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PubMed2006

The preparation of pellets containing a surfactant or a mixture of mono- and di-gylcerides by extrusion/spheronization.

The ability to incorporate either of the two components of a self-emulsifying system (polysorbate 80 (PSG80) and a mixture of mono- and di-glycerides (MDG)) separately into pellets prepared by extrusion/spheronization and the properties of any resulting pellets has been investigated. The results have established that it is possible to prepare satisfactory pellets thus adding to the range of ingredients that can be included in pellet formulations. For PS80, it was found possible to prepare pellets containing at least 92% of the surfactant/water mixture, but with a mixture of (MDG) and water, however, it was not possible to prepare pellets, which contained more than 46% of MDG. By analysis of variance significant relationships were established between the ratio of lactose to MCC and the ratio of the PS80 or MDG to water and the properties of the pellets. There were both similarities and differences of the two input factors, which provided relationships for the two materials. The quantity of liquid required, the fluid content of the pellets, the tensile strength and porosity of the pellets provided relationships for both systems, whereas the extrusion force and the median pellet size gave relationships for the PS80 systems, but they did not for the MDG systems. The opposite was true for interquartile range (IQR), the yield in the modal fraction and the shape factor. It was possible to identify global relationships for these systems and those reported previously, when the two components were combined as a self-emulsifying system, by the application of perceptual mapping. It was found that, there were relationships between the size range, expressed as the IQR and the fluid level required to make pellets; the quantity of the non-aqueous component of the fluid and the pellet shape factor; the extrusion force and the tensile strength of the pellets and the yield in the modal fraction and the ratio of the non-aqueous to aqueous content of the fluid used to prepare the pellets. The ability to use the materials independently offers further alternatives for the formulation of water insoluble drugs into pellet formulations.

Biopharmaceutics↗
PubMed2004

Nasal insulin delivery in the chitosan solution: in vitro and in vivo studies.

The effects of chitosan concentrations, osmolarity, medium and absorption enhancers in the chitosan solution on nasal insulin delivery were studied in vitro and in vivo. The penetration of insulin through the mucosa of rabbit nasal septum was investigated by measuring the transmucosal flux in vitro, while the nasal absorption of insulin in vivo was assessed by the efficiency in lowering the blood glucose levels in normal rats. It was demonstrated that increasing concentrations of chitosan up to 1.5% (w/v) caused an increase in the permeability of insulin across the nasal mucosa. Insulin given intranasally in hypo- or hyperosmotic formulation showed a higher hypoglycemic effect than insulin delivered in isoosmotic formulation. Insulin formulation in chitosan solution prepared with deionized water brought to a higher relative pharmacological bioavailability (Fr) value than that prepared with 50 mM pH 7.4 phosphate buffer. A formulation containing both 1% chitosan and 0.1% ethylenediaminetetraacetic acid (EDTA), 5% polysorbate 80 (Tween 80) or 1.2% beta-cyclodextrin (beta-CD) did not lead to a higher Fr than insulin formulated with 1% chitosan alone. The formulation containing both 5% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and 1% chitosan was more effective at reducing blood glucose levels than the formulation containing 5% HP-beta-CD or 1% chitosan alone. The studies indicated that chitosan concentrations, osmolarity, medium and absorption enhancers in chitosan solution have significant effect on the insulin nasal delivery. The results of in vitro experiments were in good agreement with that of in vivo studies.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed2005

Formulation of an ophthalmic lipid emulsion containing an anti-inflammatory steroidal drug, difluprednate.

Preparation of oil-in-water (o/w) type lipid emulsion is one of the approaches to formulate drugs that are poorly water-soluble but can be dissolved in the oil phase of the emulsions. A synthetic glucocorticoid medicine, difluprednate (DFBA), is a water-insoluble compound. We formulated DFBA (0.05%, w/v) ophthalmic lipid emulsion containing 5.0% (w/v) caster oil and 4.0% (w/v) polysorbate 80. The appearance of the emulsion was blue and translucent lipid emulsion, and the median particle size of the lipid emulsion was 104.4 nm. Neither separation nor change in particle size was observed after 6 months at 40 degrees C. Furthermore, when compared with DFBA (0.05%, w/v) ophthalmic suspension, the lipid emulsion showed 5.7-fold higher concentration of DFB that was an active metabolite of DFBA in aqueous humor at 1h after instillation. Ophthalmic lipid emulsion enhances the intraocular penetration of drugs, and it is useful as a delivery system for the ophthalmic preparations of lipophilic drugs.

Absorption↗
PubMed2005

Development of parenteral formulations and evaluation of the biological activity of the trypanocide drug benznidazole.

Chagas disease, caused by Trypanosoma cruzi, is a major public health problem in Latin America. According to the World Health Organization, around 20 million people are infected and another 40 million are at risk of acquiring the disease. One of the drugs most frequently used for the treatment of Chagas disease is benznidazole (BZL). It is practically insoluble in water (0.4 mg/ml), which precludes the preparation of liquid dosage forms, in particular, parenteral formulations. Thus, the aim of this work was to investigate the solubilization of BZL at two pH values using various cosolvents such as ethyl alcohol, propylene glycol, polyethylene glycol 400, benzyl alcohol, diethylene glycol monoethyl ether (Transcutol) and surfactants such as polysorbates (Tween) 40 and 80, and sodium dioctyl sulfosuccinate (AOT). Solvent systems based on PEG 400, with the addition ethyl alcohol and/or potassium biphthalate buffer solution, increased the BZL solubility up to 10 mg/ml. These alcoholic vehicles showed no toxicity against parasite when assayed at 1%. Physical and chemical stability studies showed that the formulations were stable for at least 1.5 years. In agreement with the biological activity results, the selected formulations are suitable for further clinical studies. Moreover, increasing the aqueous solubility of BZL reduced the problems in vitro testing techniques and bioassays leading to more reliable results and/or reproducibility.

Animals↗
PubMed2006

The effects of surfactants on the dissolution profiles of poorly water-soluble acidic drugs.

The effects of types of surfactants on the solubilization and dissolution of poorly soluble acidic drugs were compared to identify the most suitable surfactant for conducting an acidic drug dissolution test. Cetyltrimethylammonium bromide (CTAB) as a cationic surfactant, sodium lauryl sulfate (SLS) as an anionic surfactant, and polysorbate 80 as a non-ionic surfactant were used in the study. And, mefenamic acid, nimesulide, and ibuprofen were selected as model drugs. The dissolution rates of these acidic drugs were substantially enhanced in medium containing CTAB. Electrostatic interactions between acidic drugs and cationic surfactants were confirmed by measuring UV spectra of each drug. Solubility of drugs in various media and the partition coefficients of drugs into micelles were found to depend on drug characteristics. For acidic drugs, the ability of media containing a cationic surfactant to discriminate rates of dissolution of acidic drugs seemed to be greater than that of media containing other surfactant types.

Cetrimonium↗
PubMed2005

Physical characterizations of microemulsion systems using tocopheryl polyethylene glycol 1000 succinate (TPGS) as a surfactant for the oral delivery of protein drugs.

Attempts were to develop microemulsion systems using medium chain triglyceride, deionized water, and TPGS as surfactant for the oral delivery of protein drugs or poorly water-soluble drugs. Phase diagrams were constructed to elucidate the phase behavior of systems composed of Captex 300 and water with D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) as main surfactant, polysorbates (Tween 20, Tween 40, Tween 60 and Tween 80) as adjuvant surfactants, and polyethylene glycols (PEG 400 and PEG 600) and polyols (ethanediol, 1,2-propanediol, 1,3-propanediol, 1,3-butanediol, 1,4-butanediol and glycerin) as cosurfactants. The ratios of TPGS to Tweens, PEGs or polyols (K(m)) were set at 4/1, 2/1, 1/1, 1/2, and 1/4. The phase diagram for H(2)O/Captex 300/TPGS system reveals that when TPGS was used as a sole surfactant, it is not capable of producing isotropic solutions of water and oil over a wide range of the compositions. H(2)O/Captex 300/TPGS/Tweens systems with various K(m), regardless of the adjuvant surfactant used were capable of producing an isotropic phase. The extension of microemulsion phase and the presence and extension of the gel phase were found to be dependent on the surfactant mixture. The phase diagrams of H(2)O/Captex 300/TPGS systems using polyols as cosurfactants demonstrate that the types of polyols have a slight effect on the region of existence of the microemulsions. Comparison between the isotropic regions for the polyols system reveals that as the relative concentration of polyols increase, the isotropic region decrease in size. This decrease is towards the S(mix)-water axis indicating that as the relative concentration of polyols increases the maximum amount of oil solubilized decreases. The gel region decreased in size with the increase of polyols weight ratio. All polyols do not solubilized Captex 300 without using TPGS as surfactant.

Chemical Phenomena↗
PubMed2006

An attempt to directly trace polymeric nanoparticles in vivo with electron microscopy.

This work attempted to directly observe polymeric nanoparticles in vivo by analytical electron microscopy (AEM) using copper chlorophyll as the contrast agent, based on the experiments concerned with the copper chlorophyll labeled poly-DL-lactide nanoparticles and the in vivo distribution of the polysorbate 80 (T-80)-coated nanoparticles in brain tissues. With the nanoprecipitation method without surfactants, copper chlorophyll is aggregated in the coordinately saturated form and encapsulated by the matrices of nanoparticles, which may ensure the stability of copper chlorophyll during the in vivo experiments. From both morphological information and chemical information, only the labeled nanoparticles with the T-80 coating were directly traced in the brain by AEM. The results not only support the mechanism of endocytosis and/or transcytosis of T-80-coated nanoparticles targeted to the brain but also verify that it is practical to probe polymeric nanoparticles in vivo using AEM together with copper chlorophyll as the contrast agent.

Animals↗
PubMed2005

Slitlamp biomicroscopy of the tear film of patients using topical Restasis and Refresh Endura.

We describe a technique in which slitlamp biomicroscopy is performed to evaluate eyes in patients using a topical dry-eye agent; ie, topical cyclosporine A ophthalmic emulsion 0.05% (Restasis) or glycerin 1%-polysorbate 80 1% (Refresh Endura). Both are delivered in an oil-emulsion formulation. We also describe a previously unreported physical finding in the tear film of these patients. The examination technique can help confirm patient compliance and the tear-film stability of the 2 agents.

Administration, Topical↗
PubMed2002

Sustained delivery of human growth hormone from a novel gel system: SABER.

PURPOSE: The purpose of this study was to evaluate the release of recombinant human growth hormone (rhGH) from a novel non-polymeric sustained release system, SABER. METHODS: The SABER system consists of sucrose acetate isobutryate, a solvent and a polymeric release modifier. Spray dried formulations of zinc complexed rhGH in sodium bicarbonate containing sucrose and polysorbate 20 were homogenized with various SABER systems (10% w/v rhGH) and assessed in vitro and in vivo (rat studies). The effect of protein to sucrose ratio in the spray dried formulation and a release modifier, poly-D,L-lactic acid (PLA), in the SABER system, on the initial release was investigated along with the effect of dose volume. RESULTS: The in vitro release studies with rhGH SABER suspensions indicate that increasing the sucrose content from 2 to 5 mg/ml in the rhGH formulations increased the initial release (24 h) from 78.0% to 93.5%. When the protein formulation was held constant and 1.0% w/w PLA was added to the solvent phase, the initial release was reduced from 78.0% to less than 5.0%. The initial release in vivo after subcutaneous administration (SC) in rats (15 mg/kg rhGH) decreased with increasing PLA content (1.0% w/w PLA, Cmax = 342.8 ng/ml; 10% w/w PLA, Cmax = 35.4 ng/ml), while increased sucrose content increased both the initial release (AUC(0-2) days) and persistence (AUC(2-7) days) over the 7 days from 64.2 to 228.4 ng day/ml (total AUC). A linear dose response (rhGH serum levels) was observed after SC administration of different rhGH SABER volumes greater than 100 microl. Histological examination of the injection sites indicated a mild inflammatory response similar to that observed after injection of PLA microspheres. CONCLUSIONS: The addition of PLA reduced the initial release rate of protein release from SABER, while increasing the sucrose content of the protein formulation yielded increased rhGH persistence. These results demonstrate that the SABER delivery system allows weight-based dosing at volumes greater than 100 microl to achieve sustained release of intact rhGH in vivo for at least 7 days.

Animals↗
PubMed2000

Comparative enhancer effects of Span20 with Tween20 and Azone on the in vitro percutaneous penetration of compounds with different lipophilicities.

Sorbitan monolaurate (Span20) was used in this study to analyze the influence of the polar functional group on the effects that non-ionic surfactants have on skin permeability. Its ethoxylate derivative polysorbate 20 (Tween20) and Azone, both with the same C12 alkyl chain as Span20, were used for comparative purposes. We evaluated the relative potency of the three molecules as enhancers in the permeability of a series of compounds with lipophilicities ranging from log Poct=-0.95 to log Poct=2.33. The influence of the enhancer concentration was also studied. For this purpose the epidermis of Wistar rat was pretreated with ethanolic solutions (1 and 5%, w/v) of each enhancer. Our results indicate that the nature of the enhancer head group greatly influences cutaneous barrier impairment. The enhancer concentration must also be taken into account, even though the influence of the concentration seems to depend on the lipophilicity of the penetrant assayed.

Administration, Cutaneous↗
PubMed2000

Investigation of the release behavior of diethylhexyl phthalate from the polyvinyl-chloride tubing for intravenous administration.

The release behavior of diethylhexyl phthalate (DEHP) from a polyvinyl-chloride (PVC) tube, which is part of an intravenous administration set, was investigated with the coexistence of polysorbate 80 (Tween 80) in various solutions such as physiological saline (PS), distilled water for injection (DWI) and glucose solution (TZ). The cumulative amount of DEHP released after 5 h was in the following order; PS, DWI > 50% TZ. From a comparison of the amount of released DEHP and the critical micelle concentration (CMC) of various solutions, the lower the CMC of the solution, the higher the amount of DEHP released from the PVC tubing. When the concentration of Tween 80 was kept constant at 1 mg/ml, the cumulative amount of DEHP released with a flow rate 90 ml/h was higher than that at 60 ml/h. These results suggest that the release of DEHP from the PVC tubing is closely correlated with the interaction of Tween 80 and DEHP such as the formation of micelles, the collision of micelles against the surface of the PVC tubing and the diffusion properties of DEHP and or Tween 80 in the liquid medium.

Diethylhexyl Phthalate↗
PubMed2003

Preparation and purification of cationic solid lipid nanospheres--effects on particle size, physical stability and cell toxicity.

Cationic solid lipid nanospheres (SLN) were prepared by the microemulsion technique with polysorbate 80 (Tween 80) and butanol as surfactants. The SLN (diameter 100-500 nm, zetapotential around +15 mV) consisted mainly of stearylamine (SA) and different triglycerides. Three different purification methods, ultrafiltration, ultracentrifugation and dialysis, were investigated and compared with the cellular toxicity and physical stability of the dispersions. The cell toxicity was dependent on both the SLN composition and the purification method. Dialysis was found to easily and efficiently remove excessive surfactant determined by dynamic light scattering (DLS), leading to reduced cell toxicity and increased physical stability of the SLN on storage. The cationic SLN might constitute a promising DNA delivery system.

Carcinoma, Small Cell↗
PubMed2005

Effects of two eye drop products on computer users with subjective ocular discomfort.

BACKGROUND: An increasing number of people seek medical attention for symptoms of visual discomfort due to computer vision syndrome (CVS). We compared the efficacy and adverse event rates of a new eye lubricant, OptiZen (InnoZen, Inc., polysorbate 80 0.5%) and Visine Original (Pfizer Consumer Healthcare, tetrahydrozoline HCl 0.05%). METHODS: In this double-blind parallel arm trial, 50 healthy men and women, ages 18 to 65 years, with symptoms of CVS who use a video display terminal for a minimum of 4 hours per day were randomized to OptiZen (n = 25) or Visine Original (n= 25), 1 to 2 drops b.i.d. for 5 days. The primary end-points were ocular discomfort and adverse events. RESULTS: OptiZen and Visine Original had similar efficacy in alleviating symptoms of ocular discomfort (odds ratio of 1.23 [95% confidence interval, 0.63 to 2.42], P= 0.55). OptiZen and Visine Original were very similar with respect to odds ratios and 95% confidence interval (CI) for each of the measurement times (P= 0.72). Visine Original users reported a significantly higher incidence of temporary ocular stinging/burning immediately after drug instillation (28%, 7/25) than did OptiZen users (4%, 1/24) (P= 0.05). Patients using OptiZen were 89% less likely to have stinging/burning effects than those patients using Visine Original (95% CI: 0.01 to 0.95). DISCUSSION: OptiZen and Visine Original are effective at alleviating ocular discomfort associated with prolonged computer use. Adverse event findings suggest that OptiZen causes less ocular discomfort on instillation, potentially attributable to its milder ingredient profile.

Adolescent↗
PubMed2006

In vitro investigation on poly(lactide)-Tween 80 copolymer nanoparticles fabricated by dialysis method for chemotherapy.

Polysorbate 80 (Tween 80) has been widely used as an emulsifier with excellent effects in nanoparticles technology for biomedical applications. This work was thus triggered to synthesize poly(lactide)/Tween 80 copolymers with various copolymer blend ratio, which were synthesized by ring-opening polymerization and characterized by 1H NMR and TGA. Nanoparticles of poly(lactide)/Tween 80 copolymers were prepared by the dialysis method without surfactants/emulsifiers involved. Paclitaxel was chosen as a prototype anticancer drug due to its excellent therapeutic effects against a wide spectrum of cancers. The drug-loaded nanoparticles of poly(lactide)/Tween 80 copolymers were then characterized by various state-of-the-art techniques, including laser light scattering for particles size and size distribution, field emission scanning electron microscopy (FESEM) and atomic force microscopy (AFM) for surface morphology; laser Doppler anemometry for zeta potential; differential scanning calorimetry (DSC) for the physical status of the drug encapsulated in the polymeric matrix; X-ray photoelectron spectrometer (XPS) for surface chemistry; high performance liquid chromatography (HPLC) for drug encapsulation efficiency; and in vitro drug release kinetics. HT-29 cells and Glioma C6 cells were used as an in vitro model of the GI barrier for oral chemotherapy and a brain cancer model to evaluate in vitro cytotoxicity of the paclitaxel-loaded nanoparticles. The viability of C6 cells was decreased from 37.4 +/- 4.0% for poly(D,L-lactide-co-glycolic acid) (PLGA) nanoparticles to 17.8 +/- 4.2% for PLA-Tween 80-10 and 12.0 +/- 5.4% for PLA-Tween 80-20 copolymer nanoparticles, which was comparable with that for Taxol at the same 50 microg/mL drug concentration.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Mechanistic roles of neutral surfactants on concurrent polarized and passive membrane transport of a model peptide in Caco-2 cells.

The transport of the model peptide Acf(NMef)2NH2 across Caco-2 cell monolayers was studied in the apical (AP) to basolateral (BL) and the BL to AP direction in the presence of Polysorbate 80 or Cremophore EL in the AP compartment. Increasing surfactant concentrations resulted in increasing AP-->BL peptide permeability and decreasing BL-->AP permeability. In either direction, limiting permeabilities were achieved at concentrations less than the critical micellar concentrations (cmc's) of the surfactants, and remained constant at much higher concentrations. These plateau permeabilities were not equivalent in the two directions. This residual assymetry was abolished by increasing the peptide concentration. Altogether, the observations support the presence of at least two pumps in Caco-2 cells for this peptide, polarized in the BL-->AP direction. These experimental results were analyzed within the context of a quantitative biophysical model incorporating concurrent passive diffusion across the AP and BL membranes accompanied by surfactant-inhibitable active polarized efflux across the AP membrane. The model was also used to locate the additional transport activity at the BL membrane as an uptake pump. Under conditions of complete inhibition, the intrinsic passive diffusional permeability of Acf(NMef)2NH2 was found to be 13 x 10(-6) cm/s, essentially identical with results reported earlier with this peptide utilizing verapamil as an inhibitor. With respect to the mechanism of surfactant inhibition of the apical efflux transport, the monomeric species was found to be responsible with no contribution from micelles. Modeling the mode of inhibition as a noncompetitive Michaelis-Menten process gave identical Kis of 0.5 microM for the two surfactants. Finally, increase of either surfactant beyond 750 microM resulted in a decrease of peptide permeability in the AP-->BL direction. This was attributed to weak association of the peptide with micelles in the AP compartment, which effectively decreased the thermodynamic activity of the peptide at surfactant concentrations greater than 20 times their cmc. Both the experimental approach and accompanying theoretical model demonstrated in this work will allow for further characterization of the inhibitory potencies of surfactants for the nonpassive efflux pathway in vitro and in vivo.

Biological Transport↗
PubMed2001

A new colorimetric assay for studying and rapid screening of membrane penetration enhancers.

PURPOSE: This work aims to demonstrate a novel chemical assay for rapid screening and analysis of the mode of action of membrane interaction by penetration enhancers. METHODS: The new bio-mimetic membrane assembly, consisting of supramolecular aggregates of lipids and conjugated polydiacetylene, undergoes visible and quantifiable blue-red color transitions upon interaction with penetration enhancers. RESULTS: The new colorimetric model has been employed to examine various classes of penetration enhancers, including 1-dodecylhexahydro-2H-azepin-2-one (Azone), oleic acid, propylene-glycol, menthol, ethoxyglycol-diethyleneglycol-monoethyl-ether (Transcutol), polysorbate-polyethylenesorbitan-monolaurate (Tween-20), and the drug 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one (Diazepam). The assay enables to evaluate the validity of various observations and hypotheses proposed in previous studies regarding permeation enhancement activities. Our results suggest, for example. that propylene glycol (PG) by itself does not interfere with membranes, but rather exhibits synergistic effect in combination with other penetration enhancers. Similarly, our data demonstrate that Transcutol does not independently interact with membranes. The colorimetric system also indicates that interaction of penetration enhancers with membranes depend upon the lipid phase, as well as the self-assembly properties of the enhancer molecules. CONCLUSIONS: The new biomimetic model membrane system can be applied for rapid screening of the activities of penetration enhancers, and provides insight into the mechanisms of permeability of membrane-active compounds.

Acetylene↗
PubMed1997

Influence of fluorescent labelling of polystyrene particles on phagocytic uptake, surface hydrophobicity, and plasma protein adsorption.

PURPOSE: To investigate the influence of fluorescent labelling of polystyrene particles on phagocytic uptake, surface hydrophobicity and protein adsorption. METHODS: Phagocytic uptake was analysed using chemiluminescence. Hydrophobicity was quantified by adsorption measurements of a hydrophobic dye. Protein adsorption was evaluated by two-dimensional electrophoresis. RESULTS: Commercially available fluorescently labelled particles showed marked differences when compared to unlabelled particles: phagocytic uptake and surface hydrophobicity of labelled particles were diminished. Also the plasma protein adsorption pattern was found to be different from the unlabelled particles: for example, the amount of fibrinogen adsorbed was strongly reduced on the labelled particles. On the other hand, some unknown proteins could be detected on the fluorescently marked particles. In contrast, plain polystyrene particles and labelled ones could be successfully synthesised by Paulke which did not show any considerable differences in phagocytic uptake, surface hydrophobicity and protein adsorption. Polysorbate 20 added as stabilizer to particle suspensions led to completely different behaviour of the particles: the particles showed altered protein adsorption patterns, dominated by immunoglobulins and especially by apolipoproteins. Furthermore, these particles were not phagocytized at all. CONCLUSIONS: Surface hydrophobicity and phagocytic uptake in vitro as well as the interactions with plasma proteins of commercially available polystyrene particles were strongly affected by fluorescent labelling. Particles synthesised by Paulke remained unchanged after labelling. The results show the importance of thorough surface characterization for using particles in test systems in vitro and in vivo.

Adsorption↗
PubMed1997

Development of freeze-dried albumin-free formulation of recombinant factor VIII SQ.

PURPOSE: To develop a stable freeze-dried formulation of recombinant factor VIII-SQ (r-VIII SQ) without the addition of albumin. METHODS: Different formulations were evaluated for their protective effect during sterile filtration, freeze-thawing, freeze-drying, reconstitution and long term storage. Factor VIII activity (VIII:C), visual inspection, clarity, solubility, moisture content and soluble aggregates and/ or fragments were assayed. RESULTS: A combination of non-crystallising excipients (L-histidine and sucrose), a non-ionic surfactant (polysorbate 80) and a crystalline bulking agent (sodium chloride) was found to preserve the factor VIII activity during formulation, freeze-drying and storage. Calcium chloride was included to prevent dissociation of the heavy and light chains of r-VIII SQ. Sodium chloride was chosen as the primary bulking agent since the concentration of sodium chloride necessary for dissolution of r-VIII SQ in the buffer will inhibit the crystallization of many potential cake formers. It was found that L-histidine, besides functioning as a buffer, also protected r-VIII SQ during freeze-drying and storage. A pH close to 7 was found to be optimal. Some potential macromolecular stabilisers, PEG 4000, Haes-steril and Haemaccel, were evaluated but they did not improve the recovery of VIII:C. The freeze-dried formulation was stable for at least two years at 7 degrees C and for at least one year at 25 degrees C. The reconstituted solution was stable for at least 100 hours at 25 degrees C. CONCLUSIONS: The albumin-free formulation resulted in consistently high recovery of VIII:C, very low aggregate formation and good storage stability. The stability of the reconstituted solution makes the formulation suitable for continuous administration via infusion pump. The formulation strategy described here may also be useful for other proteins which require a high ionic strength.

Adsorption↗