Mira Bećirević-Laćan

Chitosan microspheres with hydrocortisone and hydrocortisone–hydroxypropyl-β-cyclodextrin inclusion complex

In the present study, an inclusion complex composed of hydrocortisone acetate (HC) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) was prepared by the spray-drying method. HC alone, HC inclusion complex or HC with HPbetaCD as a physical mixture were incorporated into chitosan microspheres by spray-drying. The inclusion complex and microspheres were characterized by X-ray powder diffractometry and differential scanning calorimetry (DSC). Microspheres were studied with respect to particle size distribution, drug content and in vitro drug release. The results indicate that the HCHPbetaCD inclusion complex is more water soluble than HC alone. The HC release rates from chitosan microspheres were influenced by the drug/polymer ratio in the manner that an increase in the release rate was observed when the drug loading was decreased. However, release data from all samples showed significant improvement of the dissolution rate for HC, with 25-40% of the drug being released in the first hour compared with about 5% for pure HC. The complexation method and microsphere preparation method (spray-drying) is simple with great potential for industrial production.

Chitosan microspheres of nifedipine and nifedipine-cyclodextrin inclusion complexes

Abstract Chitosan microspheres of nifedipine and nifedipine-cyclodextrin complexes were prepared by the glutaraldehyde cross-linking of chitosan. Microspheres having different degrees of swelling were made by varying the cross-linking density. Drug incorporation efficiencies exceeding 70% could be achieved for this drug. In vitro release rates were influenced by the cross-linking density, particle size and initial drug loading in the microspheres. While the solubility of nifedipine was enhanced by inclusion into a cyclodextrin complex, the drug release from the complex was significantly reduced. In addition the drug release mechanisms were discussed.

Liposomes Containing Drug and Cyclodextrin Prepared by the One-Step Spray-Drying Method

The one-step spray-drying method was applied in the preparation of liposomes containing drug and cyclodextrin (CD). Spray-dried lecithin liposomes, entrapping metronidazole or verapamil alone or together with hydroxypropyl-β-cyclodextrin (HPβCD), were characterized for morphology, size distribution, and drug entrapment efficiency. The main factor influencing the liposomal size was the volume of aqueous medium used for hydration of the spray-dried product. No differences in size or entrapment between liposomes prepared by immediate hydration of dried powder or by hydration after 1 year of powder storage at 4°C were observed. All liposomes were tested for their serum stability. The most stable liposomes (still retaining about 10% of the originally entrapped drug even after 24 hr incubation with serum) were liposomes prepared by the direct spray-drying of the mixture of lipid, drug, and HPβCD.

Liposomes with nifedipine and nifedipine-cyclodextrin complex: calorimetrical and plasma stability comparison

Abstract Inclusion complexes of nifedipine with 2-hydroxypropyl-s-cyclodextrin (HPβCD) were formed by the spray- and freeze-drying methods. Nifedipine or its inclusion complexes (Nifedipine-CD complex I and II) were incorporated into liposomes prepared by the ethanol injection method. The highest entrapment value (77.7% of the starting material) was achieved for liposomes with N-CD complex II. The interaction of nifedipine with lipid bilayers was measured calorimetrically. DPPC liposomes mixed with nifedipine or N-CD complex II showed a slight shift of the transition temperature of DPPC towards lower temperatures compared to DPPC liposomes alone or mixed with HPsCD. However, with nifedipine, an additional transition peak was seen at lower temperatures in the second and all subsequent scans which could not be detected for the N-CD complex. Plasma stability studies showed that liposomes containing N-CD complex II are more stable than liposomes containing nifedipine. Encapsulation of drug-cyclodextrin complexes into liposomes can increase the entrapment of the lipophilic drug and reduce its release from the carrier.

Novel cyclodextrin-based film formulation intended for buccal delivery of atenolol

Background: Unknown influence of cyclodextrin on the properties of the film formulation aimed for buccal application. Aim: Development and characterization of a novel bioadhesive film formulation for buccal atenolol delivery containing drug/cyclodextrin inclusion. Method: Interaction between atenolol and randomly methylated β-cyclodextrin (RAMEB) in solution was studied by phase solubility studies. The complex in solid state was prepared by the freeze-drying method and characterized by differential scanning calorimetry and Fourier-transformed infrared spectroscopy (FTIR). The drug, free or in complex form, was incorporated into polymeric films prepared by the casting method using ethylcellulose (EC), polyvinyl alcohol (PVA), and hydroxypropyl methylcellulose (HPMC). The prepared film formulations were characterized in terms of swelling, bioadhesion, and in vitro drug release. Results: The formation of a stabile inclusion complex (Ks = 783.4 ± 21.6 M−1) in 1:1 molar stoichiometry was confirmed in solution and in solid state. The swelling properties of films were predominated by the type of polymer used in the formulation. In vitro bioadhesive properties of the films were well correlated with the swelling properties of the polymers used in the formulation. Although incorporation of the drug, free or in complex form, decreased the bioadhesion of the films, PVA- and HPMC-based formulations retained suitable bioadhesive properties. Higher atenolol solubility upon complexation with RAMEB increased the drug dissolution rate under conditions designed to be similar to those on the buccal mucosa, but it has decreased the drug release rate from the PVA and HPMC film formulation, leading to a sustained drug release pattern. In the case of EC-based films, RAMEB promoted drug release. Other parameters that influenced the drug release rate were associated with the structure of the polymer used in the formulation, swelling characteristics of the films, and the interaction between atenolol and hydrophilic polymers that was demonstrated by FTIR analysis. Conclusion: Incorporation of atenolol in the form of an inclusion complex into hydrophilic films may be an appropriate strategy to prepare a suitable formulation for buccal drug delivery.

Multicomponent Complexes of Piroxicam with Cyclodextrins and Hydroxypropyl Methylcellulose

The purpose of the study was to investigate the effect of hydroxypropyl methylcellulose (HPMC) on the complexation of piroxicam (PX) with β‐cyclodextrin (β‐CD) and dimethyl‐β‐cyclodextrin (DM‐β‐CD) in solution and in the solid state. Phase solubility study revealed a positive effect of the polymer on the drug complexation. Improvement in stability constants values, Ks, of ternary complexes clearly proves the benefit of the HPMC addition for promoting higher complexation efficiency. Solid binary and ternary complexes were prepared by spray drying. Drug‐CD and drug‐CD‐polymer interactions were studied in the solid state by differential scanning calorimetry (DSC), zeta‐potential measurements, and particle size distribution. A marked increase in the PX dissolution rate was observed even in binary and ternary complexes. The presence of HPMC in ternary complexes slightly retarded the release of PX. Cyclodextrin complexation increased the PX concentration gradient over the semipermeable membrane, resulting in an increased PX flux. The retarded diffusion of PX to the membrane interface decreased the PX flux values of the ternary complexes.

Development of a cyclodextrin based nasal delivery system for lorazepam

A new drug delivery system containing hydroxypropyl-β-cyclodextrin (HP-β-CD) and a mucoadhesive polymer was developed with the aim to overcome the limitations connected with the nasal application of drugs with low water solubility. Lorazepam, free or as cyclodextrin inclusion complex, was loaded into mucoadhesive microparticles by spray drying, using hydroxypropylmethyl cellulose (HPMC), carbomer, and HPMC/carbomer interpolymer complex (IPC) as mucoadhesive components. Differential scanning calorimetry (DSC) indicated the presence of drug crystalline areas in microparticles loaded with free lorazepam, whereas in those loaded with HP-β-CD inclusion complex, the drug was amorphous. Zeta potential measurement revealed that the polymer was the main component on the surface of the microparticles. The swelling rate and mucoadhesive properties of the microparticles were determined by the polymer type used in formulation. IPC- and carbomer-based microparticles showed superior swelling rate and mucoadhesion compared with the HPMC-based microparticles (p < .05). Drug loading into the polymer matrix decreased the swelling rate as well as the mucoadhesive properties of microparticles (p < .05), whereas the presence of HP-β-CD in the matrix did not induce any additional reduction of those parameters (p > .05). The in vitro dissolution studies demonstrated that the microparticles containing the lorazepam inclusion complex displayed 1.8–2.5 times faster drug release compared with those containing free lorazepam. The change in the drug release rate could be connected with improved drug solubility inside the polymer matrix due to inclusion complex formation, as well as to the reduction in crystallinity following complexation, as confirmed by DSC studies.

Screening of mucoadhesive microparticles containing hydroxypropyl-beta-cyclodextrin for the nasal delivery of risperidone.

Interaction of the antipsychotic drug risperidone with hydroxypropyl-beta-cyclodextrin (HPBCD) in solution and in the solid state was studied with the aim of overcoming the limitations associated with nasal administration of low solubility drugs. Risperidone solubility studies revealed inclusion complex formation with a 1:1 stoichiometry. Low concentrations (0.1 w/v %) of hydroxypropylmethyl cellulose (HPMC) and carbomer affected risperidone solubility in water. No formation of a ternary complex was detected. The solid inclusion complex was prepared by spray drying and was characterised by thermal (DSC) and spectral (FTIR) analyses. Risperidone and the inclusion complex were loaded into microparticles by spray drying using HPMC, carbomer and HPMC/carbomer interpolymer complex (IPC) as mucoadhesive components. The microparticles were characterised with respect to drug loading, particle size distribution, thermal analysis, and zeta potential measurements. Mucoadhesive properties of the microparticles were studied by measuring the work of adhesion. Carbomer and IPC based microparticles revealed superior mucoadhesive microparticles compared to HPMC based microparticles. Drug incorporation into microparticles reduced their mucoadhesive properties, while incorporation of the cyclodextrin complex caused no additional reduction in mucoadhesion. The in vitro dissolution studies showed that formation of the inclusion complex significantly increased the risperidone dissolution rate from the microparticles, thus providing sustained drug release.