Utility of in situ sodium alginate/karaya gum gels to facilitate gastric retention in rodents

Target validation or demonstration of efficacy requires adequate in vivo exposure of tool molecules to determine their activity in order to validate the model or show the potential usefulness of the pharmacophore. Early discovery work is often carried out with compounds which possess undesirable PK properties in small rodents where the discovery formulation scientist is often forced to dose 2-4 times per day. Gastric retentive formulations in small rodents (rats/mice) could enable increased duration of exposure for compounds with narrow absorption windows or increased residence time for compounds with targets located in the GI tract. The aim of this work is to establish an easily administered gastric retentive gel for rodents in situ using a mixture of sodium alginate and karaya gum. Feasibility studies were conducted in Sprague-Dawley rats using barium sulfate as a radio-opaque tracer. The results show that gastric retention of barium was achieved for rats dosed with the gel formulation relative to a barium suspension. The gastric residence time of the gel varied from 1h to >8h (n=3). The data suggest that sodium alginate/karaya gum gels may be a useful tool to achieve gastric retention in rodent studies.     

Gastroretentive mucoadhesive tablet of lafutidine for controlled release and enhanced bioavailability

Abstract

Lafutidine a newly developed histamine H2-receptor antagonist having biological half-life of 1.92?±?0.94?h due to its selective absorption from upper part of gastrointestinal tract the development of mucoadhesive sustained release drug delivery system is recommended in order to enhance the bioavailability. A mucoadhesive tablets was developed using the natural polymer, sodium alginate, xanthan gum and karaya gum. Mucoadhesion is a complex phenomenon which involves wetting, adsorption and interpenetration of polymer chains. The prepared tablets of various formulations were evaluated for a total mucoadhesion time, buoyancy lag time and percentage drug released. The formulation with xanthan gum showed better results. Thus, it may be useful for prolonged drug release in stomach to improve the bioavailability and reduced dosing frequency. Non-fickians release transport was confirmed as the drug release mechanism from the optimized formulation by Korsmeyer–Peppas. The optimized formulation (B3) showed a mucoadhesive strength >35?g. In vivo study was performed using rabbits by X-ray imaging technique. Radiological evidences suggest that, a formulated tablet was well adhered for >10?h in rabbit’s stomach. Optimized lafutidine mucoadhesive tablets showed no significant change in physical appearance, drug content, mucoadhesive properties and in vitro dissolution pattern after storage at 40?°C temperature 75?±?5% relative humidity for 3 months.     

Natural gum as mucoadhesive controlled release carriers: evaluation of Cefpodoxime Proxetil by D-Optimal design technique

Abstract

The present study deals with the development of mucoadhesive controlled release tablets of Cefpodoxime Proxetil to increase the gastric residence time and thus prolong drug release, reduce dosing frequency and improve oral bioavailability. Tablets were prepared using sodium alginate and karaya gum, a natural polymer, with a synthetic polymer hydroxypropylmethylcellulose (K100LV) and Karaya gum with HPMC K100LV in various ratios to optimize the drug release profile using D-Optimal technique. Pre- and post-compression parameters of tablets prepared with various formulations (S1–S9, C1–C9) were evaluated. The FTIR and DSC studies revealed that no physiochemical interaction between excipients and drug. The formulation S7 showed prolonged drug release, and the mechanism of drug release from the optimized formulation was confirmed using the Korsmeyer–Peppas model to be non-Fickian release transport and n value was found 0.605 indicating both diffusion and erosion mechanism from these natural gums. The optimized formulation showed mucoadhesive strength >35?g. An in vivo study was performed on rabbits using an X-ray imaging technique. The radiological evidence suggests that the tablets adheres (more than 10 hours) to a rabbit’s stomach. No significant changes were found in the physical appearance, drug content, mucoadhesive study and in vitro dissolution pattern after storage at 40?°C/75% relative humidity for 3 months.     

Preparation and Characterisation of Mucoadhesive Nasal Gel of Venlafaxine Hydrochloride for Treatment of Anxiety Disorders

The aim of the present study is to prepare and evaluate mucoadhesive nasal gels of venlafaxine hydrochloride. Mucoadhesive nasal gels were prepared using polymers like carbopol 934 and sodium alginate and characterized in terms of viscosity, texture profile analysis, ex vivo drug permeation profiles and histopathological studies. The results show that values of viscosity, hardness and adhesiveness increase while those of cohesiveness decrease with corresponding increase in concentration of the polymers. Ex vivo drug permeation profiles showed that formulation containing 5% sodium alginate provided a better controlled release of the drug than the other formulations over a period of 12 h. Histopathological studies assured that gels containing different polymers did not produce any significant change in the nasal mucosae of goat even after 12 h permeation study. Mucoadhesive nasal gel of venlafaxine hydrochloride is a novel dosage form which delivers the drug directly into systemic circulation and provides controlled release of the drug.     

Compressed xanthan and karaya gum matrices: hydration, erosion and drug release mechanisms

Directly compressed matrices were produced containing either xanthan gum or karaya gum as a release-controlling agent. These swellable hydrophilic natural gums were used to control the release of varying proportions of two model drugs, caffeine and diclofenac sodium, which have different solubilities in aqueous medium. Gum erosion, hydration and drug release studies were carried out using a dissolution apparatus (basket method) at two agitation speeds. Xanthan gum displayed a high degree of swelling due to water uptake and a small degree of erosion due to polymer relaxation. Neither agitation speed nor drug solubility had any significant effect on water uptake, but matrices with the lower proportion of gum produced a lesser degree of hydration. In contrast, karaya gum displayed a much lower hydration capacity and a higher rate of erosion, both markedly affected by agitation speed. Drug release from xanthan and karaya gum matrices depended on agitation speed, solubility and proportion of drug. Both xanthan and karaya gums produced near zero order drug release with the erosion mechanism playing a dominant role, especially in karaya gum matrices.     

Gastroretentive Cosolvent-Based In Situ Gel as a Promising Approach for Simultaneous Extended Delivery and Enhanced Bioavailability of Mitiglinide Calcium

Ion cross-linking in situ gels are novel liquid sustained-release drug delivery systems. These systems are unsuitable for poorly water-soluble drugs such as the novel antidiabetic drug mitiglinide calcium (MTG). Thus, our goal was to assess the possibility of using cosolvency approach in formulating gastroretentive in situ gel of the short half-life MTG to simultaneously enhance its bioavailability and sustain its release. MTG in situ gel formulations were developed using propylene glycol as a cosolvent to dissolve MTG in the polymer solution, followed by characterization of viscosity, gel strength, floating ability, and in vitro MTG release and phramacokinetics evaluation. The optimized formulation (composition: 1% gellan gum, 0.75% sodium alginate, 0.75% calcium carbonate, and 7.5% propylene glycol) exhibited reasonable viscosity but on introduction into simulated gastric fluid, it formed firm gel that floated within seconds over the surface and remained buoyant for 24 h. The formula exhibited in vivo sustained release manner of MTG over 24 h and improved the bioavailability of the drug. Thus, cosolvency presents a promising approach to deliver hydrophobic drugs in sustained-release liquid formulations. These formulations will improve diabetic patients' compliance by eliminating the necessity of frequent dosing with a better disease management.     

Case Studies for Practical Food Effect Assessments across BCS/BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data

Practical food effect predictions and assessments were described using in silico, in vitro, and/or in vivo preclinical data to anticipate food effects and Biopharmaceutics Classification System (BCS)/Biopharmaceutics Drug Disposition Classification System (BDDCS) class across drug development stages depending on available data: (1) limited in silico and in vitro data in early discovery; (2) preclinical in vivo pharmacokinetic, absorption, and metabolism data at candidate selection; and (3) physiologically based absorption modeling using biorelevant solubility and precipitation data to quantitatively predict human food effects, oral absorption, and pharmacokinetic profiles for early clinical studies. Early food effect predictions used calculated or measured physicochemical properties to establish a preliminary BCS/BDDCS class. A rat-based preclinical BCS/BDDCS classification used rat in vivo fraction absorbed and metabolism data. Biorelevant solubility and precipitation kinetic data were generated via animal pharmacokinetic studies using advanced compartmental absorption and transit (ACAT) models or in vitro methods. Predicted human plasma concentration–time profiles and the magnitude of the food effects were compared with observed clinical data for assessment of simulation accuracy. Simulations and analyses successfully identified potential food effects across BCS/BDDCS classes 1–4 compounds with an average fold error less than 1.6 in most cases. ACAT physiological absorption models accurately predicted positive food effects in human for poorly soluble bases after oral dosage forms. Integration of solubility, precipitation time, and metabolism data allowed confident identification of a compound’s BCS/BDDCS class, its likely food effects, along with prediction of human exposure profiles under fast and fed conditions.     

An alternative approach to wound healing field; new composite films from natural polymers for mupirocin dermal delivery

In this study, novel adhesive films were prepared for Mupirocin dermal delivery. Natural polymers as chitosan, sodium alginate and carbopol were used for films development to evaluate possible interactions and drug release properties. Solvent evaporation method was used for films preparation. Preliminary studies involved FT-IR spectroscopy and Scanning Electron Microscopy to specify interactions and morphology. Thickness, tensile strength and water uptake in phosphate buffer saline were evaluated whereas in vitro release studies were also performed. In vitro drug release studies demonstrated that mupirocin release was improved. Ex vivo bioadhesion and permeation studies using Balb-c mice were performed to check the suitability of the films. Antimicrobial ability was evaluated by agar well diffusion tests. Finally, excisional wound model applied to test the wound healing effect and evaluated macroscopic and histopathologically. One formulation was found more effective compared to the market product for wound healing at Balb-c mice.     

Formulation of metoclopramide HCl gastroretentive film and in vitro- in silico prediction using Gastroplus® PBPK software

The new trends in pharmaceutical studies focus on targeting drug delivery and computer software that help in the body environment simulation, such as Gastroplus® software. The interest of this study is to prepare a gastroretentive film of metoclopramide HCl (MTC) that was followed by applying the in silico approach to estimate the in vivo prepared formulations. The films were prepared from HPMC E5 and sodium alginate polymers as primary polymers with the aid of secondary polymers. The sodium alginate high proportions films showed instant and long floating duration reaching 24 h but with variable folding endurance. Moreover, sodium alginate films with their secondary polymers carbopol and HPMC E5 slowed the release of MTC. The floating and slow-release patterns assessed the gastroretentive properties of sodium alginate films and were further examined by a mucoadhesive study that guaranteed mucosal adhesion, and the film’s FESEM images showed similar top morphology, but different side view structures. Last, the pharmacokinetic profile of selected films that approached the gastroretentive properties was in silico predicted depending on in vitro release study and floating duration employing the physiological-based pharmacokinetic model in Gastroplus® software. The model determines this prediction found successfully of intravenous and immediate oral release tablets (10 and 30 mg) of MTC. The simulation showed a high amount of MTC retained for long periods in the stomach to Sod.Alginate-3, Sod.Alginate-8, and Sod.Alginate-10 films (films of secondary polymers carbopol and HPMC E5) aid in reaching the optimum site of absorption jejunum 1 due to the slow MTC release.     

A Novel In Situ Gel Formulation of Ranitidine for Oral Sustained Delivery

The main purpose of this study was to develop a novel, in situ gel system for sustained delivery of ranitidine hydrochloride. Ranitidine in situ gels at 0.2%, 0.5%, and 1.0% gellan gum concentration (w/v) were prepared, respectively, and characterized in terms of preparation, viscosity and in vitro release. The viscosity of the gellan gum formulations in solution increased with increasing concentrations of gellan gum. In vitro study showed that the release of ranitidine from these gels was characterized by an initial phase of high release (burst effect) and translated to the second phase of moderate release. Single photon emission computing tomography technique was used to evaluate the stomach residence time of gel containing ^99mTc tracer. The animal experiment suggested in situ gel had feasibility of forming gels in stomach and sustained the ranitidine release from the gels over the period of at least 8 h. In conclusion, the in situ gel system is a promising approach for the oral delivery of ranitidine for the therapeutic effects improvement.     

Characterization of Supersaturatable Formulations for Improved Absorption of Poorly Soluble Drugs

With the increasing number of poorly water-soluble compounds in contemporary drug discovery pipelines, the concept of supersaturation as an effective formulation approach for enhancing bioavailability is gaining momentum. This is intended to design the formulation to yield significantly high intraluminal concentrations of the drug than the thermodynamic equilibrium solubility through achieving supersaturation and thus to enhance the intestinal absorption. The major challenges faced by scientists developing supersaturatable formulations include controlling the rate and degree of supersaturation with the application of polymeric precipitation inhibitor and maintenance of post-administration supersaturation. This review is intended to cover publications on this topic since April 2009. Scientific publications associated with characterization of supersaturatable systems and related preclinical and clinical pharmacokinetics (PK) studies are reviewed. Specifically, this review will address issues related to assessing the performance of supersaturatable systems including: (1) Diversified approaches for developing supersaturatable formulations, (2) meaningful in vitro test methods to evaluate supersaturatable formulations, and (3) in vivo PK study cases which have demonstrated direct relevance between the supersaturation state and the exposure observed in animal models and human subjects.     

Development of Press-Coated,Floating-Pulsatile Drug Delivery of Lisinopril

Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor, primarily used for the treatment of hypertension, congestive heart failure, and heart attack. It belongs to BCS class III having a half-life of 12 hrs and 25% bioavailability. The purpose of the present work was to develop a press-coated, floating-pulsatile drug delivery system. The core tablet was formulated using the super-disintegrants crosprovidone and croscarmellose sodium. A press-coated tablet (barrier layer) contained the polymer carrageenan, xanthan gum, HPMC K4M, and HPMC K15M. The buoyant layer was optimized with HPMC K100M, sodium bicarbonate, and citric acid. The tablets were evaluated for physical characteristics, floating lag time, swelling index, FTIR, DSC, and in vitro and in vivo behavior. The 5% superdisintgrant showed good results. The FTIR and DSC study predicted no chemical interactions between the drug and excipients. The formulation containing xanthan gum showed drug retaining abilities, but failed to float. The tablet containing HPMC K15M showed a high swelling index. The lag time for the tablet coated with 200 mg carrageenan was 3±0.1 hrs with 99.99±1.5% drug release; with 140 mg HPMC K4M, the lag time was 3±0.1 hrs with 99.71±1.2% drug release; and with 120 mg HPMC K15M, the lag time was 3±0.2 hrs with 99.98±1.7% drug release. The release mechanism of the tablet followed the Korsmeyer-Peppas equation and a first-order release pattern. Floating and lag time behavior have shown good in vitro and in vivo correlations.     

Polyethyleneimine-treated xanthan beads for prolonged release of diltiazem: <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis> evaluation

The purpose of the study was to develop a multiunit sustained release dosage form of diltiazem hydrochloride using a natural polymer, sodium carboxymethyl xanthan gum and polyethyleneimine (PEI) from a completely aqueous environment. PEI treated diltiazem resin complex loaded beads were characterized by morphology, drug entrapment efficiency, in vitro and in vivo release behaviour. 40% and 80% drug was released in 2 hour in pH 1.2 and in 5 to 6 h in pH 6.8 respectively depending on the formulation variables. The prolonged release was attributed to decreased swelling of the beads due to PEI treatment. Maintaining the shape throughout the dissolution process, PEI treated diltiazem resin complex beads released the drug following non-Fickian transport phenomena. In vivo pharmacokinetic evaluation in rabbits shows slow and prolonged drug release when compared with diltiazem solution. The designed beads are suitable for prolonged release of a water soluble drug under a complete aqueous environment using natural gum.     

Oral Delivery of Highly Lipophilic,Poorly Water-Soluble Drugs: Self-Emulsifying Drug Delivery Systems to Improve Oral Absorption and Enable High-Dose Toxicology Studies of a Cholesteryl Ester Transfer Protein Inhibitor in Preclinical Species

BMS-A is an inhibitor of cholesteryl ester transfer protein and is a highly lipophilic compound (clogP 10.5) with poor aqueous solubility (<0.0001 mg/mL at pH 6.5). The compound exhibits low oral exposure when dosed as cosolvent solution formulations. The purpose of this study was to evaluate lipid-based formulations for enabling high-dose toxicology studies and enhancing toxicology margins of BMS-A in preclinical studies in nonrodent species. The solubility of BMS-A was screened in lipid and cosolvent/surfactant excipients, and prototype formulations were developed. In vitro tests showed that fine/microemulsions were formed after aqueous dilution of lipid formulations, and BMS-A was transferred from oil phase to aqueous phase with enhanced solubility following lipid digestion. When dosed in dogs at 200 mg/kg, a Gelucire-based formulation exhibited more than 10-fold higher exposure compared to the solution formulation and was thus selected for toxicology studies in dogs. For monkeys, an olive oil formulation was developed, and the exposure was about 7-fold higher than that from the solution. In summary, lipid-based drug delivery could be applied in early stages of drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic compounds, while facilitating the candidate selection of a molecule which is more specifically designed for bioperformance in a lipid-based drug delivery strategy.     

Enhanced bioavailability of buspirone hydrochloride via cup and core buccal tablets: Formulation and in vitro/in vivo evaluation

This work aims to prepare sustained release buccal mucoadhesive tablets of buspirone hydrochloride (BH) to improve its systemic bioavailability. The tablets were prepared according to 5 × 3 factorial design where polymer type was set at five levels (carbopol, hydroxypropyl methylcellulose, sodium alginate, sodium carboxymethyl cellulose and guar gum), and polymer to drug ratio at three levels (1:1, 2:1 and 3:1). Mucoadhesion force, ex vivo mucoadhesion time, percent BH released after 8 h (Q8h) and time for release of 50% BH (T_50%) were chosen as dependent variables. Additional BH cup and core buccal tablets were prepared to optimize BH release profile and make it uni-directional along with the tablets mucoadhesion. Tablets were evaluated in terms of content uniformity, weight variation, thickness, diameter, hardness, friability, swelling index, surface pH, mucoadhesion strength and time and in vitro release. Cup and core formula (CA10) was able to adhere to the buccal mucosa for 8 h, showed the highest Q8h (97.91%) and exhibited a zero order drug release profile. Pharmacokinetic study of formula CA10 in human volunteers revealed a 5.6 fold increase in BH bioavailability compared to the oral commercial Buspar^® tablets. Conducting level A in vitro/in vivo correlation showed good correlation (r² = 0.9805) between fractions dissolved in vitro and fractions absorbed in vivo.     

Bioadhesive Films Containing Fluconazole for Mucocutaneous Candidiasis

Fluconazole is a broad spectrum antifungal agent that has been extensively applied for the management of oral, pharyngeal and cutaneous candidiasis. Fluconazole has a high volume of distribution (0.55–0.65 l/kg) and has systemic toxicity due to high drug-drug interaction. The present study focuses on the formulation of bioadhesive film as a controlled release carrier for fluconazole. The formulation was intended to provide localized delivery of fluconazole exclusively at the site of infection, thereby reducing its total dose and hence, dose-related toxicities. Bioadhesive films were prepared by solvent casting method using sodium alginate and polyvinyl alcohol alone as well as in various combinations. Prepared films were evaluated for physical characteristics like, weight and content uniformity, film thickness, swelling index, microenvironment pH and folding endurance. In vitro drug release, in vitro and ex vivo residence time, bioadhesive strength and skin irritation were also studied. Accelerated stability study was conducted on the optimized formulation as per ICH guidelines. Weight of all the films were not more than 20 mg. Thickness of the films ranged between 0.09 to 0.15 mm whereas swelling indices showed a high extent of variation. Films composed of polyvinyl alcohol alone provided a swelling index of 6%. Bioadhesive strength was found to be more than 18 g. Microenvironment pH was near to 7.0 for most of the formulations. Ex vivo residence time of optimized batch was more than 5 h and it provided controlled drug release up to 8 h. As revealed in FT-IR and DSC studies, drug was found to be compatible with the excipients used in this study.     

In vitro and in vivo consideration of novel environmentally responsive ophthalmic drug delivery system

In the present study, novel environmentally responsive ophthalmic drug delivery system composed of two gelling polymers with different phase transition mechanisms was developed in order to obtain sustained drug release in ocular cavity. Combination of polyacrylic acid (carbopol 934P) and xanthan gum was investigated as ophthalmic vehicle and assessed for its in vitro and in vivo performance. Different ratios of these polymers were used to prepare environmentally responsive ophthalmic drug delivery system by simple mixing procedure. Developed formulation was assessed for physical tests such as appearance/clarity, pH, gelation; and performance characteristics such as drug content, rheological measurement, in vitro release, antimicrobial efficiency, in vivo studies for eye irritation, residence time estimation. Prepared formulation showed agreeable appearance/clarity, acceptable pH and good gelation property. In vitro and in vivo studies demonstrated adequate drug content, desired rheological behavior and reasonable in vitro and in vivo drug release property. In conclusion, the optimum concentration of polymers results in increased residence time and sustained drug release. On the basis of these findings, environmentally responsive system based on combination of carbopol and xanthan gum may be considered as a promising tool for ophthalmic delivery.     

Utilizing a Novel Tandem Oral Dosing Strategy to Enhance Exposure of Low-Solubility Drug Candidates in a Preclinical Setting

Time and resource constraints necessitate increasingly early decision making to accelerate or stop preclinical drug discovery programs. Early discovery drug candidates may be potent inhibitors of new targets, but all too often exhibit poor pharmaceutical and pharmacokinetic properties that limit the in vivo exposure. Low solubility of a drug candidate often leads to poor oral bioavailability and poor dose linearity that creates an issue for efficacy and target safety studies, where high drug exposures are desired. When solubility issues are encountered, enabling formulations are often used to improve the exposure. However, this approach often requires a substantial and lengthy investment to develop the formulation. In our study, two drug candidates with poor aqueous solubility were dosed in rats as simple suspension formulations using a novel tandem dosing strategy, which employs dosing orally in 2.5 h increments up to three times to simulate an oral infusion by avoiding saturation of absorption associated with bolus dosing. These compounds were also dosed using the same suspension formulations and a standard dosing strategy. The resulting in vivo exposures were compared. It was found that this novel tandem dosing strategy significantly improved the in vivo exposures. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3132-3140, 2010     

Duel-Acting Subcutaneous Microemulsion Formulation for Improved Migraine Treatment with Zolmitriptan and Diclofenac: Formulation and In Vitro-In Vivo Characterization

Subcutaneous triptan provides immediate analgesia in migraine and cluster headache but is limited by high pain recurrence due to rapid drug elimination. A dual-acting subcutaneous formulation providing immediate release of a triptan and slow but sustained release of a nonsteroidal anti-inflammatory drug may provide a longer duration of relief. A microemulsion-based technology has various advantages over other technically complex dosage forms. Oil-in-water microemulsions of zolmitriptan and diclofenac acid using Labrafac Lipophile, Tween 80, Capryol 90 and water were prepared. One formulation was characterised in vitro and found to have uniformly dispersed nanosized globules. The formulation provided differential release of zolmitriptan and diclofenac acid both in vitro as well as in vivo that may be potentially beneficial to migraine patients.     

Effects of anticonvulsants on the in vivo and in vitro release of gaba

The actions of various anticonvulsant compounds on GABA release in vivo and in vitro were studied. An in vivo, superfusion of sensorimotor cerebral cortex was employed and drugs were administered either by intraperitoneal injection, or in superfusion fluid and release of endogenous amino acids was measured. The in vitro method involved superfusion of synaptosomes, with drugs dissolved in superfusate, with monitoring of the release of pre-loaded [U¹⁴C]-GABA. Two alkyl-GABA analogues, γ-acetylenic GABA and γ-vinyl GABA caused enhanced release of GABA to superfusate both in vivo and in vitro. However, phenobarbitone, diphenyl hydantoin, sodium n-dipropyl acetate and carbamazepine were without effect on GABA release in either test system. Taurine caused no detectable GABA release in vivo, or from purified synaptosomes in vitro, but did stimulate release in vitro, from crude synaptosome preparations containing mitochondria in large quantities, though histidine and leucine were equally effective.