Bioavailability Of Cyclosporin A Research Articles

Highly Drug-Loaded Nanoaggregate Microparticles for Pulmonary Delivery of Cyclosporin A.

Nanoparticles have the advantages of improving the solubility of poorly water-soluble drugs, facilitating the drug across biological barriers, and reducing macrophage phagocytosis in pulmonary drug delivery. However, nanoparticles have a small aerodynamic particle size, which makes it difficult to achieve optimal deposition when delivered directly to the lungs. Therefore, delivering nanoparticles to the lungs effectively has become a popular research topic. Nanoaggregate microparticles were used as a pulmonary drug delivery strategy for the improvement of the bioavailability of cyclosporine A (CsA). The nanoaggregate microparticles were prepared with polyvinyl pyrrolidone (PVP) as the excipient by combining the anti-solvent method and spray drying process. The physicochemical properties, aerodynamic properties, in vivo pharmacokinetics and inhalation toxicity of nanoaggregate microparticles were systematically evaluated. The optimal nanoparticles exhibited mainly spherical shapes with the particle size and zeta potential of 180.52 nm and -19.8 mV. The nanoaggregate microparticles exhibited irregular shapes with the particle sizes of less than 1.6 µm and drug loading (DL) values higher than 70%. Formulation NM-2 as the optimal nanoaggregate microparticles was suitable for pulmonary drug delivery and probably deposited in the bronchiole and alveolar region, with FPF and MMAD values of 89.62% and 1.74 μm. In addition, inhaled NM-2 had C max and AUC0-∞ values approximately 1.7-fold and 1.8-fold higher than oral cyclosporine soft capsules (Neoral®). The inhalation toxicity study suggested that pulmonary delivery of NM-2 did not result in lung function damage, inflammatory responses, or tissue lesions. The novel nanoaggregate microparticles for pulmonary drug delivery could effectively enhance the relative bioavailability of CsA and had great potential for clinical application.

Rapidly Dissolving Trans-scleral Microneedles for Intraocular Delivery of Cyclosporine A

Cyclosporine A (CsA) is a cyclic peptide immunosuppressant drug that is beneficial in the treatment of various ocular diseases. However, its ocular bioavailability in the posterior eye is limited due to its poor aqueous solubility. Conventional CsA formulations such as a solution or emulsion permeate poorly across the eye due to various static and dynamic barriers of the eye. Dissolvable microneedle (MN)-based patches can be used to overcome barrier properties and, thus, enhance the ocular bioavailability of CsA in the posterior eye. CsA-loaded dissolvable MN patches were fabricated using polyvinylpyrrolidone (PVP) and characterized for MN uniformity and sharpness using SEM. Further characterization for its failure force, penetration force, and depth of penetration were analyzed using a texture analyzer. Finally, the dissolution time, ex vivo permeation, and ocular distribution of cyclosporine were determined in isolated porcine eyes. PVP MNs were sharp, uniform with good mechanical properties, and dissolved within 5 min. Ocular distribution of CsA in a whole porcine eye perfusion model showed a significant increase of CsA levels in various posterior segment ocular tissues as compared to a topically applied ophthalmic emulsion (Restasis®) (P < 0.001). Dissolving MNs of CsA were prepared, and the MN arrays can deliver CsA to the back of the eye offering potential for treating various inflammatory diseases.

Cyclosporine A-loaded chitosan extra-fine particles for deep pulmonary drug delivery: In vitro and in vivo evaluation

In this study, the extra-fine dry powder inhalers (DPIs) with chitosan (CS) as carrier were successfully prepared by ionic gel method combined with spray drying technique for deep pulmonary drug delivery of Cyclosporine A (CsA), using sodium hyaluronate (SHA) and sodium polyglutamate (SPGA) as polyanions. The CsA-loaded DPIs of CS-SHA-CsA and CS-SPGA-CsA were spherical particles with wrinkles on the surface, which were more conducive to improving the aerosol properties. The aerodynamic evaluation of CS-SHA-CsA and CS-SPGA-CsA showed that the fine particle fraction (FPF) reached up to 79.22 ± 2.12% and 81.55 ± 0.43%, while the emitted fraction (EF) reached 77.15 ± 1.46% and 78.29 ± 2.10%. In addition, the mass median aerodynamic diameter (MMAD) was calculated as 1.58 ± 0.04 μm and 1.94 ± 0.02 μm for CS-SHA-CsA and CS-SPGA-CsA, indicating that they were all extra-fine particles (d < 2 μm). These in vitro aerodynamic results showed that CS-SHA-CsA and CS-SPGA-CsA could reach the smaller airways, further improving therapeutic efficiency. The cell viability on A549 cell line results showed that CS-SHA-CsA and CS-SPGA-CsA were safe to deliver CsA to lungs. The in vivo pharmacokinetics consequence proved that inhalation administration of CS-SHA-CsA and CS-SPGA-CsA could significantly improve the bioavailability of CsA in vivo compared with oral administration of Neoral®, effectively reducing the risk of a series of adverse effects caused by systemic overexposure. In addition, the safety and compatibility of DPIs using SHA, SPGA, and CS as carriers for pulmonary drug delivery was verified by in vivo repeated dose inhalation toxicity. From these findings, the extra-fine DPIs with CS as carrier could be a viable delivery option for the deep pulmonary drug delivery of CsA relative to orally administered drug.

Development of Large Hollow Particles for Pulmonary Delivery of Cyclosporine A.

The purpose of this study was to prepare large hollow particles (LHPs) by spray drying for pulmonary delivery of cyclosporine A (CsA), using L-Leucine (LEU) and hydroxypropyl methylcellulose (HPMC) as excipients and ammonium bicarbonate (AB) as a porogen. The prepared LHPs were spherical particles composed of both CsA and LEU on the surface and HPMC on the inner layer. The formulation of CsA-LEU-0.8HPMC-AB as typical LHPs showed excellent in vitro aerodynamic performance with a minimum mass median aerodynamic diameter (MMAD) of 1.15 μm. The solubility of CsA-LEU-0.8HPMC-AB was about 5.5-fold higher than that of raw CsA, and the dissolution of CsA-LEU-0.8HPMC-AB suggested that the drug was released within 1 h. The cell viability of the A549 cell line showed that CsA-LEU-0.8HPMC-AB was safe for delivering CsA to the lungs. In addition, inhalation administration of CsA-LEU-0.8HPMC-AB with the Cmax and AUC0-∞ increasing by about 2-fold and 2.8-fold compared with the oral administration of Neoral® could achieve therapeutic drug concentrations with lower systemic exposure and significantly improve the in vivo bioavailability of CsA. From these findings, the LHPs, with the advantage of avoiding alveolar macrophage clearance, could be a viable choice for delivering CsA by inhalation administration relative to oral administration.

Translation of ionic liquids to be enteric nanoparticles for facilitating oral absorption of cyclosporine A.

Ionic liquids (ILs) attract more and more interests in improving drug transport across membrane, including transdermal, nasal, and oral delivery. However, some drawbacks of ILs impede the application in oral drug delivery, such as rapid precipitation of poorly soluble drugs in stomach. This study aimed to employ enteric mesoporous silica nanoparticles (MSNs) to load ILs to overcome the shortcomings faced in oral administration. The choline sorbate ILs (SCILs) were synthesized by choline bicarbonate and sorbic acid and then adsorbed in mesopores of MSNs after dissolving cyclosporin A (CyA). MSNs loading SCILs and CyA were coated by Eudragit® L100 to form enteric nanoparticles. The in vitro release study showed that the CyA and SCILs released only 10% for 2h in simulated gastric fluids but more than 90% in simulated intestinal fluid. In addition, SCILs and CyA were able to release from MSNs synchronously. After oral administration, enteric MSNs loading SCILs were capable of improving oral absorption of CyA significantly and the oral bioavailability of CyA was similar with that of oral Neoral®. In addition, the oral absorption of enteric MSNs was higher than that of nonenteric MSNs, which showed that enteric coating was necessary to ILs in oral delivery. These findings revealed great potential of translation of ILs to be enteric nanoparticles for facilitating oral absorption of CyA. It is predictable this delivery system is promising to be a platform for delivering poorly water-soluble drugs and even biologics orally.

Liposomal Formulation for Oral Delivery of Cyclosporine A: Usefulness as a Semisolid-Dispersion System.

This study aims to understand the process and mechanism of oral drug absorption from liposomes and to verify the usefulness of liposomal formulation for poorly soluble drugs. Cyclosporine A (CsA) was used as a model drug and entrapped into Dipalmitoylphosphatidylcholine (DPPC) and distearoylphosphatidylcholine (DSPC) liposomes. Molecular state of CsA in the liposomes was analyzed using powder X-ray diffraction (PXRD) and polarized light microscopy (PLM). Release profiles of CsA from liposomes were observed in fasted state simulated intestinal fluid (FaSSIF). Oral absorption of CsA from liposomal formulations were investigated in rats. PXRD and PLM analyses suggested that CsA exists in the lipid layer of liposomes as a molecular dispersed state. Although both liposomes retained CsA stably in the simple buffer, DPPC liposomes quickly released CsA within 10min in FaSSIF due to the interaction with bile acid. In contrast, effect of bile acid was negligible in DSPC, indicating a high resistivity to membrane perturbation. Oral bioavailability of CsA from liposomal formulations were almost comparable with that from a marketed product (Neoral). However, the absorption profiles were clearly different. CsA was absorbed quickly from DPPC liposomes and Neoral, while sustained absorption profile was observed from DSPC liposomes. Further study in which ritonavir was co-entrapped in the liposomes with CsA showed the higher efficacy of ritonavir to increase oral bioavailability of CsA. Liposomes allows the appropriate formulation design for oral delivery of poorly soluble drugs, not only to increase the extent but also to control the rate of absorption.

Development of softgel capsules containing cyclosporine a encapsulated pine essential oil based self-microemulsifying drug delivery system

In this study, a new self-microemulsifying drug delivery system (SMEDDS) based on pine essential oil has been designed and successfully developed to load cyclosporine A (CsA), a poorly water-soluble immunosuppressant, for oral CsA softgel manufacturing. SMEDDS were prepared from pine essential oil and Capmul MCM as oily phases, Kolliphor RH 40 as surfactant, polyethylen glycol 400 as co-surfactant/co-solvent and none volatized co-solvent utilizing the pseudo-ternary phase diagrams. CsA SMEDDS loading 9.09% of CsA, dispersed in aqueous environments (water, pH 1.2, 4.5 and 6.8 buffers), presented an average droplet size of about 160 nm with polydispersity index (PdI) below 0.25, and were stable after 6 h of self-emulsification. Cytotoxicity of CsA SMEDDS on LLC-PK1 cells demonstrated that CsA SMEDDS had an IC50 value greater than that of the reference product, suggesting product safety against nephrotoxicity. CsA SMEDDS was filled into oval-5 soft gelatin capsules (softgels) containing 0.5% glycine which could avoid the cross-linking process. Additionally, CsA SMEDDS softgels presented the in vitro release profiles equivalent to that of Sandimmun Neoral® at pH 1.2, 4.5 and 6.8. Therefore, the pine essential oil based SMEDDS was considered to be potential and suitable for developing softgels to enhance the oral bioavailability of CsA.

Interaction of Cyclosporine A with Pomegranate Juice and Its Potential Nephroprotective Effect in Rats

Objectives: To study the effect of concomitant administering of pomegranate juice orally (PJ) on bioavailability of cyclosporine A (CsA) and independently its potential nephroprotective effect against CsA induced nephrotoxicity.&#x0D; Methods: A- Pharmacokinetic study (PK), Wister rats were divided into groups (each 6 rats) I-: CsA PO + Vehicle; II- CsA IP + Vehicle, III- CsA PO + PJ, IV- CsA IP + PJ. CsA dose was 20 mg/kg for 5 days the vehicle or PJ (2 ml) was given 1 h before drug administration. Blood samples were taken at the 1st and 5th day at specified times and CsA level was determined by immune assays. Relative bioavailability of CsA was determined.&#x0D; B- Nephroprotection study (separate study to administer bioequivalent CsA PO doses, in view of PK study), I- ( CsA 13 mg PO + 2 ml PJ .II- CsA 20 mg P0 + 2 ml vehicle (for 28 day). The design also includes two control groups (vehicle alone or PJ alone). Blood samples for drug analysis, biochemical investigations and kidney samples for histopathology were taken at the 28th day.&#x0D; Results: PJ juice enhanced the bioavailability of oral CsA by about 50% (P &gt; 0.05). But CsA (IP) was not affected after repeated administration for 5 days. Independently, the marked kidney damage induced by CsA was reversed by concomitant administration of PJ as well as it attenuated the increase in serum creatinine.&#x0D; Conclusions: Repeated administration of pomegranate juice enhance CsA oral bioavailability which likely due to inhibition of intestinal enzymes and transport pump. Independently it caused significant attenuation of CsA induced renal toxicity.

Quercetin‑3‑O‑β‑D‑glucoside decreases the bioavailability of cyclosporin A through regulation of drug metabolizing enzymes, transporters and nuclear receptors in rats.

Quercetin is a flavonoid compound that is widely present in food and drink. Quercetin-3-O-β-D-glucoside (Q3GA) is a major metabolite of quercetin. The aim of the present study was to investigate the effect of Q3GA on the pharmacokinetics of orally and intravenously administered cyclosporin A (CsA) in rats, and to assess the effect of Q3GA on drug-metabolizing enzymes (DMEs), drug transporters (DTs) and nuclear receptors (NRs). The pharmacokinetic parameters of CsA were measured following oral (10 mg/kg) and intravenous (2.5 mg/kg) administration of CsA in the presence or absence of Q3GA. The mRNA and protein expression levels of DMEs, DTs and NRs in the liver and small intestine were detected by quantitative polymerase chain reaction and western blot analysis. The results indicated that the intravenous administration of Q3GA (2.5, 5 or 10 mg/kg) for 7 consecutive days reduced the bioavailability of oral CsA. By contrast, the pharmacokinetics of the intravenous administration of CsA were not affected by Q3GA. However, the mRNA and protein expression levels of DMEs and DTs were inhibited by Q3GA. The activation of DMEs and DTs by NRs, and the interplay between DMEs and DTs, may explain these results. The present study identified a novel flavonoid-drug interaction, which may have implications for patients taking CsA and quercetin supplements or on a quercetin-containing diet.

Amorphous solid dispersion of cyclosporine A prepared with fine droplet drying process: Physicochemical and pharmacokinetic characterization

The present study aimed to develop an amorphous solid dispersion (ASD) of cyclosporine A (CsA) by a fine droplet drying (FDD) process for improvement in oral absorption of CsA. CsA and hydroxypropyl cellulose-SSL were dissolved in 1,4-dioxane, and the solution was powdered by the FDD process to obtain the ASD formulation of CsA (ASD/CsA). The ASD/CsA was characterized in terms of morphology, particle size distribution, crystallinity, dissolution behavior, physicochemical stability, and pharmacokinetic behavior in rats. The ASD/CsA was obtained in the form of uniform spherical particles, and the span factor was calculated to be ca. 0.4. CsA in the formulation existed in an amorphous state. The ASD/CsA exhibited a higher dissolution behavior of CsA than amorphous CsA, whereas storage of the ASD/CsA under accelerated conditions led to impairment in the dissolution behavior. The constant release of CsA from non-aged ASD/CsA was observed during dissolution testing. After oral administration of CsA samples (10mg-CsA/kg) in rats, the ASD/CsA showed a high and sustained plasma concentration of CsA as evidenced by a 18-fold increase in the oral bioavailability of CsA compared with amorphous CsA. From these findings, the FDD process might be an efficacious option for the ASD formulation of CsA with enhanced biopharmaceutics properties.

New nano-matrix oral formulation of nanoprecipitated cyclosporine A prepared with multi-inlet vortex mixer

We present a combined nanoparticle (NP) formation process and spray drying to create a nano-matrix formulation of cyclosporine A (CsA) and mannitol (nCsA/MAN) to increase the bioavailability of CsA. CsA NPs were prepared by flash nano precipitation (FNP) using a multi-inlet vortex mixer, and spray-dried with or without mannitol to prepare nCsA/MAN or nanoprecipitated CsA powder (nCsA), respectively. Pre-forming the NPs by FNP uncouples the sizes of the CsA inclusions from the ultimate micron-sized powders produced by spray drying. Both CsA formulations were physicochemically characterized, and a pharmacokinetic study in rats was conducted after oral administration of CsA samples (10mg-CsA/kg). In the nCsA/MAN, CsA NPs dispersed in the mannitol matrix. In water, both the nCsA and nCsA/MAN reconstituted into NP form with average sizes of 317 and 298nm, respectively. In dissolution testing, nCsA and nCsA/MAN exhibited marked improvement in the dissolution with 31- and 41-fold higher drug release at 60min, compared with amorphous CsA, suggesting the significant impact of CsA NP size on dissolution. The higher dissolution rate with the mannitol matrix indicates the role of mannitol on wetting and dispersing the NP aggregates. Both nCsA formulations provided enhancement in CsA exposure in rats with a ca. 3-fold increase of the oral bioavailability compared with amorphous CsA. The nCsA/MAN showed faster absorption in vivo than nCsA, possibly due to the improved dissolution rate. From these findings, the nano-matrix formulation appears to be an efficacious oral dosage form to enhance the biopharmaceutical properties of CsA.

Different preparations, doses, and treatment regimens of cyclosporine A cause adverse effects but no robust changes in seizure thresholds in rats

Neuronal transplantation is a promising experimental treatment approach for intractable epilepsies, but rejection of porcine or human cells in rodent epilepsy models requires adequate immunosuppression to enable long-term survival of xenografts. The commonly used immunosuppressive drug cyclosporine A (CsA) itself was suggested to affect seizure thresholds. However, putative pro- or anticonvulsant effects of CsA have not yet been sufficiently explored in a direct comparison study involving different preparations, dosages, and application routes. We therefore comprehensively investigated the effects of acute versus chronic treatment using different dosages (5mg/kg, 10mg/kg), application routes (i.p., s.c.), and preparations of CsA (pure substance solved in polyethoxylated castor oil and a ready-to-use drug additionally containing ethanol) on acute seizure thresholds in rats in the pentylenetetrazole seizure threshold test and verified the most harmless protocol in the chronic amygdala-kindling model for temporal lobe epilepsy. None of the CsA treatment regimens induced acute changes of seizure thresholds. Chronic CsA treatment also did not robustly change seizure thresholds. As evaluated by whole blood analyses, bioavailability of CsA was significantly higher after i.p. application of the ready-to-use preparation compared to the pure substance and compared to s.c. Observed adverse effects differed between CsA treatment regimens and included reversible diarrhea, lowered body temperature, and tremor, the latter two of which were also induced by vehicle injections containing ethanol and/or polyethoxylated castor oil. Our data suggest that chronic treatment (2 weeks) with 10mg/kg CsA injected i.p. in the ready-to-use preparation is an appropriate protocol for use in neural transplantation in epilepsy research applying the presently used rat models. Transplantation studies in experimental epilepsy research require a careful assessment of putative CsA effects on seizure thresholds in the specific experimental settings to be used.

Reduced bioavailability of cyclosporine A in rats by mung bean seed coat extract

Mung bean seed coat (MBSC) is a healthcare product in Asian countries. The aim of this study was to investigate the effect of an MBSC ethanol extract on the bioavailability of cyclosporine A (CsA) in rats. Rats were orally dosed with CsA alone or in combination with MBSC ethanol extracts (500 mg/kg, p.o.). The blood levels of CsA were assayed by liquid chromatography with an electrospray ionization source and tandem mass spectrometry (LC-MS/MS). The everted rat intestinal sac technique was used to determine the influence of MBSC on the absorption of CsA. The results reveal that combined CsA intake with MBSC decreased the Cmax, AUC0-t, t1/2z and MRT0-t values of CsA by 24.96%, 47.28%, 34.73% and 23.58%, respectively (P&lt;0.05), and significantly raised the CL/F by 51.97% (P&lt;0.01). The in vitro results demonstrated that significantly less CsA was absorbed (P&lt;0.05). The overall results indicate that after being concomitantly ingested, MBSC reduced the bioavailability of CsA, at least partially, in the absorption phase.

Downregulation of CYP3A and P-Glycoprotein in the Secondary Inflammatory Response of Mice With Dextran Sulfate Sodium–Induced Colitis and Its Contribution to Cyclosporine A Blood Concentrations

CYP3A and P-glycoprotein (P-gp) play important roles in drug metabolism and excretion; however, their functions in pathological conditions remain unclear. Hepatobiliary abnormalities have been described in patients with ulcerative colitis, which may affect drug metabolism and excretion in the liver and small intestine. We examined the functions of CYP3A and P-gp in the liver and small intestine of mice with dextran sodium sulfate (DSS)-induced colitis. Up to day 7, inflammatory markers were significantly increased in the livers of DSS-treated mice, accompanied by decreased CYP3A. Additionally hepatobiliary transporters and Pregnane X receptor, which regulates the transcriptional activation of CYP3A, were reduced. Both CYP3A and P-gp were significantly decreased in the upper small intestine of DSS-treated mice on day 7. This was associated with the increased expression of inducible nitric oxide synthase, but not changes in nuclear receptor expression. On day 7 of DSS treatment, the concentrations of cyclosporine A (CsA), a substrate of both CYP3A and P-gp, were significantly higher than controls. These results indicated the existence of a second inflammatory response in the liver and upper small intestine of mice with DSS-induced colitis, and bioavailability of CsA was increased by the dysfunction of CYP3A and P-gp in these organs. [Supplementary Tables and Figure: available only at http://dx.doi.org/10.1254/jphs.13141FP]

Capsaicin pretreatment increased the bioavailability of cyclosporin in rats: Involvement of P-glycoprotein and CYP 3A inhibition

Capsaicin (CAP), the main ingredient responsible for the hot pungent taste of chilli peppers. This study investigated the effect of CAP on the pharmacokinetics of Cyclosporin A (CyA) in rats and the mechanism of this food-drug interaction. The results indicated that after 7 days of low or middle dose of CAP (0.3 or 1.0 mg/kg), the blood concentration of CyA was not significantly changed compared with that of vehicle-treated rats, whereas the blood concentration of CyA in high dose group (3.0 mg/kg) was significantly increased. The total clearance (CL/F) of CyA was decreased, and the bioavailability was significantly increased to about 1.44-fold of that in vehicle-treated rats after 7 days of high dose CAP treatment. At this time, the P-gp and CYP3A1/2 in the liver and intestine were decreased at both the mRNA and protein levels. These results demonstrated that chronic ingestion of high doses of CAP will increase the bioavailability of CyA to a significant extent in rats and the food-drug interaction between CAP and CyA appears to be due to modulation of P-gp and CYP3A gene expression by CAP, with differential dose-dependence.

Enhanced oral bioavailability of cyclosporine A by liposomes containing a bile salt.

The main purpose of this study was to evaluate liposomes containing a bile salt, sodium deoxycholate (SDC), as oral drug delivery systems to enhance the oral bioavailability of the poorly water-soluble and poorly permeable drug, cyclosporine A (CyA). Liposomes composed of soybean phosphatidylcholine (SPC) and SDC were prepared by a thin-film dispersion method followed by homogenization. Several properties of the liposomes including particle size, polydispersity index, and entrapment efficiency were characterized. The in vitro release of CyA from these liposomes was less than 5% at 12 hours as measured by a dynamic dialysis method. The pharmacokinetic results in rats showed improved absorption of CyA in SPC/SDC liposomes, compared with CyA-loaded conventional SPC/cholesterol (Chol) liposomes and microemulsion-based Sandimmune Neoral®. The relative oral bioavailability of CyA-loaded SPC/SDC and SPC/Chol liposomes was 120.3% and 98.6%, respectively, with Sandimmun Neoral as the reference. The enhanced bioavailability of CyA was probably due to facilitated absorption by the liposomes containing SDC rather than improved release rate.

Improved dissolution and pharmacokinetic behavior of cyclosporine A using high-energy amorphous solid dispersion approach

The aim of the present investigation is to develop solid dispersion (SD) formulations of cyclosporine A (CsA) for improving the oral bioavailability of CsA. Amorphous SDs of CsA with eight hydrophilic polymers were prepared with wet-mill employing zirconia beads. The physicochemical properties were characterized with a focus on morphology, crystallinity, thermal behavior, dissolution, and interaction of CsA with co-existing polymer. Although CsA molecules were found to be amorphous in all wet-milled formulations, some SD formulations failed to improve the dissolution. Of all CsA formulations, SD using polymer with HPC(SSL) exhibited the largest improvement in dissolution behavior. Pharmacokinetic profiling of orally dosed CsA in rats was carried out using UPLC/ESI-MS. After the oral administration of HPC(SSL)-based SD, enhanced CsA exposure was observed with increases in C max and AUC of ca. 5-fold, and the variation in AUC was ca. 40% less than that of amorphous CsA. Infrared spectroscopic studies suggested an interaction between CsA and HPC(SSL), as evidenced by the conformational transition of CsA. From the improved dissolution and pharmacokinetic data, the amorphous SD approach using wet-milling technology should lead to consistent and enhanced bioavailability, leading to an improved therapeutic potential of CsA.

Pharmacokinetics and enhanced oral bioavailability in beagle dogs of cyclosporine A encapsulated in glyceryl monooleate/poloxamer 407 cubic nanoparticles

Efforts to improve the oral bioavailability of cyclosporine A (CyA) remains a challenge in the field of drug delivery. In this study, glyceryl monooleate (GMO)/poloxamer 407 cubic nanoparticles were evaluated as potential vehicles to improve the oral bioavailability of CyA. Cubic nanoparticles were prepared via the fragmentation of a bulk GMO/poloxamer 407 cubic phase gel by sonication and homogenization. The cubic inner structure formed was verified using Cryo-TEM. The mean diameters of the nanoparticles were about 180 nm, and the entrapment efficiency of these particles for CyA was over 85%. The in vitro release of CyA from these nanoparticles was less than 5% at 12 h. The results of a pharmacokinetic study in beagle dogs showed improved absorption of CyA from cubic nanoparticles as compared to microemulsion-based Neoral((R)); higher C(max) (1371.18 +/- 37.34 vs 969.68 +/- 176.3 ng mL(-1)), higher AUC(0-t) (7757.21 +/- 1093.64 vs 4739.52 +/- 806.30 ng h mL(-1)) and AUC(0-infinity) (9004.77 +/- 1090.38 vs 5462.31 +/- 930.76 ng h mL(-1)). The relative oral bioavailability of CyA cubic nanoparticles calculated on the basis of AUC(0-infinity) was about 178% as compared to Neoral((R)). The enhanced bioavailability of CyA is likely due to facilitated absorption by cubic nanoparticles rather than improved release.

Use of hydrophobins in formulation of water insoluble drugs for oral administration

The poor water solubility of many drugs requires a specific formulation to achieve a sufficient bioavailability after oral administration. Suspensions of small drug particles can be used to improve the bioavailability. We here show that the fungal hydrophobin SC3 can be used to make suspensions of water insoluble drugs. Bioavailability of two of these drugs, nifedipine and cyclosporine A (CyA), was tested when administered as a SC3-based suspension. SC3 (in a 1:2 (w/w) drug:SC3 ratio) or 100% PEG400 increased the bioavailability of nifedipine to a similar degree (6 ± 2- and 4 ± 3-fold, respectively) compared to nifedipine powder without additives. Moreover, SC3 (in a 7:1 (w/w) drug:hydrophobin ratio) was as effective as a 20-fold diluted Neoral ® formulation by increasing bioavailability of CyA 2.3 ± 0.3-fold compared to CyA in water. Interestingly, using SC3 in the CyA formulation resulted in a slower uptake ( p < 0.001 in T max) of the drug, with a lower peak concentration ( C max 1.8 mg ml −1) at a later time point ( T max 9 ± 2 h) compared to Neoral ® ( C max 2.2 mg ml −1; T max 3.2 ± 0.2). Consequently, SC3 will result in a more constant, longer lasting drug level in the body. Taken together, hydrophobins are attractive candidates to formulate hydrophobic drugs.

Cyclodextrins and chitosan derivatives in sublingual delivery of low solubility peptides: A study using cyclosporin A, α-cyclodextrin and quaternary chitosan N-betainate

Systemic drug delivery through intraoral membranes may offer a promising administration route for lipophilic peptide drugs. The aim of the present study was to investigate the effect of α-cyclodextrin (α-CD) and a novel chitosan derivative, chitosan N-betainate (CH), on sublingual absorption of a hydrophobic model peptide cyclosporin A (CsA), and the effect of temperature on the complexation of CsA with α-CD. Complexation of CsA with α-CD was studied using the phase-solubility method. Sublingual absorption of CsA was studied by administration of solid CsA/α-CD complex (with and without CH solution), solid CsA/α-CD/CH formulation and solid plain CsA to rabbits. The solubility of CsA in aqueous α-CD solution (14%) increased with decreasing temperature; the solubility of CsA at room temperature, +5 and +1 °C was 1.2, 12 and 19 mg/ml, respectively. The bioavailability of CsA after administration of plain CsA, solid CsA/α-CD and solid CsA/α-CD/CH (0.6 ± 0.5, 1.4 ± 0.7 and 1.7 ± 0.8%, respectively; mean ± S.D.) was further increased when solid CsA/α-CD was administered together with CH solution (3.2 ± 2.2%). The present study shows that decreased temperature can be effectively utilized to produce CsA/α-CD complexes. It was also shown that α-CD and CH may be advantageous in sublingual delivery of lipophilic peptides, although the absolute bioavailability remains low.