Influence of Process Conditions on the Crystallization and Transition of Metastable Mannitol Forms in Protein Formulations During Lyophilization

Purpose

To study the impact of different process conditions and formulation compositions on metastable mannitol forms in protein formulations during lyophilization.

Methods

Mannitol was studied with and without other formulation components. A cryostage was used to mimic the different processing steps during lyophilization. The different mannitol forms were monitored and quantified with an in situ Raman spectroscopic method. In addition, a Raman imaging method was developed to characterize the spatial distribution of mannitol forms in final lyophilization samples from the freeze-drying stage.

Results

Amorphous mannitol was observed during fast cooling (10°C/min) and with the addition of other formulation component. Amorphous mannitol crystallized into mainly ?? and hemihydrate forms during annealing at ?20°C. Under vacuum without moisture, dried amorphous mannitol could transform to mainly ?? form at 45°C and greater. The transformation mechanism of the hemihydrate mannitol was similar to that of amorphous form.

Conclusion

Mannitol tends to crystallize into stable crystalline forms by itself, but the addition of lyoprotectant (e.g. sucrose) and protein helps stabilize the metastable forms (hemihydrate and amorphous). The metastable forms are capable of transforming into mixtures of different forms, with heat and moisture being the critical processing factors.     

Freeze-Dried Mannitol for Superior Pulmonary Drug Delivery via Dry Powder Inhaler

Purpose

To show for the first time the superior dry powder inhaler (DPI) performance of freeze dried mannitol in comparison to spray dried mannitol and commercial mannitol.

Methods

Different mannitol powders were sieved to collect 63–90 μm particles and then analyzed in terms of size, shape, surface morphology, solid state, density, flowability. Salbutamol sulphate-mannitol aerosol formulations were evaluated in terms of homogeneity, SS-mannitol adhesion, and in vitro aerosolization performance.

Results

Freeze dried mannitol demonstrated superior DPI performance with a fine particle fraction believed to be highest so far reported in literature for salbutamol sulphate under similar protocols (FPF?=?46.9%). To lesser extent, spray dried mannitol produced better aerosolization performance than commercial mannitol. Freeze dried mannitol demonstrated elongated morphology, α-+β-+δ- polymorphic forms, and poor flowability whereas spray dried mannitol demonstrated spherical morphology, α-+β- polymorphic forms, and excellent flowability. Commercial mannitol demonstrated angular morphology, β- polymorphic form, and good flowability. Freeze dried mannitol demonstrated smoother surface than spray dried mannitol which in turn demonstrated smoother surface than commercial mannitol. FPF of SS increased as mannitol powder porosity increase.

Conclusions

Freeze drying under controlled conditions can be used as a potential technique to generate aerodynamically light mannitol particles for superior DPI performance.     

Inclusion Complex of Novel Curcumin Analogue CDF and β-Cyclodextrin (1:2) and Its Enhanced In Vivo Anticancer Activity Against Pancreatic Cancer

Purpose

Several formulations have been proposed to improve the systemic delivery of novel cancer therapeutic compounds, including cyclodextrin derivatives. We aimed to synthesize and characterize of CDF-??-cyclodextrin inclusion complex (1:2) (CDFCD).

Methods

The compound was characterized by Fourier transform infrared, differential scanning calorimetry, powder X-ray diffraction studies, H1 &; C13 NMR studies and scanning electron microscopic analysis. Its activity was tested against multiple cancer cell lines, and in vivo bioavailability was checked.

Results

CDF-??-cyclodextrin was found to lower IC₅₀ value by half when tested against multiple cancer cell lines. It preferentially accumulated in the pancreas, where levels of CDF-??-cyclodextrin in mice were 10 times higher than in serum, following intravenous administration of an aqueous CDF-??-cyclodextrin preparation.

Conclusions

Novel curcumin analog CDF preferentially accumulates in the pancreas, leading to its potent anticancer activity against pancreatic cancer cells. Synthesis of such CDF-??-cyclodextrin self-assembly is an effective strategy to enhance its bioavailability and tissue distribution, warranting further evaluation for CDF delivery in clinical settings for treatment of human malignancies.     

Towards a More Desirable Dry Powder Inhaler Formulation: Large Spray-Dried Mannitol Microspheres Outperform Small Microspheres

Purpose

To investigate, for the first time, the performance of a dry powder inhaler (DPI, Aerolizer^®) in the case of a model drug (i.e. albuterol sulphate) formulated with spray dried mannitol carrier particles with homogeneous shape and solid–state form but different sizes.

Methods

Spray dried mannitol (SDM) particles were characterized in terms of size, surface area, morphology, water content, solid–state, density and electrostatic charge by a novel approach. DPI formulations composed of SDM and albuterol sulphate (AS) were prepared and evaluated in terms of drug content homogeneity and in vitro aerosolization performance.

Results

All SDM particles generated similar fine particle fractions of AS. Formulations consisting of larger SDM particles demonstrated better drug content homogeneity, reduced amounts of drug loss and reduced oropharyngeal deposition. Comparing different SDM products demonstrated that SDM powders with relatively poorer flowability, wider size distributions and higher charge density generated DPI formulations with poorer drug content homogeneity and deposited higher amount of drug on the inhaler, mouthpiece adaptor and throat. DPI formulation total desirability increased linearly with the mean diameter of SDM.

Conclusion

Particle shape and solid–state form of mannitol could dominate over carrier size, bulk density, flowability and charge in terms of determining the aerosolization behaviour of AS formulated with mannitol carrier, at least within the experimental protocols applied in the present study.     

A polymorphism in the gene of the endocannabinoid-degrading enzyme FAAH (FAAH C385A) is associated with emotional–motivational reactivity

Rationale

The endocannabinoid (eCB) system is implicated in several psychiatric disorders. Investigating emotional?Cmotivational dysfunctions as underlying mechanisms, a study in humans revealed that in the C385A polymorphism of the fatty acid amide hydrolase (FAAH), the degrading enzyme of the eCB anandamide (AEA), A carriers, who are characterized by increased signaling of AEA as compared to C/C carriers, exhibited reduced brain reactivity towards unpleasant faces and enhanced reactivity towards reward. However, the association of eCB system with emotional?Cmotivational reactivity is complex and bidirectional due to upcoming compensatory processes.

Objectives

Therefore, we further investigated the relationship of the FAAH polymorphism and emotional?Cmotivational reactivity in humans.

Methods

We assessed the affect-modulated startle, and ratings of valence and arousal in response to higher arousing pleasant, neutral, and unpleasant pictures in 67 FAAH C385A C/C carriers and 45 A carriers.

Results

Contrarily to the previous functional MRI study, A carriers compared to C/C carriers exhibited an increased startle potentiation and therefore emotional responsiveness towards unpleasant picture stimuli and reduced startle inhibition indicating reduced emotional reactivity in response to pleasant pictures, while both groups did not differ in ratings of arousal and valence.

Conclusions

Our findings emphasize the bidirectionality and thorough examination of the eCB system??s impact on emotional reactivity as a central endophenotype underlying various psychiatric disorders.     

Characterisation and Deposition Studies of Recrystallised Lactose from Binary Mixtures of Ethanol/Butanol for Improved Drug Delivery from Dry Powder Inhalers

Dry powder inhaler formulations comprising commercial lactose-drug blends can show restricted detachment of drug from lactose during aerosolisation, which can lead to poor fine particle fractions (FPFs) which are suboptimal. The aim of the present study was to investigate whether the crystallisation of lactose from different ethanol/butanol co-solvent mixtures could be employed as a method of altering the FPF of salbutamol sulphate from powder blends. Lactose particles were prepared by an anti-solvent recrystallisation process using various ratios of the two solvents. Crystallised lactose or commercial lactose was mixed with salbutamol sulphate and in vitro deposition studies were performed using a multistage liquid impinger. Solid-state characterisation results showed that commercial lactose was primarily composed of the α-anomer whilst the crystallised lactose samples comprised a α/β mixture containing a lower number of moles of water per mole of lactose compared to the commercial lactose. The crystallised lactose particles were also less elongated and more irregular in shape with rougher surfaces. Formulation blends containing crystallised lactose showed better aerosolisation performance and dose uniformity when compared to commercial lactose. The highest FPF of salbutamol sulphate (38.0 ± 2.5%) was obtained for the lactose samples that were crystallised from a mixture of ethanol/butanol (20:60) compared to a FPF of 19.7 ± 1.9% obtained for commercial lactose. Engineered lactose carriers with modified anomer content and physicochemical properties, when compared to the commercial grade, produced formulations which generated a high FPF.     

Crystallization of Lactose from Carbopol Gels

Purpose. To crystallize lactose under static conditions with a view topreparing crystals of well-defined morphology. Methods. -Lactose monohydrate was crystallized from neutralizedCarbopol 934 gels. When the majority of crystals had grown to maturity,the gels were acidified using diluted hydrochloric acid and the crystalswere harvested by filtration or centrifugation and washed with ethanol-watermixtures. Results. Crystals prepared from the gel had a consistently narrowersize distribution than control crystals, prepared from solution underconstant stirring. If crystallization was effected in the gel withoutsedimentation of the crystals, then the resultant crystals had smoothsurfaces without visually detectable surface roughness or asperitiesviewed by optical microscopy. The crystals from Carbopol gels alsoexhibited the uniform shape of an elongated tomahawk regardless of thecrystallization conditions, in contrast to crystallization under constantstirring, where the crystal shape of lactose changed with crystallizationconditions especially as a function of the initial concentration of lactose.All batches of lactose crystals prepared from Carbopol gels existedas -lactose monohydrate, which showed better flowability than thecontrols of a similar particle size. Conclusions. Crystallization from Carbopol gel produces lactose crystalsof uniform size, regular shape, smooth surface, and improvedflowability.     

Improving Dry Powder Inhaler Performance by Surface Roughening of Lactose Carrier Particles

Purpose

This study investigated the impact of macro-scale carrier surface roughness on the performance of dry powder inhaler (DPI) formulations.

Methods

Fluid-bed processing and roller compaction were explored as processing methods to increase the surface roughness (R_a) of lactose carrier particles. DPI formulations containing either (a) different concentrations of fine lactose at a fixed concentration of micronized drug (isoniazid) or (b) various concentrations of drug in the absence of fine lactose were prepared. The fine particle fraction (FPF) and aerodynamic particle size of micronized drug of all formulations were determined using the Next Generation Impactor.

Results

Fluid-bed processing resulted in a modest increase in the R_a from 562 to 907 nm while roller compaction led to significant increases in R_a?>?1300 nm. The roller compacted carriers exhibited FPF?>?35%, which were twice that of the smoothest carriers. The addition of up to 5%, w/w of fine lactose improved the FPF of smoother carriers by 60–200% whereas only?<?30% increase was observed in the rough carriers. Analysis of the FPF in tandem with shifts in the mass median aerodynamic diameter of dispersed drug suggested that the finest drug particles were entrapped on rougher surfaces while larger drug particles were dispersed in the air.

Conclusions

The results showed that the processing of lactose carrier particles by roller compaction was immensely beneficial to improving DPI performance, primarily due to increased surface roughness at the macro-scale.

     

What and when to “want”? Amygdala-based focusing of incentive salience upon sugar and sex

Rationale

Amygdala-related circuitry helps translate learned Pavlovian associations into appetitive and aversive motivation, especially upon subsequent encounters with cues.

Objectives

We asked whether ??-opioid stimulation via microinjections of the specific agonist d-Ala², N-MePhe⁴, Gly-ol)-enkephalin (DAMGO) in central nucleus of amygdala (CeA), or the adjacent basolateral amygdala (BLA) would magnify sucrose or sex ??wanting??, guided by available cues.

Materials and methods

CeA or BLA DAMGO enhancement of cue-triggered ??wanting?? was assessed using Pavlovian to instrumental transfer (PIT). Unconditioned food ??wanting?? was measured via intake, and male sexual ??wanting?? for an estrous female was measured in a sexual approach test. Sucrose hedonic taste ??liking?? was measured in a taste reactivity test.

Results

CeA (but not BLA) DAMGO increased the intensity of phasic peaks in instrumental sucrose seeking stimulated by Pavlovian cues over precue levels in PIT, while suppressing seeking at other moments. CeA DAMGO also enhanced food intake, as well as sexual approach and investigation of an estrous female by males. DAMGO ??wanting?? enhancements were localized to CeA, as indicated by ??Fos plume??-based anatomical maps for DAMGO causation of behavioral effects. Despite increasing ??wanting??, CeA DAMGO decreased the hedonic impact or ??liking?? for sucrose in a taste reactivity paradigm.

Conclusions

CeA ??-opioid stimulation specifically enhances incentive salience, which is dynamically guided to food or sex by available cues.     

Formulation of inhalable lipid-based salbutamol sulfate microparticles by spray drying technique

Background

The aim of this work was to develop dry powder inhaler (DPI) formulations of salbutamol sulfate (SS) by the aid of solid lipid microparticles (SLmPs), composed of biocompatible phospholipids or cholesterol.

Methods

The SLmPs were prepared by using two different solvent systems (ethanol and water-ethanol) and lipid carriers (dipalmitoylphosphatidylcholine (DPPC) and cholesterol) with/without L-leucine in the spray drying process. The spray-dried microparticles were physically-mixed with coarse lactose monohydrate in order to make our final DPI formulations and were investigated in terms of physical characteristics as well as in vitro drug release profile and aerosolization behavior.

Results

We observed significant differences in the sizes, morphologies, and in vitro pulmonary depositions between the formulations. In particular, the SS-containing SLmPs prepared with water-ethanol (30:70 v/v) solution of DPPC and L-leucine which had then been blended with coarse lactose (1:9 w/w) exhibited the highest emitted dose (87.9%) and fine particle fraction (42.7%) among the formulations. In vitro drug release study indicated that despite of having a significant initial burst release for both cholesterol and DPPC-based microparticles, the remained drug released more slowly than the pure drug.

Conclusion

This study demonstrated the potential of using lipid carriers as well as L-leucine in DPI formulations of SS to improve its aerosolization behavior and retard the release profile of the drug.     

Rapid Intradermal Delivery of Liquid Formulations Using a Hollow Microstructured Array

Purpose

The purpose of this work is to demonstrate rapid intradermal delivery of up to 1.5 mL of formulation using a hollow microneedle delivery device designed for self-application.

Methods

3M??s hollow Microstructured Transdermal System (hMTS) was applied to domestic swine to demonstrate delivery of a variety of formulations including small molecule salts and proteins. Blood samples were collected after delivery and analyzed via HPLC or ELISA to provide a PK profile for the delivered drug. Site evaluations were conducted post delivery to determine skin tolerability.

Results

Up to 1.5 mL of formulation was infused into swine at a max rate of approximately 0.25 mL/min. A red blotch, the size of the hMTS array, was observed immediately after patch removal, but had faded so as to be almost indistinguishable 10 min post-patch removal. One-mL deliveries of commercial formulations of naloxone hydrochloride and human growth hormone and a formulation of equine anti-tetanus toxin were completed in swine. With few notable differences, the resulting PK profiles were similar to those achieved following subcutaneous injection of these formulations.

Conclusions

3M??s hMTS can provide rapid, intradermal delivery of 300?C1,500 µL of liquid formulations of small molecules salts and proteins, compounds not typically compatible with passive transdermal delivery.     

The influence of heating/drying on the crystallisation of amorphous lactose after structural collapse

This study was designed to investigate the influence of collapse of amorphous lactose on its subsequent behaviour during drying, or other processes which cause increases in the temperature of the material. Amorphous lactose was prepared by spray drying from aqueous solution. The solid was dried and then exposed to 50% RH for various times in order to induce different amounts of collapse in the amorphous structure. All the samples remained amorphous for the range of exposure times used. During heating in a differential scanning calorimeter, the non-collapsed material crystallised at ca. 180°C to give mostly α-lactose, with some β-lactose present. The collapsed lactose crystallised at ca. 70°C and yielded mostly β-lactose, with some α-lactose monohydrate present. It can be concluded that the collapsed structure will crystallise on drying at lower temperatures than the non-collapsed lactose. The non-collapsed material rapidly loses its sorbed water (this would occur during the early stages of drying), whilst the collapsed lactose loses its water suddenly during crystallisation. Thermogravimetric analysis revealed (generally) three distinct water loss peaks for the collapsed structure, two of which were believed to be due to crystallisation occurring and the final one being the loss of water of crystallisation. The sudden loss of water from the collapsed material will make a substantial contribution to the free water content of a formulation and as such could cause confusion during drying processes. Material which was partially collapsed behaved in an intermediate manner between non-collapsed and totally collapsed samples.     

New Respirable and Fast Dissolving Itraconazole Dry Powder Composition for the Treatment of Invasive Pulmonary Aspergillosis

Purpose

Novel itraconazole (ITZ)-based dry powders for inhalation (DPI) were optimized for aerodynamic and dissolution properties and contained excipients that are acceptable for inhalation.

Methods

The DPI were produced by spray drying solutions. The drug content, crystallinity state, and morphological evaluation of the dry powders were determined by high performance liquid chromatography, powder X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy, respectively. A particle size analysis was conducted using laser light scattering. The aerodynamic behaviors of the powders were characterized by impaction tests. ITZ dissolution rates were evaluated using a dissolution method adapted to inhaled products.

Results

The DPI presented very high fine particle fractions that ranged from 46.9% to 67.0% of the nominal dose. The formulations showed very fast dissolution rates compared to unformulated crystalline ITZ with the possibility of modulating the dissolution rate by varying the quantity of phospholipids (PL) incorporated. ITZ remained amorphous while the mannitol was crystalline. The α, β and δ-mannitol polymorph ratios varied depending on the formulation compositions.

Conclusion

This formulation strategy could be an attractive alternative for treating invasive pulmonary aspergillosis. The ITZ and PL content are key characteristics because of their influence on the dissolution rate and aerosol performance.     

Ingenane-type diterpenes with a modulatory effect on IFN-γ production from the roots of Euphorbia kansui

A new ingenane-type diterpene, (3S,5R)5-O-(2,3-dimethylbutanoyl)-13-O-dodecanoyl-20-O-deoxyingenol (1), and six known compounds,3-O-(2,3-dimethylbutanoyl)-13-O-dodecanoyl-20-O-deoxyingenol (2), 20-O-decanoylingenol (3), 20-O-acetylingenol-3-O-(2??E,4??Z) decadienoate (4), kansuiphorin A (5), 3-O-(2,3-dimethylbutanoyl)-13-O-dodecanoylingenol (6), and kansuinin F (7) were isolated and evaluated for their effect on IFN-?? production in NK92 cells. Interestingly, subjection to compounds 4 and 6 (10 nM) displayed the most significant response in IFN-?? production, comparable to that produced by the same dose of phorbol 12-myistate 13-acetate (PMA). High doses of compounds 3 (100 nM), 1 (1. 25 ??M) and 5 (5.0 ??M) have also been shown to activate the IFN-?? production.     

PEG-Stabilized Micellar System with Positively Charged Polyester Core for Fast pH-Responsive Drug Release

Purpose

To design functional drug carriers for fast pH-responsive drug release.

Methods

Functional diblock terpolymers of monomethoxy poly(ethylene glycol)-block- copoly(6,14-dimethyl-1,3,9,11-tetraoxa-6,14-diaza-cyclohexadecane-2,10-dione-co-??-caprolactone) [mPEG-b-poly(ADMC-co-CL)] were fabricated via biosynthetic pathway. The self-assembled nanosphere and drug-loaded micelles of the copolymers were further prepared by dialysis method. The pH-tunable morphology variation and drug release pattern were observed at different pH.

Results

A collection of three PEGylated terpolymers with varied compositions in poly(ADMC-co-CL) block was designed with high cell-biocompatibility. The copolymers could readily self-assemble into nanoscale micelles (~ 100?nm) in aqueous medium and exhibit high stability over 80-h incubation in different mediums including deionized water, neutral NaCl solution, and heparin sodium solution. Due to the protonation-deprotonation of tertiary amine groups in ADMC units, acid-induced structural deformation of micelles was disclosed in terms of the variation in CAC value and hydrodynamic size at different pH. Drug loading efficiency was comparable to that of reported PEG-polyester micelles with specifically designed structures purposed for drug-loading improvement. Remarkably accelerated drug release triggered by acidity was distinctly detected for ibuprofen-loaded mPEG-b-poly(ADMC-co-CL) micelle system, suggesting a fast pH-responsive characteristic.

Conclusion

Functional PEG-stabilized micellar carriers with positively charged polyester core were successfully developed for fast pH-responsive drug release.     

Supercritical Fluid Processing of Materials from Aqueous Solutions: The Application of SEDS to Lactose as a Model Substance

Purpose. The objective of the work was to study the factors influencing the crystallisation of -lactose monohydrate from aqueous solution using the Solution Enhanced Dispersion by Supercritical Fluids (SEDS) technique. Methods. An aqueous solution of -lactose monohydrate is dispersed with a homogeneous mixture of carbon dioxide-ethanol/methanol using a co-axial nozzle. Crystallised lactose particles were analysed for water content by Karl-Fisher analysis, anomeric composition by Differential Scanning Calorimetry (DSC) and characterised for crystallinity by powder X-ray diffraction and morphology by scanning electron microscopy. Results. Water content in the lactose recrystallised with ethanol was higher compared to the product obtained with methanol as cosolvent. Rate of crystallisation could be altered by varying the CO₂ flow thereby modifying the water content in the lactose. At low flow rates of CO₂, the crystallisation occurred in a cosolvent rich antisolvent phase causing rapid crystallisation whereas high flow rates of CO₂ favoured a much slower crystallisation mechanism in the water rich phase. As a consequence, the morphology changed from thin long bands to large agglomerated chunks with mean particle size between 5 and 31 microns. Conclusions. The SEDS process is an efficient method for forming micron sized particles of water-soluble compounds with controlled physico-chemical properties.     

Frontally mediated inhibitory processing and white matter microstructure: age and alcoholism effects

Rationale

The NOGO P3 event-related potential is a sensitive marker of alcoholism, relates to EEG oscillation in the ?? and ?? frequency ranges, and reflects activation of an inhibitory processing network. Degradation of white matter tracts related to age or alcoholism should negatively affect the oscillatory activity within the network.

Objective

This study aims to evaluate the effect of alcoholism and age on ?? and ?? oscillations and the relationship between these oscillations and measures of white matter microstructural integrity.

Methods

Data from ten long-term alcoholics to 25 nonalcoholic controls were used to derive P3 from Fz, Cz, and Pz using a visual GO/NOGO protocol. Total power and across trial phase synchrony measures were calculated for ?? and ?? frequencies. DTI, 1.5?T, data formed the basis of quantitative fiber tracking in the left and right cingulate bundles and the genu and splenium of the corpus callosum. Fractional anisotropy and diffusivity (??L and ??T) measures were calculated from each tract.

Results

NOGO P3 amplitude and ?? power at Cz were smaller in alcoholics than controls. Lower ?? total power was related to higher ??T in the left and right cingulate bundles. GO P3 amplitude was lower and GO P3 latency was longer with advancing age, but none of the time?Cfrequency analysis measures displayed significant age or diagnosis effects.

Conclusions

The relation of ?? total power at CZ with ??T in the cingulate bundles provides correlational evidence for a functional role of fronto-parietal white matter tracts in inhibitory processing.     

Targeted Delivery of Proteins into the Central Nervous System Mediated by Rabies Virus Glycoprotein-Derived Peptide

Purpose

Delivery of therapeutic proteins across the blood-brain barrier (BBB) is severely limited by their size and biochemical properties. Here we showed that a 39-amino acid peptide derived from the rabies virus glycoprotein (RDP) was exploited as an efficient protein carrier for brain-targeting delivery.

Methods

Three proteins with different molecular weight and pI, ??-galactosidase (??-Gal), luciferase (Luc) and brain-derived neurotrophic factor (BDNF), were fused to RDP and intravenously injected into the mice respectively. The slices of different tissues with X-Gal staining were used to examine whether RDP could deliver ??-Gal targeted into the CNS. The time-course relationship of RDP-Luc was studied to confirm the transport efficiency of RDP. The neuroprotective function of RDP-BDNF was examined in mouse experimental stroke to explore the pharmacological effect of RDP fusion protein.

Results

The results showed that the fusion proteins rapidly and specific entered the nerve cells in 15?min, and the t_1/2 was about 1?hr. Furthermore, RDP-BDNF fusion protein showed the neuroprotective properties in mouse experimental stroke including reduction of stroke volume and neural deficit.

Conclusions

RDP provides an effective approach for the targeted delivery of biological active proteins into the central nervous system.     

Microstructural Elucidation of Self-Emulsifying System: Effect of Chemical Structure

Purpose

Self-emulsifying systems (SES) emulsify spontaneously to produce fine oil-in-water emulsion when introduced into aqueous phase. The self-emulsification process plays an important role during formation of emulsion. The objective of current work was to understand and explore the inner structuration of SES through controlled hydration and further to study the influence of additive on the same which ultimately governs performance of final formulation in terms of droplet size.

Methods

Droplet size of final formulations containing structural analogues of ibuprofen was determined. Microstructural properties of intermediate hydrated regimes of SES were investigated using techniques such as small angle X-ray scattering, differential scanning calorimetry and rheology.

Results

The current work established inverse relationship between droplet size of the formulations containing structural analogues of ibuprofen and their Log P values. Microstructural analysis of intermediate hydrated regimes of the prepared samples showed formation of local lamellar structure. Structural analogues of ibuprofen significantly altered microstructure of lamellae which was well correlated with the droplet size of final formulations. In vitro drug release study showed increase in dissolution rate of lipophillic drugs when formulated as SES.

Conclusion

The current work emphasizes the fact that tailor-made formulations can be prepared by controlling the properties of intermediate regimes.

The Role of Polysorbate 80 and HP��CD at the Air-Water Interface of IgG Solutions

Purpose

To test the hypothesis of surface displacement as the underlying mechanism for IgG stabilization by polysorbates and HP??CD against surface-induced aggregation.

Methods

Adsorption/desorption-kinetics of IgG-polysorbate 80/-HP??CD were monitored. Maximum bubble pressure method was used for processes within seconds from surface formation. Profile analysis tensiometry was applied over long periods and to assess surface rheologic properties. Additionally, the kinetics of adsorption, desorption and surface displacement was followed by a double-capillary setup of the profile analysis tensiometer, allowing drop bulk exchange.

Results

Weak surface activity for HP??CD vs. much higher surface activity for polysorbate 80 was shown. Protein-displacement when exceeding a polysorbate 80 concentration close to the CMC and a lack of protein displacement for HP??CD was observed. The drop bulk exchange experiments show IgG displacement by polysorbate 80 independent of the adsorption order. In contrast, HP??CD coexists with IgG at the air-water interface when the surface layer is built from a mixed IgG-HP??CD-solution. Incorporation of HP??CD in a preformed IgG-surface-layer does not occur.

Conclusions

The results confirm surface displacement as the stabilization mechanism of polysorbate 80, but refute the frequently held opinion, that HP??CD stabilizes proteins against aggregation at the air-water interface in a manner comparable to non-ionic surfactants.