Avani Amin

Getting into the brain: approaches to enhance brain drug delivery.

Being the most delicate organ of the body, the brain is protected against potentially toxic substances by the blood-brain barrier (BBB), which restricts the entry of most pharmaceuticals into the brain. The developmental process for new drugs for the treatment of CNS disorders has not kept pace with progress in molecular neurosciences because most of the new drugs discovered are unable to cross the BBB. The clinical failure of CNS drug delivery may be attributed largely to a lack of appropriate drug delivery systems. Localized and controlled delivery of drugs at their desired site of action is preferred because it reduces toxicity and increases treatment efficiency. The present review provides an insight into some of the recent advances made in the field of brain drug delivery.The various strategies that have been explored to increase drug delivery into the brain include (i) chemical delivery systems, such as lipid-mediated transport, the prodrug approach and the lock-in system; (ii) biological delivery systems, in which pharmaceuticals are re-engineered to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium; (iii) disruption of the BBB, for example by modification of tight junctions, which causes a controlled and transient increase in the permeability of brain capillaries; (iv) the use of molecular Trojan horses, such as peptidomimetic monoclonal antibodies totransport large molecules (e.g. antibodies, recombinant proteins, nonviral gene medicines or RNA interference drugs) across the BBB; and (v) particulate drug carrier systems. Receptor-mediated transport systems exist for certain endogenous peptides, such as insulin and transferrin, enabling these molecules to cross the BBB in vivo.The use of polymers for local drug delivery has greatly expanded the spectrum of drugs available for the treatment of brain diseases, such as malignant tumours and Alzheimer’s disease. In addition, various drug delivery systems (e.g. liposomes, microspheres, nanoparticles, nanogels and bionanocapsules) have been used to enhance drug delivery to the brain. Recently, microchips and biodegradable polymers have become important in brain tumour therapy.The intense search for alternative routes of drug delivery (e.g. intranasal drug delivery, convection-enhanced diffusion and intrathecal/intraventricular drug delivery systems) has been driven by the need to overcome the physiological barriers of the brain and to achieve high drug concentrations within the brain. For more than 30 years, considerable efforts have been made to enhance the delivery of therapeutic molecules across the vascular barriers of the CNS. The current challenge is to develop drug delivery strategies that will allow the passage of drug molecules through the BBB in a safe and effective manner.

Gastroretentive drug delivery system of ranitidine hydrochloride: formulation and in vitro evaluation.

The purpose of this research was to prepare a gastroretentive drug delivery system of ranitidine hydrochloride. Guar gum, xanthan gum, and hydroxypropyl methylcellulose were evaluated for gel-forming properties. Sodium bicarbonate was incorporated as a gas-generating agent. The effects of citric acid and stearic acid on drug release profile and floating properties were investigated. The addition of stearic acid reduces the drug dissolution due to its hydrophobic nature. A 32 full factorial design was applied to systemically optimize the drug release profile. The amounts of citric acid anhydrous (X1) and stearic acid (X2) were selected as independent variables. The times required for 50% (t50) and 80% drug dissolution (t80), and the similarity factor f2 were selected as dependent variables. The results of the full factorial design indicated that a low amount of citric acid and a high amount of stearic acid favors sustained release of ranitidine hydrochloride from a gastroretentive formulation. A theoretical dissolution profile was generated using pharmacokinetic parameters of ranitidine hydrochloride. The similarity factor f2 was applied between the factorial design batches and the theoretical dissolution profile. No significant difference was observed between the desired release profile and batches F2, F3, F6, and F9. Batch F9 showed the highest f2 (f2=75) among all the batches, and this similarity is also reflected in t50 (∼214 minutes) and t80 (∼537 minutes) values. These studies indicate that the proper balance between a release rate enhancer and a release rate retardant can produce a drug dissolution profile similar to a theoretical dissolution profile.

Formulation design and optimization of mouth dissolve tablets of nimesulide using vacuum drying technique

The purpose of this research was to develop mouth dissolve tablets of nimesulide. Granules containing nimesulide, camphor, crospovidone, and lactose were prepared by wet granulation technique. Camphor was sublimed from the dried granules by exposure to vacuum. The porous granules were then compressed. Alternatively, tablets were first prepared percentage friability, wetting time, and disintegration time. In the investigation, a 32 full factorial design was used to investigate the joint influence of 2 formulation variables: amount of camphor and crospovidone. The results of multiple linear regression analysis revealed that for obtaining a rapidly disintegrating dosage form, tablets should be prepared using an optimum concentration of camphor and a higher percentage of crospovidone. A contour plot is also presented to graphically represent the effect of the independent variables on the disintegration time and percentage friability. A checkpoint batch was also prepared to prove the validity of the evolved mathematical model. Sublimation of camphor from tablets resulted in superior tablets as compared with the tablets prepared from granules that were exposed to vacuum. The systematic formulation approach helped in understanding the effect of formulation processing variables.

Formulation and evaluation of mucoadhesive glipizide microspheres.

The purpose of this research was to formulate and system-atically evaluate in vitro and in vivo performances of mucoadhesive microspheres of glipizide. Glipizide microspheres containing chitosan were prepared by simple emulsification phase separation technique using glutaraldehyde as a cross-linking agent. Results of preliminary trials indicate that volume of cross-linking agent, time for cross-linking, polymer-to-drug ratio, and speed of rotation affected characteristics of microspheres. Microspheres were discrete, spherical, and free flowing. The microspheres exhibited good mucoadhesive property in the in vitro wash-off test and also showed a high percentage drug entrapment efficiency. A 32 full factorial design was employed to study the effect of independent variables, polymer-to-drug ratio (X1), and stirring speed (X2) on dependent variables percentage mucoadhesion, t80, drug entrapment efficiency, and swelling index. The best batch exhibited a high drug entrapment efficiency of 75% and a swelling index of 1.42; percentage mucoadhesion after 1 hour was 78%. The drug release was also sustained for more than 12 hours. The polymer-to-drug ratio had a more significant effect on the dependent variables. In vivo testing of the mucoadhesive microspheres to albino Wistar rats demonstrated significant hypoglycemic effect of glipizide.

Process optimization and characterization of poloxamer solid dispersions of a poorly water-soluble drug.

The objective of the present investigation was to improve the dissolution rate of Rofecoxib (RXB), a poorly water-soluble drug by solid dispersion technique using a water-soluble carrier, Poloxamer 188 (PXM). The melting method was used to prepare solid dispersions. A 32 full factorial design approach was used for optimization wherein the temperature to which the melt-drug mixture cooled (X1) and the drug-to-polymer ratio (X2) were selected as independent variables and the time required for 90% drug dissolution (t90) was selected as the dependent variable. Multiple linear regression analysis revealed that for obtaining higher dissolution of RXB from PXM solid dispersions, a low level ofX1 and a high level ofX2 were suitable. The differential scanning calorimetry and x-ray diffraction studies demonstrated that enhanced dissolution of RXB from solid dispersion might be due to a decrease in the crystallinity of RXB and PXM and dissolution of RXB in molten PXM during solid dispersion preparation. In conclusion, dissolution enhancement of RXB was obtained by preparing its solid dispersions in PXM using melting technique. The use of a factorial design approach helped in identifying the critical factors in the preparation and formulation of solid dispersion.

Polysaccharides: a targeting strategy for colonic drug delivery.

Introduction: Colon targeting has gained increasing importance for the topical treatment of diseases of the colon, such as Crohns disease, ulcerative colitis, colorectal cancer and amebiasis. Various strategies used for targeting drugs to the colon include formation of a prodrug, coating with time or pH-dependent polymers, use of colon-specific biodegradable polymers, osmotic systems and pressure-controlled drug delivery systems. Among the different approaches used, polysaccharides that are precisely activated by the physiological conditions of the colon hold great promise, as they provide improved site specificity and meet the desired therapeutic needs. Areas covered: This review aims to summarize the natural and modified properties of polysaccharides that are responsible for their colon targeting abilities. Emphasis is placed on describing formulation approaches that use polysaccharides as a strategy for targeting drugs to the colon. Expert opinion: Polysaccharide-based colon-targeted drug delivery systems are effective when they are precisely activated by the physiological conditions of the colon. Absence of enzymes during colonic disorders might hinder the activation of the delivery system. To guarantee delivery of the drug to the colon, it is preferable to combine polysaccharides with enteric or cellulose polymers.

Development of modified release diltiazem HCl tablets using composite index to identify optimal formulation

Abstract This article reports the preparation of tartaric acid treated ispaghula husk powder for the development of modified release tablets of diltiazem HCl by adopting direct compression technique and a 32 full factorial design. The modified ispaghula husk powder showed superior swelling and gelling as compared to untreated powder. Addition of compaction augmenting agent such as dicalcium phosphate was found to be essential for obtaining tablets with adequate crushing strength. In order to improve the crushing strength of diltiazem HCl tablets, to modulate drug release pattern, and to obtain similarity of dissolution profiles in distilled water and simulated gastric fluid (pH 1.2), modified guar gum was used along with modified ispaghula husk powder and tartaric acid. A novel composite index, which considers a positive or a negative deviation from an ideal value, was calculated considering percentage drug release in 60, 300, and 540 min as dependent variables for the selection of a most appropriate batch. Polynomial equation and contour plots are presented. The concept of similarity factor (f2) was used to prove similarity of dissolution in water and simulated gastric fluid (pH 1.2).

Design, Development and Optimization of a Novel Time and pH-Dependent Colon Targeted Drug Delivery System

The aim of present study was to develop a time- and pH-dependent system for delivering mesalamine to the colon. The system consists of the core tablet of mesalamine which is compression coated with hydroxypropyl methylcellulose (HPMC K4M) (time-dependent factor). This is then coated with pH-dependent polymer Eudragit® L100. The simplex lattice design was adopted to optimize the independent variables i.e. amount of HPMC (X1), dextrose (X2) and polyvinyl pyrollidone (PVP) (X3) and to study their effect on the dependent variables i.e. lag time and time for 50% drug dissolution (t50). The results of the linear interactive model and graphical representation revealed that as the amount of HPMC increases, the lag time and t50 value also increases and as the amount of dextrose and PVP were increased the lag time and t50 value decreases.

Formulation and development of release modulated colon targeted system of meloxicam for potential application in the prophylaxis of colorectal cancer

The objective of the present study was to develop a colon targeted system of meloxicam for potential application in the prophylaxis of colorectal cancer. Efficacy of selective cyclooxygenase–2 inhibitors has been proven in colorectal cancer. Meloxicam is a selective cyclooxygenase–2 inhibitor with pH-dependent solubility. To achieve pH-independent drug release of meloxicam, pH modifying agents (buffering agents) were used. Meloxicam tablets containing polyethylene oxide were dually coated with ethyl cellulose containing hydrophilic material, polyethylene glycol as an inner coating layer and methyl acrylate, methyl methacrylate, and methacrylic acid copolymer (Eudragit® FS 30D) as outer coating layer for colon targeting. Optimized tablet formulations demonstrated good potential to deliver the drug to the colon by successfully exhibiting a lag time of 5 h during in vitro drug release study. An in vivo evaluation study conducted to ascertain pharmacokinetic parameters in rabbits revealed that the onset of drug absorption from the coated tablets (Tlag time = 4.67 ± 0.58 h) was significantly delayed compared to that from the uncoated tablets. The AUC0→t and AUC0→∞ for coated tablets were lower than of uncoated tablets, although the difference was not significant (p > 0.01). The roentgenography study revealed that the tablet remained intact, until it reached the colon (5 h), which demonstrates that the system can efficiently deliver the drug to the colon. This study demonstrated that a meloxicam-loaded colon targeted system exhibited promising targeting and hence may be used for prophylaxis of colorectal cancer.

Design and Optimization of Colon-Targeted System of Theophylline for Chronotherapy of Nocturnal Asthma

The objective of the present work was to develop a delayed-onset controlled-release colon-targeted system of theophylline, and to achieve the chronotherapy of nocturnal asthma. The formulation consisted of a core tablet containing hydroxypropyl methylcellulose used for achieving controlled release of drug, and a Eudragit S100:ethyl cellulose (EC) coating capable of delaying the drug release. The system was optimized using a 3(2) full factorial design, wherein two factors [ratio of Eudragit S100:EC and the coating level (% w/w)] were evaluated for lag time, t(50) and t(80) . The optimum formulation consisted of Eudragit S100:EC in a 60:40 ratio and a coating level of 7.5% (w/w). Results showed that the tablets prepared according to the optimized values released no drug in the upper part of gastrointestinal tract; drug release was initiated at pH 6.4 (colon) after a lag time of 5 h. In vivo evaluation (pharmacokinetic studies and roentgenography) in rabbits revealed that the tablet remained intact until it reaches the colon and the drug release was initiated after a lag time of 5 h. Thus, it can be concluded that the developed system exhibited a promising colonic targeting and hence may be used for chronotherapy of nocturnal asthma.