Bioadhesive Ranitidine Hydrochloride for Gastroretention with Controlled Microenvironmental pH

Ranitidine hydrochloride is a H₂ receptor blocker used in the treatment of gastric ulcers. Pharmacological factors, in addition to the dosage regimen, favor development of a sustained-release system for ranitidine especially in the therapeutic condition of erosive esophagitis. This investigation delves into the development of bioadhesive type of gastroretentive formulation (tablets) of ranitidine. The effect of mucoadhesive polymers such as Carbopol, hydroxypropyl methyl cellulose, and dextrose were studied. Mucoadhesion, in vitro drug release profile, water uptake, and swelling of the tablet were evaluated. Alkalizing agents were incorporated in an attempt to maintain an alkaline microenvironment within the tablet and improve the stability of the drug in acidic medium. The stability was evaluated using dye test and degradation studies. The drug release profiles were fit into various kinetic models.     

Fabrication of anodically electrodeposited iridium oxide film pH microelectrodes for microenvironmental studies

A new method for fabrication of anodically electrodeposited iridium oxide film pH microelectrodes has been developed in this study. Novel for its tip size (3-10-microm tip diameter), the microelectrode is fabricated in a tapered glass micropipet filled with a low melting point alloy. The tapered end is recessed and platinized. Thereafter, iridium oxide is electrodeposited over the platinized end in the recessed part. The microelectrode has a very short response time (t80 < 5 s) in the pH range of 0-12 with an accuracy of 0.05 pH unit. The pH microelectrode is not affected by most ions and complexing agents of relevance in environmental and biological studies; it can be used in fluids over wide ranges of stirring speeds (0-55 rpm) and temperatures (approximately 5-40 degrees C). Redox agents such as dissolved oxygen and hydrogen peroxide have no effect on the pH response while quinhydrone, ferro- and ferricyanide, and sodium sulfide have marked effects. However, the microelectrode can still be used in any sample when calibration is done in standards having similar redox characteristics.     

Bioadhesive mannosylated nanoparticles for oral drug delivery

The aim of this work was to design mannosylated Gantrez AN nanoparticles (M-NP) and to describe their gut bioadhesive properties in order to develop a promising carrier for future applications in oral drug delivery. For that purpose, the process of the nanoparticles coating with mannosamine was optimized by the incubation of Gantrez AN nanoparticles with different volumes of mannosamine aqueous solutions at different times. Then, the nanoparticles were characterized by measuring the size, zeta potential, mannosamine content, and concanavalin A (Con A) binding. Furthermore, in vivo quantitative bioadhesion study and kinetic analysis of the bioadhesion curves were performed after oral administration to rats of fluorescently labelled nanoparticles. The selected mannosylated nanoparticles (M-NP1 and M-NP10) were of homogenous sizes (about 300 and 200 nm), negatively charged and successfully coated with 36 and 18 microg mannosamine/mg NP, respectively. In vitro agglutination assay using Con A confirmed the successful coating of nanoparticles with mannosamine. The gut distribution profile of M-NP1 indicated a stronger bioadhesive capacity than M-NP10 and non-mannosylated ones, 1 h post-administration. Interestingly, M-NP1 showed an important ileum tropism where around 20% of the given dose remained adhered. Besides, the kinetic parameters of the bioadhesion profile of M-NP1 indicated their higher bioadhesive capacity with Q(max) and AUC(adh) about 2-times higher than control ones. Moreover, fluorescence microscopy corroborated the stronger interactions of M-NP1 with the normal mucosa and demonstrated a strong uptake of these carriers by Peyer's patches. In conclusion, we propose that mannosylated nanoparticles could be a promising non-live vector for oral delivery strategies.     

Development of hydroxyapatite bone cement for controlled drug release via tetracycline hydrochloride

The purpose of this work was to study the preparation and characterization of drug–hydroxyapatite cement. The hydroxyapatite (HA) cement has been synthesized by using tricalcium phosphate, calcium carbonate and dicalcium phosphate anhydrous with sodium hydrogen phosphate as liquid phase. The effect of added tetracycline hydrochloride (TCH) as drug on final phases, microstructure, setting behaviour and compressive strength has been studied. The drug release rate was first order within the first day and then was zero order. No obvious difference could be detected in XRD patterns of the TCH–HA cement with various amounts of drug. By increasing the drug concentration, mechanical strength of cement was decreased and its setting time was increased. The results of this study demonstrate the potential of using HA cement as a carrier for drug delivery.     

The influence of drug-excipient and drug-polymer interactions on butt adhesive strength of ranitidine hydrochloride film-coated tablets

The influence of fillers and polymeric films on adhesive strength of hydroxypropyl methylcellulose (HPMC) and Eudragit E100® films coated on ranitidine HCl tablets containing either spray-dried rice starch (SDRS) or lactose monohydrate as fillers after storage at 45°C/75% RH for four weeks was investigated by the use of butt adhesion technique. The adhesive strength of film-coated tablets of fillers without drug was found to slightly decrease after storage. In contrast, the adhesive strength of drug-containing film-coated tablets significantly reduced, the degree of which was higher for Eudragit E100® than HPMC. Physicochemical characterization by employing differential scanning calorimetry (DSC) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) revealed that the drug was obviously incompatible with lactose and possibly mild interaction with Eudragit E100® was suggested. The results indicated that the adhesive strength of film-coated tablets would be affected not only by the drug-excipient interaction, but also by the drug-polymeric film interaction.     

Nanoreactors for pH controlled sequential activity switching in multistep enzymatic processes

This theoretical model predicts that the activity of multiple enzymes may be controlled simultaneously with superior efficiency in nanosized reactors by adjusting pH. Multistep enzymatic processes employed for various purposes including organic biotransformation may require application of multiple reactions and isolation of intermediates. Sequential activity switching would offer substantial advantages. Nanoreactors would provide better option to fully appreciate the pH switching approach.     

盐酸阿霉素在纳米载体氧化石墨烯上的可控负载与释放

采用改性Hummers法制备了氧化石墨烯,并探索了其在生物医学方面作为纳米药物载体的应用。通过超声、振荡等方法制备了氧化石墨烯-盐酸阿霉素(GO-DXR),采用高分辨透射电镜(HRTEM)、傅里叶变换红外光谱(FT-IR)、紫外-可见分光光谱(UV-Vis)等测试方法对GO负载DXR前后的形貌和结构进行了研究。DXR在GO上的负载量高达4.6mg/mg,DXR的释放量可通过pH值控制,说明GO与DXR之间依靠氢键作用结合。     

Magnetic nanocarriers with tunable pH dependence for controlled loading and release of cationic and anionic payloads

Superparamagnetic nanocarriers with tunable pH dependence of the surface charge are designed by a simple co-precipitation method. By exploiting electrostatic interactions, cationic or anionic payloads can be adsorbed and desorbed depending on the pH. On three different resulting nanocarrier systems, experiments of loading and release of gold nanoparticles as well as effective siRNA loading and in vitro delivery on human cells are performed.     

Design and evaluation of soluble ocular drug insert for controlled release of ciprofloxacin hydrochloride

Purpose: Soluble ocular inserts of ciprofloxacin hydrochloride were prepared with the aim of achieving once a day administration. Design: Drug reservoir was prepared using natural hydrophilic polymer viz. gelatin while rate-controlling membrane was prepared using hydrophobic ethyl cellulose. Ocular inserts were evaluated for their physicochemical parameters like thickness, weight uniformity, drug content, percent moisture loss, and percent moisture absorption. The in vitro drug release studies were carried out using Bi-chambered donar receiver compartment model. Since targeted prolong release was observed in formulation CF2 and CF5, these formulations were further subjected to in vivo drug release study using rabbits as an animal model. In vitro drug release kinetic data was treated according to Zero, First, and Higuchi kinetics to access the mechanism of drug release. Results: Correlation between in vitro and in vivo drug release was found to be strong revealing the efficacy of the formulation. Conclusion: Formulation CF5 has achieved target of present study such as increase residence time, prolong drug release, reduction in frequency of administration, and, thus may improve the patient compliance.     

The effect of moisture on the physical characteristics of ranitidine hydrochloride tablets prepared by different binders and techniques

The effect of moisture on the physical properties of ranitidine hydrochloride tablets prepared by direct-compression and by wet-granulation method using PVP or EC as binders was studied. Tablets adsorped moisture at 50 and 75 % RH (relative humidity) but lost moisture at 30% RH. Except storage at 75% RH, however, tablet volumes did not change significantly during the test period. Moisture sorption caused a decrease in strength of tablets except low humidity (30% RH). Also, the disintegration time of tablets showed a decrease at all conditions except 30% RH. Furthermore, generally dissolution profiles of tablets prepared by direct-compression and by ethyl cellulose remained unchanged. Changes in the binder type in the tablet formulations changed the water uptake properties and also the physical properties of tablets. Directly-compressed tablets were much susceptible to change caused by humidity than tablets prepared by wet-granulation.     

The effect of moisture on the physical characteristics of ranitidine hydrochloride tablets prepared by different binders and techniques

Abstract

The effect of moisture on the physical properties of ranitidine hydrochloride tablets prepared by direct-compression and by wet-granulation method using PVP or EC as binders was studied. Tablets adsorped moisture at 50 and 75 % RH (relative humidity) but lost moisture at 30% RH. Except storage at 75% RH, however, tablet volumes did not change significantly during the test period. Moisture sorption caused a decrease in strength of tablets except low humidity (30% RH). Also, the disintegration time of tablets showed a decrease at all conditions except 30% RH. Furthermore, generally dissolution profiles of tablets prepared by direct-compression and by ethyl cellulose remained unchanged. Changes in the binder type in the tablet formulations changed the water uptake properties and also the physical properties of tablets. Directly-compressed tablets were much susceptible to change caused by humidity than tablets prepared by wet-granulation.     

Pharmaceutical and Medical Aspects of Bioadhesive Systems for Drug Administration

Abstract

Bioadhesion could lead to the solution of bioavailability problems resulting from a too short stay of the pharmaceutical dosage form at the absorption or activity level of the active ingredient. Bioadhesion stages are: intimate contact resulting from a good wetting of the bioadhesion surface and the swelling of the bioadhesive polymer, then penetration of the bioadhesive into the crevice of the tissue surface or interpenetration of bioadhesive chains with those of the mucus, and finally low chemical bonds. date, the most important bioadhesive polymers are polycarbophil a Carbopol 934. Methods of studying bioadhesion are described as well as the existing bioadhesive dosage forms.     

Bioadhesive properties of poly(alkylcyanoacrylate) nanoparticles coated with polysaccharide

Development of bioadhesive nanoparticles is of great interest to improve drug absorption through the intestinal barrier. Various Polysaccharide-coated poly(alkylcyanoacrylate) nanoparticles were prepared. The bioadhesive properties of the nanoparticles coated with dextran or chitosan in end-on or side-on conformation were evaluated with an ex-vivo adsorption experiment on rat intestine. Results show that diffusion of nanoparticles in mucus layer was governed by the nanoparticle diameter and isotherms of adsorption were influenced by the nature of polysaccharide used. High amount of nanoparticles coated with chitosan can be entrapped in the mucus layer even at low nanoparticle concentration in suspension. When nanoparticle concentration increased, a pseudo-plateau was reached. In the case of dextran-coated nanoparticles, linear increase of adsorption was observed and no saturation phenomenon was highlighted over the range of nanoparticle concentration used in this study. These results suggested that interactions involved in bioadhesion mechanism depended on the nature of polysaccharide. Electrostatic interactions are enhanced between chitosan-coated nanoparticles and glycoproteins of mucus leading to a saturated adsorption phenomenon whereas dextran-coated nanoparticles interacted by non-electrostatic interactions with mucus resulting in a non-saturated phenomenon. Polysaccharides grafted at the nanoparticle surface in the brush conformation appeared more favorable to promote interactions of nanoparticles with glycoproteins of mucus in comparison with the more compact loop conformation of polysaccharide chains.     

Development of pH sensitive polyacrylamide grafted pectin hydrogel for controlled drug delivery system

In the present study an attempt was made to graft polyacrylamide on pectin. The grafted polymer was characterized by FTIR spectroscopy, differential scanning calorimetry and X-ray diffraction. Rheological property of pectin solution was compared with the product solution. The grafted polymer was cross-linked with varying amount of glutaraldehyde. The swelling properties of the cross-linked product were also studied. The salicylic acid, an antipyretic drug, was incorporated in the cross-linked gel as a model drug and the drug release studies were done in a modified Franz’s diffusion cell. The effect of cross-linking density on the release property of salicylic acid was studied through the cross-linked product. The product showed better film forming property and gelling property than pectin. The comparative rheological properties of pectin and grafted copolymer indicated change in the property of the product. FTIR studies indicated incorporation of amide group. Differential scanning calorimetry and XRD suggested formation of a new polymer. Swelling study indicated pH dependent swelling of the cross-linked hydrogel. Salicylic acid release indicated pH dependent release from the hydrogel.     

Morphology controlled synthesis of ZnO nanostructures by varying pH

ZnO nanostructures have been synthesized in a controlled manner by varying the pH of the precursor solution using hydrothermal technique. The morphological changes of the prepared ZnO nanostructures have been investigated in the range of pH 5–10. Radial hexagonal rod-like shape is formed at lower pH values of 5 and 6 whereas, flower-like shape is obtained for higher pH values of 9 and 10. Flake-like structure is observed at moderate pH of 8. The prepared ZnO nanostructures have been characterized using X-ray diffraction technique (XRD), energy dispersive X-ray analysis, scanning electron microscope and FTIR spectroscopy. XRD results show that the prepared ZnO nanostructures exhibit hexagonal wurtzite structure. The growth mechanism suggests that the supersaturation of the precursor results in various nucleation habits, which induce the formation of ZnO nanostructures with different morphologies. UV–Vis spectroscopy and photoluminescence were applied to study the optical properties. The photoluminescence spectrum demonstrated two emission bands, a near band edge emission in the UV region and a strong deep band emission in the visible region. The change in pH from 5 to 10 results in band gap variations of 3.47–3.97 eV and blue-shift in the peak emission of visible PL from 560 to 460 nm.     

Bioadhesive Polymer Buccal Patches for Buprenorphine Controlled Delivery: Solubility Consideration

Abstract

By using a two-roll milling method, a new bioadhesive polymer patch formulation for buprenorphine controlled delivery and consisting of polyisobutylene, polyisoprene, and Carbopol® 934P was prepared. Since solubility of drug in the polymer patches is the first factor which should be considered before to modify the feasibility of delivering drug through the buccal mucosa, the effects of α-cyclodextrin, β-cyclodextrin, sodium taurocholate, and sodium glycodeoxycholate on the solubility of buprenorphine were investigated, and β-cyclodextrin was found the strongest solubility enhancer of them. The drug release profiles were significantly affected by the drug loading and the existence of β-cyclodextrin. Increasing the drug loading and solubility enhancer would increase the drug release from the buccal polymer patches. The pH value change in the microenviroment of polymer patches during the hydration of Carbopol® 934P could even release 20% of drug from the polymer patches which didn't contain any solubility enhancer.     

Design and evaluation of matrix diffusion controlled transdermal patches of verapamil hydrochloride

Transdermal patches of verapamil hydrochloride were prepared using four different polymers (individual and combination): Eudragit RL100 (ERL100), Eudragit RS100 (ERS100), hydroxypropyl methylcellulose 15 cps (HPMC), and ethyl cellulose (EC), of varying degrees of hydrophilicity and hydrophobicity. The effect of the polymers on the technological properties, i.e., drug release, water vapor transmission rate (WVTR), and percentage moisture loss (ML), percentage moisture absorption (MA), folding endurance, and thickness, was investigated. Different formulations were prepared in accordance with the 2³ factorial design, with ERL100 being the parent polymer. The patch containing ERL100 alone showed maximum WVTR, % MA, and % ML, which could be attributed to its hydrophilic nature. As expected, substitution with ERS100, HPMC, and EC decreased all the above values in accordance with their decreasing degree of hydrophilicity. In vitro release studies showed zero-order release of the drug from all the patches, and the mechanism of release was diffusion mediated. Moreover, the release of the drug was sustained and it extended over a period of 24 hr in all formulations. A12 emerged as the most satisfactory formulation insofar as its technological properties were concerned. Further, release and permeation of the drug from the most satisfactory formulation (A12) was evaluated through different biological barriers (shed snake skin, rabbit skin, and rat skin) to get an idea of the drug permeation through human skin. Shed snake's skin was found to be most permeable (82.56% drug release at 24 hr) and rat skin was least permeable (52.38%). Percutaneous absorption studies were carried out in rabbits. The pharmacokinetic parameters calculated from blood levels of the drug revealed a profile typical of a sustained release formulation, with the ability to maintain adequate plasma levels for 24 hr. [AUC: 3.09 mg/mL hr, C_max: 203.95 µg/mL, T_max: 8 hr]. It can therefore be concluded that the patch containing ERL100 and HPMC in the ratio 8:2 has achieved the objectives of transdermal drug delivery system, such as avoidance of first pass effect, extended release, and reduced frequency of administration.     

Synchronized and controlled release of metformin hydrochloride/glipizide from elementary osmotic delivery

Abstract

The combination of metformin hydrochloride (MTF) and glipizide (GLZ) is second-line medication for diabetes mellitus type 2 (DMT2). In the present study, elementary osmotic pump ( EOP) tablet is designed to deliver the combination of MTF and GLZ in a sustained and synchronized manner. By analyzing different variables of the formulation, sodium hydrogen carbonate is introduced as pH modifier to improve the release of GLZ, while ethyl cellulose acts as release retardant to reduce the burst release phase of MTF. A two-factor, three-level face-centered central composite design (FCCD) is applied to investigate the impact of different factors on drug release profile. Compared with conventional tablets, the EOP tablet demonstrates a controlled release behavior with relative bioavailability of 99.2% for MTF and 99.3% for GLZ. Data also shows EOP tablet is able to release MTF and GLZ in a synchronized and sustained manner both in vitro and in vivo.