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.     

Crosslinked poly(methyl vinyl ether-co-maleic anhydride) as topical vehicles for hydrophilic and lipophilic drugs

Poly(methyl vinyl ether-co-maleic anhydride) crosslinked with ethylene glycol (GZ-ET), 1,4-butanediol (GZ-BUT), 1,6-exandiol (GZ-EX), 1,8-octanediol (GZ-OCT), 1,10-decanediol (GZ-DEC) or 1,12-dodecanediol (GZ-DOD) was prepared and employed as a supporting material for aqueous topical gels containing pyridoxine hydrochloride (PYCL) chosen as a hydrophilic model molecule or for O/A emulsion containing β-carotene chosen as a hydrophobic model molecule. We analyzed the effect of the nature of the crosslinker on the permeation of hydrophilic and lipophilic vitamins through porcine skin by in vitro permeation studies. The vehicles formed by crosslinked poly(methyl vinyl ether-co-maleic anhydride) showed enhanced vitamins permeation with respect to the same vehicles formed by noncrosslinked poly(methyl vinyl ether-co-maleic anhydride) (GZ). The decrease in the crosslinker acyl chain length provides vehicles accelerating the drug permeability through the skin.     

High Loading of Gentamicin in Bioadhesive PVM/MA Nanostructured Microparticles Using Compressed Carbon-Dioxide

Purpose  

To investigate, for the first time, the viability of compressed antisolvent methodologies for the preparation of drug-loaded particles of the biodegradable and bioadhesive polymer poly (methyl vinyl ether-co-maleic anhydride) (PVM/MA), utilizing gentamicin (Gm) as a model drug.     

Spray-dried microspheres based on methylpyrrolidinone chitosan as new carrier for nasal administration of metoclopramide.

The work purpose was to study the application of 5-methylpyrrolidinone chitosan (MPC) for preparing mucoadhesive microparticles for the nasal administration of drugs. Microspheres were produced by the spray-drying technique using MPC; metoclopramide hydrochloride (MC) was chosen as model drug. Chitosan microparticles were prepared as a comparison. The microparticles obtained were characterised (encapsulation efficiency, morphology, size and drug release behaviour). In-vitro mucoadhesive tests, swelling tests and ex-vivo studies using sheep nasal mucosa were performed. The hydrogel formation from microspheres was studied in different media and at different pHs. Microspheres are able to control the in-vitro MC release. MPC microparticles show good in-vitro mucoadhesive properties and ex-vivo controlled permeation profiles. The hydrogel formation is dependent mainly on the medium used: ionically crosslinked hydrogel was hypothesized. These in-vitro and ex-vivo preliminary results show that spray-dried microspheres based on MPC could be a suitable nasal delivery system for the administration of metoclopramide.     

Collagen-coated polycaprolactone microparticles as a controlled drug delivery system

OBJECTIVE: Polycaprolactone (PCL) microparticles coated with acetylated collagen have been assessed for use as a controlled drug delivery system. METHOD: The surface morphology, drug encapsulation and release profile of PCL microparticles and collagen-coated PCL microparticles containing doxycycline hydrochloride (DH) have been investigated in order to develop a controlled release system which would in addition act as a scaffold for cell attachment. PCL microparticles were prepared by emulsion solvent evaporation technique and loaded with DH. Since the encapsulation was found to be low, PCL microparticles were coated with acetylated collagen containing DH, to increase the drug availability. Collagen was modified by acetylation to shift its isoelectric point and to have acetylated collagen solution at pH 7.0. The microparticles were characterized using a scanning electron microscope (SEM) and the in vitro drug release profile was determined using HPLC. RESULTS: Uniform sized (approximately 1000 nm) PCL microparticles were prepared using 4% PVA in the external water phase. Acetylated collagen at pH 7.0 was coated onto the PCL microparticles. This resulted in microparticles of uniform size at neutral pH. PCL acts as a support for collagen which acts as a scaffold for cell attachment. In vitro drug release studies show that collagen-coated PCL microparticle is a promising candidate for controlled drug delivery system having release duration of over 10 days. In vitro fibroblast culture studies reveal that collagen is a good substrate for cell attachment and would provide a stable environment for cell proliferation and regeneration. Thus, this system would be ideal for a short-term drug delivery to create an aseptic environment where cells can adhere and proliferate to regenerate the site.     

Mucoadhesive microspheres for nasal administration of an antiemetic drug, metoclopramide: in-vitro/ex-vivo studies

Microparticulate delivery systems designed for the nasal administration of an antiemetic drug, metoclopramide hydrochloride, were prepared. Microspheres composed of sodium alginate, chitosan hydrochloride, or both, were obtained using a spray-drying method; some batches of drug-free microparticles were prepared as a comparison. The morphology, in-vitro swelling behaviour, mucoadhesive properties and drug release from microparticles were evaluated. Ex-vivo drug permeation tests were carried out using sheep nasal mucosa; permeation test of the drug solution was performed as comparison. During ex-vivo permeation tests, transmission electron microscopy (TEM) analyses were carried out on the nasal mucosa to study the morphological changes of epithelial cells and tight junctions, while the change in microsphere morphology was examined using photostereo microscopy (PM). Spray-dried microparticles had a mean diameter (d(vs)) in the range of about 3-10 microm. They showed good in-vitro mucoadhesive properties. In-vitro release profiles and swelling behaviour depended on their composition: the drug release occurred in 1-3 h. Ex-vivo studies showed that drug permeation through the mucosa from microparticles based on chitosan was higher than from those consisting of alginate alone. This can be related to the penetration enhancing properties of chitosan. Complexation of chitosan with alginate led to a control of the drug release. Microscopy observation of microspheres during the permeation tests revealed that microparticles swelled and gelled, maintaining their shape. TEM analyses of the mucosa after exposure to the microparticles consisting of alginate/chitosan showed opened tight junctions. This preliminary study shows that alginate/chitosan spray-dried microspheres have promising properties for use as mucoadhesive nasal carriers of an antiemetic drug.     

Microparticulated systems based on chitosan and poly(vinyl alcohol) with potential ophthalmic applications

Abstract

Spherical microparticles for encapsulation of drugs for the treatment of diseases, with a diameter ranging between 2 and 4?µm, were obtained by double crosslinking (ionic and covalent) of chitosan and poly(vinyl alcohol) blend in a water-in-oil emulsion. Microparticles characterisation was carried out in terms of structural, morphological and swelling properties in aqueous media. The presence of chitosan in particles composition confers them a pH-sensitive character. Toxicity and hemocompatibility tests prove the biocompatible character of microparticles. The pilocarpine loading capacity is high as well as the release efficiency which increases up to 72 and 82% after 6?h. The obtained results recommend the microparticles as sustained release drug carriers for the treatment of eye diseases.     

Lipomer of doxorubicin hydrochloride for enhanced oral bioavailability

The present study discusses design of doxorubicin hydrochloride (Dox) loaded lipid based nanocarrier (LIPOMER) for oral delivery. High entrapment (>90%) and high loading (38.11 ± 0.37% w/w) of hydrophilic Dox in lipid nanocarrier of polyglyceryl-6-distearate was achieved using poly(methyl vinyl ether-co-maleic anhydride) (Gantrez^® AN 119) and a modified nanoprecipitation method. Dox-LIPOMER revealed nanosize (314 ± 16.80 nm) and negative zeta potential (−25.00 ± 2.41 mV). Dox-LIPOMER exhibits sustained release in vitro and was influenced by ionic strength of dissolution medium. DSC and XRD studies suggested amorphous nature of Dox in LIPOMER. TEM revealed spherical morphology of Dox-LIPOMER. Dox-LIPOMER was stable up to 12 months at 25 °C/60% RH. A 384% enhancement in oral bioavailability compared to Dox solution was observed following Dox-LIPOMER administration at 10 mg/kg body weight. Superoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) assay data of heart and kidney tissues of rats treated with Dox-LIPOMER were comparable with untreated rats. Dox-LIPOMER represents a potential safe drug delivery system for oral administration.     

Comparison of chitosan and gelatin coated microparticles: prepared by hot-melt method

The aim of this study was to compare the performance of microparticles and their release properties after coating by chitosan and gelatin, respectively. All of the poly(epsilon-caprolactone) (PCL) microparticles were prepared by the hot-melt encapsulation method and indomethacin was selected as a model drug to be encapsulated. All of the coated microparticles retained their spherical shape irrespective of the type of coating material, and the particle size of coated microparticles was similar to the uncoated ones. The indomethacin encapsulation efficiency was in the range of 8.65 +/- 0.08 % - 8.81 +/- 0.04% for uncoated microparticles and 8.22 +/- 0.04% - 8.68 +/- 0.08% for coated microparticles. The release of indomethacin from uncoated microparticles followed a two-exponential release profile, where indomethacin was rapidly released within 4 h during the first release phase, after that approximately 20% of the drug was continuously and slowly released for up to 24 h in the second phase. The similar release profile was observed from coated microparticles irrespective of the times of coating and the types of coating material. Both the natural coating materials, chitosan and gelatin, efficiently reduced the initial burst release and the first phase of drug release, but did not alter the second phase of drug release. In other words, chitosan and gelatin could be used to protect the drug on the surface of microparticles from immediately contacting with the release medium and both possessed the same feature in the delay of drug release.     

Collagen-coated polycaprolactone microparticles as a controlled drug delivery system

Objective: Polycaprolactone (PCL) microparticles coated with acetylated collagen have been assessed for use as a controlled drug delivery system.

Method: The surface morphology, drug encapsulation and release profile of PCL microparticles and collagen-coated PCL microparticles containing doxycycline hydrochloride (DH) have been investigated in order to develop a controlled release system which would in addition act as a scaffold for cell attachment. PCL microparticles were prepared by emulsion solvent evaporation technique and loaded with DH. Since the encapsulation was found to be low, PCL microparticles were coated with acetylated collagen containing DH, to increase the drug availability. Collagen was modified by acetylation to shift its isoelectric point and to have acetylated collagen solution at pH 7.0. The microparticles were characterized using a scanning electron microscope (SEM) and the in vitro drug release profile was determined using HPLC.

Results: Uniform sized (～1000 nm) PCL microparticles were prepared using 4% PVA in the external water phase. Acetylated collagen at pH 7.0 was coated onto the PCL microparticles. This resulted in microparticles of uniform size at neutral pH. PCL acts as a support for collagen which acts as a scaffold for cell attachment. In vitro drug release studies show that collagen-coated PCL microparticle is a promising candidate for controlled drug delivery system having release duration of over 10 days. In vitro fibroblast culture studies reveal that collagen is a good substrate for cell attachment and would provide a stable environment for cell proliferation and regeneration. Thus, this system would be ideal for a short-term drug delivery to create an aseptic environment where cells can adhere and proliferate to regenerate the site.     

Development and evaluation of sustained-release clonidine-loaded PLGA microparticles

This work describes the encapsulation of a small, hydrophilic molecule (clonidine) into a PLGA matrix to provide sustained release over more than one month after intra-articular administration. The microparticles were prepared using a double emulsion (w(1)/o/w(2)) method followed by evaporation of the organic solvent. To optimize the efficiency of encapsulation and the mean size of the microparticles, which was targeted around 30μm, the following parameters were modulated: the viscosity and the volume of the organic phase, the molecular weight of the polymer, the volume of the internal and external aqueous phases, the drug loading, the concentration of surfactant, and the stirring parameters. Blends of polymers characterized by different molecular weights (34000-96000Da) as well as copolymers of PLGA-PEG were used to enhance the entrapment of the drug. The pH of the aqueous phases was adjusted to obtain suitable encapsulation efficiency. Characterization was made of the physico-chemical properties of the microparticles, such as their crystallinity (DSC and PXRD) and microstructure (SEM). When performing in vitro dissolution studies, controlled release for up to approximately 30days was achieved with several of the formulations developed. Diffusion was found to be the dominant drug release mechanism at early time points.     

Chitosan microparticles for sustaining the topical delivery of minoxidil sulphate

Given the hypothesis that microparticles can penetrate the skin barrier along the transfollicular route, this work aimed to obtain and characterise chitosan microparticles loaded with minoxidil sulphate (MXS) and to study their ability to sustain the release of the drug, attempting a further application utilising them in a targeted delivery system for the topical treatment of alopecia. Chitosan microparticles, containing different proportions of MXS/polymer, were prepared by spray drying and were characterised by yield, encapsulation efficiency, size and morphology. Microparticles selected for further studies showed high encapsulation efficiency (～82%), a mean diameter of 3.0?µm and a spherical morphology without porosities. When suspended in an ethanol/water solution, chitosan microparticles underwent instantaneous swelling, increasing their mean diameter by 90%. Release studies revealed that the chitosan microparticles were able to sustain about three times the release rate of MXS. This feature, combined with suitable size, confers to these microparticles the potential to target and improve topical therapy of alopecia with minoxidil.     

Chitosan microparticles for sustaining the topical delivery of minoxidil sulphate

Given the hypothesis that microparticles can penetrate the skin barrier along the transfollicular route, this work aimed to obtain and characterise chitosan microparticles loaded with minoxidil sulphate (MXS) and to study their ability to sustain the release of the drug, attempting a further application utilising them in a targeted delivery system for the topical treatment of alopecia. Chitosan microparticles, containing different proportions of MXS/polymer, were prepared by spray drying and were characterised by yield, encapsulation efficiency, size and morphology. Microparticles selected for further studies showed high encapsulation efficiency (～82%), a mean diameter of 3.0?μm and a spherical morphology without porosities. When suspended in an ethanol/water solution, chitosan microparticles underwent instantaneous swelling, increasing their mean diameter by 90%. Release studies revealed that the chitosan microparticles were able to sustain about three times the release rate of MXS. This feature, combined with suitable size, confers to these microparticles the potential to target and improve topical therapy of alopecia with minoxidil.     

RP-LC determination of 5-fluorouridine in nanoparticulate formulations

5-fluorouridine (5-FUrd) is an anticancerous drug with a number of side effects due to its high toxicity. One possibility to overcome these drawbacks may consist on the use of polymeric nanoparticles to increase the therapeutic index of this drug. The objective of this study was to develop an analytical high performance liquid chromatography (HPLC) method for the determination of (i) the 5-FUrd content in poly (methyl vinyl ether-co-maleic anhydride) nanoparticles, (ii) its release from these carriers and, its eventual degradation during preparation, storage or release in 5-fluorouracil (5-FU). The chromatography was performed on a reversed-phase encapped column (LiChrospher Select B C8) with a mobile phase of 0.05 M ammonium acetate (pH 6.5). Ganciclovir (GCV) was used as internal standard and the detection wavelength was 268 nm. The limits of quantification of 5-FUrd and 5-FU were 12 and 5 ng/ml, respectively. Similarly, precision did not exceed 7%. Under our experimental conditions, the maximal drug loading capacity of 5-FUrd was around 105 microg/mg nanoparticle and the drug was released in a biphasic way from these particles. In addition, no degradation of 5-FUrd to 5-FU during either the preparative process or the release studies was observed. In summary, this HPLC method is selective, sensitive, specific and reproducible for the quantification of 5-FUrd in polymeric nanoparticles and release mediums.     

Preparation and characterization of chitosan microparticles intended for controlled drug delivery

Chitosan microparticles were prepared with tripolyphosphate (TPP) by ionic crosslinking. The particle sizes of TPP-chitosan microparticles were in range from 500 to 710 microm and encapsulation efficiencies of drug were more than 90%. The morphologies of TPP-chitosan microparticles were examined with scanning electron microscopy. As pH of TPP solution decreased and molecular weight (MW) of chitosan increased, microparticles had more spherical shape and smooth surface. Release behaviors of felodipine as a model drug were affected by various preparation processes. Chitosan microparticles prepared with lower pH or higher concentration of TPP solution resulted in slower felodipine release from microparticles. With decreasing MW and concentration of chitosan solution, release behavior was increased. The release of drug from TPP-chitosan microparticles decreased when cross-linking time increased. These results indicate that TPP-chitosan microparticles may become a potential delivery system to control the release of drug.     

Freeze dried chitosan/ poly-(glutamic acid) microparticles for intestinal delivery of lansoprazole

Lansoprazole sodium is a proton pump inhibitor used in treating gastroesophageal reflux disease (GERD). It is highly acid-labile and presents many formulation challenges. Therefore, this drug needs to be protected from the harsh environment in the stomach. In order to achieve this, a pH-sensitive microparticle system composed of chitosan and γ- poly-(glutamic acid) was prepared and loaded with Lansoprazole. The prepared microparticles were not stable in gastric pH. To overcome this problem microparticles were freez-dried and filled in an enteric-coated capsule. Upon oral administration, the enteric-coated capsule remained intact in the acidic environment of the stomach, but dissolved rapidly in the distal segment of the GIT. Consequently, all the microparticles loaded in the capsule were brought into the intestine, thus enhancing the intestinal absorption of drug. Drug encapsulation efficiency of formulation F3 was found to be 82.82 % and in vitro release of prepared formulation F3 was found to be 94% after 8 h of dissolution in 7.4 pH phosphate buffer. FTIR and DSC studies showed no interaction between the drug and polymer. The formulation showed good swelling property. SEM photographs showed that microparticles are spherical and lies in size range of 300-400 μm. From the above, it can be concluded that the prepared chitosan/ γ-poly-(glutamic acid) microparticles can be used as carriers for the intestinal delivery of acid liable drugs such as lansoprazole.     

Nanocapsule@xerogel microparticles containing sodium diclofenac: a new strategy to control the release of drugs

The aim of this work was to evaluate the potentiality to control the drug release of a new architecture of microparticles organized at the nanoscopic scale by assembling polymeric nanocapsules at the surface of drug-loaded xerogels. Xerogel was prepared by sol-gel method using sodium diclofenac, as hydrophilic drug model, and coated by spray-drying. After coating, the surface areas decreased from 82 to 28 m(2)/g, the encapsulation efficiency was 71% and SEM analysis showed irregular microparticles coated by the nanocapsules. Formulation showed satisfactory gastro-resistance presenting drug release lower than 3% (60 min) in acid medium. In water, the pure drug dissolved 92% after 5 min, uncoated drug-loaded xerogel released 60% and nanocapsule coated drug-loaded xerogel 36%. After 60 min, uncoated drug-loaded xerogel released 82% and nanocapsule coated drug-loaded xerogel 62%. In conclusion, the new system was able to control the release of the hydrophilic drug model.     

Freeze-drying of liposomes using tertiary butyl alcohol/water cosolvent systems

Polyacrylamide (pAAm) particles crosslinked with N,N-methylenebis-acrylamide/ethylene glycol dimethacrylate (NNMBA/EGDMA) have been prepared in water–methanol medium by the dispersion polymerization using poly(vinyl pyrrolidone), PVP as a steric stabilizer. 5-fluorouracil an anticancer drug, has been loaded in situ into the crosslinked pAAm particles. Plain as well as drug loaded microparticles have been characterized by differential scanning calorimetry (DSC) and X-ray diffraction studies (XRD) and scanning electron microscopy (SEM). DSC and XRD studies have indicated a molecular level dispersion of the drug in pAAm particles during in situ loading and SEM pictures have shown the formation of spherical and oval-shaped particles. In vitro release of 5-fluorouracil from the crosslinked pAAm particles has been carried out in 7.4 pH buffer medium. Both encapsulation efficiency and release patterns are found to depend on the nature of the crosslinking agent, amount of crosslinking agent used and the amount of drug loaded. In vitro release studies indicated the controlled release of 5-fluorouracil up to 12 h.     

A new bioerodible system for sustained local drug delivery based on hydrolytically activated in situ macromolecular association

To prolong the duration of polymer erosion over existing approaches for sustained local drug delivery, we investigated a new bioerodible system based on hydrolytically activated in situ formation of interpolymer complexes in binary blends of high MW poly(vinyl methyl ether-co-maleic anhydride) (PVMMA) and poly(ethylene oxide) (PEO). In an aqueous environment of use, the hydrophobic PVMMA component of the blend undergoes hydrolysis converting the anhydride to free carboxylic acid groups which in turn form in situ intermolecular complexes with the PEO component of the blend. The formation of such hydrogen-bonded complexes with a condensed structure at the blend surface helps to retard the further progression of polymer erosion and drug release. The effects of PVMMA/PEO composition on blend morphology, polymer erosion and drug release were evaluated with the aid of fluorescence labeled PVMMA. The results show a decrease in miscibility in PVMMA/PEO blend with increasing PEO content. At low PEO contents (below 40%), the in vitro rate of release of a model drug metronidazole decreases with increasing PEO content, resulting in extended release duration over several days. On the other hand, excessive phase separation at PEO contents above 40% gives rise to higher rate and shorter duration of drug release.     

Novel microparticle drug delivery systems based on chitosan and Eudragit(®)RSPM to enhance diltiazem hydrochloride release property

The aim of this study was to enhance the release properties of diltiazem hydrochloride (diltiazem HCl) by using microparticle system. For this reason, microparticle drug delivery systems based on chitosan and Eudragit(?)RSPM were developed. The microparticles were prepared by using double-emulsion solvent extraction method and the mean sizes of microparticles were less than 120?μm. The in vitro drug release from microparticles was studied in simulated gastric (pH 1.2) and intestinal media (pH 7.4) than the results were evaluated by kinetically. In vitro diltiazem HCl release from microparticles showed good zero order kinetic. For the microparticles with chitosan, the release of diltiazem HCl at pH 1.2 could be effectively sustained, while the release of diltiazem HCl increased at pH 7.4 when compared to Eudragit(?)RSPM microparticles. The highest release percent obtained was 1:1 ratio of drug: polymer at pH 1.2 and 7.4. All results clearly suggest that the release properties of diltiazem HCl were improved by using microparticle systems especially which contain chitosan.