Enhancement of Nasal Delivery of a Renin Inhibitor in the Rat Using Emulsion Formulations

Nasal absorption of O-(N-morpholino-carbonyl-3-L-phenylaspartyl-L-leucinamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (I), a renin inhibitor, was evaluated in two rat nasal models, one involving surgery and the other requiring no surgical intervention. Oleic acid/monoolein emulsion formulations were tested along with a control PEG 400 solution. The percent absolute bioavailability of the compound was enhanced from 3–6% (PEG 400 solution) to 15–27% when the emulsion formulations were used. The different nasal model techniques (with and without surgery) did not produce any statistical difference in the absolute bioavailability values for I. Emulsion formulations did not produce appreciable damage as assessed morphologically. It is suggested that emulsion formulations containing membrane adjuvants such as oleic acid and monoolein can be used to enhance the nasal delivery of low-bioavailable, lipid-soluble drugs.____________________     

Formulation of ciprofloxacin hydrochloride loaded biodegradable nanoparticles: optimization of technique and process variables

Abstract

Poly lactic-co-glycolic acid (PLGA 502 H) nanoparticles incorporating ciprofloxacin HCl (CP) were prepared by double emulsion solvent diffusion technique.

Methods: The influence of the application of probe sonication besides the high pressure homogenization in the preparation of the secondary emulsion and its application during the solidification step were studied. Their effect on the particle size, Zeta potential and the percent encapsulation efficiency of the drug (EE %) were investigated. The effect of the addition of polyvinyl alcohol (PVA) during the preparation of the primary emulsion was studied. Moreover, the effect of the addition of 0.1?M sodium chloride and/or adjusting the external and extracting phases to pH 7.4 were investigated. The selected formula was examined using IR, X-ray, DSC and SEM and in vitro drug release.

Results: These formulations showed an appropriate particle size ranges between 135.7–187.85?nm, a mean zeta potential ranging from ?0.839 to ?6.81?mV and a mean EE% which ranged from 35% to 69%.

Conclusion: The presented data revealed the superiority of using probe sonication besides high pressure homogenization during the formation of secondary emulsion. Moreover, the results indicated that the tested factors had a pronounced significant effect on the EE%.     

Bile Increases Intestinal Lymphatic Drug Transport in the Fasted Rat

Purpose This study was conducted to determine the influence of (1) the source of recruited endogenous fatty acid (FA), and (2) bile on intestinal lymphatic transport of halofantrine (Hf) in fasted rats. Methods Endogenous FA output in bile, and exogenous (¹⁴C radiolabeled) FA, endogenous FA, and Hf transport in mesenteric lymph were determined following administration of low dose lipid formulations containing either 4 or 40 mg of exogenous FA [oleic acid (OA)] and different amounts of bile salt (BS) and lysophosphatidylcholine (LPC) to fasted rats. Results Administration of 40 mg of OA recruited endogenous FA and Hf transport into intestinal lymph, whereas 4 mg OA did not. However, addition of BS to the 4-mg OA dose led to stimulation of endogenous FA recruitment into lymph and an increase in lymphatic transport of Hf and endogenous FA output in bile. Addition of LPC to the 4-mg OA dose (dispersed in BS) caused a substantial increase in endogenous FA transport in lymph; however, no coincident increase in either lymphatic transport of Hf or endogenous FA output in bile was observed. Conclusion Biliary-derived endogenous FA has a higher propensity to support lymphatic transport of Hf compared to other sources of endogenous FA. The results suggest that this is related to the disparate trafficking of these alternate sources of endogenous FA within the enterocyte.     

Microfabricated Porous Silicon Particles Enhance Paracellular Delivery of Insulin Across Intestinal Caco-2 Cell Monolayers

Purpose. Novel porous silicon microparticles were fabricated and loaded with fluorescein isothiocyanate (FITC)-insulin, a model hydrophilic pharmacologically active protein, along with varied doses of sodium laurate (C12), a well-known permeation enhancer. Methods. Particle and liquid formulations were compared as a function of apical to basolateral flux of FITC-insulin across differentiated human intestinal Caco-2 cell monolayers grown on Transwell® inserts. Results. The flux of FITC-insulin from silicon particles across cell monolayers was nearly 10-fold higher compared with liquid formulations with permeation enhancer and approximately 50-fold compared with liquid formulations without enhancer. By increasing C12 dose per particle with a concomitant decrease in total particles added per monolayer, the percent of FITC-insulin transport resulted in a linear increase up to 25% monolayer coverage. Conclusions. Although maintaining monolayer integrity and transepithelial electrical resistance, maximum drug transport (20%/h) was achieved with 0.337 g C12 dose per particle, and total particle loading at 25% monolayer coverage.     

Controlled Release of a Contraceptive Steroid from Biodegradable and Injectable Gel Formulations: In Vitro Evaluation

Purpose. The purpose of this study was to investigate the effects of formulation factors including varying wax concentration, drug loading and drug particle size, on drug release characteristics from both pure oil and gel formulations prepared with a combination of derivatized vegetable oil (Labrafil 1944 CS) and glyceryl palmitostearate (Precirol ATO 5), using levonorgestrel as a model drug. Methods. The effects of varying drug loadings, different drug particle sizes, and wax (Precirol) concentrations on in-vitro drug release rates were evaluated, and the mechanisms of drug release from the gels were determined. Results. Zero-order drug release rates from the 10% Precirol gel formulations containing 0.25, 0.50 and 2.00% w/v drug loadings were lower than those observed for oil formulations containing identical drug loadings. Higher zero-order release rates were observed from formulations containing smaller drug particles suspended in both oil and gel formulations. The mechanism of drug release from gels containing less than 0.25% w/w drug was diffusion-controlled. Increasing the wax concentrations in the gels from 5% w/w to 20% w/w significantly decreased the diffusivity of the drug through the gel formulations and markedly increased the force required to inject the gels from two different sizes of needles. Conclusions. This study shows how modification of the physicochemical properties of the gel formulations by changing the drug particle size, wax concentration and drug loading, affects drug release characteristics from the system.     

Development and characterization of itraconazole-loaded solid lipid nanoparticles for ocular delivery

Abstract

The purpose of this study was to investigate the feasibility of entrapping water-insoluble drug itraconazole into solid lipid nanoparticles (SLNs) for topical ocular delivery. The drug-loaded SLNs were prepared from stearic acid and palmitic acid using different concentrations of polyvinyl alcohol employed as emulsifier. SLNs were prepared by the melt-emulsion sonication and low temperature-solidification method and characterized for particle size, zeta potential, drug loading and drug entrapment efficiency. The mean particle size of SLNs prepared with stearic acid ranged from 139 to 199?nm, while the SLNs prepared with palmitic acid had particle size in the range of 126–160?nm. The SLNs were spherical in shape. Stearic acid-SLNs showed higher entrapment of drug compared with palmitic acid-SLNs. Differential scanning calorimetry (DSC) and X-ray diffraction measurements showed decrease in crystallinity of drug in the SLN formulations. The modified Franz-diffusion cell and freshly excised goat corneas were used to test drug corneal permeability. Permeation of itraconazole from stearic acid-SLNs was higher than that obtained with palmitic acid-SLNs. The SLNs showed clear zone of inhibition against Aspergillus flavus indicating antimicrobial efficacy of formulations.     

Disposition of lipid-based formulation in the intestinal tract affects the absorption of poorly water-soluble drugs

Solvent Green 3 (SG), a model poorly water-soluble compound, was orally administered to rats with soybean oil emulsion or the Self-microemulsifying drug delivery system (SMEDDS) composed of Gelucire44/14. The bioavailability of SG after oral administration with SMEDDS was 1.7-fold higher than that with soybean oil emulsion. The intestinal absorption of lipid-based formulations themselves was evaluated by the in situ closed loop method. The effect of lipase and bile salt on their absorption was also evaluated. SMEDDS itself was rapidly absorbed in the intestine even in the absence of lipase and bile salt, and the absorption was increased by the addition of lipase and bile salt. On the other hand, no soybean oil emulsion was absorbed in the absence of lipase and bile salt. However, mixed micelle prepared from emulsion by incubating soybean oil emulsion with lipase and bile salt was rapidly absorbed through the intestine. Without lipase and bile salt, SG was not absorbed after administration with soybean oil emulsion. Therefore, we concluded that the degradation of soybean oil emulsion was needed for SG to be absorbed through the intestine. Furthermore, we investigated the intestinal absorption of SG after oral administration to rats whose chylomicron synthesis were inhibited by pretreatment with colchicine. Colchicine completely inhibited the intestinal absorption of SG after administration with each lipid-based formulation, suggesting that SG was absorbed from the intestine via a lymphatic route. Absorption of the dosage formulation should be paid attention when poorly water-soluble drugs are orally administered with lipid-based formulation.     

Dissolution of Hydrocortisone in Human and Simulated Intestinal Fluids

Purpose. To compare solubility and dissolution rate of hydrocortisonein aspirated human intestinal fluids (HIFs) with simulated intestinalfluids (SIFs) and buffer. Methods. Solubility and flux from a rotating disk of hydrocortisonewere measured. The bile salt content, pH and osmotic pressure weredetermined in HIFs. Results. In fasted state the solubility of hydrocortisone was higher inHIFs than in the buffer and SIFs. The flux of hydrocortisone in HIFswas similar to the flux in the buffer but lower than the flux in SIFs atfasted state. Addition of intestinal surfactants in SIFs increasedsolubility and flux at both fasted and fed state. The increase in solubility wascaused by micelle formation in SIFs. The increase in flux may partlybe explained by increased solubility. The bile salt content of the HIFsdid not correlate with the solubility or the flux but pH in the HIFsseems to have some effect on the components of the HIFs resultingin increased solubility. Conclusions. It is possible to perform comparable dissolution tests inHIFs and SIFs. The lack of correlation between the results in HIFs andthe bile salt content may be explained by the relatively low lipofilicity ofthe model drug.     

Stereoselective and Carrier-Mediated Transport of Monocarboxylic Acids Across Caco-2 Cells

Purpose. To characterize the transport mechanism of monocarboxylic acids across intestinal epithelial cells by examining the stereoselectivity of the transcellular transport of several chiral monocarboxylic acids. Methods. The transport of monocarboxylic acids was examined using monolayers of human adenocarcinoma cell line, Caco-2 cells. Results. The permeability of L-[¹⁴C]lactic acid at a tracer concentration (1 µM) exhibited pH- and concentration-dependencies and was significantly greater than that of the D-isomer. The permeabilities of both L-/ D-[¹⁴C]lactic acids involve saturable and nonsaturable processes; the saturable process showed a higher affinity and a lower capacity for L-lactic acid compared with the D-isomer, while no difference between the isomers was seen for the nonsaturable process. The transport of L-lactic acid was inhibited by chiral monocarboxylic acids such as (R)/(S)-mandelic acids and (R)/(S)-ibuprofen in a stereoselective manner. Mutually competitive inhibition was observed between L-lactic acid and (S)-mandelic acid. Conclusions. Some chiral monocarboxylic acids are transported across the intestinal epithelial cells in a stereoselective manner by the specific carrier-mediated transport mechanism.     

Formulation Development and Antitumor Activity of a Filter-Sterilizable Emulsion of Paclitaxel

Purpose. Paclitaxel is currently administered i.v. as a slow infusion of asolution of the drug in an ethanol:surfactant:saline admixture. However,poor solubilization and toxicity are associated with this drug therapy.Alternative drug delivery systems, including parenteral emulsions, areunder development in recent years to reduce drug toxicity, improveefficacy and eliminate premedication. Methods. Paclitaxel emulsions were prepared by high-shearhomogenization. The particle size of the emulsions was measured by dynamiclight scattering. Drug concentration was quantified by HPLC and invitro drug release was monitored by membrane dialysis. The physicalstability of emulsions was monitored by particle size changes in boththe mean droplet diameter and 99% cumulative distribution. Paclitaxelpotency and changes in the concentration of known degradants wereused as chemical stability indicators. Single dose acute toxicity studieswere conducted in healthy mice and efficacy studies in B16 melanomatumor-bearing mice. Results. QW8184, a physically and chemically stable sub-micronoil-in-water (o/w) emulsion of paclitaxel, can be prepared at high drugloading (8-10 mg/mL) having a mean droplet diameter of <100 nmand 99% cumulative particle size distribution of <200 nm. In vitro release studies demonstrated low and sustained drug release both inthe presence and absence of human serum albumin. Based on singledose acute toxicity studies, QW8184 is well tolerated both in miceand rats with about a 3-fold increase in the maximum-tolerated-dose(MTD) over the current marketed drug formulation. Using the B16mouse melanoma model, a significant improvement in drug efficacywas observed with QW8184 over Taxol^®. Conclusions. QW8184, a stable sub-micron o/w emulsion of paclitaxelhas been developed that can be filter-sterilized and administered i.v.as a bolus dose. When compared to Taxol^®, this emulsion exhibitedreduced toxicity and improved efficacy most likely due to thecomposition and dependent physicochemical characteristics of the emulsion.     

Stereoselective Disposition of Suspensions of Conventional and Wax-matrix Sustained Release Ibuprofen Microspheres in Rats

Purpose. The aim of the study is to evaluate stereoselective in vivo disposition of suspensions of conventional and wax-matrix sustained release ibuprofen microspheres in rats. Methods. Male wistar rats were dosed IV with 20 mg/kg, or orally with conventional suspension, and three suspension formulations of sustained release microspheres (having three different particle sizes) of racemic ibuprofen. Blood samples were analyzed stereoselectively by reverse phase HPLC. Results. The mean C_max for (S)- and (R)- ibuprofen decreased with increased particle size of the drug or microspheres in the suspension dosage forms, while the T_max increased with increased particle size. The mean S/R ratio (AUC_0–48) of the suspensions decreased with increase in particle size of the drug or microspheres and these ratios (for both conventional and sustained formulations) were higher than that of the IV, an indication of presystemic inversion. Decrease in the ratios with increased particle size is suggestive of formulation dependent inversion. The plasma concentration-time data of the sustained release formulations showed bimodal profiles, irrespective of the particle size of the microspheres. The second peak observed after 8 hours is indicative of colonic absorption. Conclusions. Stereoselective disposition of ibuprofen microspheres showed higher bioavailability compared to the conventional suspension. Bimodal disposition is influenced by dosage form while presystemic inversion is both site-specific, and dosage form dependent.     

Non-linear Increases in Danazol Exposure with Dose in Older vs. Younger Beagle Dogs: The Potential Role of Differences in Bile Salt Concentration,Thermodynamic Activity,and Formulation Digestion

Purpose

To explore the possibility that age-related changes in physiology may result in differences in drug bioavailability after oral administration of lipid based formulations of danazol.

Methods

Danazol absorption from lipid formulations with increasing drug load was examined in younger (9 months) and older (8 years) beagles. Age related changes to hepatic function were assessed via changes to systemic clearance and serum bile acid concentrations. Changes to lipolytic enzyme activity and intestinal bile salt concentration were evaluated using in vitro lipolysis.

Results

Drug exposure increased linearly with dose in younger animals. In older animals, bioavailability increased with increasing dose to a tipping point, beyond which bioavailability reduced (consistent with initiation of precipitation). No differences in hepatic function were apparent across cohorts. Changes to enzyme concentrations in lipolysis studies had little impact on drug precipitation/solubilisation. In contrast, higher bile salt concentrations better supported supersaturation at higher drug loads.

Conclusions

Differences in animal cohort can have a significant impact on drug absorption from lipid based formulation. For danazol, bioavailability was enhanced under some circumstances in older animals. In vitro experiments suggest that this was unlikely to reflect changes to metabolism or lipolysis, but might be explained by increases in luminal bile salt/phospholipid concentrations in older animals.     

Solid Lipid Particles for Oral Delivery of Peptide and Protein Drugs III — the Effect of Fed State Conditions on the In Vitro Release and Degradation of Desmopressin

The effect of food intake on the release and degradation of peptide drugs from solid lipid particles is unknown and was therefore investigated in vitro using different fed state media in a lipolysis model. Desmopressin was used as a model peptide and incorporated into solid lipid particles consisting of trimyristin (TG14), tripalmitin (TG16), and tristearin (TG18), respectively. Fasted state and fed state media with varying phospholipid and bile salt concentrations, as well as fed state media with milk and oleic acid glycerides, respectively, were used as the release media. The presence of oleic acid glycerides accelerated the release of desmopressin significantly from all solid lipid particles both in the presence and absence of lipase. The presence of oleic acid glycerides also reduced the degradation rate of desmopressin, probably due to the interactions between the lipids and the protease or desmopressin. Addition of a medium chain triglyceride, trilaurin, in combination with drug-loaded lipid particles diminished the food effect on the TG18 particles, and trilaurin is therefore proposed to be a suitable excipient for reduction of the food effect. Overall, the present study shows that strategies to reduce food effect, such as adding trilaurin, for lipid particle formulations should be considered as drug release from such formulations might be influenced by the presence of food in the gastrointestinal tract.     

LIPID EMULSIONS OF PALMITOYLRHIZOXIN: EFFECTS OF PARTICLE SIZE ON BLOOD DISPOSITIONS OF EMULSION LIPID AND INCORPORATED COMPOUND IN RATS

Emulsion formulations of various particle sizes for the highly lipophilic antitumour agent, RS-1541 (13-O-palmitoylrhizoxin), were prepared using dioctanoyldecanoyl-glycerol (ODO) as lipids and polyoxyethylene-(60)-hydrogenated castor oil (HCO-60) as a surfactant. These emulsions were evaluated as injectable drug carriers and compared with a colloidal solution. Both in vitro and in vivo after i.v. administration, RS-1541 was distributed into lipoproteins from the colloidal solution. When applied as emulsions of various particle sizes (124–419 nm) in vitro, RS-1541 was retained and stabilized within the emulsions. In the in vivo study, however, retention of RS-1541 in the emulsions after i.v. injection depended on their size. The small-particle emulsions (94–112 nm) resulted in long retention, and the large-particle emulsions (415–474 nm) led to short retention. Lipolysis rates of emulsion particles by lipoprotein lipase also depended on their size, indicating rapid lipolysis for small-particle emulsions (133 nm). However, the lipolysis was not such an extensive one, showing 10–30% release of capric acid from ODO within 6 h. Blood dispositions of capric acids approximately paralleled those of RS-1541 after i.v. injection of various particle size emulsions (130–368 nm) to rats, although relatively rapid eliminations of capric acids compared with RS-1541 were observed for the small-particle size emulsions (130 nm). These results suggest that when injected as emulsion formulations, the highly lipophilic antitumour agent, RS-1541, has behaviour similar to that of the emulsion particles in the body, which is dependent on the size of the latter. Thus, by properly selecting the particle size, lipid emulsions consisting of ODO and HCO-60 are expected to be effective and useful DDS carriers for RS-1541.     

Interaction of a Self-Emulsifying Lipid Drug Delivery System with the Everted Rat Intestinal Mucosa as a Function of Droplet Size and Surface Charge

Purpose. To investigate the interaction of positively charged self-emulsifying oil formulations (SEOF) following aqueous dilution as a function of resulting emulsion droplet charge and size with rat everted intestinal mucosa, adherent mucus layer and Peyer's patches, using cyclosporine A (CsA) as a lipophilic model drug. Methods. Droplet size determination (TEM technique) and -potential measurements were used to characterize the resulting emulsions. For the ex vivo interaction study, the well-known rat intestine everted sac technique was used in combination with confocal microscopy. Results. The positively charged oil droplets formed by SEOF dilutions at ratios of 1/50 and 1/10 elicited the stronger interaction with the mucosal surface. The positive charge of the smaller droplets was more readily neutralized, and even reversed in aqueous solutions containing moderate subphysiological mucin concentrations. Parameters such as droplet size, negativity of the epithelial mucosa potential and presence of the mucus layer on the epithelial surface affected drug mucosa uptake and the adhesion of the positively charged droplets to the rat intestinal mucosa. Conclusions. The enhanced electrostatic interactions of positively charged droplets with the mucosal surface are mostly responsible for the preferential uptake of CsA from the positively charged droplets as compared to negatively charged droplets irrespective of the experimental conditions used. The increased uptake of the CsA from the negatively charged oil droplets was consistent with the dilution extent, as expected, whereas in the positively charged droplets, an intermediate droplet size range was identified resulting in optimum drug uptake and clearly suggesting that drug uptake was not consistent with either dilution extent or droplet size.     

An Acute and Coincident Increase in FABP Expression and Lymphatic Lipid and Drug Transport Occurs During Intestinal Infusion of Lipid-Based Drug Formulations to Rats

Purpose To determine a) whether administration of lipid-based formulations can acutely up-regulate the intestinal expression of I-FABP and L-FABP and b) whether this occurs coincidentally with an increase in intestinal lymphatic lipid and drug transport.Methods The expression of I-FABP and L-FABP mRNA (using q-PCR) and protein (using immunohistochemistry and Western blotting) in enterocytes was compared with data describing transport of lipid and drug into intestinal lymph following infusion of a set of lipid-based formulations.Results Administration of relatively small amounts of oleic acid (5–20 mg/h) over a 5 h period to rats acutely up-regulated the expression, and altered the intracellular distribution of, I-FABP and L-FABP in the enterocytes of the small intestinal epithelia. The increase in expression of I-FABP and L-FABP correlated well with previous data describing the transport of lipid and drug into intestinal lymph following infusion of the same formulations.Conclusion The expression and intracellular distribution of I-FABP and L-FABP are acutely influenced by lipid infusion over a time period relevant to feeding or the administration of pharmaceutical lipidic formulations, and these changes occur coincidentally with increased drug transport into the lymphatics.     

Floating microspheres of carvedilol as gastro retentive drug delivery system: 32 full factorial design and in vitro evaluation

Abstract

Context: Designing a sustained release system for Carvedilol to increase its residence time in the stomach.

Objective: Preparation of floating microsphere by the emulsion solvent diffusion method, studying the effect of various process parameters and optimize the formulation using full factorial design.

Methods: Different microsphere formulations were prepared by varying the ratio ethanol:dichloromethane (1:0 to 1:1.5), ethyl cellulose:hydroxypropyl methyl cellulose and stirring speed (800–1600?rpm). The effect of these variables on particle size, encapsulation parameters, surface topography, in vitro floatability and drug release were evaluated.

Results: 3² full factorial design was used for the optimization of the formulation. Drug entrapment efficiency, particle size and in vitro drug release were dependent on concentration of ethyl cellulose and stirring speed. Microspheres remained buoyant for more than 10?h and showed sustained release of the drug.

Conclusion: Floating microspheres of Carvedilol with good floating ability and sustained release were developed.     

Comparison of the Lymphatic Transport of Halofantrine Administered in Disperse Systems Containing Three Different Unsaturated Fatty Acids

Purpose. To compare the influence of the degree of fatty acid unsaturation (oleic [C18:1], linoleic [C18:2], or linolenic acid [C18:3]), with the intestinal lymphatic transport of halofantrine free base from disperse systems in anesthetized rats. Methods. The mesenteric lymph duct was cannulated in anesthetized rats. Lipid vehicle containing halofantrine was administered by intraduodenal infusion. The concentration of halofantrine in blood and lymph samples was analyzed. Results. The rank order of the lymphatic transport of halofantrine was C18:2 > C18:1 > C18:3. Comparison of the area under the curve (AUC) from the three fatty acids showed no statistically significant differences between the AUCs from the lymph cannulated rats. In terms of rank order effects, the plasma concentrations of halofantrine were highest for the rats dosed C18:2 followed by C18:3 and C18:1. Conclusions. Using C18:2 as a vehicle increased the lymphatic transport of halofantrine 16.6-fold over that observed for the system containing C18:3. The extent of lymphatic transport for the C18:1 system did not differ from the other two formulations, but the combined lymph and plasma data indicated that the C18:2 was the most suitable lipid vehicle for the oral delivery of halofantrine.     

Solubilization and Stabilization of an Anti-HIV Thiocarbamate,NSC 629243, for Parenteral Delivery,Using Extemporaneous Emulsions

The O-alkyl-N-aryl thiocarbamate, I, (2-chloro-5-[[(l-methyl-ethoxy)thioxomethyl]amino]benzoic acid, 1-methylethylester, NSC 629243, also known as Uniroyal Jr.) is an experimental anti-HIV drug with very low water solubility (1.5 µg/mL). Early clinical studies required an injectable solution at 15 mg/mL, representing a solubility increase of 10⁴-fold. Adequate solubilization of this hydrophobic drug was achieved in 20% lipid emulsions. Extemporaneous emulsions were prepared by adding a concentrated drug solution to a commercially available parenteral emulsion. Various methods of preparation to minimize drug precipitation during its addition and enhance redissolution of precipitated drug were evaluated. The stability and mechanism(s) of decomposition of NSC 629243 in both 20% lipid emulsions and in natural oil vehicles were examined. In lipid emulsions, the shelf life at 25°C varied from 1 to >10 weeks, depending on the extent to which air was excluded from the preparation. The shelf life of 50 mg/mL solutions in natural oils at 25°C varied from <1 to >100 days depending on the oil and its supplier. A qualitative correlation was found between the initial rate of oxidation and the peroxide concentration in the oil. The primary degradation product in both systems was shown to be a disulfide dimer, II, formed via oxidation. Oxidation was inhibited by vacuum-sealing of emulsion formulations or incorporation of an oil-soluble thiol, thioglycolic acid (TGA), into oil formulations. TGA may inhibit oxidation by consuming free radicals or peroxide initiators or by reacting with the disulfide, II, to regenerate the starting drug.     

The Relationship Between Rat Intestinal Permeability and Hydrophilic Probe Size

Purpose. The relationship between rat intestinal permeability (P_app) of a range of hydrophilic probe molecules and probe geometry was examined. Methods. Molecules studied included mannitol, the polyethylene glycols (PEGs) 400, 900, and 4000, the dextran conjugated dye Texas Red^® (MW 3000) and the polysaccharide inulin (MW 5500). Molecular surface area, volume and cross-sectional diameter for each probe were determined from computer models. The effect of the bile salt sodium cholate, and bile salt: fatty acid mixed micelles on probe intestinal permeability was also studied. Results. Of the size parameters tested, cross-sectional diameter correlated best with log intestinal permeability. The data was fitted to a relationship of the form P_app = P⁰ _app exp(–Kr_ca) where r_ca is the molecular cross sectional radius, P⁰ _app and K are constants. Estimates of equivalent pore radii (R) were also made; the use of r_ca giving the most reasonable estimate of R. Absorption of all probes was enhanced by both simple and mixed micellar systems. Conclusions. For large hydrophilic probes, and possibly protein drugs, cross sectional diameter is a more important size parameter than volume based values for evaluating size-related retarded absorption. The relationship established may be used as a tool to assess absorption enhancement potential of excipients.