pH Of Release Medium Research Articles

Development of an Accelerated Rotator-based Drug Release Method for the Evaluation of Bupivacaine Multivesicular Liposomes.

A multivesicular liposome (MVL) is a liposomal vehicle designed to achieve sustained release characteristics for drugs with short half-lives. For example, a commercial MVL formulation of bupivacaine has been approved by the U.S. Food and Drug Administration for local and regional analgesia. For complex formulations like those containing MVLs, challenges in developing an in vitro release testing (IVRT) method may hinder generic development and regulatory approval. In this study, we developed an accelerated rotator-based IVRT method with the ability to discriminate bupivacaine MVLs with different quality attributes. Three IVRT experimental setups including mesh tube, horizontal shaker, and vertical rotator were screened to ensure that at least 50% of bupivacaine can release from MVLs in 24h. Sample dilution factors, incubation temperature, and the release media pH were optimized for the IVRT. The reproducibility of the developed IVRT method was validated with commercial bupivacaine MVLs. The discriminative capacity was assessed via comparing commercial and compromised bupivacaine MVL formulations. The rotator-based release setup was chosen due to the capability to obtain 70% of drug release within 24h. The optimized testing conditions were chosen with a 50-fold dilution factor, a temperature of 37ºC, and a media pH of 7.4. An accelerated rotator-based IVRT method for bupivacaine MVLs was developed in this study, with the discriminatory ability to distinguish between formulations of different qualities. The developed IVRT method was a robust tool for generic development of MVL based formulations.

An Automated Electroanalytical Method for the Drug Release Profiling of Liposomal Doxorubicin HCl Formulations

Liposomes have emerged as a drug delivery system for various chemotherapeutics providing enhanced bioavailability and reduced toxicity. In vitro drug release profiling of liposomal formulations is one of the essential tests for the premarket approval and post market quality control. We developed an automated electroanalytical method for drug release profiling of liposomal doxorubicin formulation. In this electroanalytical method, square wave voltammetry mode was selected to determine the released drug, the only redox-active analyte, by measuring the current at the pulsed potential ranges. Therefore, no separation from liposomal encapsulated doxorubicin is needed. This electroanalytical method provided a continuous drug release measurement for 24 h. The drug release increased as the release media pH and temperature increased. At 37 °C, the drug release increased from 7 % to 40 % when the pH increased from 5.5 to 7.4, In addition, at pH 6.5, as the temperature increased from 37 °C to 52 °C, total drug release increased by more than two-fold. Complete drug release (more than 80 %) was obtained at pH 6.5 and 52 °C in less than 3 h. The brand name and the two generic formulations showed similar drug release profile in all experimental conditions. This method is an alternative to traditional methods which require separation steps such as dialysis or solid phase extraction to quantitate released doxorubicin. This method may be further applied in the in vitro release testing of other liposomal formulations containing redox-active drug substances, e.g., liposomes encapsulating daunorubicin.

Effects of synthesis conditions and release medium pH on release properties of acyclovir – mercaptopropyl modified silica composite

Objective The purpose of the present study was to evaluate the prospect of use of mercaptopropyl modified silica as a platform for development of new oral formulation of antiviral drug acyclovir (ACV) which is able to control release of the drug irrespective of release medium pH. Methods The composites of ACV with mercaptopropyl modified silica were synthesized using sol-gel technology under different conditions (synthesis pH, drug loading). The composites were characterized using scanning electron microscopy, dynamic light scattering and differential scanning calorimetry methods. The effects of the synthesis conditions on physicochemical properties of the prepared composites and their release properties were studied. Results The sol-gel synthesis conditions and release medium pH influence significantly release properties of the composites. The influence was explained by contributions of different factors, such as the drug-silica interactions in the composites, structure of the silica matrix and its stability in release media, hydrophobic nature of ACV, its pH-dependent solubility. It was found that all the synthesized composites followed the zero-order kinetics which is controlled by anomalous diffusion. Conclusion The studies showed that the composites exhibited controlled release of ACV up to 80 h. However, the release properties of the drug depend significantly on pH of release medium, i.e. the release properties (the release rate, the amount of released ACV) will change during transition of the composites through various segments of GIT. Therefore, the synthesized composites are not a promising basis for development of new oral dosage form of ACV

Facile preparation of layered double hydroxide (LDH)-alginate beads as sustainable system for the triggered release of diclofenac: Effect of pH and temperature on release rate

This paper concerns the facile preparation of alginate beads encapsulating layered double hydroxide (LDH) intercalated with diclofenac sodium as drug delivery systems. To better evaluate the effect of LDH carrier, alginate beads loaded with free diclofenac were also prepared. Composites hydrogel beads were ionotropically crosslinked in CaCl2 solution at 4 °C. Thermal and barrier properties were evaluated and correlated with the presence of the inorganic phase. Swelling behavior was investigated over time. Release kinetics of diclofenac at different pH and temperatures were evaluated. The diclofenac release behavior appeared to be affected by the presence of LDH, the pH of release medium and the temperature allowing for fabricating a sustainable composite characterized by a triggered drug release rate. Finally, empirical relationships correlating the drug diffusion as a function of temperature and pH were extrapolated.

Development of Novel Oral Formulations of Disulfide Antioxidants Based on Porous Silica for Controlled Release of the Drugs.

Powerful antioxidant α-lipoic acid (LA) exhibits limited therapeutic efficiency due to its pharmacokinetic properties. Therefore, the purpose of this work was to evaluate the ability of silica-based composites of LA as well as its amide (lipoamide, LM), as new oral drug formulations, to control their release and maintain their therapeutic concentration and antioxidant activity in the body over a long time. The composites synthesized at different sol–gel synthesis pH and based on silica matrixes with various surface chemistry were investigated. The release behavior of the composites in media mimicking pH of digestive fluids (pH 1.6, 6.8, and 7.4) was revealed. The effects of chemical structure of the antioxidants, synthesis pH, surface chemistry of the silica matrixes in the composites as well as the pH of release medium on kinetic parameters of the drug release and mechanisms of the process were discussed. The comparative analysis of the obtained data allowed the determination of the most promising composites. Using these composites, modeling of the release process of the antioxidants in accordance with transit conditions of the drugs in stomach, proximal, and distal parts of small intestine and colon was carried out. The composites exhibited the release close to the zero order kinetics and maintained the therapeutic concentration of the drugs and antioxidant effect in all parts of the intestine for up to 24 h. The obtained results showed that encapsulation of LA and LM in the silica matrixes is a promising way to improve their bioavailability and antioxidant activity.

Physical-Chemical Characterization of Octreotide Encapsulated in Commercial Glucose-Star PLGA Microspheres.

Sandostatin LAR (SLAR) is an injectable long-acting release (LAR) microsphere formulation for octreotide based on a biodegradeable glucose star copolymer of d,l-lactic and glycolic acids (PLGA-glu), which is primarily used for the treatment of patients with acromegaly. There currently is no generic SLAR approved in the United States despite expiration of patent coverage. To understand better this important formulation, SLAR was assessed for its composition and physical-chemical properties. Octreotide release kinetics was monitored under physiological conditions over 56 days together with several bioerosion parameters [mass loss, water uptake, pH of release media, polymer molecular weight (Mw), and confocal microscopy after BODIPY uptake]. A significant increase in the amount of released peptide occurred after day 14. After 1 day of incubation in PBST, octreotide was not extractable completely from SLAR during 2 h of the extraction process, but complete extraction was accomplished after 24 h, which suggested that strong and noncovalent PLGA-octreotide interactions occurred beginning in the initial release phase. Leuprolide is considered as a cationic peptide competitor for octreotide-PLGA interactions and its presence in the release medium resulted in more continuous octreotide release from SLAR, which was linearly correlated with the mass loss from the polymer (i.e., an indication of erosion-controlled release). These data strongly suggest that octreotide forms a salt with acid end groups of linear PLGA chains that are either present as impurities in, and/or produced by the degradation of, the PLGA-Glu. This salt is expected to catalyze octreotide acylation and extend peptide release beyond that driven by erosion control. The characterization studies of physicochemical properties of SLAR described here could be useful for the development and regulatory evaluation of generic octreotide microspheres as well as new polymer formulations, in which the polymer strongly interacts with encapsulated peptides.

Functionalization of ginger derived nanoparticles with chitosan to design drug delivery system for controlled release of 5-amino salicylic acid (5-ASA) in treatment of inflammatory bowel diseases: An in vitro study

The present study aimed at synthesising chitosan bound ginger nanocarriers for slow and controlled release of the drug 5-amino salicylic acid (5-ASA) against inflammatory bowel diseases (IBD). The chitosan, extracted from naturally occurring biopolymer chitin, was reacted to ginger extract (Zingiber officinale) to prepare chitosan-bounded ginger derived nanocarriers (C-GDNC) and further loaded with 5-ASA drug. The as-obtained drug loaded chitosan coated ginger derived nanocarriers (D-C-GNDC) were studied for controlled release of 5-ASA. In vitro experimental data implied slow and controlled release of 5-ASA and were kinetically justified by applying different kinetic models. The obtained percent drug loading capacity and entrapment efficiency were more than 50%. Various experimental factors affecting swelling controlled drug release of 5-ASA, such as change in pH of release medium, chemical composition of nanocarriers, percent drug loading, and simulated biofluids as release media, were investigated. The prepared nanomaterials were well characterized and examined for chemical stability and in vitro cytotoxicity to check their biocompatible nature. The overall studies concluded that the controlled release of 5-ASA was favourable at the gastrointestinal pH which is desirably beneficial against inflammation of bowl.

Stereoselectivity evaluation of chiral chitosan microspheres delivery system containing rac-KET in vitro and in vivo

The influence of chiral excipient D-chitosan (CS) on the stereoselective release of racemic ketoprofen (rac-KET) microspheres has been investigated in comparison to those microspheres containing individual enantiomers in vitro and in vivo. Stereoselectivity was observed in vitro release test, with R-KET release slightly higher than that of S-KET, especially in 3% rac-KET loading microspheres. Stereoselectivity is dependent on the content of chiral excipient and pH of release medium. A molecular docking study between CS and KET enantiomers further revealed that S-KET has a stronger interaction with CS compared to R-KET. Moreover, the plasma concentration of KET enantiomers in rats shows substantial differences, as the plasma levels of S-KET were higher than those of R-KET. Plasma levels of enantiomers from the R-KET microspheres had similar stereoselectivity as rac-KET microspheres. The S/R ratio of rac-KET microspheres was significantly lower than that of rac-KET suspension (regular-release formulation) (p<.05), and the differences is 3–5 fold. Besides, rates of R-KET converted to S-KET exhibited differences between rac-KET microspheres and suspension. Similar results were also found between R-KET microspheres and suspension. All investigations suggest that the chitosan interacting preferentially with S-KET to R-KET significantly affect the stereoselective pharmacokinetics of rac-KET from chitosan microspheres in rats.

In vitro and in vivo evaluation of controlled-release matrix tablets of highly water-soluble drug applying different mw polyethylene oxides (PEO) as retardants

The aim of the work presented is to prepare a controlled-release hydrophilic matrix tablet (CMT) controlling release of highly water-soluble drug applying pure combination of high- and low-Mw PEO as matrix materials, to avoid the lag time of drug release, and to overcome incomplete release in later stages. The influences of types and amounts of different Mw PEOs used, drug loading, pH of release medium and agitation rate on drug release were evaluated. The study of uptake and erosion of matrix was conducted and mechanism of improving drug release was discussed. In vivo pharmacokinetics of the CMT and reference preparation self-made controlled-release osmotic pump tablets (COPT) were performed in beagle dogs. The optimized formulation containing 43% PEO WSR 303 and 32% PEO N750 showed a zero order release from 1 h to 12 h. In vivo results demonstrated that the CMT had similar AUC0-48 h and Cmax with the COPT but smaller Tmax than the COPT and provided a more stable therapeutic concentration compared to the COPT. In conclusion, hydrophilic matrix tablet combining only different Mw PEOs as matrix materials had very good potential to be developed into a controlled-release drug delivery system for highly water-soluble drug. Besides, its manufacturing processes were succinct which would be preferable for modern medicine industry.

Microwave assisted synthesis of binary grafted psyllium and its utility in anticancer formulation

A binary grafted copolymer of Psyllium mucilage (Psy) with acrylic acid (AA) and acrylonitrile (An) has been successfully synthesized under microwave conditions for in vitro drug release study. The grafting was confirmed by FTIR spectroscopy, XRD, SEM, EDX, TGA analytical techniques and the intrinsic viscosity study. The swelling behavior of grafted material has been studied in solution of different pH and time. We also prepare Psy-g-Poly (AA-co-An) based beads with anti-cancer drug [(2-Chloro-3-(4-hydroxyphenylamino) naphthalene-1, 4-dione)]. The drug release behavior of Psy-g-Poly (AA-co-An) based beads has been determined in aqueous medium at different pH. It has been observed that highest drug release at pH 1.6. The drug release kinetics was analysed using the different models. This study demonstrates that the release of drug depends on the composition of beads and pH of release medium. Kinetics of drug release from beads is best fitted by zero order and first order model.

Calcium-alginate microparticles for sustained release of catechin prepared via an emulsion gelation technique

Catechin-loaded Ca-alginate beads and microparticles were prepared by an emulsion gelation method using sunflower oil for efficient sustained release of catechin. The emulsion was prepared by sequential mixing of alginate, oil, and oleic acid ester as an emulsifier. Encapsulation efficiency (EE) and inhibition of catechin release of the beads were significantly increased approximately to 453.83 and 148.71% by the emulsion gelation technique, respectively (p<0.05). For the microparticles, the highest inhibition of catechin release after 1 h of incubation (78.82%) was observed at the microparticles prepared by 5% (w/w) oil, 3% (w/w) alginate, 4% (w/v) CaCl2, and 200 mg catechin with the most hydrophilic emulsifier, decaglycerol mono-ester. Moreover, the catechin release was sustained at acidic conditions and increased with increase in pH of release medium. These results suggest that catechin encapsulation within Ca-alginate particles by emulsion gelation method can be an effective delivery system for catechin.

Grafting of pH-sensitive poly (N,N-dimethylaminoethyl methacrylate-co-2-hydroxyethyl methacrylate) onto HNTS via surface-initiated atom transfer radical polymerization for controllable drug release

ABSTRACTCopolymer brushes composed of N,N-dimethylaminoethyl methacrylate (DMAEMA) and 2-hydroxyethyl methacrylate (HEMA) were tethered on the surface of HNTs (HNTs) through surface-initiated atom transfer radical polymerization (SI-ATRP). ATRP initiator was anchored to surface and copolymers were synthesized from surface with different compositions of monomers. Successful grafting of copolymer brushes was approved by FTIR, TGA, XPS, FE-SEM, TEM, and N2 adsorption-desorption.1H NMR was used to determine the composition of copolymers. pH-sensitive properties of copolymer-grafted nanotubes were investigated by UV-visible absorbance in different pH values. Finally, loading and in vitro drug release from neat and copolymer-grafted HNTs were investigated using diphenhydramine hydrochloride as a model drug. Incorporation of DMAEMA to structure of polymers led to pH sensitivity of grafted-copolymers and controlled release of drug upon varying the pH of release medium. pH-dependent drug release showed that drug release was increased by decreasing pH of release medium and increasing DMAEMA content.

In-vitro release study of hydrophobic drug using electrospun cross-linked gelatin nanofibers

Delivering hydrophobic drug within hydrophilic polymer matrix as carrier is usually a challenge. Here we report the synthesis of gelatin nanofibers by electrospinning, followed by testing them as a potential carrier for oral drug delivery system for a model hydrophobic drug, piperine. Electrospun gelatin nanofibers were crosslinked by exposing to saturated glutaraldehyde (GTA) vapor, to improve their water resistive properties. An exposure of only 6min was not only adequate to control the early degradation with intact fiber morphology, but also significantly marginalized any adverse effects associated with the use of GTA. Scanning electron microscopy imaging, Fourier transform infrared spectroscopy and thermogravimetric analysis were done to study nanofiber morphology, stability of drug and effect of crosslinking. The pH of release medium was also varied as per the gastrointestinal tract for in-vitro drug release study. Results illustrate good compatibility of hydrophobic drug in gelatin nanofibers with promising controlled drug release patterns by varying crosslinking time and pH of release medium.

Construction of amphiphilic copolymer nanoparticles based on gelatin as drug carriers for doxorubicin delivery

Novel biodegradable amphiphilic copolymer nanoparticles based on gelatin, poly(lactide) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) (gelatin-co-PLA-DPPE) have been successfully fabricated. In order to estimate the feasibility as drug carriers, an anti-tumor model drug doxorubicin hydrochloride salt (DOX) was incorporated into polymeric nanoparticles by double emulsion or nanoprecipitation method. The nanoparticle size, size distribution and encapsulation efficiency (EE) were influenced by the feed weight ratio of the copolymer to DOX and different fabrication methods of nanoparticles. In addition, in vitro release experiments exhibited the release behavior was affected by pH of release media. The DOX-loaded nanoparticles showed that faster release at pH 5.0 than their release at pH 7.4 buffer. The DOX-loaded copolymer nanoparticles showed comparable anticancer efficacy with the free drug in vitro and in vivo. These results demonstrate a feasible application of the gelatin derivative as a promising nanocarrier for delivery of anti-tumor drugs.

Synthesis, characterization, and drug delivery research of an amphiphilic biodegradable star-shaped block copolymer

An amphiphilic biodegradable three-arm star-shaped diblock copolymer containing poly(e-caprolactone) (PCL) and poly(N-vinylpyrrolidone) (PVP) (TEA(PCL-b-PVP)3) has been successfully synthesized by the ring-opening polymerization of e-caprolactone (e-CL), RAFT polymerization of N-vinylpyrrolidone and a coupling reaction of PCL with carboxyl-terminated PVP (PVP-COOH). In aqueous media, the star-shaped copolymer self-assembled into spherical micelles with diameters of near 106 nm. The critical micelle concentration of TEA(PCL-b-PVP)3 copolymer was determined to be 5.96 × 10−3 mg/mL. Folic acid was then used as a model drug to incorporate into TEA(PCL-b-PVP)3 micelles, the drug loading content and encapsulation efficiency is 16.36 and 49.08 %, respectively. In vitro release experiments of the drug-loaded micelles exhibited sustained release behavior and it was affected by the pH of release media. These results indicate that the copolymer may serve as a promising “intelligent” drug delivery alternative.

Controlled Release from Monoolein Cubic Phase by Complexation Between Acidic Proteinoid and Basic Proteinoid

Acidic proteinoid and basic proteinoid were included in the water channel of the cubic phase to design a pH-sensitive monoolein (MO) cubic phase. Proteinoid composed of Asp and Leu (PAL) and proteinoid of Lys (PL) were prepared by a melt-condensation method and they used as acidic and basic porteinoid, respectively. Maximum complexation between PAL and PL was observed at pH 7.0 and at the PAL/PL ratio of 3/7 (v/v), evidenced by the size and the light scattering intensity of PAL/PL complexes. Fluoresceinisothiocyanate-dextran (FITC-dextran) release from cubic phase containing PAL/PL (3/7, v/v) was relatively high under an acidic and an alkali condition but the release was significantly suppressed under a neutral condition (e.g., pH 7.0), where maximum complexation was observed. The complex formed in the water channel of the cubic phase is believed to control the release in response to a change in the pH of release medium.

Direct formation of cationic polypeptide vesicle as potential carrier for drug and gene

The pH-responsive polypeptide grafted with polycation was prepared through copper(I)-catalyzed “click chemistry”. The amphiphilic polypeptide directly formed into cationic vesicle when it was dissolved in phosphate buffer solution (PBS). The hydrophilic DOX·HCl was loaded into the hollow core of vesicle. The in vitro release behavior of DOX·HCl from vesicle in PBS could be adjusted by the pH of release media. In vitro cell experiments demonstrated that the DOX·HCl loaded vesicle showed effective cellular proliferation inhibition. In addition, the preliminary gel retardation assay revealed that PLG-g-PAMA could efficiently bind to DNA, indicating its potential use as gene carrier. The more in-depth studies of PLG-g-PAMA vesicle for drug and gene co-delivery are in progress.

Formulation and Evaluation of Extended Release Asymmetric Membrane Capsules of Atenolol

The objective of this study was to demonstrate that the asymmetric membrane capsule can be used to deliver a poorly water soluble drug with a pH dependent solubility such as atenolol for extended periods of time by modulating solubility with organic acid. In osmotic systems, the release rate of an excipient relative to the release rate of the drug is an important factor that determines the duration of drug release. Consequently, for maintaining the desired pH over the entire period of drug dissolution a suitable thickening and suspending agent can be incorporated. By optimizing the concentration of thickening agent, it is possible to extend the availability of pH modifier in the core to provide an osmotic driving force or solubilization over the entire delivery period, so that the desired profile can be achieved for an active agent that has lower solubility characteristics. Finally, it was observed that the release rate of atenolol was influenced by the concentration of citric acid, mannitol and hydroxypropyl methylcellulose (HPMC). Results of scanning electron microscopy studies showed the formation of pores in the membrane from where the drug release occurred. The optimal formulation was found to be able to deliver atenolol at the rate of approximate zero-order up to 24 h, independent of pH of release media and agitation rate.

Magnetically Guided Release of Ciprofloxacin from Superparamagnetic Polymer Nanocomposites

Tailored with superparamagnetic properties the magnetic nanocomposites have been thoroughly investigated in recent past because of their potential applications in the fields of biomedicine and bioengineering such as protein detection, magnetic targeted drug carriers, bioseparation, magnetic resonance imaging contrast agents and hyperthermia. Magnetic drug targeting has come up as a safe and effective drug-delivery technology, i.e., with the least amount of magnetic particles a maximum of drug may be easily administered and transported to the site of choice. In the present work novel magnetic drug-targeting carriers consisting of magnetic nanoparticles encapsulated within a smart polymer matrix with potential of controlled drug release is described. To make such magnetic polymeric drug-delivery systems, both the magnetic nanoparticles and antibiotic drug (ciprofloxacin) were incorporated into the hydrogel. The controlled release process and release profiles were investigated as a function of experimental protocols such as percent loading of drug, chemical composition of the nanocomposite, pH of release media and strength of magnetic field on the release profiles. The structure, morphology and compositions of magnetic hydrogel nanocomposites were characterized by FT-IR, TEM, XRD and VSM techniques. It was found that magnetic nanocomposites were biocompatible and superparamagnetic in nature and could be used as a smart drug carrier for controlled and targeted drug delivery.

Egg Phosphatidylcholine Liposomes Incorporating Hydrophobically Modified Chitosan: pH-Sensitive Release

Egg phosphatidylcholine (EPC) liposomes incorporating hydrophobically modified chitosan (HmCh) were prepared by a sonication method. In order to immobilize chitosan on the surface of EPC liposomes, pentyl chains were covalently attached to chitosan. Following the proton NMR spectrum, the number of pentyl chains per chitosan molecule was calculated to be 2.5. Once the ratio of HmCh to EPC was kept below 1:5, the degrees of fluorescence quenching in the liposomal suspension were greater than 70%, indicating a high yield of liposome formation. No significant release from the liposome was observed in neutral and akali condition. The liposomes started to release their content at pH 6.5, and the release became more extensive as the pH of release medium decreased. The pH-sensitivity of the liposomes in terms of the release strongly depended on the amount of HmCh incorporated in liposomes.