In situ intestinal permeability and in vivo absorption characteristics of olmesartan medoxomil in self-microemulsifying drug delivery system

To characterize the intestinal absorption behavior of olmesartan medoxomil (OLM) and to evaluate the absorption-improving potential of a self-microemulsifying drug delivery system (SMEDDS), we performed in situ single-pass intestinal perfusion (SPIP) and in vivo pharmacokinetic studies in rats. The SPIP study revealed that OLM is absorbed throughout whole intestinal regions, favoring proximal segments, at drug levels of 10-90 μM. The greatest value for effective permeability coefficient (P(eff)) was 11.4 × 10(-6) cm/s in the duodenum (90 μM); the lowest value was 2.9 × 10(-6) cm/s in the ileum (10 μM). A SMEDDS formulation consisting of Capryol 90, Labrasol, and Transcutol, which has a droplet size of 200 nm and self-dispersion time of 21 s, doubled upper intestinal permeability of OLM. The SMEDDS also improved oral bioavailability of OLM in vivo: a 2.7-fold increase in the area under the curve (AUC) with elevated maximum plasma concentration (C(max)) and shortened peak time (T(max)) compared to an OLM suspension. A strong correlation (r(2) = 0.955) was also found between the in situ jejunal P(eff) and the in vivo AUC values. Our study illustrates that the SMEDDS formulation holds great potential as an alternative to increased oral absorption of OLM.     

In vitro and in vivo effects of morin on the intestinal absorption and pharmacokinetics of olmesartan medoxomil solid dispersions

Abstract

Purpose: In-situ evaluation to corroborate morin effects on the intestinal absorption and pharmacokinetic behavior of freeze-dried OLM-loaded solid dispersions with Caco-2 and in-vivo studies

Methods: Intestinal transport and absorption studies were examined by Caco-2 permeability, in-situ single pass perfusion and closed-loop models along with in-vivo pharmacokinetic studies to evaluate and confirm the effect of P-gp-mediated activity of morin. We evaluated the intestinal membrane damage in the presence of morin by measuring the release of protein and lactate dehydrogenase (LDH) followed by using qualitative and quantitative morphometric analysis to describe the surface characteristics of intestinal epithelium.

Results: Morin showed the highest P_eff value 13.8?±?0.34?×?10^?6?cm/s in jejunum than ileum (p?<?.01) at 100?µM with absorption enhancement of 1.31-fold together with enhanced (p?<?.01) secretory transport of 6.27?±?0.27?×?10?^?6?cm/s in Caco-2 monolayer cells. Our findings noticed 2.37 (in-situ); 2.39 (in-vivo) and 1.43 (in-situ); 1.36 (in-vivo) fold increase in AUC_0–t with elevated C_max and shortened T_max for freeze-dried solid dispersion in the presence of morin as compared to pure OLM and freeze-dried solid dispersions without morin, respectively.

Conclusions: Our study demonstrated that increased solubilization through freeze-dried OLM-loaded solid dispersion together with efflux inhibition improved intestinal permeability to one system that might lead to novel solubilization and efflux pump inhibition as a novel alternative potential to increase oral absorption and bioavailability of OLM.     

Preparation and evaluation of valsartan by a novel semi-solid self-microemulsifying delivery system using Gelucire 44/14

The aim of the present study was to develop a novel semi-solid self-microemulsifying drug delivery system (SMEDDS) using Gelucire^® 44/14 as oil with strong solid character to improve the oral bioavailability of poorly soluble drug valsartan. The solubility of valsartan in various excipients was determined, the pseudo-ternary phase diagram was constructed in order to screen the optimal excipients, and DSC analysis was performed to evaluate the melting point of SMEDDS. The optimal drug-loaded SMEDDS formulation was consisted of 30% Gelucire^® 44/14 (oil), 40% Solutol^® HS 15 (surfactant), and 30% Transcutol^® P (cosurfactant) (w/w) with 80?mg valsartan/g excipients. The average droplet sizes of the optimized blank and drug-loaded SMEDDS formulations were 26.20?±?1.43 and 33.34?±?2.15?nm, and the melting points of them were 35.6 and 36.8?°C, respectively. The in vitro dissolution rate of optimal semi-solid SMEDDS was increased compared with commercial capsules, resulting in the 2.72-fold and 2.97-fold enhancement of C_max and AUC_0–t after oral administration in rats, respectively. These results indicated that the novel semi-solid SMEDDS formulation could potentially improve the oral bioavailability of valsartan, and the semi-solid SMEDDS was a desirable system than the traditional liquid SMEDDS because it was convenient for preparation, storage and transportation due to semi-solid state at room temperature and melted state at body temperature.     

A new self-microemulsifying mouth dissolving film to improve the oral bioavailability of poorly water soluble drugs

A new self-microemulsifying mouth dissolving film (SMMDF) for poorly water-soluble drugs such as indomethacin was developed by incorporating self-microemulsifying components with solid carriers mainly containing microcrystalline cellulose, low-substituted hydroxypropyl cellulose and hypromellose. The uniformity of dosage units of the preparation was acceptable according to the criteria of Chinese Pharmacopoeia 2010. The SMMDF was disintegrated within 20 s after immersion into water, released completely at 5?min in the dissolution medium and achieved microemulsion particle size of 28.81?±?3.26?nm, which was similar to that of liquid self- microemulsifying drug delivery system (SMEDDS). Solid state characterization of the SMMDF was performed by SEM, DSC and X-ray powder diffraction. Results demonstrated that indomethacin in the SMMDF was in the amorphous state, which might be due to self-microemulsifying ingredients. Pharmacokinetic parameters in rats including T_max, C_max, AUC were similar between the SMMDF and liquid SMEDDS. AUC and C_max from the SMMDF were significantly higher than those from the common mouth dissolving film or the conventional tablet, and T_max from SMMDF group was also significantly decreased. These findings suggest that the SMMDF is a new promising dosage form, showing notable characteristics of convenience, quick onset of action and enhanced oral bioavailability of poorly water-soluble drugs.     

Two-layered dissolving microneedles for percutaneous delivery of sumatriptan in rats

A novel transdermal delivery of sumatriptan (ST) was attempted by application of dissolving microneedle (DM) technology. Dextran DM (d-DM) and hyaluronate DM (h-DM) were prepared by adding ST solution to dextran solution or hyaluronic acid solution. One DM chip, 1.0?×?1.0?cm, contains 100 microneedle arrays in a 10?×?10 matrix. The mean lengths of DMs were 496.6?±?2.9 μm for h-DM and 494.5?±?1.3 μm for d-DM. The diameters of the array basement were 295.9?±?3.9 μm (d-DM) and 291.7?±?3.0 μm (h-DM), where ST contents were 31.6?±?4.5?μg and 24.1?±?0.9?μg. These results suggest that ST was stable in h-DM. Each DM was administered to rat abdominal skin. The maximum plasma ST concentrations, C_max, and the areas under the plasma ST concentration versus time curves (AUC) were 44.6?±?4.9?ng/ml and 24.6?±?3.9?ng · h/ml for h-DM and 38.4?±?2.7?ng/ml and 14.1?±?1.5?ng · h/ml for d-DM. The bioavailabilities of ST from DMs were calculated as 100.7?±?18.8% for h-DM and 93.6?±?10.2% for d-DM. Good dose dependency was observed on C_max and AUC. The stability study of ST in DM was performed for 3 months under four different conditions, ?80, 4, 23, and 50°C. At the end of incubation period, they were, respectively, 100.0?±?0.3%, 97.8?±?0.2%, 98.8?±?0.2%, and 100.7?±?0.1%. These suggest the usefulness of DM as a noninvaisive transdermal delivery system of ST to migraine therapy.     

Nanosized nasal emulgel of resveratrol: preparation,optimization, in vitro evaluation and in vivo pharmacokinetic study

Abstract

Nano-emulgel has become one of the most significant controlled release systems, which has the advantages of both gels and nano-emulsions. This work aims at the formulation of nasal nano-emulgel for resveratrol, employing carbopol 934 and poloxamer 407 as the gelling agents. The optimum nano-emulsion was determined through further characterization of the selected system. The nasal nano-emulgel was prepared and tested for the in vitro release, the release kinetics, FTIR, ex vivo permeation, nasal mucosa toxicity, and in vivo pharmacokinetic study. The optimum nano-emulsion consisted of Tween 20, Capryol 90, and Transcutol at a ratio of (54.26: 23.81: 21.93%v/v), and it exhibited transmittance of 100%, resveratrol solubility of 159.9?±?6.4?mg/mL, globule size of 30.65?nm. The in vitro resveratrol released from nano-emulsion and nasal nano-emulgel was 96.17?±?4.43% and 78.53?±?4.7%, respectively. Ex vivo permeation was sustained during 12?h up to 63.95?±?4.7%. The histopathological study demonstrated that the formula is safe and tolerable to the nasal mucosa. C_max and AUC _(0–∞) of resveratrol obtained after nasal administration of nasal nano-emulgel was 2.23 and 8.05 times, respectively. Similarly, T_max was increased up to 3.67?±?0.82?h. The optimized nasal nano-emulgel established intranasal safety and bioavailability enhancement so it is considered as a well-designed system to target the brain.     

Examination of fatigue crack driving force parameter

Most of the previous parameters that utilized as a crack driving force were established in modifying the parameter K_op in Elber's effective SIF range ΔK_eff(=K_max?K_op). However, the parameters that replaced the traditional parameter K_op were based on different measurements or theoretical calculations, so it is difficult to distinguish their differences. This paper focuses on the physical meaning of compliance changes caused by plastic deformation at the crack tip; the tests were carried out under different amplitude loading for structural steel. Based on these test results, differences of several parameter ΔK_eff in literature are analysed and an improved two‐parameter driving force ΔK_drive(=(K_max)ⁿ(ΔK^∧)^1‐n) has been proposed. Experimental data for several different types of materials taken from literature were used in the analyses. Presented results indicate that the ΔK_drive parameter was equally effective or better than ΔK(=K_max?K_min), ΔK_eff(=K_max?K_op) and ΔK*(= (K_max)^α(ΔK⁺)^1?α) in correlating and predicting the R‐ratio effects on fatigue crack growth rate.     

Study on the Ocular Pharmacokinetics of Ion-Activated In Situ Gelling Ophthalmic Delivery System for Gatifloxacin by Microdialysis

The poor bioavailability and therapeutic response exhibited by conventional ophthalmic solutions due to rapid precorneal elimination of the drug may be overcome by the use of gel system. The present work was conducted to evaluate the relative bioavailability of ion-activated in situ ophthalmic gel of gatifloxacin by microdialysis. The conventional ophthalmic solution of gatifloxacin was used as reference. The AUC of test group is 3.8-fold vs. the reference group (1.4316 ± 0.1327 μg·mL^?1·h vs. 0.3756 ± 0.0380 μg·mL^?1·hr) (P < 0.05), and the C_max of test group vs. the control group is 3.0-fold (0.3363 ± 0.0634 μg·mL^?1 vs. 0.1112 ± 0.0151 μg·mL^?1) (P < 0.05). The T_max of test group is longer than that of reference group (2.0 ± 0.67 hr vs. 0.667 ± 0.17 hr) (P < 0.1), and K_e of test group is lower than that of reference group. The developed formulation has a higher bioavailability and longer residence time in aqueous humor than conventional ophthalmic solutions. The developed system is a viable alternative to conventional eye drops.     

In vitro–in vivo correlation study for the dermatopharmacokinetics of terbinafine hydrochloride topical cream

Background: To investigate the relationship between dermatopharmacokinetic (DPK) tape stripping from in vitro and in vivo using 1% terbinafine hydrochloride topical cream as the model formulation.

Methodology: In vitro and in vivo tape strippings were conducted on separated pig ear skin used as a biological membrane for franz diffusion cell testing and the non-hairy skin area at the ventral forearms of healthy volunteers, respectively. Terbinafine (1%) topical cream was applied to the skin for 0.5, 2, and 4?h. The drug profiles of terbinafine across the stratum corneum were determined immediately (time 0?h), and at 0.5, 1, 2, and 4?h after removing the formulation. The amounts of terbinafine were analyzed by a validated high-performance liquid chromatography-ultraviolet method. The area under the curve (AUC) and the maximum amounts of terbinafine absorption (Q_max) were obtained from pharmacokinetic software. Partition coefficient (K_SC/veh) and diffusion parameter (D/L²) were derived from the Fick’s second law equation. During the schedule time of 8?h, the deviations of in vitro and in vivo data were 6.61 and 30.46% for AUC and Q_max, respectively. There was insignificant difference of the K_SC/veh and the D/L² between excised pig ear and human skin. In addition, K_SC/veh and D/L² at T_max of 2?h were used to predict the AUC presented the value of 4.7481 %h whereas the true value calculated from pharmacokinetic software provided the value of 5.9311 %h differing from each other in approximate of 20%.

Conclusions: In vitro tape stripping using the separated pig ear skin as a viable membrane of the franz diffusion cell testing demonstrates the potential to represent in vivo tape stripping in human for topical bioavailability/bioequivalence study of terbinafine hydrochloride 1% topical cream.     

Mechanism of enhanced oral absorption of akebia saponin D by a self-nanoemulsifying drug delivery system loaded with phospholipid complex

Akebia saponin D (ASD) exhibits a variety of pharmacological activities, such as anti-osteoporosis, neuroprotection, hepatoprotection, but has poor oral bioavailability. A self-nanoemulsifying drug delivery system loaded with akebia saponin D - phospholipid complex (APC-SNEDDS) (composition: Peceol: Cremophor^® EL: Transcutol HP: ASD: phospholipid; ratio: 10:45:45:51:12.3, w:w:w:w:w) was first developed to improve the oral absorption of saponins and it was found to significantly enhance ASD’s oral bioavailability by 4.3 - fold (p?<?.01). This study was conducted to elucidate the mechanism of enhanced oral absorption of ASD by the drug delivery system of APC-SNEDDS. The aggregation morphology and particle size of ASD and APC-SNEDDS prepared in aqueous solutions were determined by transmission electron microscope and particle size analyzer, respectively. Stability of ASD and APC-SNEDDS in gastrointestinal luminal contents and mucosa homogenates were also explored. The differences of in situ intestinal permeability of ASD and APC-SNEDDS were compared. APC-SNEDDS reduced the aggregation size from 389?±?7?nm (ASD) to 148?±?3?nm (APC-SNEDDS). APC-SNEDDS increased the remaining drug in large intestine luminal contents from 47?±?1% (ASD) to 83?±?1% (APC-SNEDDS) during 4?h incubation. APC-SNEDDS provided an 11-fold increase in Ka value and an 11-fold increase in P_eff value compared to ASD. In summary, APC-SNEDDS improved ASD’s oral bioavailability mainly by increasing membrane permeability, destroying self-micelles and inhibiting the intestinal metabolism.     

Phospholipid complex as an approach for bioavailability enhancement of echinacoside

Context: Echinacoside (ECH) has been shown to possess a multitude of pharmacological activities, however, oral administered ECH failed to fulfill its therapeutic potential due to poor absorption and low bioavailability. Thus, there is a pressing need to develop a new oral dosage form to enhance its intestinal absorption and improve bioavailability.

Objective: The aim of this study was to formulate ECH into phospholipid complex (phytosome, PHY) to enhance intestinal absorption and oral bioavailability of ECH in vivo.

Methods: The PHY was prepared by a solvent evaporation method and was characterized by differential scanning calorimetry (DSC) and infrared spectroscopy (IR), and then the physicochemical properties, intestinal absorption and bioavailability of the PHY were investigated.

Results: Compared with the physical mixture (MIX) or ECH alone, the n-octanol/water partition coefficient (P) determination results showed that the lipophilicity of ECH was significantly enhanced by formation of PHY. Accordingly, the intestinal absorption rate (K_a) was improved to 2.82-fold and the effective permeability coefficient (P_eff) increased to 3.39-fold. The concentrations of ECH in rat plasma at different times after oral administration of PHY were determined by HPLC. Pharmacokinetic parameters of the PHY in rats were T_max?=?1.500?h, C_max?=?3.170?mg/mL, AUC_0–∞?=?9.375?mg/L?h and AUC_0–24?=?7.712?mg/L?h, respectively.

Conclusions: Compared with ECH alone or the MIX group, the relative bioavailability of ECH was increased significantly after formulation into PHY (p?相似文献   

Enhancing effect of Labrasol on the intestinal absorption of ganciclovir in rats

Ganciclovir (GCV), like other nucleoside analogs such as trifluridine and acyclovir (ACV), is hydrophilic, poorly permeable across membranes and orally low-bioavailable. In the present studies, Labrasol was evaluated for improving intestinal absorption of GCV through in vitro and in vivo experiments. The effect of Labrasol on absorption of GCV in rat small intestine was investigated using an in situ single-pass perfusion technique. The apparent absorptive clearance (PeA) of GCV with Labrasol in the duodenum, jejunum and ileum was 1.01, 1.28, and 1.49?mL/min/cm (n?=?6), respectively, and significant regional differences of GCV absorption among the three segments were observed (p jejunum (p duodenum (p?>?0.05). The effects of EDTA, verapamil on the permeability of GCV were conducted. The permeability of GCV was increased by EDTA, verapamil, respectively. The results indicated that paracellular absorption and efflux played important roles in GCV absorption. In vivo absorption GCV in rats was conducted. When GCV at 1?mg/kg dose was administered with Labrasol (10%, v/v), the mean AUC of was determined as 14.45?±?3.88 μg*h/mL, compared to 8.05?±?1.52 µg*h/mL without Labrasol. Based on the results, we could conclude that the absorption of GCV through GI lumen would be enhanced by Labrasol. The effect of Labrasol maybe ascribed to both (i) inhibit efflux of GCV from the enterocytes to the GI lumen; and (ii) enhance GCV absorption from the GI lumen through paracellular pathway.     

Influence of quercetin on the pharmacokinetics of ranolazine in rats and in vitro models

The aim of our study was to enhance the bioavailability of ranolazine by using herbal-bioenhancer quercetin in rats and to study the role of P-glycoprotein (P-gp) in vitro models. In single dose study (SDS), rats were divided into four groups, Group I was treated with 0.5% sodium carboxy methyl cellulose (SCMC), Group II was treated with ranolazine (14?mg/kg), Group III was treated with quercetin (20?mg/kg) and Group IV was treated with both ranolazine and quercetin. The blood samples were collected at 0.5, 1, 2, 3, 4, 6, 8 and 12?h, and the concentration of ranolazine in the plasma was estimated by reverse phase high performance liquid chromatography (RP-HPLC) method. In multiple dose study (MDS), rats were treated with same drugs for 7 days. On 8th day, the concentration of ranolazine in plasma was estimated. In vitro study performed on the rat and chick intestinal sacs to study the intestinal transport of ranolazine in the presence and absence of quercetin and verapamil (P-gp-inhibitor). Quercetin increased the peak concentration (C_max) of ranolazine from 254?±?8.45 to 324?±?10.21 and 331?±?9.65?ng/mL in SDS and MDS, respectively. Quercetin also increased area under the curve (AUC) of ranolazine from 1565.12?±?52.24 to 2016.98?±?142.65 and 2070.85?±?271.60?ng/mL/h in SDS and MDS, respectively. The transport of ranolazine from mucosal side to serosal side was increased in presence of quercetin. Quercetin is an inhibitor of CYP3A4 and P-gp. So it increased the AUC and C_max of ranolazine.     

Fabrication of novel GMO/Eudragit E100 nanostructures for enhancing oral bioavailability of carvedilol

In the present work, novel nanostructures comprising of glyceryl monooleate (GMO) and Eudragit E100 were prepared using high intensity ultrasonic homogenization. 3² Factorial design approach was used for optimization of nanostructures. Results of regression analysis revealed that the amount of GMO and Eudragit E100 had a drastic effect on particle size and percent entrapment efficiency. Optimized carvedilol-loaded nanostructures (Car-NS) were characterized by FTIR, TEM, DSC, in vitro drug release study. Pharmacokinetic parameters such as C_max, T_max, Ke, Ka, V_d and AUC were estimated for Car-NS upon its oral administration in Sprague-Dawley rats. Particle size of Car-NS was found to be 183?±?2.43?nm with an entrapment efficiency of 81.4?±?0.512%. FTIR studies revealed loading and chemical compatibility of carvedilol with the components of nanostructures. DSC thermograms did not show endothermic peak for melting of carvedilol which could be attributed to solubilization of carvedilol in molten GMO during DSC run. The prepared Car-NS released carvedilol in sustained manner over a period of 10 h as suggested by in vitro drug release study. The pharmacokinetic study of Car-NS showed significant improvement in C_max (two fold, p?p?相似文献   

Prediction of in vivo plasma concentration–time profile from in vitro release data of designed formulations of milnacipran using numerical convolution method

The aim of this study was to predict the in vivo plasma drug level of milnacipran (MIL) from in vitro dissolution data of immediate release (IR 50?mg and IR 100?mg) and matrix based controlled release (CR 100?mg) formulations. Plasma drug concentrations of these formulations were predicted by numerical convolution method. The convolution method uses in vitro dissolution data to derive plasma drug levels using reported pharmacokinetic (PK) parameters of a test product. The bioavailability parameters (C_max and AUC) predicted from convolution method were found to be 106.90?ng/mL, 1138.96?ng/mL?h for IR 50?mg and 209.80?ng/mL, 2280.61?ng/mL?h for IR 100?mg which are similar to those reported in the literature. The calculated PK parameters were validated with percentage predication error (% PE). The % PE values for C_max and AUC were found to be 7.04 and ?7.35 for IR 50?mg and 11.10 and ?8.21 for IR 100?mg formulations. The C_max, T_max, and AUC for CR 100?mg were found to be 120?ng/mL, 10?h and 2112.60?ng/mL?h, respectively. Predicted plasma profile of designed CR formulation compared with IR formulations which indicated that CR formulation can prolong the plasma concentration of MIL for 24?h. Thus, this convolution method is very useful for designing and selection of formulation before animal and human studies.     

Development and uniform evaluation of ropinirole osmotic pump tablets with REQUIP XL both in vitro and in beagle dogs

REQUIP XL, prolonged release formulation of ropinirole hydrochloride (RH) in market, could release ropinirole constantly and showed satisfactory therapeutic effect and good compliance. REQUIP XL was composed of more than 10 kinds of excipients and prepared by Geomatrix technology, which was complex and laborious. The purpose of this study was to obtain a dosage form of RH with similar in vitro release profile and bioequivalence in vivo compared to REQUIP XL. Osmotic pump tablet combined with fast release phase was selected as the delivery system of RH and similar release curves were obtained in different media. The tablets were also administered to beagle dogs and the pharmacokinetic parameters were calculated using a non-compartmental model. C_max, t_max, mean residence time (MRT), and area under the curve from 0 to 24?h (AUC_0–24) were 3.97?±?0.53?ng/mL, 3.58?±?0.49?h, 8.29?±?0.93?h, and 35.20?±?8.11?ng/mL???h for ropinirole osmotic pump tablets (ROPT) and 4.15?±?1.07?ng/mL, 2.92?±?0.49?h, 7.84?±?1.09?h, and 34.34?±?10.06?ng/mL???h for REQUIP XL. The log-transformed mean C_max and AUC_0–24 of ROPT were about 92.15% and 102.49% relative to that of REQUIP XL, respectively. The 90% confidence intervals of C_max and AUC_0–24 for ROPT were 75.69–115.31% and 88.89–122.30%, respectively. So it could be concluded that ROPT was uniform with REQUIP XL both in vitro and in beagles and the release profiles of Geomatrix technology may be obtained by osmotic pump combined with fast release technology.     

Dual-purpose vardenafil hydrochloride/dapoxetine hydrochloride orodispersible tablets: in vitro formulation/evaluation,stability study and in vivo comparative pharmacokinetic study in healthy human subjects

Erectile dysfunction (ED) is the most important disorder after premature ejaculation for sexual activity in men. Vardenafil hydrochloride (VH) is an oral therapy for the treatment of erectile dysfunction. VH oral disintegrating tablets (ODTs) have been prepared by freeze drying technique to improve its dissolution profile and the overall clinical performance. Dapoxetine hydrochloride (DH) was added to the best three formulae of the prepared VH ODTs to treat premature ejaculation. All the ODTs formulae were evaluated for weight variation, friability, drug content, in vitro disintegration time, wetting time, and the dissolution study. Gelatin as a matrix former with N-methylpyrrolidone as a solubilizer in VH/DH ODTs improved the dissolution rate and extent of release of VH and DH with 100% of drug being dissolved after 15?min. In vivo study results from six healthy male volunteers showed shorter T_max of VH from VH/DH ODT of 0.583?±?0.129?h and shorter T_max of DH from VH/DH ODT of 0.625?±?0.137?h and showed AUC_0–12 of VH from VH/DH ODT of 39.234?±?10.932?ng/ml^?h¹ and AUC_0–12 of DH from VH/DH ODT of 531.681?±?129.544?ng/ml^?h¹, with relative bioavailability values of 100.9 and 85%, respectively, compared to (Levitra^®) and (Priligy^®).     

Bortezomib-loaded solid lipid nanoparticles: preparation,characterization, and intestinal permeability investigation

Bortezomib (BTZ), a proteasome inhibitor, is clinically used for the treatment of multiple myeloma and mantle cell lymphoma via intravenous or subcutaneous administration. Since BTZ has limited intestinal permeability, in this study, solid lipid nanoparticles (SLNs) were selected as lipid carrier to improve the intestinal permeability of BTZ. The nanoparticles were prepared by hot oil-in-water emulsification method and characterized for physicochemical properties. Moreover, in situ single-pass intestinal perfusion technique was used for intestinal permeability studies. Mean particle size of the BTZ-loaded solid lipid nanoparticles (BTZ-SLNs) was 94.6?±?0.66?nm with a negative surface charge of –18?±?11?mV. The entrapment efficiency of the BTZ-SLNs was 68.3?±?3.7% with a drug loading value of 0.8?±?0.05%. Cumulative drug release (%) over 48?h, indicated a slow release pattern for nanoparticles. Moreover, the SEM image showed a spherical shape and uniform size distribution for nanoparticles. Also, FTIR analysis indicated that BTZ was successfully loaded in the SLNs. The results of the intestinal perfusion studies revealed an improved effective permeability for BTZ-SLNs with a P_eff value of about threefold higher than plain BTZ solution.     

Assessment of critical material attributes of polyethylene oxide for formulation of prolonged-release tablets

Abstract

Physicochemical evaluation of polyethylene oxide (PEO) polymers with various molecular weights was performed at molecular (polymeric dispersion) and bulk level (powders, polymeric films, and tablets) with the aim of specifying polymer critical material attributes with the main contribution to drug release from prolonged-release tablets (PRTs). For this purpose, grades of PEO with low, medium, and high viscosity were used for formulating PRTs with a good soluble drug substance (dose solubility volume 15?ml). The results revealed a good correlation (r²=0.88) between in?vivo data (pharmacokinetic parameters: C_max and AUC) and the elastic property of PEO films determined with the nanoindentation method, demonstrating that film level can also be used for the in?vivo prediction of drug dissolution. The study confirmed that polymer molecular weight and its viscosity are the most important critical material attributes affecting drug dissolution (in?vitro) and in?vivo bioavailability (e.g. C_max and AUC). Our research revealed that the nanoindentation technique can distinguish well between various types of polymers, classifying PEO as the most ductile and polyvinyl alcohol as the most brittle. Finally, our study provides an approach for the determination of exact physical attributes of PEO as a critical material attribute from clinically relevant data, and it therefore fulfills the basic principles of product development by Quality by Design.     

Sildenafil vaginal suppositories: preparation,characterization, in vitro and in vivo evaluation

Aim: The main objective was to investigate the in vitro release profile/kinetics, and in vivo plasma pharmacokinetics (PK) and organ biodistribution (BD) of the prepared sildenafil vaginal suppositories (SVS).

Methods: Suppositories containing 25?mg of sildenafil were prepared by the cream melting technique using Witepsol H-15 as a suppository base. The suppositories were characterized for weight variation, content uniformity, hardness, disintegration time and crystallinity change. The in vitro dissolution in pH 4.5, and in vivo plasma PK and organ BD of sildenafil from SVS in female Sprague Dawley rats, were also investigated.

Results: The mean weight variation, content uniformity, hardness and disintegration time of the prepared SVS were 1.127?±?0.020?g, 98.25?±?2.50%, 2.5?±?0.08?kg and 9?±?1.0?min, respectively. The release of sildenafil from the SVS was more than 90% at 30?min, with a release kinetic of Hixson--Crowell model and non-Fickian diffusion (n?=?0.464). The plasma PK study demonstrated a significantly lower C_max (～10 times) and AUC_0–24?h (～13 times) of sildenafil in plasma following intravaginal (IVG) administration of suppositories compared to oral (PO) administration of sildenafil solution. Nevertheless, the organ BD study showed a phenomenally higher C_max (～40 times) and AUC_0–24?h (～20 times) of sildenafil in uterus following IVG administration of suppositories than PO administration of sildenafil solution.

Conclusion: This study demonstrated enhanced sildenafil exposure in the uterus following IVG administration of SVS, which could be used to target the uterus for therapeutic benefits.