Spray-dried Complexes Research Articles

Novel lansoprazole/glycyrrhizin spray dried complex: Physiochemical properties, photostability, and anti-ulcer activity on rats

Lansopraole (LNS) is one of the most frequently used anti-ulcer drug, but its poor aqueous solubility, low bioavailability, and instability limits its clinical application. In this study, glycyrrhizin (GLY), a natural complexing agent obtained from licorice was used to deliver lansoprazole (LNS) for the treatment of ulcer. LNS/GLY complexes with and without magnesium oxide (MgO) as an alkalizer were prepared using spray drying method in order to improve the release and stability of LNS, and examine its anti-ulcer effects on rats. Among three developed complexes (F1-F3), F3 complex (LNS/GLY (1:1.5 w/w, with MgO) was optimized with highest process yield (85.7 ± 2.3%) and drug content (91 ± 4.3%). The optimized spray-dried complex (F3) was further evaluated for DSC, FTIR, PXRD, SEM, photostability and in-vitro release studies. An enhanced drug release and improved photo-protection was confirmed by NMR studies. Further in-vivo anti-ulcer studies showed a significant alleviated macroscopic and microscopic stomach damage and reduction in hemorrhagic lesions and ulcer index.

Development of Spray-Dried Cyclodextrin-Based Pediatric Anti-HIV Formulations.

The human immunodeficiency virus (HIV) impacts up to 37 million people globally, of which 1.8 million are children. To date, there is no cure for HIV, although treatment options such as antiretroviral therapy (ART) are available. ART, which involves a patient taking a combination of antiretrovirals, is being used to treat HIV clinically. Despite the effectiveness of ART, there is currently no palatable pediatric formulation to treat HIV in children, which has hindered patient compliance and overall treatment efficacy. In addition, anti-HIV therapeutics are often poorly water-soluble, and hence have poor bioavailability. In the present study, we developed a pediatric-friendly formulation for anti-HIV therapeutics with improved dissolution characteristics of the therapeutic agents. Lopinavir (LPV) and ritonavir (RTV), available as FDA-approved fixed-dose combination products, were chosen as model ART drugs, and the formulation and processing parameters of spray-dried cyclodextrin (CD)-based LPV and RTV complexes were studied. Results showed that the spray-dried complexes exhibited enhanced dissolution profiles in comparison to pure drugs, particularly spray-dried β-CD complexes, which showed the most favorable dissolution profiles. This current formulation with enhanced dissolution and taste-masking ability through the use of cyclodextrin has the potential to address the unmet need for the development of suitable pediatric formulations.

Spray-dried mucoadhesive microparticles based on S-protected thiolated hydroxypropyl-β-cyclodextrin for budesonide nasal delivery

Budesonide (BUD) is used as first choice therapy for the treatment of allergic rhinitis, a chronic allergic-immune condition with an increased incidence in the pediatric population. The main problem of BUD nasal formulations is related to its poor aqueous solubility (S0 = 5.03·10-5 M), sometimes compensated by the administration of high doses of the drug. The ability of thiolated hydroxypropyl-β-cyclodextrin (HP- β -CD-SH, 100 mM) to increase the water solubility of BUD (SHP- β-CD-SH = 10.9·10-3 M) more than pristine hydroxypropyl- β -cyclodextrin (HP- β-CD, SHP- β-CD = 4.3·10-3 M) has been previously demonstrated. Considering that S-protected thiomers have the advantage of increasing the stability of thiols over a wide pH range prolonging their residence time at the target site, 2-mercapto-nicotinic acid (MNA) was used in this study to protect the free thiol groups on HP- β -CD-SH generating the corresponding S-protected cyclodextrin (HP-β-CD-MNA). Besides, given the increased stability and processability of HP-β-CD-MNA, mucoadhesive microparticles (MPs) were prepared via spray-drying of aqueous solutions of the inclusion complex HP-β-CD-MNA/BUD. MPs were morphologically and dimensionally homogeneous exhibiting an average diameter of 3.24 ± 0.57 µm. Over time these MPs formed larger aggregates with an average diameter of 10–50 μm, suitable for the design of intranasal delivery systems. Differential scanning calorimetry analyses revealed the absence of crystalline BUD from spray-dried complexes. Dissolution studies shown that spray-dried MPs dissolved quickly and the complexed drug was completely solubilized within the first 20 min of the dissolution process. Cell viability assay indicated that spray-dried complexes are safe. In vitro mucoadhesion studies on freshly excised porcine nasal mucosa showed a 1.4- and 2.3-fold prolonged mucosal residence time of HP- β -CD-SH/BUD and HP-β-CD-MNA/BUD in comparison to the unmodified cyclodextrin (CD), respectively. Rheological behaviour of spray-dried MPs complexes/mucus mixtures confirmed the results of the mucoadhesion studies, as the dynamic viscosity of the spray-dried inclusion complexes HP-β-CD-SH/BUD and HP-β-CD-MNA/BUD was 1.1-fold and 2.4 fold increased in comparison to the unmodified HP-β-CD/BUD complex. According to these results, MPs comprising HP- β -CD-MNA/BUD might be a promising tool for nasal delivery of poorly water-soluble corticosteroids such as BUD.

Enhanced Nanoencapsulation of Sepiapterin within PEG-PCL Nanoparticles by Complexation with Triacetyl-Beta Cyclodextrin.

In this work, we aimed to improve the encapsulation efficiency of sepiapterin (SP), the natural precursor of the essential cofactor tetrahydrobiopterin (BH4) that displays mild water-solubility and a short biological half-life, within methoxy-poly(ethylene-glycol)-poly(epsilon-caprolactone)(mPEG-PCL) nanoparticles (NPs) by means of its complexation and hydrophobization with 2,3,6-triacetyl-β-cyclodextrin (TAβCD). For this, SP/TAβCD complexes were produced by spray-drying of SP/TAβCD binary solutions in ethanol using the Nano Spray Dryer B-90 HP. Dry powders were characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and transmission and scanning electron microscopy (TEM and SEM, respectively) and compared to the pristine components and their physical mixtures (PMs). Next, SP was encapsulated within mPEG-PCL NPs by nano-precipitation of an SP/TAβCD complex/mPEG-PCL solution. In addition to the nano-encapsulation of a preformed complex within the polymeric NPs, we assessed an alternative encapsulation approach called drying with copolymer (DWC) in which pristine SP, TAβCD, and mPEG-PCL were co-dissolved in a mixture of acetone and methanol at the desired weight ratio, dried under vacuum, re-dissolved, and nano-precipitated in water. The dissolution-drying step was aimed to promote the formation of molecular hydrophobic interactions between SP, TAβCD, and the PCL blocks in the copolymer. SP-loaded mPEG-PCL NPs were characterized by dynamic light scattering (DLS) and SEM. NPs with a size of 74–75 nm and standard deviation (S.D., a measure of the peak width) of 21–22 nm were obtained when an SP:TAβCD (1:1 molar ratio) spray-dried complex was used for the nano-encapsulation and SEM analysis revealed the absence of free SP crystals. The encapsulation efficiency (%EE) and drug loading (%DL) were 85% and 2.6%, respectively, as opposed to the much lower values (14% and 0.6%, respectively) achieved with pristine SP. Moreover, the NPs sustained the SP release with relatively low burst effect of 20%. Overall, our results confirmed that spray-drying of SP/TAβCD solutions at the appropriate molar ratio leads to the hydrophobization of the relatively hydrophilic SP molecule, enabling its encapsulation within mPEG-PCL NPs and paves the way for the use of this strategy in the development of novel drug delivery systems of this vital biological precursor.

Spray-drying microencapsulation of nisin by complexation with exopolysaccharides produced by probiotic Bacillus tequilensis-GM and Leuconostoc citreum-BMS

This work aims to encapsulate nisin by complexation with exopolysaccharides (EPS), produced by Bacillus tequilensis-GM and Leuconostoc citreum-BMS, namely EPS-GM and EPS-BMS, respectively, using spray-drying technique, and to evaluate the effect of this encapsulation on the structure of nisin. Results related to suspensions turbidity showed that EPS/nisin complexes were formed through electrostatic attractions. These interactions were confirmed by Fourier transform infrared (FTIR) analysis. Scanning electron microscopy (SEM) micrographs of the spray-dried complexes revealed the presence of well-separated spherical microcapsules. Besides, results obtained by UV spectra showed that no significant changes occurred on EPS-GM/nisin microcapsules suggesting that this EPS may act as protective agent of nisin structure against spray-drying conditions.

Cyclodextrin-based poly(pseudo)rotaxanes for transdermal delivery of carvedilol

This work aimed to design supramolecular gels combining Soluplus or Solutol and alfa- and hydroxypropyl-β-cyclodextrin (α-CD, HPβ-CD) for carvedilol (CAR) transdermal delivery. Poly(pseudo)rotaxane formation (appearance, SEM, 1H NMR), drug solubilization, rheological properties and in vitro release were investigated. CAR-CD complexes were prepared in situ or by spray drying. For Solutol, poly(pseudo)rotaxanes were formed immediately after mixing with α-CD and did not influence CAR solubility. Differently, Soluplus poly(pseudo)rotaxanes took 24–48 h to be formed and CAR solubility decreased compared to Soluplus micelles. Soluplus 20% + α-CD (5–10%) showed higher G' and G'’ but also faster CAR release than Solutol poly(pseudo)rotaxanes, which is explained by the different location of PEG chains in the two amphiphilic polymers. Faster drug release was achieved incorporating HPβ-CD or CAR-HPβ-CD spray-dried complexes. The results evidenced the versatility of the formulations in terms of rheological behavior and drug release patterns, which can be adjusted for CAR transdermal delivery.

Survival of Saccharomyces cerevisiae microencapsulated with complex coacervate after freezing process

Complex coacervate from whey protein isolate (WPI)-Saccharomyces cerevisiae (Y) was prepared for microencapsulation by spray-drying. The optimum WPI-Y complex coacervate reached the best interaction for a ratio and pH of 1:13 and 3.28, respectively. The complex coacervate was spray-dried with 10% and 20% w/w of total solids content using maltodextrin DE10 (MD) as wall material and subsequently frozen at −18 °C. DSC, FTIR and SEM analyses were carried out to characterize thermal, chemical and structural properties of pure materials and spray-dried WPI-Y complex coacervates. Thermograms of DSC reflected that the spray-dried WPI-Y complex coacervates were better protected when MD concentration increased because the denaturation peak temperature of proteins and enthalpy were higher. These results were confirmed with FTIR analysis since peaks intensity of amino groups was highest in the spray-dried WPI-Y complex coacervate containing 20% w/w of total solids content. After the freezing process, reduced decrease in the peaks intensity of the amides in the spray-dried WPI-Y complex coacervate with 20% w/w of total solids content was observed. Morphology of all spray-dried complex coacervates exhibited particles of spherical shapes with concavities, dents and hollows in the center. However, particles after the freezing process displayed fractures in the surface. Finally, yeast survival was higher in the spray-dried WPI-Y complex coacervate with higher concentration of MD and as well after freezing process. Therefore, WPI-Y complex coacervates were stable after freezing process and can be used to stabilize fermentative microorganisms in order to produce frozen dough with similar characteristics that the dough.

Characterization of a novel complex coacervate based on whey protein isolate-tamarind seed mucilage

A complex coacervate was prepared with whey protein isolate (WPI) and tamarind seed mucilage (TSM) and was compared with a commonly used whey protein isolate (WPI)-gum Arabic (GA) complex coacervate. Protolityc titration, ζ-potentiometry and turbidimetry analyses were used to determine structural transitions during coacervate formation. Hydrocolloid blending ratio and pH effects on phase transitions were examined to finding the maximum strength interaction of the complex coacervates. The optimum WPI-TSM complex coacervate ratio and the pH value were 1:0.3 and 3.68, respectively. In contrast, the WPI-GA complex coacervate reached the optimal interaction at ratio of 1.4:1 and pH = 3.46. The complex coacervates were spray-dried and analyzed to characterize structural, morphological and thermal properties. The results of FTIR showed that the formation of complexes was by means of electrostatic interactions and hydrogen bonds. The XRD analysis of WPI-TSM complex revealed higher crystallinity with respect to WPI-GA complex. The spray-dried complex coacervates exhibited clusters of amorphous aggregates, smooth and non-fractured particles. Thermal stability showed that coacervation enhanced protein stability as compared to WPI alone. Besides, WPI-TSM complex coacervate exhibited higher thermal stability than its WPI-GA counterpart. Therefore, WPI-TSM complex coacervate can be used as an economic and nutritionally valuable alternative for food additives.

Using complex coacervation for lysozyme encapsulation by spray-drying

The purpose of this study is to evaluate the properties of encapsulated lysozyme (at 0.714 g/L concentration) by spray-drying as well as the effect of complexation with increased pectin concentrations (0–4 g/L) on the preservation of lysozyme structure and activity. Maximum turbidity of spray-dried complexes was lower than unprocessed ones at a threshold pectin concentration above which turbidity was reduced. This result could be attributed to the formation of more individual complexes with decreased aggregation upon application of spray-drying due to configurational changes of the complexes. At higher pectin concentrations (above 0.5 g/L), spray-dried complexes exhibited lower antimicrobial activity compared with unprocessed complexes probably because of high limitation in diffusion and accessibility of substrate to active sites of the encapsulated enzyme within the polysaccharide network. Conformational changes of lysozyme and formation of complexes with pectin upon spray-drying were determined by using fluorescence and UV–Vis absorption measurements. The results revealed that spray-drying had a significant effect on lysozyme structure, activity, and mobility particularly at higher pectin concentrations (above 0.5 g/L).

Development and evaluation of orally disintegrating tablets of cilostazol-β-cyclodextrin inclusion complexes

Context: The clinical applications of cilostazol (CLZ) are limited by its low aqueous solubility (<5 µg/ml) and high biovariability.Objective: The aim of this study was to enhance the solubility of CLZ by forming inclusion complexes (ICs) with beta cyclodextrin (β-CD) and formulating them into oral disintegrating tablets.Methods: Phase solubility study of CLZ with β-CD was performed in water. Job’s plot was constructed to determine the stoichiometry of ICs. ICs, prepared by spray-drying technique, were characterized using Fourier transform infrared spectroscopy, differential scanning calorimetry, hot stage microscopy, powder X-ray diffraction and nuclear magnetic resonance. Molecular modeling studies were performed to understand the mode of interaction of CLZ with β-CD. The formulation process was undertaken using a reproducible design of experiment generated model, attained by variation of diluents and disintegrants at three levels. Tablets were evaluated for drug content, hardness, friability, disintegration time (DT), wetting time (WT) and dissolution profiles.Results and discussion: Phase solubility studies suggested an AL type curve with stability constant (Ks) of 922.52 M−1. Job’s plot revealed 1:2 stoichiometry. All analytical techniques confirmed inclusion complexation. Molecular modeling revealed dispersive van der Waals interaction energy as a major contributor for stabilization of complex. The spray-dried complexes showed higher solubility and faster dissolution compared to plain CLZ. The optimized formulation showed DT of 11.1 ± 0.8 s, WT of 8.7 ± 0.9 s and almost complete dissolution of CLZ in 15 min.Conclusion: The prepared tablets with low DT and fast dissolution will prove to be a promising drug delivery system with improved bioavailability and better patient compliance.

Spray-dried voriconazole–cyclodextrin complexes: Solubility, dissolution rate and chemical stability

The present work investigates the effect of complexation with hydroxypropyl-beta-cyclodextrin (HPBCD) and 2-O-methyl-beta-cyclodextrin (2-O-MBCD), on voriconazole solubility, dissolution rate and chemical stability. Drug–cyclodextrin complexes were prepared as aqueous solutions, which were spray-dried, and their properties were compared to wet ground samples and physical mixtures. DSC analysis revealed absence of crystalline voriconazole from spray-dried complexes. FTIR spectroscopy indicated changes in the H-bonding network of the hydroxyl groups of cyclodextrin following drug inclusion. Dissolution rate of voriconazole was significantly higher from spray-dried complexes with either cyclodextrin in comparison with free drug, physical mixtures, or wet ground mixtures. However, two degradation impurities were found in aged samples, with slightly higher impurity level with HPBCD. Performed solubility studies suggested that 2-O-MBCD is more efficient solubilizer. Molecular docking simulations showed a difference in the 1:1 binding affinities and sites, with HPBCD surprisingly forming complexes of much lower energy, thus suggesting a multiple rather than a 1:1 complexation.

Reduced Ulcerogenic Potential and Antiarthritic Effect of Chitosan–Naproxen Sodium Complexes

The purpose of this research was to address the utility of naproxen sodium-chitosan spray-dried complexes for antiulcer and antiarthritic activities. The cold stress technique was used to examine the ulcerogenic potential of naproxen sodium (NPX) and spray-dried formulations in the different doses. The ulcerations reduced with the dose of spray-dried complexes of naproxen sodium and chitosan. The conspicuous hemorrhagic lesions were visible in the morphological features of the animal treated with naproxen 50 mg/kg (p.o.). Thus, the results suggest that the spray-dried naproxen sodium-chitosan complex (NPXF) was not corrosive to the gastric mucosa at high doses of 50, 100, and 200 mg/kg (p.o.) under stressful conditions. It is evident from the present investigation that NPXF does not possess any ulcerogenic potential in comparison to naproxen which, under stressful conditions, led to the hypersecretion of HCl, culminating to petichial hemorrhages in the gastric mucosa of the animals. The biphasic pattern was observed in the various arthritic parameters. The rise in paw volume, joint diameter, WBC count, arthritis score, and fall in body weight was significantly ameliorated in the animals treated with NPXF (5, 10, and 20 mg/kg, p.o). At the end of the study, slight erythema was visible in the naproxen-treated animals. However, no erythema, redness, or ulcers were visible in the animals treated with NPXF. Thus, the direct compression properties and reduced ulcerogenic activity, combined with the demonstrated solubilizing power and analgesic effect enhancer ability toward the drug, make naproxen sodium-chitosan spray-dried complexes particularly suitable for developing a reduced-dose, fast-release, solid oral dosage form of naproxen.

Influence of fulvic acid and hydroxy propyl-β-cyclodextrin on aspirin degradation

Objective: The degradation of aspirin (ASA) was investigated to reveal information about the influence of complexation with fulvic acid (FA), as a new complexing agent and compared with hydroxy propyl-β-cyclodextrin complex. Materials and methods: ASA was complexed with FA in the molar ratio 1:0.5, 1:1, and 1:2 by different methods through lyophilization, solvent evaporation, and spray drying. Spray-dried (1:1) ASA–hydroxy propyl-β-cyclodextrin complex was prepared and compared with optimized complex of FA. All the complexes and ASA alone were packaged in well-labeled sealed polythene-lined aluminum pouches and stored in stability chamber at 40 ± 2°C and 75 ± 5% relative humidity for 120 days. Samples were analyzed for salicylic acid content at 0, 30, 60, 90, and 120 days. Results: Overall 4.31% salicylic acid was formed in 1:1 ASA–FA spray-dried complex, which was optimized stable complex among other complexes of FA prepared by different methods in different molar ratios. However, 2.35% salicylic acid was measured with 1:1 spray-dried ASA–hydroxy propyl-β-cyclodextrin complex. Stability of ASA increased more when complexed with hydroxy propyl-β-cyclodextrin as compared to FA. Conclusions: A novel complexing agent in the form of FA was investigated to increase the stability of ASA. A marked improvement in stability of ASA was observed when complexed with hydroxy propyl-β-cyclodextrin (1:1) by spray drying as compared to 1:1 spray-dried ASA–FA complex.

Effect of oppositely charged polymer and dissolution media on rheology of spray-dried ionic complexes.

The purpose of this research was to address the utility of rheological study in understanding the influence of oppositely charged polymers on release of naproxen sodium encapsulated in chitosan particles. The interaction between oppositely charged kappa-carrageenan (kappa-Ca) and chitosan leads to relatively higher gel strength, which is proportional to the ability to retard the drug release at acidic pH. The oscillatory tests within the linear viscoelastic range where the stress is proportional to the applied strain were performed on the hydrated sample matrices containing chitosan-naproxen sodium spray-dried complexes and k-Ca or hydroxypropyl methylcellulose (HPMC) in various ratios. It was observed that the effect of pH change on the dynamic moduli in spray-dried complexes containing kappa-Ca was much stronger than that with HPMC reflecting presence of strong ionic interaction between kappa-Ca and chitosan. The combination of oppositely charged polymers in different ratios proved to be useful in modulating the rheological properties of the hydrated formulations and their release-retarding properties. Dynamic moduli can be used to measure gel strength and are significant for the interpretation of oral sustained release spray-dried complexes.

Evaluation of gastric toxicity of indomethacin acid, salt form and complexed forms with hydroxypropyl‐β‐cyclodextrin on Wistar rats: histopathologic analysis

Indomethacin (IM) is a non-steroidal anti-inflammatory drug which inhibits prostaglandin biosynthesis. It is practically insoluble in water and has the capacity to induce gastric injury. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) is an alkylated derivative of beta-CD with the capacity to form inclusion complexes with suitable molecules. IM is considered to form partial inclusion complexes with HP-beta-CD by enclosure of the p-chlorobenzoic part of the molecule in the cyclodextrin channel, reducing the adverse effects. The aim of this paper is to evaluate the gastric damage induced by the IM inclusion complex prepared by freeze-drying and spray-drying. A total of 135 Wistar rats weighing 224.4 +/- 62.5 g were put into 10 groups. They were allowed free access to water but were maintained fasted for 18 h before the first administration until the end of the experiment. IM acid-form, IM trihydrated-sodium-salt and IM-HP-beta-CD spray and freeze-dried, at normal and toxic doses, were administered through gastric cannula once/day for 3 days. Seventy-two hours after the first administration, the animals were sacrificed and the stomachs collected and prepared for morphological study by using the haematoxylin-eosin technique. Lesion indexes (rated 0/4) were developed and the type of injury was scored according to the severity of damage and the incidence of microscopic evidence of harm. Microscopic assessment demonstrated levels of injury with index one on 10-25%. The type of complexation method had different incidence but the same degree. The results show that IM inclusion complexation protects against gastric injury, reducing the incidence and the maximum degree of severity from 4 to 1, with a better performance of the spray-dried complex.

Effect of Drying Methods on Swelling, Erosion and Drug Release from Chitosan–Naproxen Sodium Complexes

The purpose of this research was to explore theapplication of ionic interactions between naproxen sodium (NS) and chitosan (CH) in complexes (NSC) prepared by tray drying (TD) and spray drying (SD) methods. Drug-polymer ratio (1:1) in the NSC was optimized on the basis of dialysis studies. The particulate systems of NSC were prepared by tray drying (TD) and spray drying (SD) methods. Release retarding polymers were added to the NSC and to the physical mixtures containing NS-CH and their effects on water uptake, matrix erosion and drug release at different pH were compared. Spray dried complexes (SDC) were spherical, free flowing, light and fine amorphous particles in contrast to the crystalline, hard, tenacious, irregularly shaped, denser tray dried complexes (TDC) with poor flowability. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR) patterns confirm the conversion of crystalline to high energy amorphous phase suitable for ionic interactions in NSC. Presence of release retarding polymers, kappa carrageenan and hydroxypropylmethylcellulose (HPMC) in the NSC compacts retarded the drug release and improved the matrix integrity. Carrageenan matrices exhibited more retardation than HPMC tablets. FTIR patterns, erosion, swelling and drug release from matrices support ionic interactions between NS and CH in NSC. The reasons for retarded drug release from the chitosan matrices at acidic pH include poor solubility of drug at acidic pH, formation of a rate limiting polymer gel barrier along the periphery of matrices and the ionic interactions between oppositely charged moieties.

Physicochemical characterization, in vitro dissolution behavior, and pharmacodynamic studies of rofecoxib-cyclodextrin inclusion compounds. Preparation and properties of rofecoxib hydroxypropyl β-cyclodextrin inclusion complex: A technical note

An inclusion complex of rofecoxib and HPβ-CD was prepared successfully by the spray-drying method in a molar ratio of 1∶1. The inclusion complex was found to have improved in vitro drug release compared with the pure drug. The solubility profile of complexes of rofecoxib prepared using HPβ-CD as the complexing agent in a molar ratio of 1∶1 by the spray-drying method in pH 1.2 and pH 7.4 indicated that the acid solubility of rofecoxib was enhanced considerably by formation of an inclusion complex with HPβ-CD. The above results also clearly demonstrated a significant decrease in the gastric ulcerogenic activity of rofecoxib through complexation with cyclodextrins. Even though the physical mixture of rofecoxib with cyclodextrins reduced ulcer formation, it was the spray-dried complex formation approach that minimized gastric ulceration. These findings are extremely important from a commercial point of view as the prepared complex removes a major drawback for rofecoxib in therapy.

Modified polyvinylalcohol for encapsulation of all-trans-retinoic acid in polymeric micelles

All-trans-retinoic acid (ATRA) is now included in many antitumor therapeutic schemes for the treatment of acute promyelocytic leukaemia, Kaposi's sarcoma, head and neck squamous cell carcinoma, ovarian carcinoma, bladder cancer and neuroblastoma. Unfortunately its poor aqueous solubility hampers its parenteral formulation. To date, there is no parenteral formulation of ATRA commercially available and oral administration of ATRA is associated with progressively diminishing ATRA levels in plasma, which is related to induction of retinoic acid-binding protein and increased drug catabolism by cytochrome P-450-mediated reaction. An ATRA formulation, obtained by complexation of the drug into polymeric micelles, might be suitable for parenteral administration overcoming these unwanted effects. To this purpose we prepared an amphiphilic polymer by polyvinylalcohol (PVA) substitution with oleyl amine at 1.5% substitution degree (mol substituent per 100 mol hydroxyvinylmonomer) and evaluated its functional properties with regard to ATRA complexation. The substituted polymer displayed ability to interact with ATRA both in aqueous solution and in the solid state following spray-drying of drug–polymer hydro-alcoholic solutions. The spray-dried complexes rapidly dissolved in water providing high levels of ATRA solubilization as a function of the drug–polymer weight ratio. The complexes characterized by 1:5 drug–polymer weight ratio provided higher levels of ATRA solubilization than 1:3 and 1:10 drug–polymer weight ratios respectively. Pre-formed polymeric micelles in water equilibrated in the presence of excess solid ATRA provided the lowest levels of solubilization. The drug release from the complexes was very slow in PBS, indicating their suitability in antitumor drug targeting where a fundamental requirement is stability towards drug release for at least 24 h, corresponding to the average circulation time period of macromolecular carriers. The cytotoxicity studies against neuroblastoma cell lines outlined increased cytotoxicity of complexed ATRA with respect to free ATRA, likely due to the increased bioavailability of the hydrophobic drug from the complex. We conclude that ATRA entrapped into self-assembling polymer micelles may be a useful parenteral ATRA formulation overcoming the unwanted pharmacological mechanism that lead to acquired retinoid resistance.

Influence of β-cyclodextrin complexation on carbamazepine release from hydroxypropyl methylcellulose matrix tablets

The in vitro release profiles of carbamazepine and β-cyclodextrin either complexed or simply mixed and subsequently incorporated in hydrophilic matrix tablets containing 15 or 30% hydroxypropyl methylcellulose were evaluated. Solubility studies revealed a linear relationship between the increase in carbamazepine solubility and the increase in β-cyclodextrin concentration. Drying methods (spray-drying and freeze-drying) were used to obtain carbamazepine/β-cyclodextrin solid complexes in order to prepare tablets. The results demonstrated that matrix tablets containing carbamazepine/β-cyclodextrin solid complexes displayed faster carbamazepine and β-cyclodextrin release compared to that containing simple physical mixture. Gelling and matrix formation was impaired in formulation containing 15% hydroxypropyl methylcellulose and spray-dried complex. The comparison of spray-drying and freeze-drying revealed no significant influence of both drying methods on carbamazepine and β-cyclodextrin dissolution rate when carbamazepine/β-cyclodextrin complexes were incorporated in 30% hydroxypropyl methylcellulose matrix tablets. The results point to the possibility of modulating carbamazepine release using a hydroxypropyl methylcellulose matrix associated to the drug complexed with β-cyclodextrin.

Effect of the hydrophobic nature of triacetyl-beta-cyclodextrin on the complexation with nicardipine hydrochloride: physicochemical and dissolution properties of the kneaded and spray-dried complexes.

The inclusion ability of triacetyl-beta-cyclodextrin (TAbetaCD), a hydrophobic cyclodextrin (CD) derivative was examined, using nicardipine hydrochloride (NC) as model drug. The binary compounds were prepared in a 1 : 1 molar ratio by the kneading and the spray-drying techniques. In order to confirm the complexation between NC and TAbetaCD in the solid state, differential scanning calorimetry, X-ray diffractometry, Fourier transformation-infrared spectroscopy and scanning electron microscopy were carried out and the results were compared with the corresponding physical mixture in the same molar ratio. The kneaded product presented only slight modifications on the drug physicochemical and morphological properties, which could mean that no complex formation occurred during this process. In contrast, spray-drying was found to produce inclusion complexes with amorphous nature. In vitro dissolution studies were carried out in simulated gastric (pH 1.2) and intestinal (pH 6.8) fluids, according to the United States Pharmacopoeia (USP) basket method. The NC in vitro release from the kneaded and spray-dried products was markedly retarded in both dissolution media. However, this retarding effect was significantly more evident for the spray-dried compound. It was concluded that the formation of real inclusion complexes could only be achieved by the spray-drying method.