Solid lipid nanoparticles bearing flurbiprofen for transdermal delivery

Topical application of the drugs at the pathological sites offer potential advantages of delivering the drug directly to the site of action and thus producing high tissue concentrations of the drug. The solid lipid nanoparticles (SLN) bearing flurbiprofen were prepared by microemulsion method by dispersing o/w microemulsion in a cold aqueous surfactant medium under mechanical stirring. The SLN gel was prepared by adding SLN dispersion to polyacrylamide gel prepared by using polyacrylamide (0.5%), glycerol (10%), and water (69.5%). Shape and surface morphology was determined by scanning electron microscopy that revealed fairly spherical shape of the formulation. Percent drug entrapment was higher in SLN dispersion in comparison to SLN gel formulations. In vitro drug release, determined using cellophane membrane, showed that SLN dispersion exhibited higher drug release compared with SLN gel formulations. Both the SLN dispersion and SLN-gel formulation possessed a sustained drug release over a 24-hr period, but this sustained effect was more pronounced with SLN-gel formulations. The percent inhibition of edema after 8 hr was 55.51 ± 0.26% in case of SLN-T4-gel, whereas flurbiprofen and SLN-T4 dispersion exhibited 28.81 ± 0.46 and 31.89 ± 0.82 inhibition of edema. The SLN-T4-gel not only decreased the inflammation to larger magnitude, but also sustained its effect.     

Formulation and evaluation of flurbiprofen microemulsion

The purpose of the present study was to investigate the microemulsion formulations for topical delivery of Flurbiprofen (FP) in order to by pass its gastrointestinal adverse effects. The pseudoternary phase diagrams were developed and various microemulsion formulations were prepared using Isopropyl Myristate (IPM), Ethyl Oleate (EO) as oils, Aerosol OT as surfactant and Sorbitan Monooleate as cosurfactant. The transdermal permeability of flurbiprofen from microemulsions containing IPM and EO as two different oil phases was analyzed using Keshary-Chien diffusion cell through excised rat skin. Flurbiprofen showed higher in vitro permeation from IPM as compared to that of from EO microemulsion. Thus microemulsion containing IPM as oil phase were selected for optimization. The optimization was carried out using 2(3) factorial design. The optimized formula was then subjected to in vivo anti-inflammatory study and the performance of flurbiprofen from optimized formulation was compared with that of gel cream. Flurbiprofen from optimized microemulsion formulation was found to be more effective as compared to gel cream in inhibiting the carrageenan induced rat paw edema at all time intervals. Histopathological investigation of rat skin revealed the safety of microemulsion formulation for topical use. Thus the present study indicates that, microemulsion can be a promising vehicle for the topical delivery of flurbiprofen.     

Solid lipid nanoparticle and microemulsion for topical delivery of triptolide.

Triptolide (TP) has been shown to have anti-inflammatory, immunosuppressive, anti-fertility and anti-neoplastic activities. However, its clinical use is restricted to some content due to its poor water solubility and some toxic effects. In order to find innovative ways for administering TP and alleviating its disadvantages, the controlled release delivery systems such as solid lipid nanoparticle (SLN) and microemulsion have been developed. In the present paper we describe the preparation and some characterization of specialized delivery systems for TP. The transdermal delivery capacity and anti-inflammatory activity were also evaluated. The results indicated that these SLN dispersions and microemulsions could serve as efficient promoters for the TP penetrating into skin. Furthermore, different formulations were optimized in this study. The best formulation of SLN dispersion consisted of 5% tristearin glyceride, 1.20% soybean lecithin and 3.60% polyethylene glycol (400) monosterate, while the best formulation of microemulsion consisted of 40% isopropyl myristate, 50% Tween-80: 1,2-propylene glycol (5:1, v/v) and water. The steady-state flux (Js) and permeability coefficient (Kp) of triptolide for the SLN dispersion of the first 6 h were 3.1+/-0.4 microg/cm2 per h and 0.0124+/-0.001 cm/h or 6.4+/-0.7 microg/cm2 per h and 0.0256+/-0.002 cm/h for the microemulsion, which was 3.45 and 7.02 times higher than those of triptolide solution, respectively. The anti-inflammatory activity of SLN dispersion was stronger than that of microemulsion in carrageenan induced rat paw edema. However, the results were the reverse in complete Frenud's adjuvant induced paw edema. Further investigations should be carried out on the toxicity of different formulations of triptolide to tissues.     

Modulation of drug release from nanocarriers loaded with a poorly water soluble drug (flurbiprofen) comprising natural waxes

In this study, flurbiprofen (FLB) Solid Lipid Nanoparticles (SLN) composed from a mixture of beeswax and carnauba wax, Tween 80 and egg lecithin as emulsifiers have been prepared. FLB was incorporated as model lipophilic drug to assess the influence of matrix composition in the drug release profile. SLN were produced by microemulsion technique. In vitro studies were performed in Phosphate Buffered Saline (PBS). The FLB loaded SLN showed a mean particle size of 75 +/- 4 nm, a polydispersity index approximately 0.2 +/- 0.02 and an entrapment efficiency (EE) of more than 95%. Suspensions were stable, with zeta potential values in the range of -15 to -17 mV. DSC thermograms and UV analysis indicated the stability of nanoparticles with negligible drug leakage. Nanoparticles with higher beeswax content in their core exhibited faster drug release than those containing more carnauba wax.     

Pluronic lecithin organogel as a topical drug delivery system

The objective of this study was to formulate and evaluate the pluronic lecithin organogel containing flurbiprofen for topical application. Different formulations of pluronic lecithin organogels were prepared by using pluronic F127, lecithin, flurbiprofen, isopropyl palmitate, water, sorbic acid, and potassium sorbate. To study the in vitro potential of these formulations, permeation studies were performed with Keshary-Chien diffusion cells. The results of the in vitro permeation studies found that release of flurbiprofen from dialysis membrane-70 was more than excised dorsal rat skin. Gelation temperature study was carried out to determine the temperature where sol-gel transformation takes place. The viscosities of different formulations were determined by using Brookfield Viscometer at 25°C, the viscosity of formulations increases as the lecithin concentration increases. Also the formulations were tested for appearance and feel psychorheologically, pH, and drug content. Interactions between the components of the gel have been investigated by differential scanning calorimetry and X-ray powder diffractometry. The optimized formulation subjected to differential scanning calorimetry shows no drug–polymer interaction. To investigate the in vivo performance of the formulations, a carrageenan-induced rat paw edema model and skin irritation study was used. The stability studies and freeze–thaw thermal cyclic test were carried out, showing no phase separation of gel, and representing gel stability. Statistical analysis of the data of animal study (anti-inflammatory activity) was done by using one way analysis of variance (ANOVA) followed by Dunnett’s test. The formulation shows a statistically significant anti-inflammatory activity and is non-irritant to skin.     

Preparation,characterization, and in vivo study of rhein solid lipid nanoparticles for oral delivery

In this study, rhein‐SLN s were successfully produced by hot homogenization followed by ultrasonication. Precirol ATO 5 in which rhein exhibited higher partition coefficient was selected for preparation of SLN s. In the dynamic light scattering, the rhein‐SLN s showed a smaller size with a mean value of 120.8 ± 7.9 nm and with zeta potential of ?16.9 ± 2.3 mV. SLN s exhibited a good stability during the period of 2 months. The SLN s indicated faster drug release with a burst release within 2 hr and followed by a sustained release with a biphasic drug‐release pattern. Comparing with the same concentration (free drug), the cellular cytotoxicity of rhein‐loaded SLN s increased significantly at the same incubation condition. In vivo, the AUC _0‐t of rhein in the form of SLN s was significantly increased and was 2.06‐fold that of suspensions group. The results showed an increased oral absorption and improved the oral bioavailability of rhein by the formulation of SLN s.     

In vitro cytotoxicity and bioavailability of solid lipid nanoparticles containing tamoxifen citrate

Abstract

The objective of this study was to evaluate the influence of solid lipid nanoparticles (SLN) loaded with the poorly water-soluble drug tamoxifen citrate (TC) on the in vitro antitumor activity and bioavailability of the drug. TC-loaded SLN were prepared by solvent injection method using glycerol monostearate (GMS) or stearic acid (SA) as lipid matrix. Poloxamer 188 or tween 80 were used as stabilizers. TC-loaded SLN (F3 and F4) prepared using GMS and stabilized by poloxamer 188 showed highest entrapment efficiency % (86.07?±?1.74 and 90.40?±?1.22%) and reasonable mean particle sizes (130.40?±?9.45 and 243.80?±?12.33?nm), respectively. The in vitro release of TC from F3 and F4 exhibited an initial burst effect followed by a sustained drug release. In vitro cytotoxicity of F3 against human breast cancer cell line MCF-7 showed comparable antitumor activity to free drug. Moreover, the results of bioavailability evaluation of TC-loaded SLN in rats compared to free TC indicated that 160.61% increase in the oral bioavailability of TC. The obtained results suggest that incorporation of the poorly water-soluble drug TC in SLN preserves the in vitro antitumor activity and significantly enhance oral bioavailability of TC in rats.     

Pluronic lecithin organogel as a topical drug delivery system

The objective of this study was to formulate and evaluate the pluronic lecithin organogel containing flurbiprofen for topical application. Different formulations of pluronic lecithin organogels were prepared by using pluronic F127, lecithin, flurbiprofen, isopropyl palmitate, water, sorbic acid, and potassium sorbate. To study the in vitro potential of these formulations, permeation studies were performed with Keshary-Chien diffusion cells. The results of the in vitro permeation studies found that release of flurbiprofen from dialysis membrane-70 was more than excised dorsal rat skin. Gelation temperature study was carried out to determine the temperature where sol-gel transformation takes place. The viscosities of different formulations were determined by using Brookfield Viscometer at 25°C, the viscosity of formulations increases as the lecithin concentration increases. Also the formulations were tested for appearance and feel psychorheologically, pH, and drug content. Interactions between the components of the gel have been investigated by differential scanning calorimetry and X-ray powder diffractometry. The optimized formulation subjected to differential scanning calorimetry shows no drug-polymer interaction. To investigate the in vivo performance of the formulations, a carrageenan-induced rat paw edema model and skin irritation study was used. The stability studies and freeze-thaw thermal cyclic test were carried out, showing no phase separation of gel, and representing gel stability. Statistical analysis of the data of animal study (anti-inflammatory activity) was done by using one way analysis of variance (ANOVA) followed by Dunnett's test. The formulation shows a statistically significant anti-inflammatory activity and is non-irritant to skin.     

Benzydamine hydrochloride buccal bioadhesive gels designed for oral ulcers: Preparation,rheological, textural,mucoadhesive and release properties

This study developed and examined the characterization of Benzidamine hydrochloride (BNZ) bioadhesive gels as platforms for oral ulcer treatments. Bioadhesive gels were prepared with four different hydroxypropylmethylcellulose (HPMC) types (E5, E15, E50 and K100M) with different ratios. Each formulation was characterized in terms of drug release, rheological, mechanical properties and adhesion to a buccal bovine mucosa. Drug release was significantly decreased as the concentration and individual viscosity of each polymeric component increased due to improved viscosity of the gel formulations. The amount of drug released for the formulations ranged from 0.76?±?0.07 and 1.14?±?0.01 (mg/cm²?±?SD). Formulations exhibited pseudoplastic flow and all formulations, increasing the concentration of HPMC content significantly raised storage modulus (G′), loss modulus (G″), dynamic viscosity (?′) at 37°C. Increasing concentration of each polymeric component also significantly improved the hardness, compressibility, adhesiveness, cohesiveness and mucoadhesion but decreased the elasticity of the gel formulations. All formulations showed non-Fickian diffusion due to the relaxation and swelling of the polymers with water. In conclusion, the formulations studied showed a wide range of mechanical and drug diffusion characteristics. On the basis of the obtained data, the bioadhesive gel formulation which was prepared with 2.5% HPMC K 100M was determined as the most appropriate formulation for buccal application in means of possessing suitable mechanical properties, exhibiting high cohesion and bioadhesion.     

Formulation and ex vivo evaluation of rofecoxib gel for topical application

The potential gastrointestinal disorders associated with oral administration of rofecoxib can be avoided by delivering the drug to the inflammation site at a sustained, concentrated level over an extended period of time. Hydroxypropylmethylcellulose (HPMC), sodium alginate and Carbopol 940 were used in an attempt to develop topical gel formulations of rofecoxib. The effects of polymer composition on the rate of drug release from the gel formulations were examined through cellulose membrane mounting on a Keshary-Chien diffusion cell. The effects of initial drug concentration and viscosity on the permeation rate of rofecoxib from the gel formulations were evaluated using rat epidermis at 37 +/- 0.5 degrees C. The anti-inflammatory activity of the rofecoxib gel formulation was evaluated using the rat hind paw edema model. The gel formulation consisting of 4% w/w sodium alginate-Carbopol 940 at 3:1 ratio was found to be suitable for topical application based on in vitro evaluation and ex vivo permeation studies. The drug permeation rate increased with an increase of the initial drug concentration in gels up to 25% w/w. An inverse relationship was observed between the in vitro drug release rate/ex vivo permeation rate and viscosity of the gel formulations. The anti-inflammatory activity of 4% w/w sodium alginate-Carbopol 940 gel containing 25% w/w rofecoxib in the rat hind paw edema model reveals that the drug was delivered to the inflammation site at a controlled level over a period of 6 h. These results suggest the feasibility of the topical gel formulation of rofecoxib.     

SLN and NLC for topical delivery of ketoconazole

The clinical use of ketoconazole has been related to some adverse effects in healthy adults, specially local reactions, such as severe irritation, pruritus and stinging. The purpose of the present work is the assessment of ketoconazole stability in aqueous SLN and NLC dispersions, as well as the physicochemical stability of these lipid nanoparticles, which might be useful for targeting this drug into topical route, minimizing the adverse side effects and providing a controlled release. Lipid particles were prepared using Compritol 888 ATO as solid lipid. The natural antioxidant alpha-tocopherol was selected as liquid lipid compound for the preparation of NLC. Ketoconazole loading capacity was identical for both SLN and NLC systems (5% of particle mass). SLN were physically stable as suspensions during 3 months of storage, but the SLN matrix was not able to protect the chemically labile ketoconazole against degradation under light exposure. In contrast, the NLC were able to stabilize the drug, but the aqueous NLC dispersion showed size increase during storage. Potential topical formulations are light-protected packaged SLN or NLC physically stabilized in a gel formulation.     

Novel Topical Ophthalmic Formulations for Management of Glaucoma

Purpose

Preparation of topical ophthalmic formulations containing brimonidine-loaded nanoparticles prepared from various biodegradable polymers—PCL, PLA and PLGA—for sustained release of brimonidine as a once daily regimen for management of glaucoma.

Methods

Nanoparticles were prepared using spontaneous emulsification solvent diffusion method then characterized regarding their particle size, zeta potential, morphology and drug contents. Brimonidine-loaded nanoparticles were incorporated into eye drops, temperature-triggered in situ gelling system and preformed gel and characterized regarding their pH, viscosity, uniformity of drug contents, in vitro release study, in vitro cytotoxicity and in vivo intraocular pressure (IOP) lowering effects.

Results

The results of optimized brimonidine-loaded PCL-, PLGA- and PLA-NPs respectively, are: particle sizes of 117.33?±?4.58 nm, 125.67?±?5.15 nm and 131.67?±?3.79 nm; zeta potentials of ?18.5?±?2.87 mV, ?21.82?±?2.7 mV and ?28.11?±?2.21 mV; and encapsulation efficiencies of 77.97?±?1.38%, 68.65?±?3.35% and 73.52?±?2.92%. TEM analyses revealed that all NPs have spherical shapes with dense core and distinct coat. In vitro release data showed a sustained release without any burst effect with Higuchi non-Fickian diffusion mechanism. Cytotoxicity studies revealed that all formulations are non-toxic. Also all formulations possessed a sustained IOP lowering effect compared to Alphagan® P eye drops.

Conclusions

Our formulations showed prolonged management of glaucoma that should meet with better patient compliance as a once-daily formulation.     

SLN and NLC for topical delivery of ketoconazole

The clinical use of ketoconazole has been related to some adverse effects in healthy adults, specially local reactions, such as severe irritation, pruritus and stinging. The purpose of the present work is the assessment of ketoconazole stability in aqueous SLN and NLC dispersions, as well as the physicochemical stability of these lipid nanoparticles, which might be useful for targeting this drug into topical route, minimizing the adverse side effects and providing a controlled release. Lipid particles were prepared using Compritol®888 ATO as solid lipid. The natural antioxidant α-tocopherol was selected as liquid lipid compound for the preparation of NLC. Ketoconazole loading capacity was identical for both SLN and NLC systems (5% of particle mass). SLN were physically stable as suspensions during 3 months of storage, but the SLN matrix was not able to protect the chemically labile ketoconazole against degradation under light exposure. In contrast, the NLC were able to stabilize the drug, but the aqueous NLC dispersion showed size increase during storage. Potential topical formulations are light-protected packaged SLN or NLC physically stabilized in a gel formulation.     

Formulation of sustained release bioadhesive minitablets containing solid dispersion of levofloxacin for once daily ocular use

This study aimed to increase ocular residence time of levofloxacin by formulation into zero-order sustained release mucoadhesive minitablets for once daily administration using a hydrophobic–hydrophilic polymeric matrix. Levofloxacin was first formulated into solid dispersion with different ratios of Eudragit^® RS then the resulting solid dispersion was mixed with different concentrations of Carbopol^® and other excipients to be finally compressed into minitablets. A 2⁴ full factorial design was employed to estimate the effects and interactions of two formulation factors, and to establish their relationships with selected responses in the developed minitablets. The studied factors were: drug to Eudragit^® RS ratio, and percent of Carbopol^® in the minitablets. Sixteen ocular minitablets formulations were prepared and evaluated for the cumulative percentages drug release at 6, 12, and 24?h, as well as mucoadhesion time, mucoadhesive strength, and swelling index as response variables. After optimizing the responses, the optimized formulation was found to be stable on sterilization using gamma-irradiation and storage at 40?°C/75% RH for six months. In vivo testing of the optimized formulation showed that the minitablets extended levofloxacin release up to 24?h without causing any ocular irritation. The optimized formulation exhibited superior microbiological activity compared to the commercial product.     

蓝萼甲素固体脂质纳米粒的制备及理化性质研究

目的:制备蓝萼甲素固体脂质纳米粒,并对其理化性质进行研究。方法:用乳化-溶剂挥发法制得蓝萼甲素固体脂质纳米粒,并对其粒径、形态、表面电位、包封率、体外释药性质等进行研究。结果:所得蓝萼甲素固体脂质纳米粒的粒径分布均匀,平均粒径为(190±10·3)nm,Zeta电位为—31·2mV,平均包封率为(50·45±0·804)%;药物体外释放符合Higuchi线性方程,具有显著缓释作用。结论:固体脂质纳米粒可作为蓝萼甲素新型缓释给药系统。     

盐霉素钠纳米脂质体的制备及表征

目的制备并表征盐霉素钠纳米脂质体(SLN)。方法采用薄膜分散法制备盐霉素钠纳米脂质体,通过调节脂质体中胆固醇比例,以盐霉素钠包封率为评价指标,筛选盐霉素钠纳米脂质体的优化处方。结果透射电镜显示盐霉素钠纳米脂质体形态圆整,分散性良好,激光粒度仪显示盐霉素钠纳米脂质体平均粒径为99.0nm,Zeta电位为-33.5mV,包封率为85.7%,载药量为6.7%。通过脂质体包裹,盐霉素钠在水中的最高浓度可提高15倍,并证明其具有一定缓释效果。结论笔者得到了粒径大小在100nm左右,形态均一,包封率和载药量较高的盐霉素钠纳米脂质体,为进一步测定其杀伤肿瘤活性奠定了坚实的制剂学基础。     

Preparation and evaluation of flurbiprofen-loaded microemulsion for parenteral delivery.

The purpose of this study was to improve the solubility of flurbiprofen, a poorly water-soluble drug, in an oil-in-water (o/w) microemulsion that is suitable for parenteral administration. Microemulsions with varying ratios of oil to surfactant were prepared with ethyl oleate, Tween 20 and isotonic solution. The effect of formulation variables on the particle size of microemulsion and solubility of flurbiprofen in microemulsion system was investigated. The pharmacokinetic parameters of flurbiprofen after intravenous administration of flurbiprofen-loaded microemulsion were compared with those of a solution of the drug. The mean droplet diameter of microemulsion containing less than 1% (w/w) of flurbiprofen was below 100 nm. The maximum solubility of flurbiprofen in the microemulsion system was found to be 10 mg/ml. However, the mean droplet diameters of flurbiprofen-loaded o/w microemulsions tend to be increased at room temperature. The pharmacokinetic parameters of flurbiprofen after intravenous administration of flurbiprofen-loaded microemulsion to rats were not significantly different from those of flurbiprofen in phosphate-buffered saline solution. It can be concluded that microemulsions of flurbiprofen prepared with ethyl oleate and Tween 20 can be used as a parenteral drug carrier for this and other poorly water-soluble drugs, provided that physical stability can be properly addressed. Copyright     

Rheological and in vitro release behaviour of clotrimazole-containing aqueous SLN dispersions and commercial creams

Clotrimazole is a wide spectrum local imidazolic antifungal agent used in several dermatological creams, having e.g. 1% (m/m) such as Canesten and Fungizid-ratiopharm cream. In the present work, a new system based on solid lipid nanoparticles (SLN) containing the identical concentration of drug has been developed. A comparative study between the rheological properties of the referred creams and the developed aqueous SLN dispersions was carried out. The influence of incorporation of SLN in a standard hydrophilic cream on its flow curves was also assessed. In addition, the release of clotrimazole from the two commercial creams, as well as from aqueous SLN dispersions was studied. Concerning the rheological investigations, all tested commercial creams revealed very low shear rates and no yield points. Lipid nanoparticles having a mean diameter of approx. 200 nm have been incorporated into a hydrophilic cream, in a concentration of 20%, 30% or 40% (m/m). The hydrophilic cream containing 20% of SLN showed a dilatant-like character; however, increasing the percentage of incorporated lipid nanoparticles to 30% and 40% the formulation changed to a more pseudoplastic character, showing yield values of 28 Pa and 39 Pa, respectively. For in vitro release studies, Franz diffusion cells with a cellulose acetate membrane were used to measure the release of clotrimazole from two different commercial formulations in comparison to the aqueous SLN dispersion. After 6 h the amount of drug released was higher than 48% when delivered from both investigated commercial formulations and not higher than 25% when delivered from the aqueous SLN dispersion. The percentage of drug released determined after 24 h was more than 50% for Canesten cream and Fungizid-ratiopharm cream and not higher than 30% for the developed SLN formulation showing its prolonged release character.     

Enhanced skin permeation of rofecoxib using topical microemulsion gel

Microemulsion gels containing rofecoxib and rofecoxib solid dispersion with polyethylene glycol (PEG) 4000 were prepared for the study of rapid percutaneous absorption. The solubility of rofecoxib in oil phase of microemulsion, e.g., isopropyl myristate, was increased by the addition of dimethyl formamide and ethanol. Topical microemulsion gels (MEGs) were prepared by using neat rofecoxib as well as its solid dispersion to compare the efficacy of individual MEG with conventional gel (CG). MEGs showed better spreadability than CG and also showed increased globular size with increasing concentration of the oil phase. The release of rofecoxib through dialysis membrane and excised rat abdominal skin was affected by the size of the oil globule in MEGs. Rofecoxib release was higher for MEGs when compared to CG. MEGs containing rofecoxib‐PEG 4000 solid dispersion exhibited higher cumulative drug permeation when compared to MEG containing neat rofecoxib. MEGs containing rofecoxib‐PEG 4000 solid dispersion exhibited faster antiinflammatory activity than CG. Drug Dev. Res. 63:33–40, 2004. © 2004 Wiley‐Liss, Inc.