Helicobacter pylori: past, current and future treatment strategies with gastroretentive drug delivery systems.

Helicobacter pylori have been subject to intense investigation since its discovery from gastric biopsy in 1982. This gastropathogen has been regarded as serious public health problem due to its association with dyspepsia, gastritis, gastroduodenal ulcers, mucus-associated lymphoid tissue lymphoma and gastric carcinoma. In vivo eradication of established H. pylori infections is difficult due to several factors such as gastric niche, coccoid form due to sub-minimum inhibitory concentration of antimicrobials, bacterial load, primary antibiotic resistance, patient compliance and stability of therapeutics in gastric acid secretion. Considering these factors, a logical way to improve the outcome of the treatment is to develop dosage forms which are able to deliver the anti-helicobacter agents in the gastric niche for both local and systemic actions, simultaneously taking care of stability of therapeutics in acidic environment. Such dosage forms, which are popularly known as gastro retentive drug delivery systems (GRDDS), have the immense potential to effectively counter the problem of high bacterial load; prevent induction of coccoid bacteria thereby improving treatment outcome and compliance. This review describes efficacy of various therapeutic agents, treatment strategies and status of different GRDDS until now.

Chitosan coated sodium alginate-chitosan nanoparticles loaded with 5-FU for ocular delivery: in vitro characterization and in vivo study in rabbit eye.

The objective of the study was to develop chitosan (CH) coated sodium alginate-chitosan (SA-CH) nanoparticles, i.e. CH-SA-CH NPs loaded with 5-FU for ophthalmic delivery. Drug loaded nanoparticles (DNPs) were prepared by ionic gelation technique using sodium alginate (SA) and chitosan (CH) and then suspended in chitosan solution. The mean size of nanoparticles and morphology were characterized by dynamic light scattering, scanning electron microscopy, atomic force microscopy and zeta potential. The in vitro release was studied by dialysis membrane technique. The size and drug encapsulation efficiency were dependent on molar ratio of SA and CH. The size of SA-CH nanoparticles was significantly increased with changed morphology after CH coating. SA-CH nanoparticles did not show any interaction with mucin while an enhanced viscosity was observed on coating of nanoparticles with CH. CH-SA-CH DNPs presented a sustained release of 5-FU compared to the 5-FU solution with high burst effect. In vivo study in rabbit eye showed significantly greater level of 5-FU in aqueous humor compared to 5-FU solution. The enhanced mucoadhesiveness of CH-SA-CH DNPs results in higher bioavailability as compared to the uncoated nanoparticles. Optimized formulation was found non-irritant and tolerable when tested by modified Draize test in rabbit eye.

Modified PLA nano in situ gel: a potential ophthalmic drug delivery system.

A novel nano in situ gel forming system of 5-Fluorouracil (5-FU) was investigated for its potential use for conjunctival/corneal squamous cell carcinoma (CCSC). The study was conducted in two steps, in the first step PLA nanoparticles were prepared and characterized; in the second step the drug loaded PLA nanoparticles were dispersed in sodium alginate solution yielding the modified nano in situ system, which were evaluated in rabbit eye. Size and morphology of prepared PLA particles were verified by using dynamic light scattering (DLS), atomic force microscope (AFM) and scanning electron microscope (SEM). In vitro and in vivo study of free 5-FU, PLA nanoparticles and modified nano in situ system were conducted in simulated tear fluid and in rabbit eye respectively. PLA nanoparticles were in size range of 128-194 nm with spherical shape and smooth surface with narrow size distribution. No polymer drug interaction was found as confirmed by FTIR, NMR and DSC. XRD of PLA nanoparticles confirmed that 5-FU was present in the crystalline state. In vitro experiments indicated a diffusion controlled release of 5-FU from both PLA nanoparticles and modified nano in situ system with high burst effect. Modified nano in situ gel system (MNS) significantly increased the Cmax and AUC0-8 in aqueous humor as compared to 5-FU solution and PLA nanoparticles. Higher 5-FU level in aqueous humor was possibly because of increased retention time of gel matrix-embedded drug loaded nanoparticles. Overall results showed the potential of MNS for ophthalmic delivery in the therapy of CCSC.

Nanocrystal technology in the delivery of poorly soluble drugs: an overview.

Extensive attempts to overcome problems related to solubility of drugs for maximizing bioavailability at targeted sites in the body have been made. The issue of drug solubility appears to attract the continued interest of pharmaceutical manufacturers. In this context, nanocrystallization has emerged as an important tool. In the present review, the authors discuss the advantages of nanocrystallized drugs and examine the products available in the market as well as drugs in the pipeline using nanocrystal-based formulations, which are being developed by pharmaceutical companies for drug delivery.

Newer approaches for optimal bioavailability of ocularly delivered drugs: review.

Eye diseases can cause discomfort and anxiety in patients, with the ultimate fear of loss of vision and facial disfigurement. Many regions of the eye are relatively inaccessible to systemically administered drugs and, as a result, topical drug delivery remains the preferred route in most cases. Drugs may be delivered to treat the precorneal region for conjunctivitis and blepharitis, or to provide intraocular diseases such as glaucoma, uveitis, and cytomegalovirus retinitis. Most of the ophthalmic formulation strategies aim at maximizing ocular drug permeability through prolongation of the drug residence time in the cornea and conjunctival sac, as well as minimizing precorneal drug loss. The conventional topical ocular drug delivery systems show drawbacks such as increased precorneal elimination and high variability in efficacy. Attempts have been made to overcome these problems and enhance ocular bioavailability by the development of newer drug delivery systems. This review is concerned with classification, recent findings and applications and biocompatibility of newer drug delivery systems for the treatment of ocular diseases.

In vitro release kinetics and bioavailability of gastroretentive cinnarizine hydrochloride tablet.

An oral sustained release dosage form of cinnarizine HCl (CNZ) based on gastric floating matrix tablets was studied. The release of CNZ from different floating matrix formulations containing four viscosity grades of hydroxypropyl methylcellulose, sodium alginate or polyethylene oxide, and gas-forming agent (sodium bicarbonate or calcium carbonate) was studied in simulated gastric fluid (pH 1.2). CNZ release data from the matrix tablets were analyzed kinetically using Higuchi, Peppas, Weibull, and Vergnaud models. From water uptake, matrix erosion studies, and drug release data, the overall release mechanism can be explained as a result of rapid hydration of polymer on the surface of the floating tablet and formation of a gel layer surrounding the matrix that controls water penetration into its center. On the basis of in vitro release data, batch HP1 (CNZ, HPMC-K100LV, SBC, LTS, and MgS) was subjected to bioavailability studies in rabbits and was compared with CNZ suspension. It was concluded that the greater bioavailability of HP1 was due to its longer retention in the gastric environment of the test animal. Batch no. HP1 of floating tablet in rabbits demonstrated that the floating tablet CNZ could be a 24-h sustained release formulation.

Chitosan coated PLA nanoparticles for ophthalmic delivery: characterization, in-vitro and in-vivo study in rabbit eye.

The objective of the present study is to develop a poly (D, L-lactic acid) (PLA) nano-carrier for topical ocular applications. PLA nanoparticles (PLA-NPs) with 5-fluorouracil were prepared using varying concentration and molecular weight of PLA to regulate the particle size. The dimension and shape of nanoparticles were verified by using dynamic light scattering (DLS), atomic force microscope (AFM) and scanning electron microscope (SEM). Ex-vivo permeation study was conducted by goat and rabbit excised cornea. In-vivo experiment was conducted in rabbit eye and 5-FU concentration was measured in aqueous and vitreous humor by HPLC. In-vitro experiments indicated a diffusion controlled release of 5-FU. No significant interaction was observed in between mucin and PLA NPs that measured in terms of viscosity change. Ex-vivo permeation was significantly higher with rabbit cornea as compared to goat cornea. PLA and CH-PLA DNPs showed increased level of 5-FU as comparison to 5-FU solution. In-vivo study showed significantly higher concentration in case of uncoated and CH coated PLA nanoparticles in rabbit eye as compared to free 5-FU solution. PLA nanoparticle was found non-irritant in nature by modified Draize test.

Development in malarial vaccine: A review.

Malaria, a vector-borne infectious disease, is currently a grave and universal concern with a significant social, economic, and human cost, mainly in developing countries. In addition, the emergence and spread of resistance to antimalarial therapies have further aggravated the global situation. Currently most of the research is focused on development of antimalarial drugs, drug resistance, and novel formulations to maximize the therapeutic effect. A number of novel molecules potentially active against malarial parasites are being developed. A vaccine is still viewed as a critical part of a long-term malaria control strategy. In the last several years various studies have shown significant progress in the development of vaccines against malaria. Advancement in vaccine technology and immunology is being used to develop malaria subunit vaccines that would open up new vistas for effective treatment and control of malaria. The development of an effective malaria vaccine represents one of the most important approaches that would provide a cost-effective intervention in addition to currently available malaria control strategies. An overview on progress in antimalarial vaccines is presented.

Formulation of controlled release gellan gum macro beads of amoxicillin.

Gellan gum has been reported to have wide pharmaceutical applications such as tablet binder, disintegrant, gelling agent and as a controlled release polymer. Multiparticulate delivery systems spread out more uniformly in the gastrointestinal tract and reduce the local irritation. The purpose of this study is to explore possible applicability of gellan macro beads as an oral controlled release system of a sparingly soluble drug, amoxicillin. Gellan gum beads were prepared by ionotropic gelation with calcium ions. The effect of drug loading, stirring time, polymer concentration, electrolyte (CaCl2) concentration, curing time etc. influencing the preparation of the gellan gum macro beads and the drug release from gellan gum beads were investigated in this study. Optimal preparation conditions allowed very high incorporation efficiency for amoxicillin (91%) The release kinetics of amoxicillin from gellan beads followed the diffusion model for an inert porous matrix in the order: 0.1 N HCl > phosphate buffer > distilled water. Change in curing time did not significantly affect the release rate constant, but drug concentration, polymer concentration and electrolyte concentration significantly affect the release rate of amoxicillin from the beads. The gellan macro beads may be suitable for gastro retentive controlled delivery of amoxicillin.

Development of extended release divalproex sodium tablets containing hypdrophobic and hydrophilic matrix.

Bilayered tablets of Divalproex sodium for once-a-day administration were prepared using a hydrophilic and hydrophobic polymer as release retarding agents. This technology was found to be more effective than a simple matrix tablet with a mixture of the above polymers in order to retard the drug release for a period of 24 h. The drug release profile was strongly dependent on the presence of wicking agent, pathlength of hydrophobic layer, and hardness of tablet. f(1) value of 6.92 and f(2) value of 76.72 indicated similarity between the release profiles of batch BT3 and reference tablet (Depakote((R)) ER) with the target release of over 55% within 12 h and over 85% within 18 h. Mathematical modeling using Korsmeyer-Peppas equation indicated that the release followed a combination of diffusion and erosion mechanism.

Polymeric nanoparticulate system: a potential approach for ocular drug delivery.

Various efforts in ocular drug delivery have been made to improve the bioavailability and to prolong the residence time of drugs applied topically onto the eye. The potential use of polymeric nanoparticles as drug carriers has led to the development of many different colloidal delivery vehicles. Drug loaded polymeric nanoparticles (DNPs) offer several favorable biological properties, such as biodegradability, nontoxicity, biocompatibility and mucoadhesiveness. These submicron particles are better than conventional ophthalmic dosage forms to enhance bioavailability without blurring the vision. DNPs have been shown to be amenable to targeting of the drug to the site of action, leading to a decrease in the dose required and a decrease in side effects. Additionally, DNPs can be fabricated by simple techniques with better physical stability than liposomes. This unique combination of properties makes DNPs a novel polymeric drug delivery device, which fulfils the requirements for ophthalmic application. This review discusses the polymeric nanoparticles, physiochemical characterization, fabrication techniques, therapeutic significances, patented technology of nanoparticles and future possibility in the field of ocular drug delivery.

Phase transition system: novel oral in-situ gel.

Inspite of the various impediments in the bioavailability of orally delivered drugs, oral dosage forms, both solid and liquid, occupy a center stage in the therapeutic regimen of diseases. However, liquid dosage forms are more prone to low bioavailability because of their quick transit from the stomach/ duodenum. This could be a serious problem for drugs, which are absorbed from these sites of the GIT. The gastric retention of an oral liquid formulation could be successfully augmented substantially through a strategy of liquid in-situ gelling system. Natural polymers like alginate, gellan and chitosan can undergo sol to gel transformation in the presence of either divalent cations or due to a change in pH. The gel so formed, being lighter than gastric fluids, floats over the stomach contents and is retained there in for periods upto 24 hours. The in-situ gel formation enhances the local or systemic bioavailability of the administered drug. This concept is a redesign of liquid oral dosage form, which fulfills the requirement for a sustained release liquid preparation. This review discusses the various aspects associated with the in-situ gelling systems and their therapeutic applications.

Cardiovascular effects of transdermally delivered bupranolol in rabbits: effect of chemical penetration enhancers.

Bupranolol is a promising candidate for transdermal drug delivery system (TDDS) development. The effect of permeation enhancers on the in vivo delivery and beta-blocking effect of reservoir type TDDS was studied in comparison with intravenous BPL in rabbits. The beta-blocking effect was quantified by measuring the inhibition of isoprenaline induced tachycardia in rabbits after BPL administration via transdermal and intravenous routes. The reservoir type TDDS containing a hydroxypropyl cellulose gel and polyethylene membrane was used as a control device. In comparison, the TDDS containing skin penetration enhancers, either 2-pyrrolidone or partially methylated beta cyclodextrin (PMbetaCD) were evaluated. The control device (no enhancer) produced about 52% inhibition of isoprenaline induced tachycardia at 2 h and the effect continued over 24 h application period, however, the devices with 2-pyrolidone or PMbetaCD produced about 85% inhibition of isoprenaline induced tachycardia at 3 h and the same effect continued over 24 h application period. Likewise, the AUC of these devices were significantly higher than that of control device. The intravenous bupranolol showed rapid decline in the pharmacodynamic effect with time indicating its rapid elimination. The in vivo delivery of bupranolol (as estimated by a mass balance study) from the devices made with pyrolidone or PMbetaCD was 3-fold higher than that of control. The results of this study strongly suggest that the penetration enhancers in the TDDS increased the in vivo delivery of BPL, thereby increased the beta-blocking activity of BPL by 50-60% higher than control, enabling the reduction of the TDDS patch size, accordingly.

Ionic Cross-linked Chitosan Beads for Extended Release of Ciprofloxacin: In vitro Characterization.

Chitosan beads loaded with ciprofloxacin hydrochloride were fabricated by ionic cross-linking with sodium tripolyphosphate. The beads showed an excellent water retention property. The degradation of fabricated beads was influenced by the pH of test medium. High drug load was achieved within the bead with a short curing time. Drug release was high in acidic medium (pH 1.2) vis-à-vis intestinal medium (pH 7.4). Ciprofloxacin hydrochloride release increased with an increasing concentration of ciprofloxacin and decreasing proportion of chitosan. Drug release followed both first-order and Higuchi's root time kinetics showing non-Fickian release mechanism.

Studies on Indomethacin Intraocular Implants Using Different in vitro Release Methods.

Intra ocular implants of sodium alginate alone and in combination with hydroxypropylmethylcellulose with or without calcium chloride were formulated with indomethacin as a model drug. The drug release from the implants was evaluated using static method, continuous flow through apparatus (developed in house), USP dissolution and agar diffusion. Except in the static method, indomethacin particle size did not impart any effect on the drug release. In agar diffusion method, an increase in agar concentration from 1 to 2% resulted in a significant decrease (P< 0.005) in the amount of drug released. Inclusion of hydroxypropylmethylcellulose (33.3, 41.6 and 50% w/w), resulted in decrease of indomethacin release irrespective of the method of dissolution study. The agar diffusion method and the continuous flow through methods seem to simulate to a certain extent the in vivo conditions as far as the placement of the device and the hydrodynamic diffusion layer around the intra ocular implant is concerned. The static method and USP method affected the hydrodynamic diffusion layer either too slowly or too fast.

Niridazole biodegradable inserts for local long-term treatment of periodontitis: possible new life for an orphan drug.

Periodontal pocket inserts of niridazole (NZ) made with Resomer(R) (grades RG 503H and RG858, designated as RH and RG, respectively) were studied. Various formulation variables were evaluated to obtain a biodegradable delivery systems showing device degradation and drug depletion parallel to each other in vitro. Drug release from the prepared inserts was evaluated using a static dissolution setup (for 1 month). Incorporation of 3 parts of RG in 1 part of RH inserts caused a 50% decrease in the initial release rate. The RH-NZ inserts showed a spurt in release around the 10th day of the study, which coincided with the decrease in device weight, suggesting onset of device degradation. Pilot-scale clinical trials in 12 patients indicated improvements in clinical indices from the baseline values. The average pocket depth was reduced significantly (alpha = 0.05) from 6.34 +/- 1.86 mm at baseline to 5.94 +/- 0.28 mm after 28 days of treatment.

Effect of penetration enhancers on the release and skin permeation of bupranolol from reservoir-type transdermal delivery systems.

A reservoir-type transdermal delivery system (TDS) of bupranolol (BPL) was designed and evaluated for different formulation variables like gel reservoirs (made with anionic and nonionic polymers), rate controlling membranes and penetration enhancers on the drug release and in vitro skin permeation kinetics of the devices. Keshary-Chien type diffusion cells and pH 7.4 phosphate buffered saline (PBS) were used for drug release studies and excised rat skin was used as a barrier for permeation experiments. The release rate of BPL from nonionic polymer gel reservoirs [hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC)] was much higher than anionic polymer gel reservoirs [carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (Na CMC) and sodium alginate)]. Among different rate controlling membranes, Cotran-polyethylene microporous membrane demonstrated highest release rate for BPL than all other membranes. An optimized TDS formulation with HPC gel and Cotran-polyethylene microporous membrane was used to study the effect of penetration enhancers on the release and skin permeation rate of BPL from the TDS. Permeation rates of the devices containing 5% (w/v) pyrrolidone (PY) or 1-methyl-2-pyrrolidone (MPY) were about 3- and 1.5-fold higher than control (no enhancer, P<0.01) indicating PY to be better penetration enhancer for BPL than MPY. The permeation rates of devices containing partially methylated beta-cyclodextrin (PMbetaCD) and PMbetaCD-BPL complex were about 2.5- and 1.4-fold higher than control (P<0.01). Inclusion of 10 and 30% w/v propylene glycol (PG) in the devices increased the permeation rate by 1.4- and 1.8-fold higher than control (P<0.05). In conclusion, reservoir-type TDS of BPL was developed and penetration enhancers increased the skin permeation of BPL at 4-5 times higher levels than the desired target delivery rate.

Effect of cyclodextrins on the complexation and transdermal delivery of bupranolol through rat skin.

Bupranolol (BPL) is a potent beta-blocking agent, the extensive first-pass metabolism (>90%) and rapid elimination half-life (1.5-2.0 h) of this drug make it well suited to be developed as a transdermal delivery system (TDS). Hydroxypropyl betaCD (HPbetaCD) and partially methylated betaCD (PMbetaCD) were used as penetration enhancers for BPL. The formation of inclusion complex of BPL with these cyclodextrins (CDs) was characterized in solution and solid states by phase solubility, X-ray diffractometry and differential scanning calorimetry (DSC) analyses. The effect of CDs on the permeation enhancement of BPL through rat skin was studied using side-by-side diffusion cells and pH 7.4 phosphate-buffered saline (PBS). CDs were employed at different concentrations with 0.4% (w/v) BPL as well as with excess quantity of BPL (1.0%, w/v) that CDs could not complex all the BPL and the drug was in the form of an aqueous suspension. The permeation of BPL from its aqueous suspension (0.4%, w/v) significantly increased when CDs were used at low concentrations (up to 2 and 5%, w/v concentration for HPbetaCD and PMbetaCD, respectively) (P < 0.01). At higher CD concentrations, the permeation of BPL decreased; and both CDs at 10% (w/w), showed similar flux values to that of control (no enhancer, P > 0.05). The permeation of BPL from its 1.0% (w/v) aqueous suspension increased with increase in concentration of CD up to 10% (w/v) for HPbetaCD and PMbetaCD. At 10% (w/v) concentration of HPbetaCD and PMbetaCD, the flux of BPL from its 1.0% aqueous suspension increased 3.8- and 4.6-fold (P < 0.01 and P < 0.001, respectively). The permeation data of skin pretreatment with CDs indicate that HPbetaCD had no effect on the skin, whereas PMbetaCD significantly reduced the skin barrier for BPL, as shown by 1.7-fold increase in the flux by PMbetaCD pretreatment (P < 0.001). Overall, both HPbetaCD and PMbetaCD were found to be suitable for improving the solubility and penetration enhancement of BPL.

Gellan-based scleral implants of indomethacin: in vitro and in vivo evaluation.

Film-type scleral implants of indomethacin with gellan gum were prepared by solvent casting and evaluated for uniformities of thickness, weight, drug content, and surface pH. The effect of plasticizers like glycerol, propylene glycol (PG), and polyethylene glycol 200, and 400 on the void volume of free gellan films (placebo) was calculated from the water content of the films. The drug release from the prepared implants was determined using a static dissolution set-up developed and optimized in our laboratory. Based on the results of the void volume and initial drug release studies, glycerol and PG were selected as the plasticizers for the gellan-based implants. The morphology of the drug-free films (containing 10% and 40% of PG) and the drug-loaded films (before and after dissolution and crosslinked) was studied using scanning electron microscopy. Further, the effect of plasticizer concentration, gellan concentration, effect of crosslinking technique, and duration of crosslinking using calcium chloride on in vitro drug release characteristics were evaluated. Selected batches of the implants were subjected to pharmacodynamic studies, after scleral placement, in uveitis-induced (intravitreal injection of bovine serum albumin 50 microg/ml) rabbit eyes. The release of indomethacin from the prepared implants followed matrix diffusion kinetics with diffusion co-efficient (n) values ranging between 0.358 to 0.708 and seemed to depend on both gellan and plasticizer concentration. Surface crosslinking with 10% calcium chloride for 8 hr retarded drug release (1.42 times less than noncrosslinked implant) and was optimum. The pharmacodynamic studies showed a marked improvement in the various clinical parameters (congestion, keratitis, flare, clot, aqueous cells, and synechias) in the implanted eye compared with the control eye in the rabbits. The scleral implants survived up to 3 weeks in vivo.

In vitro and in vivo characterization of scleral implant of indomethacin: role of plasticizer and cross-linking time.

Film-type scleral implants of indomethacin using sodium alginate and PEG 400 and 600 (3, 5, 8, and 10% w/w w.r.t. sodium alginate) as plasticizers were fabricated by solvent casting. The prepared implants were cross-linked by treatment with calcium chloride 10, 20, and 30% w/v solution, for periods between 1 to 24 hr. Uniformity of thickness, weight, and drug content and surface pH of the implants were evaluated. The influence of plasticizer type/concentration and crosslinking time/concentration of calcium chloride on indomethacin release was studied on a static dissolution setup developed by us. Selected batches of the implants were subjected to pharmacodynamic studies, after scleral placement, in uveitis-induced (intravitreal injection of bovine serum albumin 50 microg/ml) rabbit eyes. The release of indomethacin from the implants was influenced by the concentration and nature of plasticizers used. Chemical cross-linking with calcium chloride was successful in retarding the drug release. The pharmacodynamic studies showed a marked improvement in the various clinical parameters (congestion, keratitis, flare, clot, aqueous cells, and synechias) in the implanted eye when compared with the control eye in the rabbits. The implants survived for 2 weeks in vivo.