with polyvinylpyrrolidone (PVP) K-30 (MEL/PVP), HPC-SSL (MEL/HPC), and Eudragit EPO (MEL/EPO) were prepared. The physicochemical properties were characterized by focusing on morphology, crystallinity, dissolution properties, stability, and the interaction of MEL with coexisting polymers. MEL/EPO was physicochemically stable after storage at 40°C/75% RH for 30 days. In contrast, recrystallization of MEL was observed in MEL/PVP and MEL/HPC at 40°C/50% RH for 30 days. Infrared spectroscopic studies and ¹H NMR analyses of MEL/EPO revealed that Eudragit EPO interacted with MEL and reduced intermolecular binding between MEL molecules. Intermolecular interaction of drug molecules is necessary for the formation of crystalline. Thus, the interaction of MEL with Eudragit EPO and interruption of the formation of supramolecular interaction between MEL molecules might lead to the inhibition of crystal growth of MEL. Of all the MEL solid dispersions prepared, MEL/EPO showed the largest improvement in dissolution behavior. Oral administration of MEL/EPO to rats showed rapid and enhanced MEL exposure with a 2.4-fold increase in bioavailability compared with crystalline MEL. Based on these findings, MEL/EPO was physicochemically stable and provided a rapid onset of action and enhanced bioavailability after oral administration.     

Conjugation of Hot-Melt Extrusion with High-Pressure Homogenization: a Novel Method of Continuously Preparing Nanocrystal Solid Dispersions

Over the past few decades, nanocrystal formulations have evolved as promising drug delivery systems owing to their ability to enhance the bioavailability and maintain the stability of poorly water-soluble drugs. However, conventional methods of preparing nanocrystal formulations, such as spray drying and freeze drying, have some drawbacks including high cost, time and energy inefficiency, traces of residual solvent, and difficulties in continuous operation. Therefore, new techniques for the production of nanocrystal formulations are necessary. The main objective of this study was to introduce a new technique for the production of nanocrystal solid dispersions (NCSDs) by combining high-pressure homogenization (HPH) and hot-melt extrusion (HME). Efavirenz (EFZ), a Biopharmaceutics Classification System class II drug, which is used for the treatment of human immunodeficiency virus (HIV) type I, was selected as the model drug for this study. A nanosuspension (NS) was first prepared by HPH using sodium lauryl sulfate (SLS) and Kollidon® 30 as a stabilizer system. The NS was then mixed with Soluplus® in the extruder barrel, and the water was removed by evaporation. The decreased particle size and crystalline state of EFZ were confirmed by scanning electron microscopy, zeta particle size analysis, and differential scanning calorimetry. The increased dissolution rate was also determined. EFZ NCSD was found to be highly stable after storage for 6 months. In summary, the conjugation of HPH with HME technology was demonstrated to be a promising novel method for the production of NCSDs.     

Stability-enhanced Hot-melt Extruded Amorphous Solid Dispersions via Combinations of Soluplus? and HPMCAS-HF

The aim of this study was to evaluate a novel combination of Soluplus® and hypromellose acetate succinate (HPMCAS-HF) polymers for solubility enhancement as well as enhanced physicochemical stability of the produced amorphous solid dispersions. This was accomplished by converting the poorly water-soluble crystalline form of carbamazepine into a more soluble amorphous form within the polymeric blends. Carbamazepine (CBZ), a Biopharmaceutics Classification System class II active pharmaceutical ingredient (API) with multiple polymorphs, was utilized as a model drug. Hot-melt extrusion (HME) processing was used to prepare solid dispersions utilizing blends of polymers. Drug loading showed a significant effect on the dissolution rate of CBZ in all of the tested ratios of Soluplus® and HPMCAS-HF. CBZ was completely miscible in the polymeric blends of Soluplus® and HPMCAS-HF up to 40% drug loading. The extrudates were characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy and dissolution studies. DSC and XRD data confirmed the formation of amorphous solid dispersions of CBZ in the polymeric blends of Soluplus® and HPMCAS-HF. Drug loading and release of CBZ was increased with Soluplus® (when used as the primary matrix polymer) when formulations contained Soluplus® with 7–21% (w/w) HPMCAS-HF. In addition, this blend of polymers was found to be physically and chemically stable at 40°C, 75% RH over 12 months without any dissolution rate changes.KEY WORDS: carbamazepine, hot-melt extrusion, HPMCAS-HF, Soluplus®, stability     

Controlled Release of 5-Fluorouracil from Alginate Beads Encapsulated in 3D Printed pH-Responsive Solid Dosage Forms

Three-dimensional printing is being steadily deployed as manufacturing technology for the development of personalized pharmaceutical dosage forms. In the present study, we developed a hollow pH-responsive 3D printed tablet encapsulating drug loaded non-coated and chitosan-coated alginate beads for the targeted colonic delivery of 5-fluorouracil (5-FU). A mixture of Eudragit® L100-55 and Eudragit® S100 was fabricated by means of hot-melt extrusion (HME) and the produced filaments were printed utilizing a fused deposition modeling (FDM) 3D printer to form the pH-responsive layer of the tablet with the rest comprising of a water-insoluble poly-lactic acid (PLA) layer. The filaments and alginate particles were characterized for their physicochemical properties (thermogravimetric analysis, differential scanning calorimetry, X-ray diffraction), their surface topography was visualized by scanning electron microscopy and the filaments’ mechanical properties were assessed by instrumented indentation testing and tensile testing. The optimized filament formulation was 3D printed and the structural integrity of the hollow tablet in increasing pH media (pH 1.2 to pH 7.4) was assessed by means of time-lapsed microfocus computed tomography (μCT). In vitro release studies demonstrated controlled release of 5-FU from the alginate beads encapsulated within the hollow pH-sensitive tablet matrix at pH values corresponding to the colonic environment (pH 7.4). The present study highlights the potential of additive manufacturing in fabricating controlled-release dosage forms rendering them pertinent formulations for further in vivo evaluation.     

A Design and Evaluation of Layered Matrix Tablet Formulations of Metoprolol Tartrate

The aim of this paper was to evaluate the performance of different swellable polymers in the form of layered matrix tablets to provide controlled therapeutic effect of metoprolol tartrate for twice daily administration. Seven different swellable polymers (carrageenan, hydroxypropylmethyl cellulose, pectin, guar gum, xanthan gum, chitosan, and ethyl cellulose) were evaluated alone or in combination as release-retardant layer. Tablets were tested for weight variation, hardness, diameter/thickness ratio, friability, and drug content uniformity and subjected to in vitro drug-release studies. In addition, the target-release profile of metoprolol tartrate was plotted using its clinical pharmacokinetic data, and the release profiles of the tablets were evaluated in relation to the plotted target release profile. Carrageenan was determined as the best polymer in two-layered matrix tablet formulations due to its better accordance to the target release profile and was selected for preparing three-layered matrix tablets. Carrageenan formulations exhibited super case II release mechanism. Accelerated stability testing was performed on two- and three-layered matrix tablet formulations of carrageenan. The tablets were stored at 25°C/60% relative humidity and 40°C/75% relative humidity for 6 months and examined for physical appearance, drug content, and release characteristics. At the end of the storage time, formulations showed no change either in physical appearance, drug content, or drug-release profile. These results demonstrated the suitability of three-layered tablet formulation of carrageenan to provide controlled release and improved linearity for metoprolol tartrate in comparison to two-layered tablet formulation.     

Stabilization of hot-melt extrusion formulations containing solid solutions using polymer blends

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. Published: June 29, 2007     

Formulation and Evaluation of Bioadhesive Buccal Drug Delivery of Tizanidine Hydrochloride Tablets

The study aim was concerned with formulation and evaluation of bioadhesive buccal drug delivery of tizanidine hydrochloride tablets, which is extensively metabolized by liver. The tablets were prepared by direct compression using bioadhesive polymers such as hydroxylpropyl methylcellulose K4M, sodium carboxymethyl cellulose alone, and a combination of these two polymers. In order to improve the permeation of drug, different permeation enhancers like beta-cyclodextrin (β-CD), hydroxylpropyl beta-cyclodextrin (HP-β-CD), and sodium deoxycholate (SDC) were added to the formulations. The β-CD and HP-β-CD were taken in 1:1 molar ratio to drug in formulations. Bioadhesion strength, ex vivo residence time, swelling, and in vitro dissolution studies and ex vivo permeation studies were performed. In vitro release of optimized bioadhesive buccal tablet was found to be non-Fickian. SDC was taken in 1%, 2%, and 3% w/w of the total tablet weight. Stability studies in natural saliva indicated that optimized formulation has good stability in human saliva. In vivo mucoadhesive behavior of optimized formulation was performed in five healthy male human volunteers and subjective parameters were evaluated.     

Design and Optimization of Sustained-Release Divalproex Sodium Tablets with Response Surface Methodology

Response surface methodology is defined as a collection of mathematical and statistical methods that are used to develop, improve, or optimize a product or process. In the present study, a statistical design (Mixture Design) was employed for formulation and optimization of a sustained-release hydrophilic divalproex sodium matrix tablet. Different excipients were used to improve the drug’s poor flowability. The hardness of the prepared tablets and also their release pattern were tested. The formulation design was carried out employing mixture design using four excipients in three levels. The Carr’s index of formulations and tensile strength were determined and analyzed using Minitab software. The suitable formulations regarding flowability and tablet tensile strength were selected by this software for subsequent drug release studies. The dissolution tests were carried out in acidic and basic phases which were previously proved to be biomimetic. Samples were analyzed using HPLC, and release data were compared to Depakine® (sustained-release divalproex from Sanofi). Release kinetics was also determined for selected formulations. Selected formulations were subjected to dissolution test and showed similar dissolution profiles with Depakine® based on difference and similarity factor calculations. The software selected an optimized formulation which had a slightly different release pattern in vitro compared to innovator but of nearly zero-order kinetics. It can be concluded that application of Mixture Design is a shortcut method to design suitable formulations of sustained-release divalproex sodium containing hydrophilic matrix tablets by direct compression method.     

Influence of Formulation Factors on Tablet Formulations with Liquid Permeation Enhancer Using Factorial Design

For a drug with low bioavailability, a matrix tablet with liquid permeation enhancer (Labrasol®) was formulated. Factorial design was used to evaluate the effect of three formulation factors: drug percentage, polymer type (Methocel® K100M or Eudragit® L 100-55), and tablet binder percentage (Plasdone® S-630) on tablet characteristics. Tablets were prepared by direct compression and characterized. Compressibility index values ranged between 15.90% and 29.87% and tablet hardness values from 7.8 to 29.78 Kp. Eudragit®-containing formulations had better compressibility index values with higher tablet hardness. Time for 75% of drug release (T ₇₅) was calculated, and formulations containing Eudragit® L 100-55 had faster release rates than tablet formulations with Methocel® K100M. Formulations with Methocel® K100M fit well in the Higuchi model as indicated by their R ² values (>0.98). Among all the formulation factors studied, polymer type displayed the highest and statistically significant effect on compressibility index, tablet hardness, and dissolution rate. Statistical design helped in better understanding the effect of formulation factors on tablet characteristics important for designing formulations with desired characteristics.     

Effect of hydrophilic polymers on buccoadhesive eudragit patches of propranolol hydrochloride using factorial design

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 3² 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. Published: June 22, 2007     

Development and Evaluation of Buccal Bioadhesive Tablet of an Anti-emetic Agent Ondansetron

The aim of the present study was to develop and evaluate a buccal adhesive tablet containing ondansetron hydrochloride (OH). Special punches and dies were fabricated and used while preparing buccal adhesive tablets. The tablets were prepared using carbopol (CP 934), sodium alginate, sodium carboxymethylcellulose low viscosity (SCMC LV), and hydroxypropylmethylcellulose (HPMC 15cps) as mucoadhsive polymers to impart mucoadhesion and ethyl cellulose to act as an impermeable backing layer. The formulations were prepared by direct compression and characterized by different parameters such as weight uniformity, content uniformity, thickness, hardness, swelling index, in vitro drug release studies, mucoadhesive strength, and ex vivo permeation study. As compared with the optimized formulation composed of OH—5 mg, CP 934—30 mg, SCMC LV—165 mg, PEG 6000—40 mg, lactose—5 mg, magnesium stearate—1.5 mg, and aspartame—2 mg, which gave the maximum release (88.15%), non-bitter (OH) that form namely ondansetron base and complexed ondansetron was used in order to make the selected formulation acceptable to human. The result of the in vitro release studies and permeation studies through bovine buccal mucosa revealed that complexed ondansetron gave the maximum release and permeation. The stability of drug in the optimized adhesive tablet was tested for 6 h in natural human saliva; both the drug and device were found to be stable in natural human saliva. Thus, buccal adhesive tablet of ondansetron could be an alternative route to bypass the hepatic first-pass metabolism and to improve the bioavailability of (OH).     

Floating Elementary Osmotic Pump Tablet (FEOPT) for Controlled Delivery of Diethylcarbamazine Citrate: a Water-Soluble Drug

The present work investigates the feasibility of the design of a novel floating elementary osmotic pump tablet (FEOPT) to prolong the gastric residence of a highly water-soluble drug. Diethylcarbamazine citrate (DEC) was chosen as a model drug. The FEOPT consisted of an osmotic core (DEC, mannitol, and hydrophilic polymers) coated with a semipermeable layer (cellulose acetate) and a gas-generating gelling layer (sodium bicarbonate, hydrophilic polymers) followed by a polymeric film (Eudragit RL 30D). The effect of formulation variables such as concentration of polymers, types of diluent, and coat thickness of semipermeable membrane was evaluated in terms of physical parameters, floating lag time, duration of floatation, and in vitro drug release. The Fourier transform infrared and X-ray diffraction analysis were carried out to study the physicochemical changes in the drug excipients powder blend. The integrity of the orifice and polymeric film layer was confirmed from scanning electron microscopy image. All the developed FEOPT showed floating lag time of less than 8 min and floating duration of 24 h. A zero-order drug release could be attained for DEC. The formulations were found to be stable up to 3 months of stability testing at 40°C/75% relative humidity.     

Buccal Drug Delivery of Pravastatin Sodium

The purpose of this study was to develop and optimize formulations of mucoadhesive bilayered buccal tablets of pravastatin sodium using carrageenan gum as the base matrix. The tablets were prepared by direct compression method. Polyvinyl pyrrolidone (PVP) K 30, Pluronic® F 127, and magnesium oxide were used to improve tablet properties. Magnesium stearate, talc, and lactose were used to aid the compression of tablets. The tablets were found to have good appearance, uniform thickness, diameter, weight, pH, and drug content. A 2³ full factorial design was employed to study the effect of independent variables viz. levels of carrageenan gum, Pluronic F 127 and PVP K30, which significantly influenced characteristics like in vitro mucoadhesive strength, in vitro drug release, swelling index, and in vitro residence time. The tablet was coated with an impermeable backing layer of ethyl cellulose to ensure unidirectional drug release. Different penetration enhancers were tried to improve the permeation of pravastatin sodium through buccal mucosa. Formulation containing 1% sodium lauryl sulfate showed good permeation of pravastatin sodium through mucosa. Histopathological studies revealed no buccal mucosal damage. It can be concluded that buccal route can be one of the alternatives available for the administration of pravastatin sodium.