Oral Delivery of Bovine Lactoferrin Using Pectin‐ and Chitosan‐Modified Liposomes and Solid Lipid Particles: Improvement of Stability of Lactoferrin

A critical problem associated with delivery of bovine lactoferrin (bLf) by the oral route is low bioavailability, which is derived from the enzymatic degradation in the gastrointestinal tract and poor permeation across the intestinal epitheliums. Particulate carrier systems have been identified to protect bLf against proteolysis via encapsulation. This study aimed to evaluate the physico‐chemical stability of bLf‐loaded liposomes and solid lipid particles (SLPs) modified by pectin and chitosan when exposed to various stress conditions. Transmission electron microscopy results showed liposomes and SLPs had a classic shell‐core structure with polymer layers surrounded on surface, but the structure appeared to be partially broken after digestion in simulated intestinal fluid (SIF). Although HPLC and sodium dodecyl sulphate–polyacrylamide gel electrophoresis methods qualitatively and quantitatively described either liposomes or SLPs could retain intact bLf against proteolysis in SIF to some extent, all liposome formulations showed rapid rate of lipolysis mediated by pancreatic enzymes. On the other hand, all SLP formulations showed higher heat resistance and greater electrolyte tolerance compared to liposome formulations. After 180 days storage time, liposome‐loaded bLf was completely degraded, whereas almost 30% of intact bLf still remained in SLP formulations. Overall, SLPs are considered as primary choice for oral bLf delivery.     

Stability of Bovine Lactoferrin in Luminal Extracts and Mucosal Homogenates from Rat Intestine: A Prelude to Oral Absorption

Oral delivery is the most common method for bovine lactoferrin (bLf) administration. However, the presence of proteolytic enzymes in the stomach and intestine limits the effective absorption of bLf within the gastrointestinal (GI) tract. To determine the extent of bLf proteolysis, several digestion models were developed using luminal extracts and mucosal homogenates isolated from four regions of rat intestine: duodenum, jejunum, ileum, and proximal colon. The kinetics of bLf degradation followed a pseudo‐first‐order rate, and almost complete hydrolysis of bLf was observed in the luminal extracts, indicating that bLf is more susceptive to luminal peptidases rather than mucosal enzymes. Moreover, a significant reduction in bLf proteolysis was observed in the presence of soybean trypsin inhibitor (SBTI), bestatin, and bacitracin, suggesting that there exist trypsin‐like and aminopeptidase‐like proteases, which play a key role in the degradation of bLf in the intestine. Lactoferrin was then encapsulated in several lipid‐based delivery systems including liposomes and solid lipid particles (SLPs) with polymer modification, showing at least 50% of intact bLf remaining after 6 h of digestion compared with native bLf. These findings suggest that particle encapsulation may modulate protein digestion and possibly achieve sufficient oral bioavailability of bLf.     

两亲性壳聚糖包覆紫杉醇脂质体的制备及体外释放研究

目的:制备两亲性壳聚糖N-辛基-N,O-羧甲基壳聚糖包覆紫杉醇脂质体(PTX-LP-OCC),并考察其理化性质及体外释放行为。方法:采用基于乙醇的前体脂质体法制备紫杉醇脂质体并以OCC包覆,并以普通脂质体(PTX-LP)为对照,测定其包封率、粒径大小、电位,观测其形态及稳定性,然后采用全体液平衡反向透析法研究体外释放行为。结果:紫杉醇脂质体包封率为89.5%,粒径为236.5 nm,Zeta电位为-31.4 mV,多糖包覆修饰后药物包封率无显著变化,粒径及Zeta电位显著增加,脂质体稳定性显著提高,药物释放呈缓释特征,且突释显著降低。结论:两亲性壳聚糖包覆脂质体是一个有前景的抗肿瘤药物递送载体     

Chitosan-coated liposomes: characterization and interaction with leuprolide

The objective of the present work was to investigate the effect of chitosan concentration and lipid type on the characteristics of chitosan-coated liposomes and their interactions with leuprolide. Liposomes from lipid of high purity and low purity were prepared and coated by chitosan. Physical properties, drug entrapment efficiency, and stability upon dilution were respectively compared. Results showed that the particle size increment of liposomes from low purity lipid was larger than that from high purity lipid, indicating a thicker coating layer. The high zeta potential of particles from low purity lipid was thought to play an important role in the resistance to flocculation. As to particles from high purity lipid, polymer bridging caused flocculation at low polymer concentration while at high concentration, the adsorbed chitosan molecule led to steric stabilization. Drug entrapment efficiency decreased as chitosan was added to liposomes, showing the disturbance of bilayers. Upon dilution, the leakage of leuprolide from low purity liposomes was larger than that from high purity liposomes. In conclusion, low purity lipid possessed more negative charge and formed thicker adsorptive layer by stronger electrostatic attraction with chitosan. The interaction between chitosan and the polar head groups on the surface of phospholipid bilayers may interfere with leuprolide entrapped in liposomes and result in the leakage of leuprolide.     

卡波姆包衣姜黄素脂质体的制备及体外黏附性考察

目的探讨提高难溶性药物口服生物利用度的方法。方法采用薄膜分散法制备姜黄素脂质体,采用孵育法对姜黄素脂质体进行卡波姆包衣并考察姜黄素脂质体包衣前后稳定性、包封率及相对包衣率的变化,采用离体大鼠小肠孵育法考察卡波姆包衣姜黄素脂质体体外黏附性。结果卡波姆包衣对脂质体的稳定性影响较大,当卡波姆的质量浓度为5.0 g.L-1时脂质体最稳定;脂质体包衣后包封率略有下降,相对包衣率随着卡波姆质量浓度的增大而增大;质量浓度同为5.0 g.L-1的条件下,卡波姆包衣脂质体的体外生物黏附性比壳聚糖包衣的体外生物黏附性大,未包衣的脂质体体外生物黏附性很小。结论作为药物载体,卡波姆包衣脂质体具备了难溶性药物姜黄素口服给药的条件,将有很好的应用前景。     

In vivo efficacy of a novel double liposome as an oral dosage form of salmon calcitonin

A simple method for the preparation of the inner liposomes for double liposomes (DL) was developed. The encapsulation efficiency of erythrosine in liposomes prepared by this new method is superior to that of the previous method because of the concentration of the drug in the lipid membrane. To evaluate the usefulness of DL prepared by the glass‐filter method modified in this study as an oral dosage form of salmon calcitonin (SCT), a suspension of liposomes containing SCT was administered to rats at a dose of 10 μg SCT/kg. Each type of DL showed better efficacy than its inner liposomes alone. The decrease in plasma calcium level was dependent on the electrical charge and particle size of the inner liposomes. The hypocalcemic efficacy of DL encapsulating SCT‐loading cationic liposomes relative to that after subcutaneous administration of SCT at a dose of 1 μg/kg was 6.47%, which was the largest value obtained. These results indicated that not only the particle size but also the electrical charge of inner liposomes affect intestinal absorption. This study verified that the efficacy was increased because of the decrease in diameter of the inner liposomes and the use of lipid with a positive charge. These findings concluded that DL might be useful as an oral dosage form of SCT. Drug Dev. Res. 58:253–257, 2003. © 2003 Wiley‐Liss, Inc.     

Novel mucoadhesion tests for polymers and polymer-coated particles to design optimal mucoadhesive drug delivery systems

To design an effective particulate drug delivery system having mucoadhesive function, several mucoadhesion tests for polymers and the resultant particulate systems were developed. Mucin particle method is a simple mucoadhesion test for polymers, in which the commercial mucin particles are used. By measuring the change in particle size or zeta potential of the mucin particle in a certain concentration of polymer solution, we could estimate the extent of their mucoadhesive property. BIACORE method is also a novel mucoadhesion test for polymers. On passing through the mucin suspension on the polymer-immobilized chip of BIACORE instrument, the interaction was quantitatively evaluated with the change in its response diagram. By using these mucoadhesion tests, we detected a strong mucoadhesive property of several types of chitosan and Carbopol. Evaluation of mucoadhesive property of polymer-coated particulate systems was demonstrated with the particle counting method developed by us. To detect the mucoadhesive phenomena in the intestinal tract, we observed the rat intestine with the confocal laser scanning microscope (CLSM) after oral administration of the particulate systems. The resultant photographs clearly showed a longer retention of submicron-sized chitosan-coated liposomes (ssCS-Lip) in the intestinal tract than other liposomal particles tested such as non-coated liposomes and chitosan-coated multilamellar one. These observations explained well the superiority of the ssCS-Lip as drug carrier in oral administration of calcitonin in rats than other liposomal particles.     

Drug release property of chitosan–pectinate beads and its changes under the influence of microwave

The effects of microwave irradiation on the drug release property of pectinate beads loaded internally with chitosan (chitosan–pectinate beads) were investigated against the pectinate beads and beads coacervated with chitosan externally (pectinate–chitosonium beads). These beads were prepared by an extrusion method using sodium diclofenac as the model water-soluble drug. The beads were subjected to microwave irradiation at 80 W for 5, 10, 21 and 40 min. The profiles of drug dissolution, drug content, drug–polymer interaction and polymer–polymer interaction were determined by drug dissolution testing, drug content assay, drug adsorption study, differential scanning calorimetry (DSC) and Fourier transform infra-red spectroscopy (FTIR) techniques. Treatment of pectinate beads by microwave did not lead to a decrease, but an increase in the extent of drug released at 4 h of dissolution owing to reduced pectin–pectin interaction via the CO moiety of polymer. In addition, the extent of drug released from the pectinate beads could not be reduced merely through the coacervation of pectinate matrix with chitosan. The reduction in the extent of drug released from the pectinate–chitosonium beads required the treatment of these beads by microwave, following an increase in drug–polymer and polymer–polymer interaction in the matrix. The extent of drug released from the pectinate beads was reduced through incorporating chitosan directly into the interior of pectinate matrix, owing to drug–chitosan adsorption. Nonetheless, the treatment of chitosan–pectinate matrix by microwave brought about an increase in the extent of drug released unlike those of pectinate–chitosonium beads. Apparently, the loading of chitosan into the interior of pectinate matrix could effectively retard the drug release without subjecting the beads to the treatment of microwave. The microwave was merely essential to reduce the release of drug from pectinate beads when the chitosan was introduced to the pectinate matrix by means of coacervation. Under the influences of microwave, the drug release property of beads made of pectin and chitosan was mainly modulated via the CH, OH and NH moieties of polymers and drug, with CH functional group purported to retard while OH and NH moieties purported to enhance the drug released from the matrix.     

Properties of liposomes coated with hydrophobically modified chitosan in oral liposomal drug delivery

Chitosan (CS) has been widely used as an adhesive coating polymer for oral liposomal drug delivery systems because of its adhesive properties on mucous layers. The coating mechanism or interaction of chitosan and liposomes or mucin mainly depends on electrostatic forces. Thus, to enhance the adhesive properties of chitosan, a hydrophobically modified chitosan, i.e., dodecylated chitosan (DC), was synthesized. BIACORE results showed that both CS and DC could interact with mucin. Differences in sensorgram patterns between chitosan-mucin and dodecylated chitosan-mucin were observed and tentatively attributed to differences in binding kinetics. The zeta potential of dodecylated chitosan-coated liposomes (DC-Lip) showed positive values in both liposomal formulations, i.e., negatively charged and neutral-charge liposomes. These results indicated that DC could be considered a more suitable polymer for coating neutral-charge liposomes than CS because the hydrophobic side chain of DC inserts itself into the lipid bilayer of liposomes. Moreover, CS seemed to be less effective in the coating of a neutral-charge liposome because of the low positive values of its zeta potential. CS provided solely electrostatic forces when used for coating liposomes while DC provided electrostatic and hydrophobic forces due to the long alkyl chain in its backbone. Confocal Laser Scanning Microscopy (CLSM) images indicated that both chitosan-coated liposomes (CS-Lip) and DC-Lip could adhere to and penetrate through the small intestine of rats after oral administration. The pharmacological results showed that DC-Lip had a greater effect in decreasing blood calcium concentration during the first 12 h compared with CS-Lip. Therefore, it can be concluded that dodecylated chitosan can be useful in designing oral liposomal drug delivery systems.     

结肠癌细胞及线粒体双级靶向脂质体的处方工艺筛选研究

目的：研究结肠癌细胞及线粒体双级靶向脂质体（HA/TPP-TPGS LP/DOX）的最佳处方工艺。方法：用薄膜分散法结合微孔滤膜法制备;以细胞抑制率为指标,用MTT法筛选最佳聚脂比;以包封率为指标,用正交试验筛选最佳胆脂比、药脂比和超声时间;以粒径为指标,筛选最佳透聚比;以复溶后粒径和包封率为指标,筛选冻干保护剂的品种;用荧光显微镜和流式细胞术考察脂质体的靶向性;用透析法考察体外释药行为。结果：最佳处方是聚脂比1∶7、胆脂比1∶10、药脂比1∶15、超声时间15 min、透聚比2∶1,冻干保护剂为蔗糖。制备的脂质体呈类球形,粒径（142.20±0.54）nm,Zeta电位-（24.06±0.25）mV,包封率（98.20±0.18）%,稳定性高,有双级靶向性和体外药物缓释性。结论：本研究制备的脂质体有包封率高、粒径小、双级靶向性和缓释性等优点,为进一步研究奠定了基础。     

Development and characterization of different low methoxy pectin microcapsules by an emulsion-interface reaction technique

In the controlled release area, biodegradable microcapsules are one of the most useful devices to deliver materials in an effective, prolonged and safe manner. A new charged film microcapsular carrier system, using three different pectins, is described. The study utilized pectin microcapsules prepared by two encapsulation mechanisms of interfacial reaction explored through interaction of charged droplet-oil-anionic surfactant-calcium or oil-cationic surfactant with negatively charged pectin. A method for drug encapsulation was developed based on the type of pectin, surfactants and emulsification technique. Both types of surfactant, anionic sodium dodecyl sulphate (SDS) and cationic benzalkonium chloride (BzACl) promoted polymer film formation on the oil droplet surfaces, probably through cross-linking and electrostatic interaction, respectively. Microcapsules consisting of pectin as shell and hydrophobic oil as core were characterized. The resulting microcapsules were relatively small particles (d< 3 microm), had high total particle number, specific surface area and drug encapsulation efficiency. They also demonstrated good stability with minimum particle aggregation. Correlation between physicochemical and drug release kinetic parameters were investigated with regard to the effect of pectin macromolecular structure and nature of surfactant used as a counterion in the manufacturing of microcapsules. The release rate of the encapsulated material (prednisolone) in three microcapsules can be controlled by manipulating the conformational flexibility of pectins in the presence of different counterions. As a result, biodegradable pectin microcapsules offer a novel approach for developing sustained release drug delivery systems that have potential for colonic drug delivery.     

Preparation and properties of poly(vinyl alcohol)-stabilized liposomes

The purpose of this work is to evaluate the improvement in physical stability of poly(vinyl alcohol) (PVA) modified liposomes. Liposomes composed of soya phosphatidylcholile (SPC) and cholesterol (1:1 molar ratio) were prepared by reverse phase evaporation method. Two types of interaction between liposome and PVA were investigated: PVA addition into lipid bilayer during liposome preparation and coating of already formed liposomes with PVA. The microparticles system was morphologically characterized by transmission electron microscopy (TEM) and particles analysis. Changes in particles size and zeta potential confirmed the existence of a thick polymer layer on the surface of liposomes. The amount of PVA adsorbing to liposomes and the encapsulation efficiency increased with increasing polymer concentration. The physical stability was evaluated by measuring the release rate of contents at 20 and 37 degrees C, the PVA modified liposomes were more stable than the conventional liposomes. Comparing with PVA-coated liposomes, the liposomes with PVA addition to the bilayer were more stable, and had higher entrapment efficiency.     

Development and characterization of different low methoxy pectin microcapsules by an emulsion–interface reaction technique

In the controlled release area, biodegradable microcapsules are one of the most useful devices to deliver materials in an effective, prolonged and safe manner. A new charged film microcapsular carrier system, using three different pectins, is described. The study utilized pectin microcapsules prepared by two encapsulation mechanisms of interfacial reaction explored through interaction of charged droplet–oil-anionic surfactant-calcium or oil-cationic surfactant with negatively charged pectin. A method for drug encapsulation was developed based on the type of pectin, surfactants and emulsification technique. Both types of surfactant, anionic sodium dodecyl sulphate (SDS) and cationic benzalkonium chloride (BzACl) promoted polymer film formation on the oil droplet surfaces, probably through cross-linking and electrostatic interaction, respectively. Microcapsules consisting of pectin as shell and hydrophobic oil as core were characterized. The resulting microcapsules were relatively small particles (d<3?µm), had high total particle number, specific surface area and drug encapsulation efficiency. They also demonstrated good stability with minimum particle aggregation. Correlation between physicochemical and drug release kinetic parameters were investigated with regard to the effect of pectin macromolecular structure and nature of surfactant used as a counterion in the manufacturing of microcapsules. The release rate of the encapsulated material (prednisolone) in three microcapsules can be controlled by manipulating the conformational flexibility of pectins in the presence of different counterions. As a result, biodegradable pectin microcapsules offer a novel approach for developing sustained release drug delivery systems that have potential for colonic drug delivery.     

Pectin‐based microspheres for colon‐specific delivery of vancomycin

Objectives The aim of this study was to describe a colon‐specific delivery system based on pectin hydrogels formed by complexation with chitosan. Methods Hydrogels were prepared at different weight ratios (4: 1, 7: 1, 10: 1; pectin/chitosan), loaded with vancomycin hydrochloride (2: 1, 4: 1; polymer/drug weight ratio) and collected by spray‐drying. The microspheres obtained were characterized in terms of morphology, swelling behaviour, mucoadhesive properties and drug loading efficiency. The influence of different pectin/chitosan hydrogels on the release behaviour of microspheres at pH 2.0, 5.5 and 7.4 were evaluated in vitro with and without pectinolytic enzyme. Key findings The results showed that water uptake was increased by raising the environmental pH (from 2.0 to 7.4) and the pectin/chitosan weight ratio, while drug availability was increased by raising the environmental pH (from 2.0 to 7.4) and decreased by raising the pectin/chitosan weight ratio. In the presence of pectinase, the glycoside bonds of pectin were degraded and a considerable amount of drug was released in a short time. Conclusions This study suggested that pectin/chitosan microspheres were able to limit the release of vancomycin under acidic conditions and release it under simulated colonic conditions, confirming their potential for a colon‐specific drug delivery system.     

The effect of particle structure of chitosan-coated liposomes and type of chitosan on oral delivery of calcitonin

To optimize the properties of chitosan-coated liposomes for oral administration of peptide drugs, we examined the effect of type of chitosan and the structure of liposomal systems on the mucoadhesiveness of liposomes and resultant pharmacological effects of the liposomal peptide drug. A low-molecular weight chitosan (LCS) and a high-molecular weight chitosan (CS) were used as coating polymers of liposomes containing elcatonin (eCT). The muco-penetrative behaviors across the mucous gel layer covering the intestinal epithelial cells and the pharmacological effect after intragastric administration were determined in rats. The results showed that both LCS-coated liposomes (LCS-Lips) and CS-coated liposomes (CS-Lips) could permeate the mucous layer in the small intestine. The most interesting result was that LCS-Lips containing eCT showed remarkably more prolonged effectiveness in decreasing the blood calcium concentration than did CS-Lips containing eCT, moreover, it was also found that LCS had more efficiency to protect eCT from the enzymatic degradation than CS. In comparing the area above the plasma calcium concentration time curves (AAC) values among eCT-containing liposomes with different structures, i.e. eCT adsorbed on coated liposomes (eCT-ad-CS-Lip, eCT-ad-LCS-Lips) and eCT encapsulated in coated liposomes (eCT-encap-CS-Lips, eCT-encap-LCS-Lips), eCT-encap-CS-Lip showed much higher effectiveness than eCT-ad-CS-Lip. However, the AAC value for eCT-ad-LCS-Lip was comparable to that for eCT-encap-CS-Lip, while the value for eCT-ad-CS-Lip was nearly zero. These results suggested that LCS is a good mucoadhesive polymer candidate for enhancing the bioavailability of orally administered peptide containing liposomes, while encapsulation of eCT within the liposomal particles is important to protect eCT against enzymatic degradation in the gastrointestinal (GI) tract.     

The effect of particle structure of chitosan-coated liposomes and type of chitosan on oral delivery of calcitonin

To optimize the properties of chitosan-coated liposomes for oral administration of peptide drugs, we examined the effect of type of chitosan and the structure of liposomal systems on the mucoadhesiveness of liposomes and resultant pharmacological effects of the liposomal peptide drug. A low-molecular weight chitosan (LCS) and a high-molecular weight chitosan (CS) were used as coating polymers of liposomes containing elcatonin (eCT). The muco-penetrative behaviors across the mucous gel layer covering the intestinal epithelial cells and the pharmacological effect after intragastric administration were determined in rats. The results showed that both LCS-coated liposomes (LCS-Lips) and CS-coated liposomes (CS-Lips) could permeate the mucous layer in the small intestine. The most interesting result was that LCS-Lips containing eCT showed remarkably more prolonged effectiveness in decreasing the blood calcium concentration than did CS-Lips containing eCT, moreover, it was also found that LCS had more efficiency to protect eCT from the enzymatic degradation than CS. In comparing the area above the plasma calcium concentration time curves (AAC) values among eCT-containing liposomes with different structures, i.e. eCT adsorbed on coated liposomes (eCT-ad-CS-Lip, eCT-ad-LCS-Lips) and eCT encapsulated in coated liposomes (eCT-encap-CS-Lips, eCT-encap-LCS-Lips), eCT-encap-CS-Lip showed much higher effectiveness than eCT-ad-CS-Lip. However, the AAC value for eCT-ad-LCS-Lip was comparable to that for eCT-encap-CS-Lip, while the value for eCT-ad-CS-Lip was nearly zero. These results suggested that LCS is a good mucoadhesive polymer candidate for enhancing the bioavailability of orally administered peptide containing liposomes, while encapsulation of eCT within the liposomal particles is important to protect eCT against enzymatic degradation in the gastrointestinal (GI) tract.     

Evaluation of percutaneous absorption of the repellent diethyltoluamide and the sunscreen ethylhexyl p‐methoxycinnamate‐loaded solid lipid nanoparticles: an in‐vitro study

Objectives Diethyltoluamide and ethylhexyl p‐methoxycinnamate (OMC) are two active ingredients in insect repellent and sunscreen products, respectively. The concurrent application of these two substances often increases their systemic absorption, compromising the safety and efficiency of the cosmetic product. In this study, diethyltoluamide and OMC were incorporated into solid lipid nanoparticles, a colloidal drug delivery system, to reduce percutaneous absorption and avoid toxic effects and also maintain the efficacy of the two active compounds on the skin surface for a long duration. Methods Solid lipid nanoparticles were prepared based on an ultrasonication technique and characterized by differential scanning calorimetry (DSC) analyses. In‐vitro studies determined the percutaneous absorption of diethyltoluamide and OMC. Key findings DSC data carried out on unloaded and diethyltoluamide‐ and/or OMC‐loaded solid lipid nanoparticles highlighted that diethyltoluamide and OMC modified the temperature and the enthalpy change associated to the calorimetric peak of solid lipid nanoparticles. The concurrent presence of the two compounds in the solid lipid nanoparticles caused a synergic effect, indicating that the lipid matrix of nanoparticles guaranteed a high encapsulation of both diethyltoluamide and OMC. Results from the in‐vitro study demonstrated that the particles were able to reduce the skin permeation of the two cosmetic ingredients in comparison with an oil‐in‐water emulsion. Conclusions This study has provided supplementary evidence as to the potential of lipid nanoparticles as carriers for topical administration of cosmetic active compounds.     

Chitosan and poly(methyl vinyl ether-co-maleic anhydride) microparticles as nasal sustained delivery systems.

An original dosage form for nasal delivery based on the encapsulation of hydrophilic drug in chitosan-poly(methyl vinyl ether-co-maleic anhydride) (CH-PVM/MA) microparticles prepared by spray-drying technique was developed. Microparticles were characterized in terms of morphology, size, swelling properties, encapsulation efficiency and drug release. The physical state of the drug and the polymer was determined by scanning electron microscopy (SEM) and infrared spectroscopy (IR). Propranolol hydrochloride (PH) was a beta-blocker, used for the treatment of hypertension and was chosen as a model of hydrophilic drug. SEM studies showed spherical particles with smooth surfaces for chitosan hydrochloride (CH-HCl), whereas rather gross surface defects resulted from the incorporation of poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA). In vitro release studies revealed a sustained release of propranolol HCl from microparticles and in particular chitosan hydrochloride provided the lowest release of drug.     

The effects of lyophilization on the stability of liposomes containing 5-FU

Multilamellar liposomes containing 5-fluorouracil (5-FU) were prepared by modified lipid film hydration method and were lyophilized with or without saccharose as cryoprotectant. The effect of lyophilization on the stability of liposomes was evaluated by comparing the vesicle size, encapsulation efficiency and the drug release rate before and after lyophilization/rehydration. The process of lyophilization, without cryoprotectant, resulted in particle size increase and significant content leakage. By the addition of saccharose, the lipid bilayers become more stable and less permeable to the encapsulated drug, saccharose imparted 5-FU retention of about 80% after lyophilization/rehydration. Freeze-drying did not affect the particle size of liposomes containing saccharose as cryoprotectant. The drug release profiles of rehydrated liposomes followed Higuchi's square root model. Also, the obtained release profiles were all biphasic: a rapid initial drug release phase (burst release of the portion of the drug that leaked out of liposomes during the lyophilization) was followed by a slower, approximately constant drug release phase (zero-order kinetics).     

Chitosan and poly(methyl vinyl ether-co-maleic anhydride) microparticles as nasal sustained delivery systems

An original dosage form for nasal delivery based on the encapsulation of hydrophilic drug in chitosan-poly(methyl vinyl ether-co-maleic anhydride) (CH-PVM/MA) microparticles prepared by spray-drying technique was developed. Microparticles were characterized in terms of morphology, size, swelling properties, encapsulation efficiency and drug release. The physical state of the drug and the polymer was determined by scanning electron microscopy (SEM) and infrared spectroscopy (IR). Propranolol hydrochloride (PH) was a β-blocker, used for the treatment of hypertension and was chosen as a model of hydrophilic drug. SEM studies showed spherical particles with smooth surfaces for chitosan hydrochloride (CH-HCl), whereas rather gross surface defects resulted from the incorporation of poly(methyl vinyl ether-co-maleic anhydride) (PVM/MA). In vitro release studies revealed a sustained release of propranolol HCl from microparticles and in particular chitosan hydrochloride provided the lowest release of drug.