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 beta-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 (K(s) = 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.

Development of a cyclodextrin-based nasal delivery system for lorazepam.

A new drug delivery system containing hydroxypropyl-beta-cyclodextrin (HP-beta-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-beta-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-beta-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.

Hydroxypropyl methylcellulose microspheres with piroxicam and piroxicam-hydroxypropyl-beta-cyclodextrin inclusion complex.

Inclusion complexation between piroxicam (PX) and hydroxypropyl-beta-cyclodextrin (HPbetaCD) in the presence of hydroxypropyl methylcellulose (HPMC) was studied in aqueous solution and in the solid state. Phase solubility studies were used to evaluate the HPbetaCD complexation in the presence of HPMC. Stability constants, Ks, of the complexes were determined. The stability of the inclusion complex was improved in the presence of HPMC. Solid microspheres were obtained by spray drying, and were characterized by differential scanning calorimetry (DSC), regarding drug content, and particle size distribution. Scanning electron microscopy (SEM) was also used to characterize the systems prepared. In the solid system HPMC facilitated to some extent the drug dissolution due to increased solubility. The presence of HPMC and HPbetaCD in the microspheres promoted dissolution rate. Cyclodextrin complexation increased PX flux through a semipermeable membrane. Presence of HPMC in the system additionally increased the drug flux more than 80%, by increasing the drug solubility and consequently the affinity of the ternary complex for the aqueous diffusion layer in the donor compartment.

Effect of hydroxypropyl-beta-cyclodextrin on hydrocortisone dissolution from films intended for ocular drug delivery.

The formation of an inclusion complex between hydrocortisone and hydroxypropyl-beta-cyclodextrin can affect the in vitro transfer rate of hydrocortisone from the aqueous to the organic phase. The observed first order transfer rate constants showed that the complexation of hydrocortisone with hydroxypropyl-beta-cyclodextrin decreased significantly the transport of the drug depending on the partition coefficient of the drug, and the relative magnitude of the stability constant of the inclusion complex. To optimize the ocular drug delivery, high molecular weight cellulosis and PVA polymeric films were prepared. No unified mathematical model can predict the release profile of drug and complex from films. The drug and complex-polymer interactions in each system could be responsible for the solubility of the drug, and different release behaviours of hydrocortisone and cyclodextrin inclusion complex from the films prepared.

Chitosan microspheres with hydrocortisone and hydrocortisone-hydroxypropyl-beta-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.

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-beta-cyclodextrin (HP beta CD), 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 degrees 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 HP beta CD.