Mucoadhesive microspheres for nasal administration of cyclodextrins

The aim of this study was to examine the in vitro capacity of cyclodextrins to interfere on the β-amyloid fibril formation; then, mucoadhesive microspheres containing cyclodextrins were prepared and characterised as nasal delivery system for brain targeting. Eight batches of microspheres containing chitosan or alginate loaded with β-cyclodextrin or hydroxypropyl-β-cyclodextrin in two different cyclodextrin to polymer ratios were produced by spray drying. The results show that none of the tested CDs has direct cellular toxicity and they protect the cell viability from β-peptide. The microspheres prepared are characterised by small particle sizes, ability to absorb water and to delay the in vitro dissolution rate of the CDs; good ex vivo mucoadhesive properties of the formulations are assessed. The microsphere properties are influenced by the kind of polymer, of cyclodextrin and by cyclodextrin to polymer ratio used. In particular, the alginate formulation containing the higher cyclodextrin content shows the best performance.     

Preparation and in vitro characterization of gelatin microspheres containing Levodopa for nasal administration

The dissolution properties of twomodel compounds, brilliant blue and tumour necrosis factor (TNF-alpha), from poly(D,L- .lactic-co-glycolic acid) (PLGA) multiphasemicrospheres wereinvestigated. In addition, the invivo releaseof TNF-alpha from the microspheres, in mice, was studied. The microspheres were prepared by an anhydrous multiple emulsion solvent evaporation method. Multiphase microspheres containing brilliant blue exhibited athree phase release profile in vitro, and displayed a significantly lower level of dye released during the initial phase compared to conventional matrix-type microspheres. Slow release of the dye was observed during the second phase, which was followed by a disintegration of the polymer wall during the third phase of the release process. In vitro dissolution profiles of TNF-alpha were calculated by compensation for the simultaneous degradation of the protein in the dissolution medium. The initial burst release of TNF-alpha was significantly reduced with the multiphase microspheres. The three phase release profile, as seen with the dye, was not observed for the microspheres containing the TNF-alpha. The rate of release of the protein from the microspheres was determined in vivo by analysing the residual level of TNF-alpha remaining in the particles following intraperitoneal administration of the microspheres to mice. The release of the protein from the microspheres in vivo was significantly faster than predicted from the results of the in vitro studies. The absence of an initial burst release of TNF-alpha from the multiphase microspheres was reflected in a significant reduction in the plasma level of TNF-alpha when compared to the matrix-type microspheres and a solution of the protein. The controlled release property of the multiphase microspheres is expected to overcome the adverse reactions due to dose dumping that occurs following the local administration of TNF-alpha.     

Lyophilized inserts for nasal administration harboring bacteriophage selective for Staphylococcus aureus: in vitro evaluation

Nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA) poses an infection risk and eradication during hospitalization is recommended. Bacteriophage therapy may be effective in this scenario but suitable nasal formulations have yet to be developed. Here we show that lyophilization of bacteriophages in 1 ml of a viscous solution of 1-2% (w/v) hydroxypropyl methylcellulose (HPMC) with/without the addition of 1% (w/v) mannitol, contained in Eppendorf tubes, yields nasal inserts composed of a highly porous leaflet-like matrix. Fluorescently labeled bacteriophage were observed to be homogenously distributed throughout the wafers of the dried matrix. The bacteriophage titer fell 10-fold following lyophilization to 10⁸ pfu per insert, then falling a further 100- to 1000-fold over 6 to 12 months storage at 4 °C. This compares well with a total dose of 6 × 10⁵ pfu in 0.2 ml liquid applied into the ear during a recent clinical trial in humans. The residual water content of the lyophilized inserts was reduced upon the addition of mannitol to HPMC, but this did not have any correlation to the lytic activity. Mannitol underwent a transition from its amorphous to crystalline state during exposure of the inserts to increasing relative humidities (as would be experienced in the nose), although this transition was suppressed by higher HPMC concentrations and the presence of buffer containing gelatin and bacteriophages. Our results therefore suggest that lyophilized inserts harboring bacteriophage selective for S. aureus may be a novel means for the eradication of MRSA resident in the nose.     

Preparation and in vitro characterization of gelatin microspheres containing Levodopa for nasal administration

Transnasal absorption of pharmaceutical drugs has been recognized as an interesting alternative to the more conventional routes of administration. The aim of this paper was to develop a method of administrating L-dopa following the transnasal route. Gelatin microspheres were prepared by the w/o emulsification solvent extraction technique: the microspheres had a median particle size of 16.2 +/- 4.2 microm and were prepared using a stirring speed of 600 rpm for 5 min at 80 degrees C. The microspheres obtained were spherical and smooth-surfaced, and the microsphere size was inversely proportional to stirring speed (300-700 rpm) and to the percentage of the emulsifier (Tween 85, 1.4-2.7% v/v). L-dopa was incorporated into the microspheres with an efficiency of 65 +/- 6.7%. L-dopa was released from the microspheres, showing an initial fast release rate, followed by a second slower release rate.     

PLGA包埋硫酸庆大霉素缓释微球的制备及体外释放行为

以生物可降解乙交酯和丙交酯的无规共聚物(PLGA)为载体,将硫酸庆大霉素分散在PLGA的有机溶液中,采用复乳溶剂挥发法制备了药物缓释微球。研究搅拌速度、PLGA浓度、乳化剂浓度和硫酸庆大霉素溶液体积对微球粒径的影响,观察微球的表面形貌,测定微球粒径、粒径分布和包封率,评价载药微球的体外释放行为。结果表明,采用甲基纤维素为乳化剂制备的微球形态完整,中粒径为(130±30)μm,微球中硫酸庆大霉素的包封率均在36%以上,平均42%,最高达56%。硫酸庆大霉素/PLGA微球具有显著的药物缓释作用,体外释放30d的累积释药率达80%以上。     

Galactomannan gum coated mucoadhesive microspheres of glipizide for treatment of type 2 diabetes mellitus: In vitro and in vivo evaluation

Type 2 diabetes mellitus is a heterogeneous disease of polygenic origin and involves both defective insulin secretion and peripheral insulin resistance. Studies have shown that post-meal hyperglycemic spikes are associated with increased cardiovascular mortality in type 2 diabetes. Over the past decade, a major interest in control of postprandial glucose excursion has emerged and a plethora of new medications that specifically target postprandial hyperglycemia were discovered. Despite the availability of new agents for treatment of type 2 diabetes mellitus, oral sulfonylureas remain a cornerstone of therapy, because they are relatively inexpensive and are well tolerated. However, hypoglycemia is a major safety concern with sulfonylureas and it is one major risk factor requiring hospitalization. Glipizide is a potent, rapid-acting with short duration of action and well tolerated second-generation sulfonylurea effective in reducing postprandial glucose levels. However, risk of postprandial hypoglycemia and post-meal glucose excursions, if dose missed before meal; are always associated with the use of glipizide for treatment of type 2 diabetes mellitus. Since, the site of absorption of glipizide is from stomach thus dosage forms that are retained in stomach by mucoadhesion; would increase absorption, improve drug efficiency and decrease dose requirements. Microsphere carrier systems made by using polymer galactomannan having strong mucoadhesive properties and easily biodegradable could be an attractive strategy to formulate. The purpose of this research work is to formulate galactomannan coated mucoadhesive microspheres of glipizide and systematically evaluate its in vitro characteristics and in vivo performance for sustained glucose lowering effect and improvement in diabetic condition as compared to immediate release of glipizide.     

苦参碱壳聚糖微球的制备及体外释药

目的:以壳聚糖为囊材制备苦参碱结肠靶向给药微球及评价其体外释药情况。方法:用乳化化学交联法制备微球,以微球的粒径分布百分数、载药量及包封率为优化指标对影响微球制备的主要因素用正交试验设计优化制备条件;并对最佳制备工艺制得的微球进行3种不同递质(人工胃液、人工肠液及大鼠结肠液)中的体外释放度评价。结果:制得的苦参碱壳聚糖微球在电镜下,球形表面圆整,粒径分布适宜,微球平均粒径为(68.3±2.7)μm,平均载药量为(16.0±0.5)%,平均包封率为(66.3±4.2)%。苦参碱壳聚糖微球在人工胃液中2h不释药;在人工肠液中4h内释放不到1%,96h释药不到10%;在含大鼠结肠内容物的磷酸盐缓冲液(pH6.8)中4h释放10%左右,36h释药近50%,此后释药趋于缓慢,96h释药近80%。结论:苦参碱壳聚糖微球几乎不在上消化道释药,而是在结肠靶向释药。     

Mucoadhesive bilayer buccal tablet of carvedilol-loaded chitosan microspheres: in vitro,pharmacokinetic and pharmacodynamic investigations

A multiple-unit system comprising mucoadhesive bilayer buccal tablets of carvedilol-loaded chitosan microspheres (CMs) was developed to improve bioavailability and therapeutic efficacy of carvedilol. Drug-loaded CMs were prepared by spray drying, evaluated for powder and particle characteristics, and optimized batch of CMs was compressed into bilayer buccal tablets using Carbopol. Tablets were evaluated for physicochemical parameters, in vitro drug release, in vivo pharmacokinetic and pharmacodynamic studies. Optimized formulation, CMT1 (CMT, chitosan microsphere tablet) showed maximum mucoadhesive force (50?±?1.84?dyne/cm²), exhibited 73.08?±?3.05% drug release and demonstrated zero-order kinetics with non-Fickian release mechanism. Pharmacokinetic studies in rabbits showed significantly higher C_max (71.26?±?6.45?ng/mL), AUC_0–10 (AUC, area under the curve 390.75?±?5.23?ng/mL/h) and AUC_0–∞ (664.72?ng/mL/h) than carvedilol oral tablet. Pharmacodynamic studies confirmed reduction in mean arterial pressure, heart rate, body weight and triglyceride on administration of bilayer buccal tablet compared to oral carvedilol tablet. Multiple-unit system exhibited enhanced bioavailability and sustained release of carvedilol, indicating its improved therapeutic potential for the treatment of hypertension.     

Resveratrol solid lipid microparticles as dry powder formulation for nasal delivery,characterization and in vitro deposition study

This study focuses on development and in vitro characterisation of a nasal delivery system based on uncoated or chitosan-coated solid lipid microparticles (SLMs) containing resveratrol, a natural anti-inflammatory molecule, as an effective alternative to the conventional steroidal drugs. The physico-chemical characteristics of the SLMs loaded with resveratrol were evaluated in terms of morphology, size, thermal behaviour and moisture sorption. The SLMs appeared as aggregates larger than 20?μm. In vitro nasal deposition was evaluated using a USP specification Apparatus E 7-stage cascade impactor equipped with a standard or a modified nasal deposition apparatus. More than 95% of resveratrol was recovered onto the nasal deposition chamber and stage 1 of impactor, suggesting that the SLMs mostly deposited in the nasal cavity. Additionally, the SLMs were not toxic on RPMI 2650 nasal cell line up to a concentration of approximately 40?μM of resveratrol.     

替莫唑胺壳聚糖缓释微球的制备及体外释药特性

目的:制备替莫唑胺壳聚糖缓释微球,并对其体外释药模式进行研究.方法:以替莫唑胺为模型药物,采用乳化交联法制备壳聚糖微球,两步优化法优化处方和制备工艺.通过测定微球的粒径及其分布、载药量、包封率和体外释放速度对微球进行质量评价.结果:优化工艺制得的微球平均粒径为(3.9±1.6)μm,载药量为(7.1±0.5)%(n=3),包封率为(25.0±0.8)%(n=3),体外释药特性研究具有良好的缓释特性,在0～8 h符合Higuchi方程,Q=11.717 26.951t1/2(r=0.980),8～24 h符合一级释放曲线,lnQ=4.37 0.007 5t(r=0.983).结论:通过优化处方和制备工艺,采用乳化交联法可制备出以壳聚糖为载体、替莫唑胺为模型药物的缓释微球,其体外释药具有明显的缓释作用.     

Development and characterization of Eudragit based mucoadhesive buccal patches of salbutamol sulfate

For systemic drug delivery, the buccal region offers an attractive route of drug administration. Salbutamol sulfate is a short-acting β₂-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease. It’s oral bioavailability is ∼40% due to extensive first pass metabolism. Salbutamol sulfate patches were prepared using Eudragit L-100, HPMC, PVA and Carbopol 934 in various proportions and combinations using PEG-400/PG as plasticizers. Patches were laminated on one side with a water impermeable backing layer for unidirectional drug release. The thickness of medicated patches were ranged between 0.23 ± 0.008 and 0.59 ± 0.007 mm and mass varied between 65.23 ± 3.3 and 117.92 ± 4.2 mg. Patches showed an increase in mass and swelling index with PEG-400 when compared with PG. The surface-pH of patches ranged between 6 and 7. Formulations E7 (7.5 mL Eudragit L-100, 15 mL HPMC K4M, 7.5 mL PVA and 2 mL PEG-400), E12 (7.5 mL Eudragit L-100, 7.5 mL PVA, 15 mL Carbopol and 2 mL PEG-400), F7 (7.5 mL Eudragit L-100, 15 mL HPMC K4M, 7.5 mL PVA and 2 mL PG), and F12 (7.5 mL Eudragit L-100, 7.5 mL PVA, 15 mL Carbopol and 2 mL PG) showed high folding endurance. Residence time of the tested patches ranged between 101 and 110 min. The maximum in vitro release was found to be 99.93% over a period of 120 min for formulation F12. Data of in vitro release from patches were fitted to different kinetic models such as Higuchi and Korsmeyer–Peppas models to explain the release profile. Formulations E7 and F7 were best fitted to the non-Fickian, where as formulations E12 and F12 showed Fickian/anomalous drug release. Stability studies indicated that there was no change in the chemical and physical characteristics during the test period.     

Self-assembled nanoparticles of reduction-sensitive poly (lactic-co-glycolic acid)-conjugated chondroitin sulfate A for doxorubicin delivery: preparation,characterization and evaluation

In this study, reduction-sensitive self-assembled polymer nanoparticles based on poly (lactic-co-glycolic acid) (PLGA) and chondroitin sulfate A (CSA) were developed and characterized. PLGA was conjugated with CSA via a disulfide linkage (PLGA-ss-CSA). The critical micelle concentration (CMC) of PLGA-ss-CSA conjugate is 3.5?µg/mL. The anticancer drug doxorubicin (DOX) was chosen as a model drug, and was effectively encapsulated into the nanoparticles (PLGA-ss-CSA/DOX) with high loading efficiency of 15.1%. The cumulative release of DOX from reduction-sensitive nanoparticles was only 34.8% over 96?h in phosphate buffered saline (PBS, pH 7.4). However, in the presence of 20?mM glutathione-containing PBS environment, DOX release was notably accelerated and almost complete from the reduction-sensitive nanoparticles up to 96?h. Moreover, efficient intracellular DOX release of PLGA-ss-CSA/DOX nanoparticles was confirmed by CLSM assay in A549 cells. In vitro cytotoxicity study showed that the half inhibitory concentrations of PLGA-ss-CSA/DOX nanoparticles and free DOX against A549 cells were 1.141 and 1.825?µg/mL, respectively. Therefore, PLGA-ss-CSA/DOX nanoparticles enhanced the cytotoxicity of DOX in vitro. These results suggested that PLGA-ss-CSA nanoparticles could be a promising carrier for drug delivery.     

Design and development of nasal mucoadhesive microspheres containing tramadol HCl for CNS targeting

In the present study, tramadol HCl microspheres were designed in order to accomplish rapid delivery of drug to the brain. For this purpose, lower viscosity grade HPMC (E15) was chosen as mucoadhesive polymer and used at different drug/polymer ratios in the microspheres formulations. The spray-dried microspheres were evaluated with respect to the production yield, incorporation efficiency, particle size, mucoadhesive property, in vitro drug release, histopathological study, and radio imaging study in rabbits. DSC and XRD study showed molecular dispersion and conversion of the drug into amorphous form. Size and surface morphology of microspheres was analyzed by SEM and found to be spherical in shape with smooth surface. It was found that the particle size, swelling ability, and incorporation efficiency of microspheres increase with increasing drug-to-polymer ratio. Microspheres show adequate mucoadhesion and do not have any destructive effect on nasal mucosa. In vitro drug release of optimized formulation was found to be 94% after 90?min. The radio imaging study indicated localization of drug in the brain. Hence, tramadol HCl microspheres based on a HPMC E15 may be a promising nasal delivery system for CNS targeting.     

In vitro and in vivo evaluation of ranitidine hydrochloride loaded hollow microspheres in rabbits

The objective of this investigation was to develop the hollow microspheres as a new dosage form of floating drug delivery systems with prolonged stomach retention time. Hollow microspheres containing ranitidine hydrochloride (RH) were prepared by a novel solvent diffusion-evaporation method using ethyl cellulose (EC) dissolved in a mixture of ethanol and ether (6:1.0, v/v). The yield and drug loading amount of hollow microspheres were 83.21±0.28% and 20.71±0.32%, respectively. The in vitro release profiles showed that the drug release rate decreased with increasing viscosity of EC and the diameter of hollow microspheres, while increased with the increase of RH/EC weight ratio. Hollow microspheres could prolong drug release time (approximately 24 h) and float over the simulate gastric fluid for more than 24 h. Pharmacokinetic analysis showed that the bioavailability from RH-hollow microspheres alone was about 3.0-times that of common RH gelatin capsules, and it was about 2.8-times that of the solid microspheres. These results demonstrated that RH hollow microspheres were capable of sustained delivery of the drug for longer period with increased bioavailability.     

Effect of sodium taurodihydrofusidate on nasal drug delivery: Differences in its concentration and penetrant molecular weight

The effect of sodium taurodihydrofusidate (STDHF) on drug permeation across nasal mucosa was studied in vitro using Ussing type diffusion chamber. Disodium cromoglicate (DSCG, M.W. 512.3) and fluorescein isothiocyanate-dextran (FD) of different molecular weights (M.W. 4400-71200) were used as model drugs. Permeation profiles of DSCG and FDs showed a typical pseudo steady-state curve with short lag time. The permeability coefficient of FD (M.W. 9400) sigmodially increased with increasing STDHF concentration. It also enhanced the DSCG permeation. Interestingly the enhancement efficacy was independent of molecular weight of penetrants.     

Nasal administration of metoclopramide from different dosage forms: in vitro,ex vivo,and in vivo evaluation

Nasal drug delivery is an interesting route of administration for metoclopramide hydrochloride (MTC) in preventing different kind of emesis. Currently, the routes of administration of antiemetics are oral or intravenous, although patient compliance is often impaired by the difficulties associated with acute emesis or invasiveness of parenteral administration. In this perspective, nasal dosage forms (solution, gel, and lyophilized powder) of MTC were prepared by using a mucoadhesive polymer sodium carboxymethylcellulose (NaCMC). In vitro and ex vivo drug release studies were performed in a modified horizontal diffusion chamber with cellulose membrane and excised cattle nasal mucosa as diffusion barriers. The tolerance of nasal mucosa to the formulation and its components were investigated using light microscopy. In vivo studies were carried out for the optimized formulations in sheep and the pharmacokinetics parameters were compared with oral solution and IV dosage form. The release of MTC from solution and powder formulations was found to be higher than gel formulation (p?<?0.05). Histopathological examination did not detect any severe damage. Hydroxypropyl-β-cyclodextrin (HPβCD) used in powder formulations was found to be effective for enhancing the release and absorption of MTC. In contrast to in vitro and ex vivo experiments nasal bioavailability of gel is higher than those of solution and powder (p?<?0.05). In conclusion, the NaCMC gel formulation of MTC with mucoadhesive properties with increased permeation rate is promising for prolonging nasal residence time and thereby nasal absorption.     

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.     

Nasal administration of ondansetron using a novel microspheres delivery system Part II: Ex vivo and in vivo studies

Gellan gum-based mucoadhesive microspheres of ondansetron hydrochloride for intranasal systemic delivery were prepared to avoid first pass effect, an alternative route of administration to injection and to enhance systemic bioavailability of ondansetron hydrochloride. The microspheres were prepared using spray method. The evaluation results of microspheres were reported in our previous study. The aim of this work was to study the in vivo performance of mucoadhesive microspheres in comparison with oral and intravenous preparations of ondansetron hydrochloride. The nasal delivery system gave increased AUC_0-240 and C_max as compared to those of oral delivery. In conclusion, the gellan gum-based microsphere formulation of ondansetron hydrochloride with mucoadhesive properties with increased permeation rate is promising for prolonging nasal residence time and thereby nasal absorption.     

Preparation,characterization and in vitro intestinal absorption of a dry emulsion formulation containing atorvastatin calcium

A redispersible dry emulsion (DE) formulation of atorvastatin calcium (AC) was developed to enhance the in vitro dissolution of AC, thereby increasing its gastrointestinal absorption. The spray-drying technology was used where Plurol Oleique CC 497 was chosen as the oil phase. Effects of carriers, surfactants, and homogenizers on the characteristics of DE containing AC were systematically investigated. The final formulation consisted of dextrin and Poloxamer 188 as carrier and surfactant, respectively, and was homogenized by a high pressure homogenizer before spray drying. The in vitro release of AC from the optimized DE was significantly higher than that of pure AC powder (76% vs. 30% at 24 hr). The in vitro intestinal absorption of AC from the DE formulation was 0.77 μg/cm² at 2 hr, which was a 2.33-fold increase compared to the pure unformulated AC powder. These results suggest that the oral dry emulsion formulation could improve the intestinal absorption of AC.     

PLGA-based biodegradable microspheres in drug delivery: recent advances in research and application

Biodegradable microspheres have been widely used in the field of medicine due to their ability to deliver drug molecules of various properties through multiple pathways and their advantages of low dose and low side effects. Poly (lactic-co-glycolic acid) copolymer (PLGA) is one of the most widely used biodegradable material currently and has good biocompatibility. In application, PLGA with a specific monomer ratio (lactic acid and glycolic acid) can be selected according to the properties of drug molecules and the requirements of the drug release rate. PLGA-based biodegradable microspheres have been studied in the field of drug delivery, including the delivery of various anticancer drugs, protein or peptide drugs, bacterial or viral DNA, etc. This review describes the basic knowledge and current situation of PLGA biodegradable microspheres and discusses the selection of PLGA polymer materials. Then, the preparation methods of PLGA microspheres are introduced, including emulsification, microfluidic technology, electrospray, and spray drying. Finally, this review summarizes the application of PLGA microspheres in drug delivery and the treatment of pulmonary and ocular-related diseases.