Dosage Form

In recent years scientific and technological advancements have been made in the research and development of rate-controlled oral drug delivery systems by overcoming physiological adversities, such as short gastric residence times (GRT) and unpredictable gastric emptying times (GET). Several approaches are currently utilized in the prolongation of the GRT, including floating drug delivery systems (FDDS), also known as hydrodynamically balanced systems (HBS), swelling and expanding systems, polymeric bioadhesive systems, modified-shape systems, high-density systems, and other delayed gastric emptying devices. In this review, the current technological developments of FDDS including patented delivery systems and marketed products, and their advantages and future potential for oral controlled drug delivery are discussed.

Hydrogels are crosslinked hydrophilic polymer structures that can imbibe large amounts of water or biological fl uids. Hydrogels are one of the upcoming classes of polymer-based systems that embrace numerous biomedical and pharmaceutical applications. Th is review discusses various parameters of hydrogels such as surface properties, water content and swelling behavior, eff ect of nature of polymer, ionic content, and thermodynamics, all of which can infl uence the biomedical usage of hydrogels. Meanwhile, intelligent or environment-sensitive hydrogels and bioadhesive hydrogels continue to be important materials for medical applications; therefore, a part of this review is devoted to some of their important classes. Hydrogels are extensively used for various biomedical applications-tissue engineering, molecular imprinting, wound dressings materials, immunoisolation, drug delivery, etc. Th us, this review aims to throw light on immense AU: "THE NUMEROUS"? applications that hydrogels have in the biomedical arena.

Lipid-based oral drug delivery Lipase activity Lymphatic uptake Bioavailability enhancement Solid dosage form Adsorption Lipid digestion products In vitro lipolytic model In vitro-in vivo correlation Solid lipid nanoparticles a b s t r a c t

In this study, matrix-type transdermal patches containing diclofenac diethylamine were prepared using different ratios of polyvinylpyrrolidone (PVP) and ethylcellulose (EC) by solvent evaporation technique. The drug matrix film of PVP and EC was casted on a polyvinylalcohol backing membrane. All the prepared formulations were subjected to physical studies (moisture content, moisture uptake, and flatness), in vitro release studies and in vitro skin permeation studies. In vitro permeation studies were performed across cadaver skin using a modified diffusion cell. Variations in drug release profiles among the formulations studied were observed. Based on a physicochemical and in vitro skin permeation study, formulation PA4 (PVP/EC, 1:2) and PA5 (PVP/EC, 1:5) were chosen for further in vivo experiments. The antiinflammatory effect and a sustaining action of diclofenac diethylamine from the two transdermal patches selected were studied by inducing paw edema in rats with 1% w/v carrageenan solution. When the patches were applied half an hour before the subplantar injection of carrageenan in the hind paw of male Wistar rats, it was observed that formulation PA4 produced 100% inhibition of paw edema in rats 12 h after carrageenan insult, whereas in the case of formulation PA5, 4% mean paw edema was obtained half an hour after the carrageenan injection and the value became 19.23% 12 h after the carrageenan insult. The efficacy of transdermal patches was also compared with the marketed Voveran 1 gel and it was found that PA4 transdermal patches produced a better result as compared with the Voveran 1 gel. Hence, it can be reasonably concluded that diclofenac diethylamine can be formulated into the transdermal matrix type patches to sustain its release characteristics and the polymeric composition (PVP/EC, 1:2) was found to be the best choice for manufacturing transdermal patches of diclofenac diethylamine among the formulations studied. ß

In this study, the aim was to apply different comparison methods to dissolution profiles of immediate release commercial film-coated tablets of naproxen sodium in order to (1) evaluate each method in terms of easy application and usefulness and (2) identify the advantages and disadvantages of each method. Dissolution testing was conducted using the USP monograph of naproxen sodium. The applied methods for the comparison of in vitro dissolution profiles are ANOVA-based methods, model-dependent methods, and model-independent methods including difference factor, f 1 , and similarity factor, f 2 . All the methods appear to be applicable and useful in comparing dissolution profiles. The results show that ANOVA-based methods and model-dependent methods are more discriminative than the f-factors. f-Factors seem to be easier to apply and interpret; only one value is obtained to describe the closeness of the two dissolution profiles. However, a last point for dissolution had to be determined, since the values of the f-factors depend on this point. The application and evaluation of model-dependent methods are more complicated; these methods present an acceptable model approach to the true relationship between percent dissolved and time variables, including statistical assumptions which could be checked. Dissolution profiles can be tested for differences in both level and shape by ANOVA-based methods and these methods provide detailed information about dissolution data which can be useful also in formulation development to match release to a reference product.

Oral sustained release gastroretentive dosage forms offer many advantages for drugs having absorption from upper gastrointestinal tract and improve the bioavailability of medications that are characterized by a narrow absorption window. A new gastroretentive sustained release delivery system was developed with floating, swellable and bioadhesive properties. All these properties were optimized and evaluated. Various release retarding polymers like psyllium husk, HPMC K100M and a swelling agent, crosspovidone in combinations were tried and optimized to get the release profile for 24 h. Formulations were evaluated for in vitro drug release profile, swelling characteristics and in vitro bioadhesion property. The in vitro drug release followed Higuchi kinetics and the drug release mechanism was found to be of anomalous or non-Fickian type. For the developed formulation, the value of n was found to be 0.5766 while for the marketed formulation the value was 0.5718 indicating the anomalous transport. The high water uptake leading to higher swelling of the tablet supported the anomalous release mechanism of ofloxacin. The similarity factor f2 was found to be 91.12 for the developed formulation indicating the release was similar to that of the marketed formulation (Zanocin OD). The swelling properties were increased with increasing crosspovidone concentration and contributed significantly in drug release from the tablet matrix. The bioadhesive property of the developed formulation was found to be significant (P < 0.005) in combination as compared to HPMC K100M and psyllium husk alone.

The aim of the present work was to investigate the swelling behavior and the in vitro release of the antihypertensive drug verapamil hydrochloride from calcium alginate and chitosan treated calcium alginate beads. Calcium-alginate beads, chitosan-coated alginate beads and alginate-chitosan mixed beads were synthesized and their morphology was investigated by scanning electron microscopy. The swelling ability of the beads in different media was found to be dependent on the presence of the polyelectrolyte complex between alginate and chitosan, the pH of the aqueous media and the initial physical state of the beads. The results revealed that the encapsulation of verapamil in both calcium-alginate and calcium alginate-chitosan mixed beads exceeded 80%. Considering the in vitro stability of verapamil encapsulating beads, 70% of the drug released from wet and dry plain calcium alginate beads within 1 and 3h, respectively. The presence of chitosan was found to retard significantly the rele...

Purpose: This study describes the development and validation of dissolution tests for fexofenadine hydrochloride capsules and coated tablets using an HPLC method. Method: The appropriate conditions were determinate after testing sink conditions, dissolution medium, and agitation intensity. The apparatus, paddle and basket, were applied to tablets and capsules, respectively. Fexofenadine hydrochloride capsules, products A and B, and coated tablets, products A, B and C were evaluated. The best dissolution conditions tested, for the products in each respective pharmaceutical dosage form were applied to evaluate the dissolution profiles. The parameters of difference factor, similar factor, and dissolution efficacy were employed. Results: Optimal conditions to carry out the dissolution tests were 900 ml of 0.01 M hydrochloric acid as dissolution medium, basket at 100 rotation per minute (rpm) stirring speed for capsules and paddle at 75 rpm for tablets. The dissolution profiles for tablets products A, B, and C and for capsules products A and B were not similar. CONCLUSION:

Solid lipid nanoparticles (SLN) introduced in 1991 represent an alternative carrier system to traditional colloidal carriers, such as emulsions, liposomes and polymeric micro-and nanoparticles. SLN combine advantages of the traditional systems but avoid some of their major disadvantages. This paper reviews the present state of the art regarding production techniques for SLN, drug incorporation, loading capacity and drug release, especially focusing on drug release mechanisms. Relevant issues for the introduction of SLN to the pharmaceutical market, such as status of excipients, toxicity/tolerability aspects and sterilization and long-term stability including industrial large scale production are also discussed. The potential of SLN to be exploited for the different administration routes is highlighted. References of the most relevant literature published by various research groups around the world are provided. q

The advent of high through-put screening in the drug discovery process has resulted in compounds with high lipophilicity and poor solubility. Increasing the solubility of such compounds poses a major challenge to formulation scientists. Various approaches have been adopted to address this including preparation of solid dispersions and solid solutions. Hot-melt extrusion is an efficient technology for producing solid molecular dispersions with considerable advantages over solvent-based processes such as spray drying and co-precipitation. Hot-melt extrusion has been demonstrated to provide sustained, modified, and targeted drug delivery. Improvements in bioavailability utilizing the hot-melt extrusion technique demonstrate the value of the technology as a potential drug delivery processing tool. The interest in hot-melt extrusion technology for pharmaceutical applications is evident from the increasing number of patents and publications in the scientific literature. Part II of this article reviews the myriad of hot-melt extrusion applications for pharmaceutical dosage forms including granules, pellets, tablets, implants, transmucosal, and transdermal systems.

Cyclodextrins are cyclic oligosaccharides with a hydrophilic outer surface and a somewhat lipophilic central cavity. Cyclodextrins are able to form water-soluble inclusion complexes with many lipophilic water-insoluble drugs. In aqueous solutions drug molecules located in the central cavity are in a dynamic equilibrium with free drug molecules. Furthermore, lipophilic molecules in the aqueous complexation media will compete with each other for a space in the cavity. Due to their size and hydrophilicity only insignificant amounts of cyclodextrins and drug/cyclodextrin complexes are able to penetrate into lipophilic biological barriers, such as intact skin. In general, cyclodextrins enhance topical drug delivery by increasing the drug availability at the barrier surface. At the surface the drug molecules partition from the cyclodextrin cavity into the lipophilic barrier. Thus, drug delivery from aqueous cyclodextrin solutions is both diffusion controlled and membrane controlled. It appears that cyclodextrins can only enhance topical drug delivery in the presence of water.

The advent of high through-put screening in the drug discovery process has resulted in compounds with high lipophilicity and poor solubility. Increasing the solubility of such compounds poses a major challenge to formulation scientists. Various approaches have been adopted to address this including preparation of solid dispersions and solid solutions. Hot-melt extrusion is an efficient technology for producing solid molecular dispersions with considerable advantages over solvent-based processes such as spray drying and co-precipitation. Hot-melt extrusion has been demonstrated to provide sustained, modified, and targeted drug delivery. Improvements in bioavailability utilizing the hot-melt extrusion technique demonstrate the value of the technology as a potential drug delivery processing tool. The interest in hot-melt extrusion technology for pharmaceutical applications is evident from the increasing number of patents and publications in the scientific literature. Part II of this article reviews the myriad of hot-melt extrusion applications for pharmaceutical dosage forms including granules, pellets, tablets, implants, transmucosal, and transdermal systems.

Aim of the study: Hypericum perforatum L. (Hypericaceae), olive oil (Oleaceae), Origanum Tourn ex L. and Salvia L. species (Lamiaceae) are used against inflammatory disorders and for healing of skin wounds in traditional Turkish medicine. A new ointment formulation was developed to provide more efficient wound healing activity. The content of the formulation was as follows; olive oil extract of flowering aerial parts of Hypericum perforatum L., olive oil, an equivalent mixture of Origanum majorana L. and Origanum minutiflorum Schwrd. et Davis essential oils (Origani aetheroleum), Salvia triloba L. essential oil. The aim of the present study is to assess the wound healing potential of this new formulation by using in vivo and in vitro models as well as histopathological methods. Materials and methods: For the evaluation of wound healing potential of this formulation (HPP crème mit Rotöl ointment) in vivo wound healing experimental models were employed on rats and mice and the efficiency was comparatively assessed against a reference ointment Madecassol ® . Tissue sections were also evaluated histopathologically. Furthermore, the wound healing activity of each component was also investigated individually to determine the improvement in the healing capacity of the formulation. Results: The ointments of HPP crème mit Rotöl and Hypericum perforatum L. demonstrated the highest activities on both wound models when compared to reference ointment Madecassol ® , while the other ingredients did not show any remarkable wound healing effect. However, the efficacy of the formulation was remarkably higher than the Hypericum L. ointment alone which was also confirmed by histopathological evaluation. On the other hand, the formulation did not reduce elastase activity in vitro, but inhibited the collagenase activity. HPP crème mit Rotöl also exerted bactericidal and candicidal activities. Conclusions: The experimental studies revealed that HPP crème mit Rotöl formulation displays remarkable wound healing activity. To be acting on the different stages of wound healing process could be considered as a beneficial effect of the formulation for the treatment of wounds.

Background: Drugs must be properly formulated for administration to patients, regardless of age. Pediatric patients provide some additional challenges to the formulator in terms of compliance and therapeutic efficacy. Due to the lack of sufficient drug products for the pediatric population, the pharmaceutical industry and compounding pharmacies must develop and provide appropriate medications designed for children.

The compensation method and other chemometric methods (derivative, orthogonal function and difference spectrophotometry) have been applied to the direct determination of omeprazole, lansoprazole and pantoprazole in their pharmaceutical preparations. The methods have been validated; the limits of detection were found to be 3.3×10−2, 3.0×10−2 and 3.5×10−2 μg ml−1 for the three drugs, respectively. The repeatabililty of the methods were found to be 0.3–0.5%. The linearity ranges were found to be 0.5–3.5 μg ml−1. The proposed methods have been applied to the determination of the three drugs in their grastro-resistant formulations. The difference spectrophotometric (ΔA) method is unaffected by the presence of acid induced degradation products; hence can be used as a stability indicating assay.

In this study, metformin hydrochloride (MH) sustained-release pellets were successfully prepared by centrifugal granulation. Seed cores preparation, drug layering, talc modification and coating of polymeric suspensions were carried out in a centrifugal granulator. Talc modification was performed before coating in order to overcome the high water solubility of metformin. The influence of surface modification by talc, the effects of Eudragit Ò types and ratios, as well as the correlation between in vitro release and in vivo absorption were investigated in detail. Experimental results indicated that talc modification made a decisive contribution to controlling the drug release by avoiding drug dumping. Three dissolution media: 0.1 M HCl, distilled water and pH 6.8 phosphate buffer were employed to determine the in vitro release behaviors of the above metformin hydrochloride pellets. The relative bioavailability of the sustainedrelease pellets was studied in 12 healthy volunteers after oral administration in a fast state using a commercially available immediate release tablet (Glucophage) as a reference. Following coating with a blend of Eudragit Ò L30D-55 and Eudragit Ò NE30D (1:20), at 7% or 10% coating level, respectively (referred to as F-2, F-3), the pellets acquired perfect sustained-release properties and good relative bioavailability. The C max , T max and relative bioavailability for F-2 and F-3 coated pellets were 1.21 lg/ml, 6 h, 97.6% and 1.65 lg/ml, 8 h, 165%, respectively. Combined use of two Eudragit Ò polymers with different features as coating materials produced the desired results. Restricted delivery of metformin hydrochloride to the small intestine from differently coated pellets resulted in increased relative bioavailability and a sustained release effect. The adoption of several different pH dissolution media established a better relationship between the in vitro release and in vivo absorption of the sustained-release pellets.

Polyvinyl alcohol (PVA)/sodium alginate (SA) hydrogel matrix-based wound dressing systems containing nitrofurazone (NFZ), a topical anti-infective drug, were developed using freeze-thawing method. Aqueous solutions of nitrofurazone and PVA/SA mixtures in different weight ratios were mixed homogeneously, placed in petri dishes, freezed at −20 • C for 18 h and thawed at room temperature for 6 h, for three consecutive cycles, and evaluated for swelling ratio, tensile strength, elongation and thermal stability of the hydrogel. Furthermore, the drug release from this nitrofurazone-loaded hydrogel, in vitro protein adsorption test and in vivo wound healing observations in rats were performed. Increased SA concentration decreased the gelation%, maximum strength and break elongation, but it resulted into an increment in the swelling ability, elasticity and thermal stability of hydrogel film. However, SA had insignificant effect on the release of nitrofurazone. The amounts of proteins adsorbed on hydrogel were increased with increasing sodium alginate ratio, indicating the reduced blood compatibility. In vivo experiments showed that this hydrogel improved the healing rate of artificial wounds in rats. Thus, PVA/SA hydrogel matrix based wound dressing systems containing nitrofurazone could be a novel approach in wound care.

A simple spectrophotometric method is used for the resolution of the binary mixtures of ampicillin sodium and sulbactam sodium. In aqueous solution, zero-order spectra are subject to interference, so first-derivative spectrophotometry was used to enhance the spectral details allowing the determination of ampicillin sodium from the signal at the zero-crossing point for sulbactam sodium at 268 nm. In 0.1 N sodium hydroxide, sulbactam sodium was determined from the absorbance at 260 nm with negligible contribution from ampicillin sodium. Also, sulbactam sodium was determined without interference using first- and second-derivative spectra in 0.1 N sodium hydroxide at 276 nm (peak-height) and 262–284 nm (peak-to-peak), respectively. The method is rapid, simple, does not require a separation step and allows the determination of each drug without interference from the other. The proposed method has been applied successfully to the assay of these drugs in mixtures and in commercial injections.

This article reviews recent advances in transmission Raman spectroscopy and its applications, from the perspective of pharmaceutical analysis. The emerging concepts enable rapid non-invasive volumetric analysis of pharmaceutical formulations and could lead to many important applications in pharmaceutical settings, including quantitative bulk analysis of intact pharmaceutical tablets and capsules in quality and process control.

Asulacrine (ASL) is an inhibitor of topoisomerase II, which has shown potential against breast and lung cancer. It is a poorly water soluble drug. To allow intravenous (i.v.) administration, ASL was formulated as a nanocrystalline suspension by high pressure homogenization. The nanosuspension was lyophilized to obtain the dry ASL nanoparticles (average size, 133 ± 20 nm), which enhanced both the physical and chemical stability of the ASL nanoparticles. ASL dissolution and saturation solubility were enhanced by the nanosuspension. Differential scanning calorimetry and X-ray diffraction analysis showed that the crystallinity of the ASL was preserved during the high pressure homogenization process. The pharmacokinetics and tissue distribution of ASL administered either as a nanosuspension or as a solution were compared after i.v. administration to mice. In plasma, ASL nanosuspension exhibited a significantly (P < 0.01) reduced C max (12.2 ± 1.3 g ml −1 vs 18.3 ± 1.0 g ml −1 ) and AUC 0-∞ (18.7 ± 0.5 g ml −1 h vs 46.4 ± 2.6 g ml −1 h), and a significantly (P < 0.01) greater volume of distribution (15.5 ± 0.6 l kg −1 vs 2.5 ± 0.1 l kg −1 ), clearance (1.6 ± 0.04 l h −1 kg −1 vs 0.6 ± 0.04 l h −1 kg −1 ) and elimination half-life (6.1 ± 0.1 h vs 2.7 ± 0.2 h) compared to the ASL solution. In contrast, the ASL nanosuspension resulted in a significantly greater AUC 0-∞ in liver, lung and kidney (all P < 0.01), but not in heart.

A spectrophotometric method was described for the determination of the antibacterial quinolone derivatives, ciprofloxacin, enrofloxacin and pefloxacin through charge transfer complex formation with three different acceptors. Chloranilic acid (CL) was utilized for their determination, forming charge transfer complex with umax 520 nm. The proposed method was applied for determination of Ciprocin tablets, Enroxil oral solution, Peflacin ampoules and Peflacin tablets, with mean percentage accuracies, 99.58 91.25, 99.94 9 0.96, 100.91 9 1.59 and 99.86 9 1.003. Also, tetracyanoethylene (TCNE) was utilized in the determination of the concerned compounds forming charge transfer complexes with maximum absorbances at umax 335 nm for ciprofloxacin and at umax 290 nm for both enrofloxacin and pefloxacin. The procedure was applied for determination of Ciprocin tablets, Enroxil 10% oral solution, Peflacine tablets and Peflacine ampoules with mean percentage accuracies 99.40 9 1.27, 99.95 9 0.90, 98.98 9 1.565 and 99.88 9 0.998, respectively. Also, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) was utilized for determination of pefloxacin forming charge transfer complex with maximum absorbance at umax 460 nm. The procedure was applied for determination of peflacine tablets and peflacine ampoules with mean percentage accuracies 100.40 9 0.76 and 99.91 90.623, respectively. Statistical analysis of the obtained results showed no significant difference between the proposed method and other official and reported methods as evident from the t-test and variance ratio.

Two improved, simple, selective and sensitive reversed-phase HPLC methods were developed for the determination of diosmin and hesperidin simultaneously or separately, using external or internal standard techniques, respectively. The methods were applied for determination of the diosmin and/or hesperidin in Buchu leaves and pharmaceutical dosage forms (three tablets). The methods involved very simple efficient extraction procedures, the use of a LiChrosorb RP-18 column, a mixture of methanol-water (60:40, v/v) as a mobile phase in an isocratic mode at a flow rate of 1.5 ml/min and UV detection at 345 nm. In all HPLC analysis the relative standard deviation did not exceed 1.9%. As low as 50 and 25 ng (per injection) could be detected in less than 6 min with a high degree of accuracy. This is the first report for the determination of the two flavonoids simultaneously in Buchu leaf and tablets containing them.

The aim of the present study was first to develop a robust near infrared (NIR) calibration model able to determine the acetaminophen content of a low-dose syrup formulation (2%, w/v). Therefore, variability sources such as production campaigns, batches, API concentration, syrup basis, operators and sample temperatures were introduced in the calibration set. A prediction model was then built using partial least square (PLS) regression. First derivative followed by standard normal variate (SNV) were chosen as signal pre-processing. Based on the random subsets cross-validation, 4 PLS factors were selected for the prediction model. The method was then validated for an API concentration ranging from 16 to 24 mg/mL (1.6-2.4%, w/v) using an external validation set. The 0.26 mg/mL RMSEP suggested the global accuracy of the model. The accuracy profile obtained from the validation results, based on tolerance intervals, confirmed the adequate accuracy of the results generated by the method all over the investigated API concentration range. Finally, the NIR model was used to monitor in real time the API concentration while mixing syrups containing various amounts of API, a good agreement was found between the NIR method and the theoretical concentrations.

In this study, we report the use of attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FT-IR) for the identification and quantitation of two polymorphs of Aprepitant, a substance P antagonist for chemotherapy-induced emesis. Mixtures of the polymorph pair were prepared by weight and ATR-FT-IR spectra of the powdered samples were obtained over the wavelength range of 700-1500 cm -1 . Significant spectral differences between the two polymorphs at 1140 cm -1 show that ATR-FT-IR can provide definitive identification of the polymorphs. To investigate the feasibility of ATR-FT-IR for quantitation of polymorphic forms of Aprepitant, a calibration plot was constructed with known mixtures of the two polymorphs by plotting the peak ratio of the second derivative of absorbance spectra against the weight percent of form II in the polymorphic mixture. Using this novel approach, 3 wt % of one crystal form could be detected in mixtures of the two polymorphs. The accuracy of ATR-FT-IR in determining polymorph purity of the drug substance was tested by comparing the results with those obtained by X-ray powder diffractometry (XRPD). Indeed, polymorphic purity results obtained by ATR-FT-IR were found to be in good agreement with the predictions made by XRPD and compared favorably with actual values in the known mixtures. The present study clearly demonstrates the potential of ATR-FT-IR as a quick, easy, and inexpensive alternative to XRPD for the determination of polymorphic identity and purity of solid drug substances. The technique is ideally suited for polymorph analysis, because it is precise, accurate, and requires minimal sample preparation. Reinhardt, R. R.; Gralla, R. J.; Kris, M. G.; Hesketh, P. J.; Khojasteh, A.; Kindler, H.; Grote, T. H.; Pendergrass, K.; Grunberg, S. M.; Carides, A. D.; Gertz, B. J. New Eng. J. Med. 1999, 340, 190-195. (5) Hale, J. J.; Sander, G. M.; MacCoss, M.; Finke, P. E.; Hesketh, P. J.; Cascieri, M. A.; Sadowski, S.; Ber, E.; Chicchi, G. G.; Kurtz, M.; Metzger, J.; Eiermann, G.; Tsou, N. N.; Tattersall, F. D.; Rupnaik, N. M. J.; Williams, A. R.; Rycroft, W.; Hargreaves, R.; MacIntyre, D. E.

Inactivated vaccines require adjuvants to stimulate an immune response. The choice of adjuvant or immune enhancer determines whether the immune response is effective, ineffective or damaging. Accordingly, there is a need for new adjuvants that stimulate the appropriate immunity, for example, T cell immunity for intracellular pathogens and cancer vaccines. In several adjuvants, the identification of chemical groups that interact with specific cell toll-like receptors (innate immunity) or receptors for costimulatory ligands (adaptive immunity), has enabled the establishment of structure-function relationships that are useful in the design of new adjuvants. Because of the crucial immunomodulating role of adjuvants, sub-unit vaccine development will remain dependent on new adjuvants. www.drugdiscoverytoday.com M References 1 Jenner, E. (1798) An inquiry into the causes and effects of the variolae vaccinae, or cow-pox.

The focus of present investigation was to assess the utility of non-destructive techniques in the evaluation of risperidone solid dispersions (SD) with methyl-β-cyclodextrin (MBCD) and subsequent incorporation of the SD into orally disintegrating tablets (ODT) for a faster release of risperidone. The SD was prepared by a solvent evaporation method and evaluated by scanning electron microscopy (SEM), Fourier transform infrared (FTIR), near infrared spectroscopy (NIR), NIR-chemical imaging (NIR-CI), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). DSC and XRD analysis indicated that crystallinity of SD has reduced significantly. FTIR showed no interaction between risperidone and MBCD. Partial least square (PLS) was applied to the NIR data for the construction of chemometric models to determine both components of the SD. Good correlations were obtained for calibration and prediction as indicated by correlation coefficients >0.9965. The model was more accurate and less biased in predicting the MBCD than risperidone as indicated by its lower mean accuracy and mean bias values. SD-3 (risperidone:MBCD, 1:3) was incorporated into ODT tablets containing diluent (D-mannitol, FlowLac® 100 or galenIQ™-721) and superdisintegrant (Kollidon® CL-SF, Ac-Di-Sol or sodium starch glycolate). Disintegration time, T50 and T90 were decreased in the formulations containing mannitol and Kollidon® CL-SF, but increased with galenIQ™-721 and sodium starch glycolate, respectively. NIR-CI images confirmed the homogeneity of SD and ODT formulations.

A new formulation for topical administration of drugs in the oral cavity has been developed using several film-forming and mucoadhesive polymers. The films have been evaluated in terms of swelling, mucoadhesion and organoleptic characteristics. The best film, containing polyvinylpyrrolidone (PVP) as film-forming polymer and carboxymethylcellulose sodium salt (NaCMC) as mucoadhesive polymer, was loaded with ibuprofen as a model compound and in vitro and in vivo release studies were performed. Statistical investigation of in vitro release revealed that the diffusion process was the main drug release mechanism and the Higuchi's model provided the best fit. In vivo studies showed the presence of ibuprofen in saliva (range 70 -210 Ag/ml) for 5 h and no irritation was observed. These mucoadhesive formulations offer many advantages in comparison to traditional treatments and can be proposed as a new therapeutic tool against dental and buccal diseases and disturbs. D

Near infrared spectroscopy (NIRS) is a nondestructive analytical technique that enables simultaneous measurements of chemical composition (viz. the content in active pharmaceutical ingredient, API) and various physical properties (viz. tablet hardness and dissolution profile) in pharmaceutical tablets. In this work, partial least squares (PLS) calibration models and discriminant partial least squares (DPLS) classification models were constructed by using calibration sets consisting of laboratory samples alone. The laboratory samples were mixtures of the API and excipients that were pressed into tablets. API content, tablet hardness, and dissolution measurements of intact tablets were made by using three different calibration models that are fastresults can be obtained within a few seconds-, simple and robust-they involve minimal analyst intervention-, and clean-they use no toxic reagent and produce no toxic waste. Based on the results, the proposed NIR method is an effective alternative to current reference methods for the intended purpose. The advantages provided by NIR spectroscopy in this context confirm its potential for inclusion in process analytical technologies in the pharmaceutical industry. ß

The aim of this study was to investigate the influence of pH, buffer species and ionic strength on the release mechanism of chlorpheniramine maleate (CPM) from matrix tablets containing chitosan and xanthan gum prepared by a hot-melt extrusion process. Drug release from hot-melt extruded (HME) tablets containing either chitosan or xanthan gum was pH and buffer species dependent and the release mechanisms were controlled by the solubility and ionic properties of the polymers. All directly compressed (DC) tablets prepared in this study also exhibited pH and buffer species dependent release. In contrast, the HME tablets containing both chitosan and xanthan gum exhibited pH and buffer species independent sustained release. When placed in 0.1N HCl, the HME tablets formed a hydrogel that functioned to retard drug release in subsequent pH 6.8 and 7.4 phosphate buffers even when media contained high ionic strength, whereas tablets without chitosan did not form a hydrogel to retard drug release in 0.1N HCl. The HME tablets containing both chitosan and xanthan gum showed no significant change in drug release rate when stored at 40 • C for 1 month, 40 • C and 75% relative humidity (40 • C/75% RH) for 1 month, and 60 • C for 15 days.

Lipid-based liquid crystalline materials have been proposed as controlled drug delivery systems. Differences in liquid crystal nanostructure have previously been shown to change drug diffusion and hence release, however there has been little progress towards the use of in situ changes to nanostructure to control drug release. In this study, phytantriol and glyceryl monooleate-based bicontinuous cubic (Q 2 ) and inverse hexagonal (H 2 ) nanostructures have been designed to allow change to the nanostructure in response to external change in temperature, with a view to controlling drug release rates in vivo. Changes to nanostructure with temperature were confirmed by crossed polarised optical microscopy and small angle X-ray scattering. Phytantriol containing 3% (w/w) vitamin E acetate provided the necessary phase transition behaviour to progress this system to in vitro release and in vivo proof of concept studies. Using glucose as a model hydrophilic drug, drug diffusion was shown to be reversible on switching between the H 2 and Q 2 nanostructures at temperatures above and below physiological temperature respectively. An in vivo proof of concept study in rats showed that after subcutaneous administration of these materials, the changes in nanostructure induced by application of a heat or cool pack at the injection site stimulated changes in drug release from the matrix anticipated from in vitro release behaviour, thereby demonstrating the potential utility of these systems as 'on demand' drug release delivery vehicles.

The focus of in vitro dissolution testing during early development of modified release (MR) formulations is to provide predictive estimates of drug release in respect to in vivo performance of a drug product. However, there are enormous challenges in MR drug development to establish proper dissolution conditions for a predictive test.

A non-aqueous titration method has been reported in USPXXII for the assay of the raw material in addition to a HPLC method for determination of the drug in tablets . HPLC have been applied for the analysis of microquantities (nano-levels) of the drug in biological samples. Some of these methods involve several manipulation steps, which are not simple for routine analysis of pharmaceutical formulations and need sophisticated instruments. On the other hand, a few spectrophotometric [9-11] and polarographic [12,13] methods have been reported for famotidine determination as a drug substance or in commercial dosage forms. This paper describes the formation of a 1:1 ion-pair complex between famotidine and each of bromocresol green (BCG) and bromothymol blue (BTB) in order to develop a new spectrophotometric method for the drug determination. These results showed that the suggested method may be suitable for the routine quality control of famotidine in pharmaceutical formulations.

Background: Naproxen sodium!paracetamol (acetaminophen) is a combination for the treatment of symptomatic pain and fever marketed both as a prescription and an over-the-counter product in Mexico. generally well tolerated. (Clin Ther. 2009;31:399-410)

Hydrogels are one of the upcoming classes of polymer-based controlledrelease drug delivery systems. Besides exhibiting swelling-controlled drug release, hydrogels also show stimuli-responsive changes in their structural network and hence, the drug release. Because of large variations in physiological pH at various body sites in normal as well as pathological conditions, pH-responsive polymeric networks have been extensively studied. This review highlights the use of hydrogels (a class of polymeric systems) in controlled drug delivery, and their application in stimuliresponsive, especially pH-responsive, drug release. Bioinformatics: the role and limitations of patents by Teresa J. Welch

This is the first report on the use of a "dual asymmetric centrifuge (DAC)" for preparing liposomes. DAC differs from conventional centrifugation by an additional rotation of the sample around its own vertical axis: While the conventional centrifugation constantly pushes the sample material outwards, this additional rotation constantly forces the sample material towards the center of the centrifuge. This unique combination of two contra rotating movements results in shear forces and thus, in efficient homogenization. We demonstrated that it is possible to prepare liposomes by DAC, by homogenizing a rather concentrated blend of hydrogenated phosphatidylcholine and cholesterol (55:45 mol%) and 0.9% NaCl-solution, which results in a viscous vesicular phospholipid gel (VPG). The resulting VPG can subsequently be diluted to a conventional liposome dispersion. Since DAC is intended to make sterile preparations of liposomes, or to entrap toxic/radioactive compounds, the process was performed within a sealed vial. It could be shown that the DAC speed, the lipid concentration, the homogenization time and the addition of a mixing aid (glass beads) are all critical for the size of the liposomes. Optimized conditions resulted in liposomes of 60 ± 5 nm and a trapping efficacy of 56 ± 3.3% for the model compound calcein.

During the last decade, the US Food and Drug Administration (FDA) have regulated a wide range of products, (foods, cosmetics, drugs, devices, veterinary, and tobacco) which may utilize micro and nanotechnology or contain nanomaterials. Nanotechnology allows scientists to create, explore, and manipulate materials in nano-regime. Such materials have chemical, physical, and biological properties that are quite different from their bulk counterparts. For pharmaceutical applications and in order to improve their administration (oral, pulmonary and dermal), the nanocarriers can be spread into microparticles. These supramolecular associations can also modulate the kinetic releases of drugs entrapped in the nanoparticles. Different strategies to produce these hybrid particles and to optimize the release kinetics of encapsulated drugs are discussed in this review.

The present study investigates the use of nimodipine-polyethylene glycol solid dispersions for the development of effervescent controlled release floating tablet formulations. The physical state of the dispersed nimodipine in the polymer matrix was characterized by differential scanning calorimetry, powder X-ray diffraction, FT-IR spectroscopy and polarized light microscopy, and the mixture proportions of polyethylene glycol (PEG), polyvinyl-pyrrolidone (PVP), hydroxypropylmethylcellulose (HPMC), effervescent agents (EFF) and nimodipine were optimized in relation to drug release (% release at 60 min, and time at which the 90% of the drug was dissolved) and floating properties (tablet's floating strength and duration), employing a 25-run D-optimal mixture design combined with artificial neural networks (ANNs) and genetic programming (GP). It was found that nimodipine exists as mod I microcrystals in the solid dispersions and is stable for at least a three-month period. The tablets showed good floating properties and controlled release profiles, with drug release proceeding via the concomitant operation of swelling and erosion of the polymer matrix. ANNs and GP both proved to be efficient tools in the optimization of the tablet formulation, and the global optimum formulation suggested by the GP equations consisted of PEG = 9%, PVP = 30%, HPMC = 36%, EFF = 11%, nimodipine = 14%. Ó

The main objective of the present work is to check the feasibility of supercritical fluid (SCF) technologies in the screening and design of cocrystals (novel crystalline solids). The cocrystal formation tendencies in three different SCF techniques, focusing on distinct supercritical fluid properties -solvent, anti-solvent and atomization enhancer -were investigated. The effect of processing parameters on the cocrystal formation behaviour and particle properties in these techniques was also studied.

The objective of the present study was to determine the effects of hydroxypropyl-b-cyclodextrin (HPCD) complexation on the transdermal penetration and photostability of a model ultraviolet A (UVA) absorber, butyl methoxydibenzoylmethane (avobenzone), and to determine the influence of complexation on in vivo photoprotection. Avobenzone-HPCD complexation was demonstrated by differential scanning calorimetry. Formulations containing 0.12 mg/ml avobenzone and up to 30% (w/w) HPCD were prepared. Transdermal penetration was conducted using a modified Franz diffusion cell apparatus. As the concentration of HPCD was increased from 0% to 20%, transdermal permeation increased. Maximum flux occurred at 20% HPCD, where sufficient cyclodextrin was present to completely solubilize all avobenzone. When the concentration of HPCD was increased to 30%, transdermal penetration decreased, suggesting the formation of an avobenzone reservoir on the skin surface. Photostability of avobenzone was investigated under 100, 250, and 500 kJ/m 2 UVA irradiation. The 30% HPCD formulation was the most photostable, followed by 20%, 10%, and 0% formulations. In vivo, the 30% HPCD formulation afforded the best photoprotection, as evidenced by the lowest extent of sunburn cell formation and edema induction. This work indicates that inclusion of HPCD in sunscreen formulations may enhance photoprotection by reducing both skin penetration and photodecomposition of UV absorbers.

A reversed-phase HPLC method with fluorescence detection for the determination of the aflatoxins B1, B2, G1 and G2 in 42 animal feeds, comprising corn (16), soya bean meal (8), mixed meal (13), sunflower, wheat, canola, palm kernel, copra meals (1 each) was carried out. The samples were first extracted using acetonitrile:water (9:1), and was further cleaned-up using a multifunctional column. Optimum conditions for the extraction and chromatographic separation were investigated. By adopting an isocratic chromatographic system using a mobile phase comprising acetonitrile:methanol:water (8:27:65, v/v/v), the separation of the four aflatoxins was possible within 30 min. Recoveries for aflatoxins B1, B2, G1 and G2 were 98 ± 0.7%, 95 ± 1.0%, 94 ± 3.6% and 97 ± 4.3%, respectively. The results show that eight samples (19%) were contaminated with aflatoxins, ranging from 6.5 to 101.9 ng g À1 . Total aflatoxin levels in three samples exceed the legal limits of many countries of 20 ng g À1 .

Poly(DL-lactide-co-glycolide acid) (PLGA) is an attractive polymer for delivery of biopharmaceuticals owing to its biocompatibility, biodegradability and outstanding controlled release characteristics. The purpose of this study was to understand and define optimal parameters for preparation of small interfering RNA (siRNA)-loaded PLGA nanoparticles by the double emulsion solvent evaporation method and characterize their properties. The experiments were performed according to a 2 5À1 fractional factorial design based on five independent variables: The volume ratio between the inner water phase and the oil phase, the PLGA concentration, the sonication time, the siRNA load and the amount of acetylated bovine serum albumin (Ac-BSA) in the inner water phase added to stabilize the primary emulsion. The effects on the siRNA encapsulation efficiency and the particle size were investigated. The most important factors for obtaining an encapsulation efficiency as high as 70% were the PLGA concentration and the volume ratio whereas the size was mainly affected by the PLGA concentration. The viscosity of the oil phase was increased at high PLGA concentration, which explains the improved encapsulation by stabilization of the primary emulsion and reduction of siRNA leakage to the outer water phase. Addition of Ac-BSA increased the encapsulation efficiency at low PLGA concentrations. The PLGA matrix protected siRNA against nuclease degradation, provided a burst release of surface-localized siRNA followed by a triphasic sustained release for two months. These results enable careful understanding and definition of optimal process parameters for preparation of PLGA nanoparticles encapsulating high amounts of siRNA with immediate and long-term sustained release properties.

Modern thermal analysis techniques are frequently used because of their ability to provide detailed information about both the physical and the energetic properties of a substance. In the present work, the thermal decomposition of zidovudine (AZT) was studied using differential scanning calorimetry (DSC) and thermogravimetry/derivative thermogravimetry (TG/DTG). Thermal analysis was supplemented using elemental analysis (C, H, and N), infrared (IR) spectroscopy, and X-ray powder diffraction to characterize the solid intermediates products. Volatile products of the thermal decomposition of AZT were studied by a system composed of the TG/DTA coupled gas chromatography/mass spectrometry (GC/MS). The physical-chemical properties and compatibilities of several commonly used pharmaceutical excipients with AZT were evaluated using thermal methods. The results showed that the product originated from the first thermal decomposition stage corresponds to the cleavage followed by elimination of the azide group and consequent formation of thymine. The second event corresponds to thermal decomposition of thymine. TG/DTA-GC/MS system identified thymine's decomposition products as furan and 2-furanmethanol like volatile species. Comparison of the thermoanalytical profiles of the mixtures with individual compounds did not give any evidence of interactions.

This investigation deals with the development of buccal formulations (tablets) based on chitosan microspheres containing chlorhexidine diacetate. The microparticles were prepared by a spray-drying technique, their morphological characteristics were studied by scanning electron microscopy and the in vitro release behaviour was investigated in pH 7.0 USP buffer. Chlorhexidine in the chitosan microspheres dissolves more quickly in vitro than does chlorhexidine powder. The anti-microbial activity of the microparticles was investigated as minimum inhibitory concentration, minimum bacterial concentration and killing time. The loading of chlorhexidine into chitosan is able to maintain or improve the anti-microbial activity of the drug. The improvement is particularly high against Candida albicans. This is important for a formulation whose potential use is against buccal infections. Drug-empty microparticles have an anti-microbial activity due to the polymer itself. Buccal tablets were prepared by direct compression of the microparticles with mannitol alone or with sodium alginate. After their in vivo administration the determination of chlorhexidine in saliva showed the capacity of these formulations to give a prolonged release of the drug in the buccal cavity. q

This study reports the preparation of starch-based tableted microspheres that are crosslinked with epichlorohydrin (EPI) using a modified water-in-oil (w/o) emulsification technique. Ampicillin (AMP), a broad spectrum antibiotic was encapsulated up to the extent of 70% into the microspheres. The microspheres were characterized by Fourier transform infrared spectroscopy (FT-IR) to confirm the crosslinking reaction and chemical stability of AMP. Differential scanning calorimetry (DSC) was studied on the placebo and drugloaded microspheres to confirm the polymorphism of AMP. Results of this study indicated a molecular level dispersion of AMP in the developed microspheres. Scanning electron microscopy (SEM) confirmed the spherical nature and smooth surfaces of the microspheres produced. Mean particle size of the microspheres as measured by laser light scattering ranged between 96 and 158 lm. Diffusion coefficients (D) of water transport through the microspheres were determined using an empirical equation. Values of D decrease with increasing crosslinking as well as increasing content of starch in the microspheres. In-vitro release studies were performed in 1.2 and 7.4 pH media to simulate the gastric and intestinal conditions. The results indicated a dependence on the amount of polymer and extent of crosslinking. Release data were fitted to an empirical relation to estimate transport parameters and to understand the transport mechanism. Statistical analyses of release data was performed using analysis of variance (ANOVA) method. Suitable microspheres were selected and compressed into tablets using the directly compressible excipients. SEM photographs of the fractured part of the tablet revealed the presence of discrete microspheres in the tablets, suggesting that the system chosen is ideal for tableting. Tablets significantly lowered the initial burst effect when compared to microsphere formulations. The tablets were effective in releasing the AMP over an extended period of about 24 h.