Weight Ratio Of Drug Research Articles

Polymer Hydrophobicity Has a Positive Effect on the Oral Absorption of Cyclosporine A from Poly(ethylenimine) Based Nanomedicines

Hydrophobic drugs are problematic to deliver. We have previously shown that poly(ethylenimine) (PEI) amphiphile nanoparticles facilitate the oral absorption of the model drug cyclosporine A (CsA). We hypothesised that polymer molecular features (molecular weight, a branched or linear polymer architecture, polymer hydrophobicity) would drive this oral absorption enhancement. To test this hypothesis, we synthesised five linear PEI amphiphiles (Mn ~ 1.3 kDa or 13 kDa) and two branched PEI amphiphiles (Mn ~ 4 kDa or 10 kDa) by cetylation of PEI, followed by methylation to give N-cetyl, N-methyl, N,N-dimethyl, N,N,N-trimethyl poly(ethylenimines). Polymer aggregation, CsAencapsulation, polymer in vitro cytotoxicity and polymer enabled oral drug absorption were all studied. The polymers aggregated in aqueous media, with critical micellar concentrations (CMCs) ranging from 0.2 – 0.9 mg mL-1. The polymer CMCs, CsA encapsulation (up to 0.36 g CsA per g of PEI amphiphile) within the 60 – 200 nm nanoparticles and rat oral drug absorption after a 7.5 mg kg-1 dose of CsA, polymer nanoparticles (polymer, drug weight ratio – 5: 1) all increased with polymer hydrophobicity, although these parameters were not affected by polymer molecular weight or polymer branching. Release of CsA from a tablet dosage form was enhanced in the presence of the more hydrophilic branched polymer, however, as the more hydrophobic polymers endowed the tablets with longer disintegration times. Cell cytotoxicity (A431 cells and rat erythrocytes) was similar for all polymers (A431 IC50 = 10 – 50 μg mL-1 and 50% haemolysis = 30 – 55 μg mL-1).We conclude that the most important parameter controlling amphiphilic polymer nanoparticle enabled oral drug absorption is the hydrophobicity of the polymer amphiphile. Keywords: Bioavailability, cyclosporine A, nanomedicines, nanoparticles, oral absorption, poly(ethylenimine).

Improvement of drug loading onto ion exchange resin by cyclodextrin inclusion complex

Context: Ion exchange resins have ability to exchange their counter ions for ionized drug in the surrounding medium, yielding “drug resin complex.” Cyclodextrin can be applied for enhancement of drug solubility and stability.Objective: Cyclodextrin inclusion complex of poorly water-soluble NSAIDs, i.e. meloxicam and piroxicam, was characterized and its novel application for improving drug loading onto an anionic exchange resin, i.e. Dowex® 1×2, was investigated.Methods: β-cyclodextrin (β-CD) and hydroxypropyl β-cyclodextrin (HP-β-CD) were used for the preparation of inclusion complex with drugs in solution state at various pH. The inclusion complex was characterized by phase solubility, continuous variation, spectroscopic and electrochemistry methods. Then, the drug with and without cyclodextrin were equilibrated with resin at 1:1 and 1:2 weight ratio of drug and resin.Results and discussion: Solubility of the drugs was found to increase with increasing cyclodextrin concentration and pH. The increased solubility was explained predominantly due to the formation of inclusion complex at low pH and the increased ionization of drug at high pH. According to characterization studies, the inclusion complex was successfully formed with a 1:1 stoichiometry. The presence of cyclodextrin in the loading solution resulted in the improvement of drug loading onto resin.Conclusions: Enhancing drug loading onto ion-exchange resin via the formation of cyclodextrin inclusion complex is usable in the development of ion-exchange based drug delivery systems, which will beneficially reduce the use of harmful acidic or basic and organic chemicals.

Covalent Modification of Reduced Graphene Oxide by Means of Diazonium Chemistry and Use as a Drug‐Delivery System

Under acidic conditions, reduced graphene oxide (rGO) was functionalized with p-aminobenzoic acid, which formed the diazonium ions through the diazotization with a wet-chemical method. Surfactants or stabilizers were not applied during the diazotization. After the functionalized rGO was treated through mild sonication in aqueous solution, these functionalized rGO sheets were less than two layers, which was determined by atomic force microscopy (AFM) imaging. The water solubility of functionalized rGO after the introduction of polyethyleneimine (PEI) was improved significantly; it was followed by covalent binding of folic acid (FA) molecules to the functionalized rGO to allow us to specifically target CBRH7919 cancer cells by using FA as a receptor. The loading and release behaviors of elsinochrome A (EA) and doxorubicin (DOX) on the functionalized rGO sheets were investigated. The EA loading ratio onto rGO-C(6)H(4)-CO-NH-PEI-NH-CO-FA (abbreviated rGO-PEI-FA, the weight ratio of drug loaded onto rGO-PEI-FA) was approximately 45.56 %, and that of DOX was approximately 28.62 %. It was interesting that the drug release from rGO-PEI-FA was pH- and salt-dependent. The results of cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and flow cytometry (FCM) assays, as well as cell morphology observations) clearly showed that the concentration of rGO-PEI-FA as the drug-delivery composite should be less than 12.5 mg L(-1). The conjugation of DOX and rGO-PEI-FA can enhance the cancer-cell apoptosis effectively and can also push the cancer cells to the vulnerable G2 phase of the cell cycle, which is most sensitive and susceptible to damage by drugs or radiation.

A pH‐sensitive chitosan‐tripolyphosphate hydrogel beads for controlled glipizide delivery

A chitosan(CS)-tripolyphosphate (TPP) hydrogel bead was prepared by the ionic gelation method for the controlled delivery of glipizide. The structure and surface morphology of the beads were characterized by FT-IR and SEM, separately. Factors influencing the swelling behavior of the hydrogel beads were also investigated, such as CS concentration (X(1)), TPP concentration (X(2)), the weight ratio of drug to polymer (X(3)), crosslinking time (X(4)), and the volume ratio of CS to TPP (X(5)). In addition, the swelling property and the delivery behavior of the hydrogel bead was studied as well. With decreasing of pH value, the swelling ratio of the bead was increasing. The swelling ratio of hydrogel bead at pH 1.5 was relatively high, while this value was low at pH 6.8. The amount of glipizide released from the hydrogel bead at pH 1.5 was about 90%, while this value approached 36% at pH 6.8. The results clearly suggested that the CS-TPP hydrogel beads were used as a pH-sensitive controlled release system for the delivery of glipizide.

Ibuprofen-loaded poly(lactic-co-glycolic acid) films for controlled drug release

Ibuprofen- (IBU) loaded biocompatible poly(lactic-co-glycolic acid) (PLGA) films were prepared by spreading polymer/ibuprofen solution on the nonsolvent surface. By controlling the weight ratio of drug and polymer, different drug loading polymer films can be obtained. The synthesized ibuprofen-loaded PLGA films were characterized with scanning electron microscopy, powder X-ray diffraction, and differential scanning calorimetry. The drug release behavior of the as-prepared IBU-loaded PLGA films was studied to reveal their potential application in drug delivery systems. The results show the feasibility of the as-obtained films for controlling drug release. Furthermore, the drug release rate of the film could be controlled by the drug loading content and the release medium. The development of a biodegradable ibuprofen system, based on films, should be of great interest in drug delivery systems.

Dissolution enhancement of a poorly water-soluble antimalarial drug by means of a modified multi-fluid nozzle pilot spray drier

A spray drier with a modified multi-fluid nozzle was used to prepare microparticles of a poorly water-soluble antimalarial drug, artemisinin (ART), with the aim of improving its dissolution in water. ART was co-spray dried with a hydrophilic polymer, polyethylene glycol (PEG). The differential scanning calorimetry and X-ray diffraction studies showed that the crystallinity of ART decreased after spray drying. Compared to the physical mixture of ART and PEG, the amorphous phase of ART in the spray dried ART–PEG composites increased, which depended on the weight ratio of drug to polymer. The phase-solubility studies revealed that the aqueous solubility of ART was improved by the presence of PEG. The dissolution of ART from the spray dried ART–PEG composites was more rapid than that from their respective physical mixture and the original ART powder. For example, the dissolution of ART from the spray dried ART–PEG composite (1:6) was 6.5 times higher than that from the original ART powder in the first 30min. In the mathematical modeling, the Weibull and Korsemeyer–Peppas models were found to best fit to the in vitro dissolution data and then the drug release mechanism was considered as the Fickian diffusion.

Optimization of extended-release hydrophilic matrix tablets by support vector regression

Background: In this work, support vector regression (SVR) was applied to the optimization of extended release from swellable hydrophilic pentoxifylline matrix-tablets and compared to multiple linear regression (MLR). Methods: Binary mixtures comprising ethylcellulose and sodium alginate were used as the matrix-former. The matrix-former : drug weight ratio and the percentage of sodium alginate in the matrix-former were the formulation factors (independent variables) and the percentages of drug release at four different time intervals were the responses (dependent variables). Release was determined according to United States Pharmacopeia 31 for 11 pentoxifylline matrix-tablet formulations of different independent variable levels and the corresponding results were used as tutorial data for the construction of an optimized SVR model. Six additional checkpoint matrix-tablet formulations, within the experimental domain, were used to validate the external predictability of SVR and MLR models. Results: It was found that the constructed SVR model fitted better to the release data than the MLR model (higher coefficients of determination, R 2, lower prediction error sum of squares, narrower range of residuals, and lower mean relative error), outlining its advantages in handling complex nonlinear problems. Superimposed contour plots derived by using the SVR model and describing the effects of polymer and sodium alginate content on pentoxifylline release showed that formulation of optimal release profiles, according to United States Pharmacopeia limitations, could be located at drug : matrix ratio of 1 and sodium alginate content 25% w/w in the matrix-former. Conclusion: The results indicate the high potential for SVR in formulation development and Quality by Design.

Fabrication of composite microparticles of artemisinin for dissolution enhancement

The main aim of this study is to enhance the dissolution of a poorly water soluble antimalarial drug, artemisinin (ART) by fabricating its microparticles and composites with selected hydrophilic polymers using a spray drier with a modified multi-fluid nozzle. We investigated the spray drying of ART with polyvinylpyrrolidone (PVP) considering the effect of feed ratio (ART:PVP) on the physical properties and dissolution of spray dried ART. Other hydrophilic carriers such as polyethylene glycol (PEG) were selected for comparing the dissolution with that of spray dried ART with PVP. The drug and polymer solutions were supplied through different liquid passages of the modified four-fluid nozzle to fabricate ART and composite microparticles. Characterization of the original ART powder, spray dried ART microparticles and ART-polymer composite microparticles was carried out by scanning electron microscopy (SEM), Fourier transform infrared (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and dissolution tester. The DSC and XRD studies suggested that the crystallinity of ART decreased after spray drying and depended on the weight ratio of drug to polymer. Percent dissolution efficiency (%DE); relative dissolution (RD); mean dissolution time (MDT); difference factor ( f 1) and similarity factor ( f 2) were calculated for the statistical analysis. The dissolution of ART from the spray dried ART–PVP composite microparticles was more rapid than that from their respective physical mixture, spray dried ART–PEG composite microparticles and original ART powder. In the mathematical modeling, the Weibull and Korsmeyer-Peppas model were found to best fit to the in vitro dissolution data and the drug release kinetics could be recognized as Fickian diffusion. This study demonstrated that the modified multi-fluid spray drier can be used for the preparation of drug microparticles to improve the dissolution ability of poorly water soluble drugs and overcome the problem of finding a common solvent for drugs and carriers.

A novel pH-sensitive magnetic alginate–chitosan beads for albendazole delivery

Background: Drug delivery system using polymer-coated magnetic carriers is considered as an effective strategy for passive targeting, which can not only increase drug utilization but also reduce the adverse reaction. With the carriers, sensitivity to physical stimuli (e.g., magnetic field, pH) has been developed and drugs were conjugated to form incorporating magnetic particles, so that drugs could be located to desire position. Method: Novel magnetic alginate (Alg)–chitosan (CS) beads loaded with albendazole (ABZ) were prepared and evaluated for pH sensitivity and drug release characteristics. The effects of six different factors (Alg concentration, the weight ratio of drug to polymer, the weight ratio of magnetite nanoparticles to polymer, CaCl2 concentration, CS concentration, the volume ratio of Alg to CS) were studied on the swelling ability of the magnetic beads. The magnetic beads were characterized by Fourier transform infrared spectroscopy, scanning electron microscope, and vibrating sample magnetometry. In addition, the delivery behavior of ABZ from the magnetic beads was studied. Result: The magnetic Alg–CS beads had showed unique pH-dependent swelling behaviors and a continuous release of ABZ. From the magnetometer measurements data, the beads also had superparamagnetic property as well as fast magnetic response. Conclusion: The pH-sensitive magnetic beads may be used as a magnetic drug targeting system for ABZ in the gastrointestinal tract.

A novel pH sensitive N‐succinyl chitosan/alginate hydrogel bead for nifedipine delivery

A novel N-succinyl chitosan(Suc-Chi)/alginate hydrogel bead was prepared by the ionic gelation method for the controlled delivery of nifedipine. The structure and surface morphology of the hydrogel were characterized by FTIR and SEM, respectively. Factors influencing the swelling ability of the hydrogel bead were also investigated, such as the ratio of Suc-Chi and alginate (X(1)), the weight ratio of drug to polymer (X(2)), the volume ratio of alginate/Suc-Chi to CaCl(2) (X(3)), crosslinking time (X(4)), CaCl(2) concentration (X(5)). In addition, the delivery behavior of nifedipine from the hydrogel bead was studied. The amount of nifedipine released from the hydrogel bead at pH 1.5 was relatively low (11.6%), while this value approached 76% at pH 7.4. The results clearly suggested that the Suc-Chi/alginate hydrogel bead may be a potential polymeric carrier for drug delivery in the intestinal tract. The release of nifedipine from the hydrogel bead at various pH values was analysed by a semi-empirical equation and it was found that the drug release mechanisms were either 'anomalous transport' or 'case-II transport'.

Preparation and Characterization of Poly-(methyl ethyl cyanoacrylate) Particles Containing 5-Aminosalicylic acid

Poly-(alkylcyanoacrylate) ester particles have been used for the preparation of different formulations ranging from ophthalmic delivery systems to cancer chemotherapy carriers in clinic. The aim of this study was to prepare and characterize poly-(methyl ethyl cyanoacrylate) (PMECA) particles containing 5-aminosalicylic acid (5-ASA). PMECA particles were prepared using the inverse emulsification polymerization technique. The effects of various formulation parameters such as dispersed phase volume, polymer to drug weight ratio, and surfactant concentration on loading efficiency and size of the prepared particles were investigated. The amount of drug was determined by UV spectrophotometery at 331 nm. Morphological characteristics of particles and particle size analysis were studied by Scanning Electron Microscopy (SEM) and Laser Light Scattering techniques, respectively. The results showed that there was no linear relationship between the dispersed phase volume (DPV) and loading efficiency of 5-ASA in the range of 20-50%. Increasing polymer/drug weight ratio in the range of 1-15, enhanced the loading efficiency from 11.4 to 78.2% in a linear mode (r=0.987). Increasing the surfactant concentration in the range of 1-3% did not increase the loading efficiency of the prepared particles, and increasing the concentration to 5% even decreased the loading efficiency of particles. Laser light scattering and SEM evaluations showed that in all prepared formulations, particles were in a mixture of micro and nanospheres and micro and nanocapsules and 50 percent of particles had mean sizes in the range of 6.4-10.1 micrometer. Although our results showed significant differences in the mean particle size between some of the prepared formulations, this variation was not practically important. It was concluded that by using proper conditions, it is possible to use PMECA as a polymeric matrix for loading of 5-ASA and the other hydrophilic drugs.

Drug release from tableted wet granulations comprising cellulosic (HPMC or HPC) and hydrophobic component

The effects of component nature, proportion and processing on the release rate and mechanism were investigated for tablets comprising drug, cellulosic polymer and hydrophobic components. Four drugs differing in solubility (diclofenac sodium, ibuprofen, naproxen and indomethacin), two cellulosic polymers (HPC and HPMC) and hydrophobic Emvelop ® were used in two levels of mass fraction and weight ratio of drug:carrier and of cellulosic–hydrophobic component. Compression was applied after granulation or physical mixing. Drug release was evaluated in pH 6.5 phosphate buffer BP and elucidation of the release mechanism was attempted by fitting kinetic models. Statistical significance of the effects of formulation variables on the release rate and mechanism expressed by the coefficient, k, and exponent, n, of the power law kinetic model, respectively, was evaluated by ANOVA. It was found that for the release mechanism most significant is the effect of drug solubility followed by cellulosic polymer type, mixing procedure and drug mass fraction. Significant interaction between drug solubility and type of cellulosic polymer indicated that alteration in the swelling of HPMC and HPC is caused by the drug solubility. Weight ratio of cellulosic–hydrophobic component does not affect the release mechanism, but only the release rate. Similarly, for the release rate most significant was found the effect of drug solubility, followed by cellulosic polymer type, weight ratio of cellulosic–hydrophobic component, mixing method and drug mass fraction. Also significant were the interactions of drug solubility with the type and proportion of the cellulosic polymer and the processing applied. Depending on the drug solubility and type of polymer present, wet granulation can increase or decrease the release rate.

Some Factors Influencing the Dissolution of Solid Dispersions with Nicotinamide and Hydroxypropylmethylcellulose as Combined Carriers.

The dissolution characteristics of solid dispersions with nicotinamide and hydroxypropylmethylcellulose (HPMC) as combined carriers were investigated in water, using nifedipine and nitrendipine as model drugs. The solid dispersions were obtained by the fusion method; after both drug and HPMC dissolved in the fused liquid of nicotinamide at 140°C, the fused mixtures were cooled to solidify them. For nifedipine solid dispersions, the supersaturation behavior was enhanced with a decrease in the viscosity or an increase in the weight fraction of HPMC. Nifedipine was present as an amorphous state even in the solid dispersion with a 1 : 3 : 0.2 weight ratio of drug : nicotinamide : HPMC. Also, the more the weight fraction of nifedipine increased, the more the formation of amorphous drug in solid dispersions was suppressed, thereby lowering the drug supersaturation level. Moreover, the effect of humidity during storage on the dissolution profiles of nifedipine solid dispersions was examined. The humidity caused crystallization of amorphous nifedipine in solid dispersions, and decreased the drug supersaturation level. For nitrendipine solid dispersions, similarly to the nifedipine system, amorphous nitrendipine was obtained in solid dispersions, and this led to the supersaturation phenomenon. However, the inhibitory effect of HPMC on the crystallization of nitrendipine from supersaturated solution was less than that for nifedipine; this is attributable to the lower solubility of nitrendipine crystals. Therefore, the drug dissolution of this ternary dispersion system was influenced by the viscosity and weight fraction of HPMC, the solubility and weight fraction of the drug and the humidity during storage.

Casein Hydrolysate as a Rapid and/or Enteric Dissolving Additive for Oral Drugs

ABSTRACTTwo types of casein hydrolysates, casein A (mean peptide length 3.3) and casein B (mean peptide length 17.4) were prepared by the enzymatic hydrolysis of casein, and their effects on in vitro dissolution rates and oral bioavailability of drugs were evaluated. The in vitro dissolution behavior of the kneaded mixture of three drugs (diclofenac acid, diazepam, and prednisolone) with caseins A and B were significantly improved compared to the drugs alone, even at 1:1 weight ratio of drug and casein hydrolysate, even though casein A and casein B did not interact with drug molecules in the kneaded mixture. Only diclofenac, an acidic drug, showed an increased dissolution rate with added casein hydrolysates, and a more rapid dissolution with casein A than with casein B was observed. When the dissolution of prednisolone from kneaded mixture was compared at pH 1.2 and 6.8, the dissolution rate of prednisolone from the casein A kneaded mixture was considerably higher than that of prednisolone powder at both pHs, and the rate from the casein B kneaded mixture was higher only at pH 6.8. The plasma concentration-time profile showed that prednisolone was completely and rapidly absorbed from the casein A kneaded mixture as well as the prednisolone solution. In addition, prednisolone in the kneaded mixture with casein B was more difficult to absorb up to 1 hr after administration in comparison to prednisolone powder. The slow and lowered absorption of prednisolone by casein B might be explained by conversion of casein B to a shorter soluble peptide in the gastrointestinal tract and by the slow dissolution of prednisolone at acidic conditions. The toxicological tests revealed that casein hydrolysate is a safe drug carrier. Consequently, casein hydrolysates might be safely used to control the dissolution rate and bioavailability of a variety of drugs, depending on the peptide length of the casein fragments.

Physical properties of solid dispersions of poorly water-soluble drugs with enteric coating agents.

Enteric coating agents, such as hydroxypropylmethylcellulose phthalate, methacrylic acidmethacrylic acid methyl ester copolymer, cellulose acetate phthalate, carboxymethylethylcellulose, were investigated as possible carriers for poorly water-soluble drugs in solid dispersions. In most cases, the drugs were present in amorphous form in the solid dispersions of 1 : 3 weight ratio of drug to polymer, though griseofulvin and phenytoin were not. Dissolution behavior was investigated using nifedipine, griseofulvin or spironolactone as a drug. The amorphous solid dispersions showed supersaturation phenomena in JPX 2nd fluid (pH 6.8), but the dissolution rate was suppressed in JPX 1st fluid (pH 1.2). It was confirmed that the physicochemical state of solid dispersions plays a predominant role in the dissolution of the drug from the solid dispersions.