In Vitro and In Vivo Performance of a Multiparticulate Pulsatile Drug Delivery System

ABSTRACT

The objective of this study was to investigate the in vitro and in vivo drug release performance of a rupturable multiparticulate pulsatile system, coated with aqueous polymer dispersion Aquacoat® ECD. Acetaminophen was used as a model drug, because in vivo performance can be monitored by measuring its concentration in saliva. Drug release was typical pulsatile, characterized by lag time, followed by fast drug release. Increasing the coating level of outer membrane lag time was clearly delayed. In vitro the lag time in 0.1 N HCl was longer, compared to phosphate buffer pH 7.4 because of ionisable ingredients present in the formulation (crosscarmelose sodium and sodium dodecyl sulphate). In vitro release was also longer in medium with higher ion concentration (0.9% NaCl solution compared to purified water); but independent of paddle rotation speed (50 vs.100 rpm). Macroscopically observation of the pellets during release experiment confirms that the rupturing of outer membrane was the main trigger for the onset of release. At the end of release outer membrane of all pellets was destructed and the content completely released.

However, pellets with higher coating level and correspondingly longer lag time showed decreased bioavailability of acetaminophen. This phenomenon was described previously and explained by decreased liquid flow in the lower part of intestine. This disadvantage can be considered as a limitation for drugs (like acetaminophen) with high dose and moderate solubility; however, it should not diminish performance of the investigated system in principle.     

Evaluation of Monolithic Osmotic Tablet System for Nifedipine Delivery In Vitro and In Vivo

Abstract

The aim of this study was to evaluate the monolithic osmotic tablet system (MOTS) containing a solid dispersion with the practically water-insoluble drug nifedipine in vitro and in vivo. In the drug release study in vitro, the release profiles of this system had almost zero-order kinetics. The influences of tablet formulation variables, sizes of the delivery orifice, membrane variables, and values of pH in the dissolution medium on nifedipine release from MOTS have been investigated. The results provided evidence that the tablet core played an important role in MOTS. While orifice sizes and membrane variables affected the nifedipine release rate, MOTS was independent of the dissolution medium. The appropriate orifice size was found to be in the range of 0.5–1.0 mm. The coating membrane incorporating hydrophilic polyethylene glycol (PEG) formed a porous structure. The human pharmacokinetics and relative bioavailability of MOTS containing nifedipine were compared with a commercial Adalat® osmotic tablet system containing an equivalent dose of nifedipine following an oral single dose of 30 mg given to each of 11 healthy volunteers in an open, randomized crossover study in vivo. The relative bioavailability for MOTS was 112%. There was no statistically significant difference in the pharmacokinetic parameters between two dosage forms. It is concluded that the monolithic osmotic tablet controlled release system is feasible for a long-acting preparation as a once-daily treatment.     

In Vitro and In Vivo Adhesion Testing of Mucoadhesive Drug Delivery Systems

Bioadhesive tablets were prepared by physical mixing of polymers and drug, then granulating and compressing into a tablet. The mucoadhesion was evaluated by shear stress measurement, detachment force measurement, and X-ray photography of the rabbit gastrointestinal tract. The strong interaction between the polymer and the mucous lining of the tissue helps increase contact time and permit localization. Polymers like hydroxypropyl methylcellulose K4M (HPMC K4M), hydroxypropyl methylcellulose 100 cps (HPMC 100 cps), carbopol-934, sodium carboxy methylcellulose (Na CMC), guar gum, and polyvinylpyrrolidone (PVP) were tested by shear stress measurement and detachment force measurement methods. HPMC K4M, showing maximum bioadhesion, was used in further studies. Adhesion was maximum between pH 5 and pH 6. Maximum adhesion was observed in the duodenum, followed by the jejunum and ileum. Barium sulfate (BaSO₄) matrix tablets containing polymer and drug were subjected to X-ray studies in rabbits, and it was found that the tablet was mucoadhesive even after 8 hr. Enteric coating did not show any effect on mucoadhesion after passing from the stomach.     

Preparation and In Vitro Evaluation of pH,Time-Based and Enzyme-Degradable Pellets for Colonic Drug Delivery

The preparation of pH-dependent, time-based and enzyme degradable pellets was investigated for use as an oral colonic drug delivery system. It was expected that drug would be released immediately once the pellets reached the colon. The pellets were prepared using extrusion-spheronizing equipment and subsequently coated with three layers of three functional polymers by an air-suspension technique. The core consisted of 5-aminosalicylic acid (5-ASA) as a model drug, CaP as an enzyme-degradable material and microcrystalline cellulose (MCC) as an additive. As far as the three coated layers were concerned, the outer layer was coated with Eudragit L30D-55 for protection against gastrointestinal juices, the intermediate layer was coated with ethylcellulose (EC) to inhibit drug release during passage through the small intestine, and the inner film was coated with pectin for swelling and enzyme-degradation, which required a 30, 10, and 12% weight gain, respectively. Several micromeritic properties of the core pellets, including particle size distribution, particle size, degree of circularity, and friability, were evaluated to investigate the effects of the formulations of the cores and preparation conditions. Also, dissolution testing of the cores showed that the presence of calcium pectinate (CaP) markedly increased the drug release rate from the cores, as determined by scanning electron microscopy (SEM). In-vitro release studies indicated that the coated pellets completely protected the drug release in 0.1 mol/L HCl, while the drug release was delayed for 3–4 hr in pH 6.8 PBS. A synergistic effect of enzyme dependence for the coated pellets was seen following removal of the coated layer and during contact with colonic enzymes. Consequently, it was possible to achieve colon-specific drug delivery using this triple-dependence system.     

Development of Monolithic Osmotic Pump Tablet System for Isosorbide-5-Mononitrate Delivery and Evaluation of it In Vitro and In Vivo

The objective of this study is to develop the monolithic osmotic pump tablet system (MOTS) containing isosorbide-5-mononitrate (5-ISMN), and to evaluate its in vitro and in vivo properties. The influences of tablet formulation variables, size and location of the delivery orifice, membrane variables, and pH value of the dissolution medium on 5-ISMN release from MOTS have been investigated. These results demonstrated that the tablet core played an important role in MOTS, and membrane variables could affect the 5-ISMN release rate. The optimal formulation of 5-ISMN MOTS was determined by uniform design. Furthermore, the dog pharmacokinetics and relative bioavailability of the test formulation (5-ISMN MOTS) have been compared with the reference formulation (Imdur^®: 60 mg/tablet, a sustained release, SR, tablet system) following an oral single dose of 60 mg given to each of six Beagle dogs. The mean drug fraction absorbed by the dog was calculated by the Wagner–Nelson technique. The results showed that drug concentration in plasma could be maintained more stable and longer after the administration of 5-ISMN MOTS compared with the matrix tablets of Imdur^®, and a level A “in vitro–in vivo correlation” was observed between the percentage released in vitro and percentage absorbed in vivo. It is concluded that 5-ISMN MOTS is more feasible for a long-acting preparation than 5-ISMN SR tablet system as once-a-day treatment, and it is very simple in preparation, and can release 5-ISMN at the rate of approximately zero order for the combination of hydroxypropylmethyl cellulose as retarder and NaCl as osmogent.     

Moment Analysis for the Evaluation of In Vitro Drug Release and In Vivo Bioavailability of Theophylline Microcapsules

Abstract

Statistical moment analysis has been used to establish an in vitro-in vivo correlation for five types of theophylline ethylcellulose microcapsules prepared by using various concentrations of ethylene-vinyl acetate (EVA) copolymer as a coacervation-inducing agent. The concentration of EVA copolymer was found to be played an important function in the controlled release of theophylline microcapsules. Correlations were found between the in vitro dissolution behavior, e.g., MDT _0→7, in vitro' and the rate of bioavailability, e.g., Cmax, Tmax, MDT _{in vivo} or MRT_0→2, although there was no valid correlation with the extent of bioavailability, e.g., AUC_0→27. Thus, moment analysis by studying the quantitative in vitro-in vivo correlations relating to drug release was validated.     

In Vitro Release Kinetics of Gentamycin from a Sodium Hyaluronate Gel Delivery System Suitable for the Treatment of Peripheral Vestibular Disease

For certain patients who experience intense vertigo arising from unilateral vestibular lesions, the primary therapy is a vestibular nerve section, an intracranial surgical procedure. One alternative to this treatment is therapeutic ablation of vestibular function on the unaffected side using an ototoxic agent. We prepared a biodegradable sustained-release gel delivery system using sodium hyaluronate that can be administered into the middle ear using only a local anesthetic. The gel contains gentamycin sulfate, the ototoxic agent of choice for treatment of unilateral vestibulopathy, and it exhibits diffusion-controlled release of the drug over a period of hours. The released gentamycin could then diffuse into the inner ear through the round membrane. This represents an important advance over previous formulations, which used only gentamycin sulfate solutions, in that it should allow more careful control of the dose, it should reduce loss of the drug from the middle ear site, and it should maintain intimate contact with the round membrane. By carefully controlling the dose, it should be possible to inhibit vestibular function while minimizing hearing loss. Herein we describe the in vitro release kinetics of gentamycin sulfate from sodium hyaluronate gels and find that the system obeys Fickian behavior.     

Elastic Liposomal Formulation for Sustained Delivery of Antimigraine Drug: In Vitro Characterization and Biological Evaluation

The aim of this study was to prepare and characterize a topical formulation for sustained delivery of rizatriptan. Elastic liposomal formulation of rizatriptan was prepared and characterized for different characteristics by evaluating in vitro and in vivo parameters. The in vivo performance of optimized formulation was evaluated for antimigraine activity in mice using morphine withdrawal-induced hyperalgesia. The in vitro skin permeation study across rat skin suggested carrier-mediated transdermal permeation for different elastic liposomal formulation to range between 18.1 ± 0.6 and 42.7 ± 2.3 μg/h/cm², which was approximately 8–19 times higher than that obtained using drug solution. The amount of drug deposited was 10-fold higher for elastic liposome (39.9 ± 3.2%) than using drug solution (3.8 ± 1%); similarly the biological activity of optimized elastic liposome formulation was found to be threefold higher than the drug solution. On the basis of the results, it can be concluded that the elastic liposomal formulation provided sustained action of rizatriptan due to depot formation in the deeper layer of skin.     

介入性心血管内药物和基因纳米控释体系

通过介入导管将药物和基因载运到血管内病灶部位,并在血管组织中长期释放。以生物可降解聚合物PLGA为基材,采用超声乳化／溶剂挥发法分别制备包载药物和基因的纳米粒子,对纳米粒子进行了表面修饰提高血管吸收性;用载反义MCP-1基因的纳米粒子转染平滑肌细胞,对平滑肌细胞基因组DNA进行PCR扩增;用兔髂总动脉和颈总动脉血管损伤模型进行灌注实验。体外释放实验表明均具有缓慢释放作用,凝胶电泳实验证明基因的结构未遭破坏。说明纳米粒子是非常理想的血管内导向定位药物和基因控释的载体。     

Lonidamine Solid Dispersions: In Vitro and In Vivo Evaluation

ABSTRACT

Solid dispersions of lonidamine in PEG 4000 and PVP K 29/32 were prepared by the spray-drying method. Then, the binary systems were studied and characterized using differential scanning calorimetry, hot stage microscopy, and x-ray diffractometry. In vitro dissolution studies of the solid dispersed powders were performed to verify if any lonidamine dissolution rate or water solubility improvement occurred. In vivo tests were carried out on the solid dispersions and on the cyclodextrin inclusion complexes to verify if this lonidamine water solubility increase was really able to improve the in vivo drug plasma levels. Drug water solubility was increased by the solid dispersion formation, and the extent of increase depended on the polymer content of the powder. The greater increase of solubility corresponded to the highest content of polymer. Both the solid dispersions and the cyclodextrin complexes were able to improve the in vivo bioavailability of the lonidamine when administered per os. Particularly, the AUC of the drug plasma levels was increased from 1.5 to 1.9-fold depending on the type of carrier.     

Eudragit Coating of Chitosan-Prednisolone Conjugate Microspheres and In Vitro Evaluation of Coated Microspheres

Chitosan-prednisolone conjugate microspheres (Ch-SP-MS) were prepared, and Eudragit coating was applied in order to efficiently deliver the microspheres and drug to the intestinal disease sites. The Eudragit L100-coated microspheres (Ch-SP-MS/EuL100) were examined for particle characteristics and the release of drug and Ch-SP-MS in different pH media at 37°C. Ch‐SP-MS were spherical, with a mean size of 4.5 μm and prednisolone content of 3.3% (w/w). Ch-SP-MS/EuL100 were fairly spherical, with a mean size of 22. 5 μm and drug content of 0.32% (w/w). At pH 1.2, the release extent was less than 5% even at 48 h, and Eudragit coating tended to suppress the release. In contrast, at pH 6.8 and 7.4, Ch-SP-MS/EuL100 tended to show somewhat faster drug release than Ch-SP-MS. Ch-SP-MS/EuL100 displayed a release extent of 23 and 27% at pH 6.8 and 7.4, respectively. Ch-SP-MS aggregated at pH 1.2, but almost kept their initial size and shape at pH 6.8 and 7.4. Ch-SP-MS/EuL100 almost maintained their original shape and size at pH 1.2, and gradually released Ch-SP-MS at pH 6.8 and 7.4 due to dissolution of the Eudragit layer. Eudragit coating is suggested to be useful to efficiently deliver Ch-SP-MS to the intestinal disease sites.     

Preparation of Novel Cationic Copolymer Microspheres and Evaluation of Their Function by In Vitro and In Vivo tests as Ph-Sensitive Drug Carrier Systems

ABSTRACT

Novel pH-sensitive copolymer microspheres containing methylacrylic acid and styrene cross-linking with divinylbenzene were synthesized by free radical polymerization. The microspheres that were formed were then characterized by Fourier-Transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), size analysis, and X-ray analysis. The copolymer microspheres showed pulsatile swelling behavior whenthe pH of the media changed. The pH-sensitive microspheres were loaded with diltiazem hydrochloride (DH). The release characteristics of the free drug and the drug-loaded microspheres were studied under both simulated gastric conditions and intestinal pH conditions. The in vivo evaluation of the pulsatile preparation was subsequently carried out using beagle dogs as experimental subjects. The results demonstrated that the drug release exhibited a pulsatile character both in vitro and in vivo.     

Development of Nitrendipine Controlled Release Formulations Based on SLN and NLC for Topical Delivery: In Vitro and Ex Vivo Characterization

The aim of the investigation is to develop solid lipid nanoparticles (SLN) and nano-structured lipid carrier (NLC) as carriers for topical delivery of nitrendipine (NDP). NDP-loaded SLN and NLC were prepared by hot homogenization technique followed by sonication, and they were characterized for particle size, zeta potential, entrapment efficiency, stability, and in vitro release profiles. Also the percutaneous permeation of NDPSLN A, NDPSLN B, and NDPNLC were investigated in abdominal rat skin using modified Franz diffusion cells. The steady state flux, permeation coefficient, and lag time of NDP were estimated over 24 h and compared with that of control (NDP solution). The particle size was analyzed by photon correlation spectroscopy (PCS) using Malvern zeta sizer, which shows that the NDPSLN A, NDPSLN B, and NDPNLC were in the range of 124–300 nm during 90 days of storage at room temperature. For all the tested formulations (NDPSLN A, NDPSLN B, and NDPNLC), the entrapment efficiency was higher than 75% after 90 days of storage. The cumulative percentage of drug release at 24 h was found to be 26.21, 30.81, and 37.52 for NDPSLN A, NDPSLN B, and NDPNLC, respectively. The results obtained from in vitro release profiles also indicated the use of these lipid nanoparticles as modified release formulations for lipophilic drug over a period of 24 h. The data obtained from in vitro release from NDPSLN A, NDPSLN B, and NDPNLC were fitted to various kinetic models. High correlation was obtained in Higuchi and Weibull model. The release pattern of drug is analyzed and found to follow Weibull and Higuchi equations. The permeation profiles were obtained for all formulations: NDPSLN A, NDPSLN B, and NDPNLC. Of all the three formulations, NDPNLC provided the greatest enhancement for NDP flux (21.485 ± 2.82 μg/h/cm²), which was fourfold over control (4.881 ± 0.96 μg/h/cm²). The flux obtained with NDPSLN B (16.983 ± 2.91 μg/h/cm²) and NDPNLC (21.485 ± 2.82 μg/h/cm²) meets the required flux (16.85 μg/h/cm²).     

In Vitro and In Vivo Evaluation of Two Extended Release Preparations of Combination Metformin and Glipizide

A system that can deliver multi-drugs at a prolonged rate is very important to the treatment of various chronic diseases such as diabetes, asthma, and heart disease. Two controlled-release systems, which exhibited similar release profiles of metformin and glipizide, i.e., elementary osmotic pump tablets (EOP) and bilayer hydrophilic matrix tablet (BT), were designed. The effects of pH and hydrodynamic conditions on drug release from two formulations were investigated. It was found that both drug releases from EOP were not sensitive to dissolution media pH and hydrodynamics change, while the release of glipizide from BT was influenced by the stirring rate. Moreover, in vivo evaluation was performed, relative to the equivalent dose of conventional metformin tablet and glipizide tablet, by a three-crossover study in six Beagle dogs. Cumulative percent input in vivo was compared to in vitro release profiles. The linear correlations of metformin and glipizide between fraction absorbed in vivo and fraction dissolved in vitro were established for EOP—a true zero-order release formula, whereas only nonlinear correlations were obtained for BT. In conclusion, drug release from EOP was both independent of in vitro and in vivo conditions, where the best sustained release effect was achieved, whereas the in vitro dissolution test employed for BT needed to be further optimized to be biorelevant.     

Simultaneous Estradiol and Levonorgestrel Transdermal Delivery from a 7-day Patch: In Vitro and In Vivo Drug Deliveries of Three Formulations

ABSTRACT

A new drug-in-adhesive transdermal patch was developed to deliver both estradiol and levonorgestrel through the skin over a 7-day period, but at different rates. This report elucidates the in vitro and in vivo biopharmaceutical studies that were necessary during the development of this product. Three test patches had to be manufactured, all delivering estradiol at the same rate, but delivering levonorgestrel at three different rates so that a levonorgestrel dose response could be studied in the clinic. An in vitro hairless mouse skin model (HMS) using modified Franz diffusion cells was used to select the test products delivering levonorgestrel in the order of 1:2:3. HMS experiments also demonstrated that the presence of estradiol did not affect the flux of levonorgestrel. Two in vivo studies in postmenopausal women showed that at steady state (four weeks of once-weekly dosing) the three test products all delivered estradiol at comparable rates. Similarly, the levonorgestrel deliveries for the three test products were in the order expected. The target fluxes of both drugs were achieved in these three test products by varying the drug loads and patch size. That this approach was successful is evidence of the value of using the HMS penetration experiments in transdermal product development and should provide useful insights for other formulations having to develop complex systems. One of the test products is now marketed as Climara Pro^TM.     

Preparation and In Vitro/In Vivo Evaluation of Gliclazide Loaded Eudragit Nanoparticles as a Sustained Release Carriers

ABSTRACT

The aim of this study was to formulate and optimize gliclazide-loaded Eudragit nanoparticles (Eudragit L100 and Eudragit RS) as a sustained release carrier with enhanced efficacy. Eudragit L 100 nanoparticles (ELNP) were prepared by controlled precipitation method whereas Eudragit RSPO nanoparticles (ERSNP) were prepared by solvent evaporation method. The influence of various formulation factors (stirring speed, drug:polymer ratio, homogenization, and addition of surfactants) on particle size, drug loading, and encapsulation efficiency were investigated. The developed Eudragit nanoparticles (L100 and RS) showed high drug loading and encapsulation efficiencies with nanosize. Mean particle size altered by changing the drug:polymer ratio and stirring speed. Addition of surfactants showed a promise to increase drug loading, encapsulation efficiency, and decreased particle size of ELNP as well as ERSNP. Dissolution study revealed sustained release of gliclazide from Eudragit L100 as well as Eudragit RSPO NP. SEM study revealed spherical morphology of the developed Eudragit (L100 and RS) NP. FT-IR and DSC studies showed no interaction of gliclazide with polymers. Stability studies revealed that the gliclazide-loaded nanoparticles were stable at the end of 6 months. Developed Eudragit NPs revealed a decreased t_min (ELNP), and enhanced bioavailability and sustained activity (ELNP and ERSNP) and hence superior activity as compared to plain gliclazide in streptozotocin induced diabetic rat model and glucose-loaded diabetic rat model. The developed Eudragit (L100 and RSPO) NP could reduce dose frequency, decrease side effects, and improve patient compliance.     

Design and Evaluation In Vitro of Controlled Release Mucoadhesive Tablets Containing Chlorhexidine

ABSTRACT

This investigation deals with the development of buccal tablets containing chlorhexidine (CHX), a bis-bis-guanide with antimicrobial and antiseptic effects in the oral cavity, and able to adhere to the buccal mucosa to give local controlled release of drug. A mucoadhesive formulation was designed to swell and form a gel adhering to the mucosa and controlling the drug release into the oral cavity.

Some batches of tablets were developed by direct compression, containing different amounts of hydroxypropylmethylcellulose (HPMC) and carbomer; changing the amount ratio of these excipients in formulations, it is possible easily modulate the mucoadhesive effect and release of drug. The in vitro tests were performed using the USP 26/NF paddle apparatus, a specifically developed apparatus, and a modified Franz diffusion cells apparatus. This last method allows a simultaneous study of drug release rate from the tablets and drug permeation through the buccal mucosa.

Similar tests have also been carried out on a commercial product, Corsodyl gel^®, in order to compare the drug release control of gel with respect to that of the mucoadhesive tablet, as a formulation for buccal delivery of CHX. While the commercial formulation does not appear to control the release, the formulation containing 15% w/w methocel behaves the best, ensuring the most rapid and complete release of the drug, together with a negligible absorption of the active agent as required for a local antiseptic action in the oral cavity.     

Wax-Matrix Tablet for Time-Dependent Colon-Specific Delivery System of Sophora Flavescens Aiton: Preparation and In Vivo Evaluation

A wax-matrix time-dependent colon-specific tablet (WM-TDCS) was studied. Wax-matrix tablet core consisting of semi-synthetic glycerides, as a wax polymeric expanding agent, carboxymethyl starch sodium (CMS-Na), and NaCl was prepared, and Sophora flavescens Aiton (ASF, extracts of traditional Chinese medicine) was used as model drug. The wax-matrix ASF tablets core was coated with Eudragit NE 30 D as the inner coating materials and with Opadry OY-P-7171 as the outer coating materials. The in vitro release behaviors of the coated tablets were examined and then in vivo absorption kinetics of the coated tablets in dogs was further investigated. The volume of the tablet core was markedly increased at 37°C because of the expand effect of polymer semi-synthetic glycerides and CMS-Na. The drug release from WM-TDCS was more stable than TDCS in vitro and in vivo. The lag time of ASF release was also controlled by the thickness of the inner coating layer. In vivo evaluation demonstrated that in vivo lag time of absorption was in a good agreement with in vitro lag time of release. ASF wax-matrix tablets coated with Eudragit NE 30 D and Opadry OY-P-7171 using the regular coating technique could be designed to achieve a lag time of 3 h in the small intestinal tract.     

Ophthalmic Delivery of Ciprofloxacin Hydrochloride from Different Polymer Formulations: In Vitro and In Vivo Studies

Abstract

Reservoir-type ocular inserts were fabricated using sodium alginate containing ciprofloxacin hydrochloride as the core (drug reservoir) that was sandwiched between the Eudragit and/or polyvinylacetate films. Ocular inserts were packaged in aluminium foil and sterilized by gamma radiation. These were tested for sterility as per British Pharmacopoeia (BP). Ocular inserts were evaluated for in vitro release rate studies, microbial efficacy, in vivo release studies, efficacy against induced bacterial conjunctivitis in rabbit's eyes, concentration in the aqueous humor, and stability studies as per the International Conference on Harmonization (ICH) guidelines. Ocular inserts passed the test for sterility. They showed zero-order release of the drug in the in vitro and in vivo release studies over a period of 120 hr. The drug was found to be active against selected microorganisms as was proved by microbial efficacy studies. A high correlation coefficient was found between in vitro and in vivo release rate studies. Better improvement was observed in artificially induced bacterial conjunctivitis in rabbit's eyes, compared with marketed eye drops and placebo. Drug concentration in the aqueous humor was found above Minimum Inhibitory Concentration (MIC-90) against selected microorganisms. Shelf-life of the product was found to be more than 2 years.