Development and Evaluation of Sustained-Release Ibuprofen–Wax Microspheres. II. In Vitro Dissolution Studies

A modified USP paddle method using minibaskets was used to study the effects of various formulations on in vitro dissolution of ibuprofen microspheres. Formulations containing waxes such as paraffin or ceresine wax without modifiers exhibited very slow dissolution profiles and incomplete release, which did not improve with increased drug loading or the preparation of smaller microspheres. The addition of modifiers such as stearyl alcohol and glyceryl mono-stearate greatly increased the dissolution rate, with 20% (w/w) near the optimum for predictable dissolution. Higher drug loading and decreased microsphere size increased the dissolution rate from microspheres containing modifier. Optimum formulations contained ceresine wax or microcrystalline wax and stearyl alcohol as a modifier, with a drug content of 17%. An increase in the encapsulation dispersant concentration had little effect on the dissolution profiles. The dissolution data from narrow size fractions of microspheres indicated spherical matrix drug release kinetics; the 50% dissolution time decreased with the square of the microsphere diameter. With appropriate modifiers, wax microsphere formulations of drugs with solubility characteristics similar to those of ibuprofen can offer a starting basis for predictable sustained release dosage forms.     

Formulation and evaluation of reconstitutable suspensions containing ibuprofen-loaded Eudragit microspheres

The objective of this work was to develop and evaluate reconstitutable suspensions of ibuprofen-loaded microspheres prepared with an acrylic polymer (Eudragit RS-PM). The microspheres were prepared by the quasi-emulsion solvent diffusion technique. To prepare reconstitutable suspension formulation, the microspheres used had a mean particle size of 316.6 microm and 99.8% loading efficiency. Xanthan gum was chosen as the suspending agent for the suspension formulations. D-sorbitol was used to impart palatability of suspensions. The amount of D-sorbitol affected sedimentation volume and redispersibility properties of suspensions. The highest improving effect was shown with 20.0% and 25.0% of D-sorbitol concentrations. It was observed that dispersion media of suspensions showed non-Newtonian flow characteristics. To ensure minimum drug leakage from the microspheres into the suspension, the pH was buffered at 3.60 using citrate buffer. The ibuprofen content calculated from the suspended microspheres was consistent with that from microspheres alone. This result indicated that no leakage of drug occurred from the microspheres in the suspension on storage. Moreover, the same release rate of ibuprofen from the microspheres suspension and microspheres alone indicated that the suspension medium studied did not affect the property of drug release. This study suggested that stable suspensions of ibuprofen-loaded microspheres could be formulated with 0.6% w/v xanthan gum by the addition of 20% w/v D-sorbitol.     

Multivesicular liposome formulations for the sustained delivery of ropivacaine hydrochloride: Preparation,characterization, and pharmacokinetics

The aim of the present study was to design a depot delivery system of ropivacaine hydrochloride using multivesicular liposomes (RP-MVLs) to overcome the limitations of conventional therapies and to investigate it’s in vivo effectiveness for sustained delivery. RP-MVLs were prepared by the multiple emulsion method. Appearance, particle size, encapsulation efficiency, zeta potential, and initial stability of RP-MVL were also studied. The in vitro release of RP-MVLs formulations was found to be in a sustained manner. Three batches of RP-MVLs were prepared and the release profile in vitro fitted to a first-order equation. RP-MVLs releasing mechanism was also studied and it was indicated that the drug released from MVLs by diffusion and erosion. Following subcutaneous administration to rats, the time to reach maximum (T_max) of RP-MVLs formulations was significantly (p?<?0.01) later than that of RH solution. The concentrations of RP-MVLs have steadily changed in the low level, which significantly (p?<?0.01) lower than RH solution. T_1/2 and MRT were significantly prolonged (p?<?0.01). Besides, AUC was also increased significantly (p?<?0.01). The increase in AUC and decrease in C_max reflects that the MVL formulations could reduce the toxic complications and limitations of conventional injected formation therapies.     

Formulation and characterization of albumin microspheres containing norcantharidate for liver tumor targeting

Abstract

The objectives of this study were first to encapsulate norcantharidate into albumin microspheres by the emulsion crosslinking method and second to characterize the microspheres in terms of the morphological examination, particle size, and encapsulation efficiency. The in vitro release of norcantharidate from the microspheres was studied by using the dialysis bag method. Pharmacokinetics and biodistribution studies were used to evaluate the advantages of microspheres than the conventional formulations. The microspheres prepared by crosslink emulsion were with uniform size, smooth surface, spherical shape, and disperse evenly. The particle size was uniform (13.3?±?0.4?µm) and the encapsulation efficiency was 54.3?±?4.18%. In vitro release indicated that the norcantharidate microspheres had a well-sustained release efficacy and fitted Korsmeyer’s Peppas release model. In vivo studies showed that pharmacokinetics of norcantharidate microspheres could be described by the model of two-compartment after i.v. administration and had higher AUC inside liver and spleen than the injection group. No histological change occurred to the rat liver after the administration of norcantharidate microspheres.     

Statistical optimization of controlled release microspheres containing cetirizine hydrochloride as a model for water soluble drugs

Abstract

The purpose was to improve the encapsulation efficiency of cetirizine hydrochloride (CTZ) microspheres as a model for water soluble drugs and control its release by applying response surface methodology. A 3³ Box–Behnken design was used to determine the effect of drug/polymer ratio (X₁), surfactant concentration (X₂) and stirring speed (X₃), on the mean particle size (Y₁), percentage encapsulation efficiency (Y₂) and cumulative percent drug released for 12?h (Y₃). Emulsion solvent evaporation (ESE) technique was applied utilizing Eudragit RS100 as coating polymer and span 80 as surfactant. All formulations were evaluated for micromeritic properties and morphologically characterized by scanning electron microscopy (SEM). The relative bioavailability of the optimized microspheres was compared with CTZ marketed product after oral administration on healthy human volunteers using a double blind, randomized, cross-over design. The results revealed that the mean particle sizes of the microspheres ranged from 62 to 348?µm and the efficiency of entrapment ranged from 36.3% to 70.1%. The optimized CTZ microspheres exhibited a slow and controlled release over 12?h. The pharmacokinetic data of optimized CTZ microspheres showed prolonged t_max, decreased C_max and AUC_0–∞ value of 3309?±?211 ng?h/ml indicating improved relative bioavailability by 169.4% compared with marketed tablets.     

Improving Relative Bioavailability of Dicumarol by Reducing Particle Size and Adding the Adhesive Poly(Fumaric-Co-Sebacic) Anhydride

Purpose. This study was carried out to show the effect of particle size reduction and bioadhesion on the dissolution and relative bioavailability of dicumarol. Methods. Formulations were produced by a variety of methods including a novel technique to reduce particle size as well as phase inversion with poly(fumaric-co-sebacic)anhydride p(FA:SA) to create nanospheres. Drug was administered to groups of pigs and rats via oral gavage of a suspension, and dicumarol concentration in the blood was measured using a double extraction technique.Results. In vitro results showed improved dissolution in both the micronized formulation and the encapsulated p(FA:SA) nanospheres. In vivo, relative bioavailability of a spray-dried formulation was increased by 17% in the rat and 72% in the pig by further reduction in particle size. The bioadhesive p(FA:SA) formulation also improved relative bioavailability over the spray-dried drug, increasing it by 55% in the rat and 96% in the pig. Additionally, the p(FA:SA) formulation prolonged T_max and decreased C_max in both species. Conclusion. This work demonstrates the importance of particle size and bioadhesion to improve oral bioavailability of ducumarol.     

Formulation and in vitro–in vivo evaluation of ketoprofen-loaded albumin microspheres for intramuscular administration

Abstract

The objective of this work was to prepare and evaluate ketoprofen-loaded albumin microspheres for intramuscular administration. Microspheres were prepared by emulsion cross-linking method using a 2³ factorial design and the effect of different factors on entrapment efficiency was determined. Microspheres were evaluated for entrapment efficiency, percentage yield, particle size and release behaviour. Selected formulations were then tested by differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. Further they were analysed for residual solvents, syringeability and stability. Microspheres were then sterilized and bioavailability studies were carried out in New Zealand white rabbits. The physical characteristics of microspheres showed that they were suitable for IM administration. The sterilization technique adopted was adequate to maintain sterility. In vivo studies showed increase in C_max, AUC, t_1/2 and MRT (p < 0.05) administered in the form of microspheres. MRT of ketoprofen was almost 3.2-times in the form of microspheres. From these results it was concluded that the developed albumin microspheres of ketoprofen is a potential delivery system for once-a-day intramuscular administration.     

Predicting rapid analgesic onset of ibuprofen salts compared with ibuprofen acid: Tlag,Tlow, Tmed,and a novel parameter,TCmaxRef

Objective: This study evaluated the early absorption characteristics of ibuprofen salt formulations and standard ibuprofen acid (the reference).

Methods: In this open-label, crossover, single-center study (NCT02452450) in 32 healthy, fasted adults receiving single oral doses (400?mg ibuprofen) of ibuprofen lysine, ibuprofen liquid capsule, ibuprofen sodium, ibuprofen acid, and paracetamol, intensive blood sampling was conducted for up to 6?h. Time between dosing and the start of absorption (T_lag); a novel parameter, time at which the test formulations (ibuprofen salts) reached the observed maximum plasma concentration (C_max) of the reference (standard ibuprofen acid) (T_CmaxRef); and time to achieve therapeutic plasma concentration were measured.

Results: Ibuprofen was absorbed more rapidly from the salt formulations than the reference; T_lag was 3.3–6.4?min for salt formulations compared with 10.9?min for the reference, and 100% of subjects had a T_lag ≤ 5?min for ibuprofen lysine, compared with 61% for ibuprofen liquid capsule, 21% for ibuprofen sodium, and 7% for the reference. T_CmaxRef was 3.22–5.74-times shorter for salt formulations than for the reference (all p?p?Conclusions: This study shows that ibuprofen salts are absorbed faster than ibuprofen acid. T_lag and T_CmaxRef demonstrated early start and increased speed of absorption of salts compared with the reference, and may predict more rapid onset of analgesia.     

Formulation and evaluation of controlled-release of telmisartan microspheres: In vitro/in vivo study

The aim of this work was to design a controlled-release drug-delivery system for the angiotensin-II receptor antagonist drug telmisartan. Telmisartan was encapsulated with different EUDRAGIT polymers by an emulsion solvent evaporation technique and the physicochemical properties of the formulations were characterized. Using a solvent evaporation method, white spherical microspheres with particle sizes of 629.9–792.1 μm were produced. The in vitro drug release was studied in three different pH media (pH 1.2 for 2 hours, pH 6.8 for 4 hours, and pH 7.4 for 18 hours). The formulations were then evaluated for their pharmacokinetic parameters. The entrapment efficiency of these microspheres was between 58.6% and 90.56%. The obtained microspheres showed good flow properties, which were evaluated in terms of angle of repose (15.29–26.32), bulk and tapped densities (0.37–0.53 and 0.43–0.64, respectively), Carr indices and Hausner ratio (12.94–19.14% and 1.14–1.23, respectively). No drug release was observed in the simulated gastric medium up to 2 hours; however, a change in pH from 1.2 to 6.8 increased the drug release. At pH 7.4, formulations with EUDRAGIT RS 100 showed a steady drug release. The microsphere formulation TMRS-3 (i.e., microspheres containing 2-mg telmisartan) gave the highest C_max value (6.8641 μg/mL) at 6 hours, which was three times higher than C_max for telmisartan oral suspension (TOS). Correspondingly, the area under the curve for TMRS-3 was 8.5 times higher than TOS. Particle size and drug release depended on the nature and content of polymer used. The drug release mechanism of the TMRS-3 formulation can be explained using the Higuchi model. The controlled release of drug from TMRS-3 also provides for higher plasma drug content and improved bioavailability.     

Fluphenazine release from biodegradable microparticles: Characterization and modelling of release

Abstract

The release of actives encapsulated in biodegradable poly-lactide-co-glycolide (PLGA)-based microparticles may be diffusion controlled, dependent on polymer degradation, or may occur by a combination of drug diffusion and polymer degradation. This report applies a model, describing combined diffusional and polymer degradation-assisted drug release, to quantify the release of fluphenazine HCl (F-HCl) from PLGA microspheres. Parameters for the release process showed that both the initial drug release phase and the polymer controlled drug release phase were dependent on the F-HCl loading of the microspheres. The percentage drug released in the burst phase and the length of the lag phase were dependent on F-HCl loading. In the degradation controlled release phase, drug release was faster the higher the loading, as shown by the decrease in t_max from 27 to 10 days, as F-HCl loadings increased from 4.2 to 16.6%w/w. The presence of F-HCl was found to catalyse the degradation of PLGA polymer during particle manufacture and during dissolution. When compared to drug free microspheres, F-HCl accelerated PLGA degradation as shown by the ～5-fold increase in both PLGA degradation rate constant (k) and reduction in t_max.     

布洛芬微球的制备及影响因素考察

目的研究乳化溶剂扩散法制备布洛芬微球的工艺。方法采用乳化溶剂扩散法制备布洛芬微球,以粒度分布、载药量以及包封率为指标,对处方及工艺进行单因素考察,选出较佳的处方和工艺条件,并对所得微球的外观及体外释放度进行研究。结果该法所制微球外观圆整,流动性好,粒径分布集中在2~20μm,包封率为69.74%,载药量为68.37%。结论布洛芬微球的制备工艺简单,所制微球粒径小,分布窄。体外释药试验表明所得布洛芬微球在人工肠液中有明显的缓释作用。     

Floating microspheres of carvedilol as gastro retentive drug delivery system: 32 full factorial design and in vitro evaluation

Abstract

Context: Designing a sustained release system for Carvedilol to increase its residence time in the stomach.

Objective: Preparation of floating microsphere by the emulsion solvent diffusion method, studying the effect of various process parameters and optimize the formulation using full factorial design.

Methods: Different microsphere formulations were prepared by varying the ratio ethanol:dichloromethane (1:0 to 1:1.5), ethyl cellulose:hydroxypropyl methyl cellulose and stirring speed (800–1600?rpm). The effect of these variables on particle size, encapsulation parameters, surface topography, in vitro floatability and drug release were evaluated.

Results: 3² full factorial design was used for the optimization of the formulation. Drug entrapment efficiency, particle size and in vitro drug release were dependent on concentration of ethyl cellulose and stirring speed. Microspheres remained buoyant for more than 10?h and showed sustained release of the drug.

Conclusion: Floating microspheres of Carvedilol with good floating ability and sustained release were developed.     

Evaluation of in vivo behavior of controlled and pulsatile release pastilles using pharmacokinetic and γ-scintigraphic techniques

Objective: To evaluate the in vivo behavior of controlled and pulsatile release pastilles for chronic treatment of asthma and chronic obstructive pulmonary disease (COPD) and for the chronotherapeutic management of nocturnal asthma, respectively.

Research design & methods: The prepared immediate release and controlled release pastilles were subjected to in vivo pharmacokinetic studies in rats. Whereas, pulsatile release formulation was subjected to γ-scintigraphic study in rats to study the gastrointestinal transit of the formulations and its results were correlated with the previous pharmacokinetic data.

Results: The in vivo pharmacokinetic study of controlled release pastille formulation showed significant decrease in C_max with increase in t_max, which indicates that the effect of dosage form would last for longer duration. Thus, the prepared formulation can be useful for the chronic treatment of asthma and COPD. The γ-scintigraphic study and pharmacokinetic data indicated that the pastilles coated with the enteric coat and the additional floating coat were effective in significantly delaying the in vivo drug release (by 4–5 h) required for the chronotherapeutic treatment of nocturnal asthma.

Conclusion: This study opens a new alternative to the conventional tablet or capsule dosage form for the development of both immediate and modified release drug delivery systems.     

Characterization of drug release from diltiazem-loaded polylactide microspheres prepared using sodium caseinate and whey protein as emulsifying agents

The influence of milk protein emulsifying agents on the characteristics, particularly drug release, of polylactide microspheres was investigated. Diltiazem loaded polylactide (PL) microspheres were successfully prepared using the dairy proteins, sodium casinate (SC) and whey protein isolate (WPI) as the emulsifying agents. Microspheres were characerized in terms of microsphere yield, electron microscopy, particle size, drug loading, DSC and XRD analysis and drug release. The yields of microspheres obtained were 53-63% and were independent of the emulsifying agent used. SEM revealed that, regardless of the emulsifying agent employed, the microspheres were of good sphericity, but the surface appearance of the microspheres was not the same in all cases. The milk proteins resulted in microspheres approximately half the size of those obtained with methylcellulose (MC). Significant differences in drug loading were observed between the three emulgents, the MC systems giving the highest values. Release profiles were sigmoidal in shape and were well fitted to the equation ln (x/1-x) = k·t - k·t_max, reflecting degradation controlled drug release. The parameter k increased with drug loading, while t_max decreased. The relationships between the release parameters [P(k and t_max)] and loading (L) could be quantified by equations of the form P = a·L^N, N being negative in the case of t_max. Apart from the effect on loading efficiency, neither SC nor WPI appeared to significantly alter drug release. The quantitative relationships observed in this study may have more general application in quantifying drug release from drug polymer composites at low loadings where polymer degradation controls drug release.     

Long-acting delivery microspheres of levo-norgestrolpoly(3-hydroxybutyrate): their preparation,characterization and contraceptive tests on mice

The preparative technology for sustained release drug delivery microspheres of levo-norgestrol-poly(3-hydroxybutyrate) was optimized based on the in-liquiddrying method. The formation of the drug microspheres was confirmed with differential thermal analysis. The appearance, particle size and distribution, residual CHCl₃, drug content, drug release characteristics in vitro     

Use of Stable Isotopes for Evaluation of Drug Delivery Systems: Comparison of Ibuprofen Release in Vivo and in Vitro from Two Biphasic Release Formulations Utilizing Different Rate-Controlling Polymers

Certain delivery systems are intended to release the active ingredient in different phases to obtain the desired therapeutic effect. For these formulations, such as a bilayer tablet, it is desirable to distinguish and measure the release of drug from the different phases simultaneously. Mass spectrometric methods were developed to measure three ibuprofen isotopomers in serum and two in dissolution fluid. The analytical methods were linear (r 0.992) over the concentration range of interest and recovery was greater than 99.2% for all isotopomers. Coadministration of [²H₀]ibuprofen, [²H₄]ibuprofen, and [²H₇]ibuprofen to male beagles demonstrated that the isotopomers were bioequivalent and verified the absence of any kinetic isotope effect due to deuterium incorporation (p = 0.286). These methods were then used to evaluate a bilayer tablet formulation composed of an immediate release layer of 100 mg [²H₄]ibuprofen and a sustained release layer with a drug load of 300 mg [²H₀]ibuprofen. Two different rate-controlling polymer matrices that provided similar in vitro dissolution profiles were compared in the sustained release phase, while the immediate release formulation remained the same. In male beagles, the HPMC matrix delivered a significantly greater amount of ibuprofen (p < 0.05). The AUC was threefold greater for HPMC (1067 ± 437 nmole * h/ml) versus EUDRAGIT^® (320 ± 51), and C_max was nearly four times greater (145 ± 62.1 nmole/ml for HPMC versus 37.9 ± 14.4 for EUDRAGIT^®). Although T_max for HPMC (3.4 ± 1.9 h) lagged behind EUDRAGIT^® (2.0 ± 0.82 h), the difference was not significant (p > 0.05). The immediate release layer was absorbed to the same extent as an oral solution (containing [²H₇]ibuprofen) that was administered concomitantly with the bilayer tablet. Using the stable isotope markers also demonstrated that the release rates of the two layers were independent of each other, both in vivo and in vitro. Stable isotope techniques are a useful tool in the development of biphasic release formulations since they can be used to determine proper drug load of each phase as well as the appropriate rate of release.     

Pharmacokinetics of Ibuprofen Enantiomers in Humans Following Oral Administration of Tablets with Different Absorption Rates

Ibuprofen (IB) is a racemic drug and is administered as such. While activity is due mainly to the S enantiomer, pharmacokinetic interpretations, as well as criteria to assess the bioequivalence of IB formulations, are based on measurements of the total (S + R) drug concentrations. IB enantiomers possess different disposition properties mainly as a result of R-to-S isomeric bioinversion. Inversion is maximal during the absorption phase, suggesting, perhaps, involvement of a presystemic process. This concept was evaluated in healthy subjects by crossover administration of four IB tablets having different absorption rates. The plasma concentrations of the individual isomers were measured using a stereospecific gas chromatographic assay. Differences among the products were insignificant with respect to the extent to the absorption. The S:R concentration ratios rose for 4 to 6 hr and then remained relatively unchanged. This observation was consistent with equal terminal t _1/2 values for the enantiomers. There were significant differences between the peak times (T _max) of the products. The S:R ratios of the concentrations at T _max of S and AUC also differed; significant positive correlations were found between T _max and the S:R ratios of C _max. Thus the extent of R-to-S inversion, and hence the potency of a racemic dose of IB, may be absorption rate dependent.     

Preparation and Characterization of a Composite PLGA and Poly(Acryloyl Hydroxyethyl Starch) Microsphere System for Protein Delivery

Purpose. To prepare and characterize a novel composite microsphere system based on poly(D,L-lactide-co-glycolide) (PLGA) and poly(acryloyl hydroxyethyl starch) (acHES) hydrogel for controlled protein delivery. Methods. Model proteins, bovine serum albumin, and horseradish peroxidase were encapsulated in the acHES hydrogel, and then the protein-containing acHES hydrogel particles were fabricated in the PLGA matrix by a solvent extraction or evaporation method. The protein-loaded PLGA-acHES composite microspheres were characterized for protein loading efficiency, particle size, and in vitro protein release. Protein stability was examined by size-exclusion chromatography, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and monitoring the enzymatic activity. Results. Scanning electron microscopy showed discrete PLGA microspheres containing many acHES particles. The composite microspheres were spherical and smooth in size range of 39-93 m. The drug loading efficiency ranged from 51 to 101%. The composite microspheres showed more favorable in vitro release than conventional PLGA microspheres. The composite microspheres showed 20% less initial with a gradual sustained release compared to high burst (60%) followed by a very slow release with the conventional PLGA microspheres. The composite microspheres also stabilized encapsulated proteins from the loss of activity during the microsphere preparation and release. Proteins extracted from the composite microspheres showed good stability without protein degradation products and structural integrity changes in the size-exclusion chromatography and SDS-PAGE analyses. Horseradish peroxidase extracted from microspheres retained more than 81% enzymatic activity. Conclusion. The PLGA-acHES composite microsphere system could be useful for the controlled delivery of protein drugs.     

Formulation and characterization of catalase in albumin microspheres

Abstract

Catalase in albumin microspheres were formulated for intravenous administration to antagonize the effects of over-production of reactive oxygenated species (ROS) such as hydrogen peroxide (H₂O₂) in septic shock. The aim was to increase effective half-life of catalase and take advantage of the phagocytic uptake of the encapsulated catalase by the vascular endothelium. Catalase microspheres were prepared by spray-drying. The microspheres were evaluated for particle size, particle shape and surface morphology by scanning electron microscopy (SEM), drug encapsulation efficiency, chemical stability, thermal stability and in vitro drug release characteristics. The microspheres had a mean particle size of 4.7 ± 2 µm, optimal for phagocytic uptake, as demonstrated by Makino et al. SEM revealed that microspheres were spherical with smooth surface morphology. An encapsulation efficiency of 91.5 ± 3% was achieved and the encapsulated catalase was chemically and thermally stable. Application of in vitro drug release data to the Higuchi kinetic equation indicated matrix diffusion-controlled catalase release from albumin microspheres.     

Controlled release of nifedipine from gelatin microspheres and microcapsules: in vitro kinetics and pharmacokinetics in man

Abstract

Nifedipine was embedded in a gelatin matrix to develop a prolonged release dosage form. The effects of polymer/drug ratio, size of the beads, cross-linking with formaldehyde and ethylcellulose coating of the gelatin microspheres on the in vitro release rate of the drug were investigated. The data were analysed according to different laws that can govern the release mechanism: first-order, Higuchi square root of time, spherical matrix and zero-order. The in vitro release kinetics of nifedipine from gelatin microspheres were mainly first-order; from formaldehyde hardened gelatin microspheres, complied with the diffusion model for a spherical matrix, and from ethylcellulose-coated gelatin microspheres, obeyed zero-order kinetics. These findings suggest the possibility of modifying the formulation in order to obtain the desired controlled release of the drug for a convenient oral sustained delivery system. The pharmacokinetic parameters of nifedipine, after adminstration of a single oral dose of nifedipine-loaded hardened gelatin microspheres to volunteers, suggest that the preparation can be considered as a sustained release delivery system for nifedipine.