Dexamethasone sodium phosphate-loaded Chitosan based delivery systems for buccal application

Chitosan (CH) was used as a biocompatible and bioadhesive polymer material to prepare solid dispersions as well as hydrogels loaded with dexamethasone sodium phosphate (DSP), a steroidal anti-inflammatory agent clinically used for treatment of different mouth diseases. Binary solid dispersions at various drug-to-polymer weight ratios were prepared by freeze-drying; their direct compression gave tablets which were characterized for the swelling behaviour and drug release in vitro. Similarly, DSP-loaded hydrogels composed of CH and glycerine were prepared and characterized. CH and DSP showed a good physical compatibility. A slow and prolonged release of the drug was observed in vitro from both kinds of systems. The swelling properties of the polymer seemed to be the main parameter affecting the drug release profile from both tablets and hydrogels at the pH value of mouth. In vivo buccal application of both the systems allowed to obtain a prolonged release of DSP, as compared with a glycerine solution of the drug. From the in vitro swelling studies and in vivo test, the 2:1 CH-DSP solid dispersion in particular can be designated for further investigation.     

In vitro and in vivo evaluation of cubosomes containing 5-fluorouracil for liver targeting

The objective of this study was to prepare cubosomal nanoparticles containing a hydrophilic anticancer drug 5-fluorouracil (5-FU) for liver targeting. Cubosomal dispersions were prepared by disrupting a cubic gel phase of monoolein and water in the presence of Poloxamer 407 as a stabilizer. Cubosomes loaded with 5-FU were characterized in vitro and in vivo. In vitro, 5-FU-loaded cubosomes entrapped 31.21% drug and revealed nanometer-sized particles with a narrow particle size distribution. In vitro 5-FU release from cubosomes exhibited a phase of rapid release of about half of the entrapped drug during the first hour, followed by a relatively slower drug release as compared to 5-FU solution. In vivo biodistribution experiments indicated that the cubosomal formulation significantly (P<0.05) increased 5-FU liver concentration, a value approximately 5-fold greater than that observed with a 5-FU solution. However, serum serological results and histopathological findings revealed greater hepatocellular damage in rats treated with cubosomal formulation. These results demonstrate the successful development of cubosomal nanoparticles containing 5-FU for liver targeting. However, further studies are required to evaluate hepatotoxicity and in vivo antitumor activity of lower doses of 5-FU cubosomal formulation in treatment of liver cancer.Key words: 5-Fluorouracil, Hydrophilic drug, Cubosomes, Liver targeting, Hepatotoxicity     

Formulation and evaluation of an in situ gel forming system for controlled delivery of triptorelin acetate

The novel physical hydrogels composed of chitosan or its water soluble derivatives such as carboxymethyl chitosan (CMCh) and sodium carboxymethyl chitosan (NaCMCh) and opened ring polyvinyl pyrrolidone (OP-PVP) were used as a controlled delivery system for triptorelin acetate, a luteinizing-releasing hormone agonist. The in situ gel forming system designed according to physical interactions such as chains entanglements and hydrophilic attractions especially h-bonds of chitosan and/or NaCMCh and OR-PVP. In order to increase in situ gel forming rate the chitosan microspheres prepared through spray drying technique. The chitosan or NaCMCh/OR-PVP blends prepared at different ratios (0.05, 0.10, 0.12, 0.16, 0.20 and 0.24) and suspended in sesame oil as non-aqueous vehicle at different solid content (10-30%). The suitable ratio of polymers with faster in situ gel forming rate was selected for in vivo studies. The gel formation and drug release from the system was evaluated both in vitro and in vivo. In vitro and in vivo results were compared with Diphereline SR 3.75mg, a commercially available controlled delivery system of triptorelin. In vitro release studies showed a sustained release profile for about 192h with first order kinetics. In vivo studies on male rats by determination of serum testosterone were confirmed the acceptable performance of in situ gel forming system compared with Diphereline SR in decreasing the serum testosterone level for 35days, demonstrating the potential of the novel in situ gel forming system for controlled delivery of peptides.     

In vitro characterization and release study of Ambroxol hydrochloride matrix tablets prepared by direct compression

A series of either hydrophilic or hydrophobic polymers were used to prepare controlled release Ambroxol hydrochloride (AMX) matrix tablets by direct compression. Both the compatibility and flow properties of AMX/polymer mixtures were investigated. The effect of the amount and type of polymer on the physical properties and in vitro drug release was studied and compared to commercially available Ambroxol(?) SR capsules. A kinetic study of the release profile of AMX from the prepared matrix tablets was performed. All excipients used in the study were compatible with the model drug. AMX/drug mixtures containing sodium alginate (NA) and hydroxypropylmethyl cellulose (HPMC) showed better flow properties than other polymers used in the study. The in vitro drug release studies showed that matrix tablets formulae containing 10% HPMC (S7) or a combination of 30% NA and 5% HPMC (Ah) exhibited a higher ability to control the release of AMX. The kinetic study revealed that a diffusion controlled mechanism prevailed except when carbopol was used. Formula Ah followed a non-fickian diffusion mechanism similar to Ambroxol(?) SR capsules. Both formulae S7 and Ah could be considered as potential candidates for formulation of AMX controlled release matrix tablets.     

Development and characterization of mucoadhesive microspheres for nasal delivery of ketorolac

The objective of the present investigation was to prepare mucoadhesive microspheres of ketorolac for nasal administration by means of a solvent evaporation technique using carbopol (CP), polycarbophil (PL) and chitosan (CS) as mucoadhesive polymers. The prepared microspheres were characterized for morphology, swelling behavior, mucoadhesion, interaction studies, drug encapsulation efficiency, in vitro drug release, release kinetics, and ex vivo nasal cilio toxicity studies. The effects of various process variables on the particle size of the microspheres were investigated. Drug encapsulation efficiency and particle size of the microspheres ranged from 52-78% w/w and 14-46 microm respectively. Interaction studies revealed that there were no drug-polymer interactions. The in vitro release profiles showed prolonged-release of the drug. In vitro release data showed a good fit with the Higuchi model, and indicated Fickian diffusion. No severe damage was found to the integrity of nasal mucosa after ex vivo experiments.     

Improvement of solubility and dissolution properties of clotrimazole by solid dispersions and inclusion complexes

Solid dispersions of a slightly water-soluble drug, clotrimazole, were prepared in different weight ratios using polyethyleneglycol 4000 and different molecular weight polyvinyl pyrrolidones as carriers. Moreover, binary and ternary β-cyclodextrin complexes were prepared in different molar ratios. Both solid dispersions and β-cyclodextrin complexes were prepared by solvent evaporation technique. A phase solubility method was used to evaluate the effect of the tested carriers on the aqueous solubility of clotrimazole. The dissolution of all the preparations was tested using the USP paddle method. The selected solid dispersions and inclusion complexes were characterized by differential scanning calorimetry and X-ray powder diffractometry studies, and results clarified the role of the tested carriers in decreasing the crystallinity of clotrimazole and complexing abilities. Based on physical characters and in vitro drug release pattern, polyvinylpyrrolidone solid dispersions (1:1 weight ratio) and ternary cyclodextrin complexes (clotrimazole-β-cyclodextrin complexes with either polymer, 1:1 molar ratio) were selected as ideal batches for suppositories. Suppocire AM/50 mg carbopol 940, was chosen as a suppository base and the suppositories were prepared by molding technique. The prepared suppositories were characterized for weight variation, softening time and drug content. All these properties were found to be ideal. The in vitro drug release pattern was determined in citrate buffer (pH 4.5) containing 1% sodium lauryl sulfate. The in vitro release of clotrimazole from its solid dispersions and inclusion complexes incorporated suppositories was markedly improved when compared to the intact drug incorporated suppositories. Polyvinyl pyrrolidone solid dispersions incorporated suppositories were found to possess excellent antifungal activity.     

Formulation and evaluation of sustained release floating capsules of nicardipine hydrochloride

Nicardipine hydrochloride, a calcium channel blocker with significant vasodilating and antihypertensive activities, was formulated in this work as sustained release floating capsules. A hydrocolloid of high viscosity grade was used for the floating systems. The inclusion of sodium bicarbonate to allow evolution of CO2 to aid buoyancy was studied. Polymers that retard drug release were included as coprecipitates with the drug and/or as additives in the formulated capsules. Both simple powder mixing of the ingredients and granule preparation via wet granulation were used. Seven capsule formulae were prepared. The prepared capsules were evaluated in vitro by testing drug dissolution, floating time and the kinetics of drug release. In vitro evaluation of a commercially available conventional 20 mg capsule of nicardipine hydrochloride, "Micard", was carried out for comparison. The hydrocolloid used succeeded in effecting capsule buoyancy. Floating time increased with increasing the proportion of the hydrocolloid. Inclusion of sodium bicarbonate increased buoyancy. All of the seven floating capsule formulae prepared proved efficient in controlling drug release. The sustained release floating capsule formulation of choice was evaluated in vivo in comparison to "Micard" capsules using rabbits. Reversed phase HPLC with UV detection was used for drug determination in rabbit plasma. Plasma concentration time curves revealed a longer drug duration for administration in the sustained release formula than the conventional "Micard" capsule being 16 h in the former versus 8 h for the latter.     

Comparison of chitosan nanoparticles and chitosan hydrogels for vaccine delivery

In this work the potential of chitosan nanoparticles (CNP) and thermosensitive chitosan hydrogels as particulate and sustained release vaccine delivery systems was investigated. CNP and chitosan hydrogels were prepared, loaded with the model protein antigen ovalbumin (OVA) and characterised. The immunostimulatory capacity of these vaccine delivery systems was assessed in‐vitro and in‐vivo. Particle sizing measurements and SEM images showed that optimised OVA‐loaded CNP had a size of approximately 200 nm, a polydispersity index < 0.2, and a positive zeta‐potential of approximately 18 mV. The amount of OVA adsorbed onto CNP was high with an adsorption efficacy of greater than 96%. Raman spectroscopy indicated conformational changes of OVA when adsorbed onto the surface of CNP. Uptake of the dispersions and immunological activation of murine dendritic cells in‐vitro could be demonstrated. Investigation of the release of fluorescently‐labelled OVA (FITC‐OVA) from CNP and chitosan hydrogels in‐vitro showed that approximately 50% of the total protein was released from CNP within a period of ten days; release of antigen from chitosan gel occurred in a more sustained manner, with < 10% of total protein being released after 10 days. The slow release from gel formulations may be explained by the strong interactions of the protein with chitosan. While OVA‐loaded CNP showed no significant immunogenicity, formulations of OVA in chitosan gel were able to stimulate both cell‐mediated and humoral immunity in‐vivo.     

Resveratrol-Loaded Vesicular Elastic Nanocarriers Gel in Imiquimod-Induced Psoriasis Treatment: In Vitro and In Vivo Evaluation

This work aimed to develop a new efficient approach for safe treatment of psoriasis. To achieve that, resveratrol-loaded spanlastics(F1-F12) were prepared and evaluated by complete in vitro characterization. The two optimal formulations (F10 and F11) had their particle size in the nano range with high entrapment efficiency and sustainable drug release. These two formulae were incorporated in carbopol 934 gel formulations (G1-G8) with different concentrations of drug and carbopol 934 polymer. G1 and G5 (1% w/w Carbopol 934 gel and 0.1% resveratrol) showed 40.13% ± 2.017% and 73.76% ± 2.46%,8 hours drug release, respectively. Their pH was accepted and non-irritant. At a shear stress of 500 s^?1, G1 and G5 showed a reasonable viscosity of 1048.5 ± 2.12 cps and 954 ± 2.15 cps, respectively. In the in vivo psoriasis study, mice treated by G5 gel showed significant improvement of erythema and scaling compared to positive control group and they maintained healthy skin as shown in histopathological observations. Moreover, this group showed the least changes in mRNA expression of inflammatory cytokines. Concisely, our results suggest that selected carbopol gel of resveratrol-loaded spanlastics could maximize resveratrol topical anti-psoriatic effect.     

Ocular ciprofloxacin hydrochloride mucoadhesive chitosan-coated liposomes

The aim of this work is to improve the ocular bioavailability of ciprofloxacin hydrochloride (CPX) through the preparation of ocular mucoadhesive chitosan (CS)-coated liposomes. Liposomes were prepared by the thin film hydration technique, using different molar ratios of L-α-phosphatidylcholine (PC), cholesterol (CH), stearylamine (SA) and dicetyl phosphate (DP). CS was used to coat the optimal liposomal formulae. The prepared formulae were characterized regarding encapsulation efficiency (%EE), particle size, physical morphology and in vitro drug release. The in vivo characterization of the prepared formulae was performed through evaluating the level of CPX in the external eye tissue of nine albino rabbits. Results showed an alteration in release rate and %EE of CPX from liposomal formulae upon varying the molar ratios of the lipid bilayer composition. The optimal liposomal formulae F1 (10:0, PC:CH), F12 (10:0:0.5, PC:CH:SA) and F15 (10:0:1, PC:CH:DP), showed % EE of 38.5?±?2.10, 39.65?±?1.85 and 30.05?±?0.75 and % in vitro release after 8 hours (Q_8h) of 78.15?±?2.4, 54.07?±?2.3 and 62.14?±?2.9, respectively. In vitro drug release and in vivo results confirmed that CS-coated liposomal formulae have exhibited a higher retention of CPX. Consequently, CS-coated liposomes could be a promising approach to increase the ocular bioavailability of CPX.     

Chitosan glutamate hydrogels with local anesthetic activity for buccal application

Hydrogels for the buccal application of the anesthetic drug lidocaine hydrochloride (LDC) were prepared using chitosan glutamate (CHG), a soluble salt of chitosan, or a binary mixture of CHG and glycerin, at different weight ratios. The in vitro drug release was studied at the pH value of saliva to assess the effect of the different formulations on drug delivery. The anesthetic activity of mucoadhesive LDC-CHG hydrogels was assessed in vivo after application on the buccal mucosa, compared to commercial semisolid formulations containing the same drug. LDC-loaded hydrogels can be proposed for the symptom relief of aphthosis or other painful mouth diseases.     

硝苯地平缓释凝胶的制备工艺及其释药性能研究

目的:制备硝苯地平缓释凝胶并考察其体外释药情况。方法:采用复凝聚法制备硝苯地平缓释凝胶,以壳聚糖、海藻酸钠的浓度、搅拌速度和壳聚糖溶液与海藻酸钠溶液的体积比为因素进行正交试验;用转篮法测定所制凝胶的释放度,通过改变释放介质的pH值,考察该缓释药物对pH的敏感性。结果:最佳工艺为壳聚糖浓度0.4%、海藻酸钠浓度1.5%、搅拌速度160r.min-1、壳聚糖溶液与海藻酸钠溶液的体积比为6:1。硝苯地平缓释凝胶在pH1.5的人工胃液中4h释放度为13.43%;在pH6.8的人工肠液中4h释放度为52.30%,12h释放度为81.72%。结论:所制硝苯地平缓释凝胶具有明显的缓释作用,体外释放具有较强的pH敏感性。     

Design and evaluation of gastroretentive mucoadhesive cephalexin tablets

The aim of this investigation was to develop gastroretentive mucoadhesive tablets of cephalexin, which will retain in the stomach for 10?h. Cephalexin, a first-generation cephalosporin, becomes ionized in intestinal pH because pKa is 4.5 and thus reducing its bioavailability. The various batches were prepared by wet granulation method using variety of mucoadhesive polymers such as hydroxyl propyl methyl cellulose K4M, hydroxyl propyl cellulose, chitosan, carbopol 934P and sodium carboxymethylcellulose and subjected to various evaluation parameters such as mucoadhesive strength, in vitro drug release profile, swelling characteristics and physical properties. It was evident from the study that the formulation containing HPMC K4M and carbopol 934P in combination exhibited maximum mucoadhesive strength of 144.42?gms, in vitro residence time was 8.73?h and in vitro drug release was found to be 75.03% in 10?h with non-Fickian diffusion mechanism. So, the optimized formulation F₂ was further subjected to in vivo retention time in rabbit by X-ray technique, SEM and Accelerated stability studies. Regarding all the properties evaluated, the formulation containing HPMC K4M and carbopol 934P in combination was found to be the best to achieve the aim of this study.     

Application of novel chitosan derivatives in dissolution enhancement of a poorly water soluble drug

Solid dispersions of the poorly water soluble drug dexamethasone and newly synthesized chitosan derivatives (chitosan succinate, CS, and chitosan phthalate, CP) were prepared by spray drying. The resulting microspheres were evaluated in terms of their drug loading or encapsulation efficiency as well as drug release profile. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD) and infrared spectroscopy (IR) were used to evaluate the solid dispersion for possible interactions between drug and polymers. The pure drug was evaluated in the same manner for comparison purposes. High loading levels (>74%) were achieved using CP and CS as polymer matrices. Drug release rate was accelerated significantly upon the formation of the solid dispersions; the drug release rate was increased with increasing percentage of the chitosan derivatives in the microspheres. IR studies showed no chemical interaction while the X-ray studies showed a significant change in the crystallinity of the drug upon formation of solid dispersions.     

5-Fluorouracil in topical liposome gels for anticancer treatment--formulation and evaluation

Liposome gels bearing an antineoplastic agent, 5-fluorouracil, intended for topical application have been prepared and drug release properties in vitro have been evaluated. Different formulations of liposomes were prepared by the film hydration method by varying the lipid phase composition (PL 90H/cholesterol mass ratio) and hydration conditions of dry lipid film (drug/aqueous phase mass ratio). Topical liposome gels were prepared by incorporation of lyophilized liposomes into a structured vehicle (1%, m/m, chitosan gel base). Also, hydrogels containing different concentrations of 5-fluorouracil were prepared and drug release properties were investigated. The rate of drug release from liposome gels was found to be dependent on the bilayer composition and the dry lipid film hydration conditions. Also, liposomes embedded into a structured vehicle of chitosan showed significantly slower release than hydrogels. The drug release obeyed the Higuchi diffusion model, while liposomes acted as reservoir systems for continuous delivery of the encapsulated drug.     

Biopolymeric microparticles combined with lyophilized monophase dispersions for controlled flutamide release

Despite its short half-life, no controlled release formula of flutamide (FLT) was prepared until now. Therefore, 15 chitosan microparticle formulations were prepared for oral prolonged delivery of FLT via ionotropic gelation and emulsification-ionic gelation techniques then characterized for various parameters. FLT was successfully encapsulated into microparticles with loading capacity up to 39.98% and entrapment efficiency up to 97.16% using emulsification technique. Differential scanning calorimetry indicated that FLT was retained in a crystalline form in the microparticles prepared using ionotropic gelation whereas its crystallinity was significantly reduced using emulsification technique. Relationship between formulation variables and release behavior of FLT was explored. Chitosan microparticles prepared by ionotropic gelation showed a slower FLT release with a T(25%) of 7.9h whereas microparticles prepared by emulsification-ionic gelation under the same conditions showed a quick release profile with a T(25%) of 0.3h. Using 3 different hydrophilic carriers, immediate release FLT dispersions were prepared via lyophilization of monophase solution technique then combined with prolonged release chitosan microparticles to develop 6 controlled release formulae of FLT. A wide range of FLT release profiles were generated providing a prolonged release of drug after a suitable initial burst release.     

Design and in vitro evaluation of formulations with pH and transit time controlled sigmoidal release profile for colon-specific delivery

The primary objective of the study was to develop a pH and transit time controlled sigmoidal release polymeric matrix for colon-specific delivery of indomethacin. Tablet matrices were prepared using a combination of hydrophilic polymers (polycarbophil or carbopol) having pH sensitive swelling properties with hydrophobic polymer ethyl cellulose. The prepared matrices were characterized for physical properties and in vitro release kinetics. The presence of ethyl cellulose in a hydrophilic polymer matrix resulted in a sigmoidal in vitro drug release pattern with negligible to very low drug release in the initial phase (0–6?h) followed by controlled release for 14–16?h. The retardation in initial release can be attributed to the presence of ethyl cellulose that reduced swelling of hydrophilic polymer(s) while in the later portion, polymer relaxation at alkaline pH due to the ionization of acrylic acid units on carbopol and polycarbophil resulted in enhanced drug release. Thus, a sigmoidal release pattern was obtained that could be ideal for colonic delivery of indomethacin in the potential treatment of colon cancer.     

Preparation and characterization of spray-dried mucoadhesive microspheres of ketorolac for nasal administration

The objective of this investigation was to prepare mucoadhesive microspheres of ketorolac for nasal delivery to avoid gastrointestinal side effects of conventional dosage form. Mucoadhesive microspheres were prepared using carbopol, polycarbophil and chitosan as polymer by spray drying method. The process and formulation parameters were varied to study the effect on the yield and particle size. Microspheres were characterized for surface morphology, encapsulation efficiency, swelling behavior, mucoahesion properties, interaction studies using FTIR and DSC, in vitro drug release, ex vivo nasal cilio toxicity studies and in vivo anti-inflammatory and analgesic activity. Prepared microspheres were discrete, bulky, free flowing and showed an average encapsulation efficiency ranging from 79-92%. The results showed that the process parameters significantly affect the particle size (10.29-16.75 μm) and yield of microspheres (36.53-56.69%). Interaction studies revealed that there were no drug to polymer interactions. Prepared microspheres exhibited good swelling and mucoadhesion strength which confined the strong mucoadhesive property of microspheres. Ketorolac release from the microspheres was extended up to 8 h and exhibited fickian drug release kinetics with best fit to higuchi model. The drug loaded microspheres were found to be nontoxic to nasal mucosa. The anti-inflammatory and analgesic effects of formulation showed a significant increase (p < 0.05) in percent inhibition value of up to 8 h when compared with ketorolac. In conclusion, spray dried microspheres based on chitosan could be suitable nasal delivery system for the administration of ketorolac.     

pH敏感型羧甲基壳聚糖水凝胶的制备及体外释药考察

目的:研制一种新型羧甲基壳聚糖基pH敏感性水凝胶,考察其在药物传输体系中的应用.方法:采用钙离子交联方法制备有良好pH响应性能的羧甲基壳聚糖基水凝胶,并对其pH响应性能进行相关的表征.以磺胺嘧啶钠为模型药物,考察载药水凝胶在不同pH环境条件下(pH =2和pH =7.4)的药物释放行为.结果:所制备的羧甲基壳聚糖水凝胶具有明显的孔洞结构和良好的pH响应性能,在中性磷酸盐缓冲溶液(pH=7.4)中吸水率显著大于在酸性溶液(pH=2)中的吸水率.载有磺胺嘧啶钠的羧甲基壳聚糖水凝胶在中性磷酸盐缓冲溶液(pH=7.4)中的4h的药物累计释放率达到95％,而在酸性溶液(pH=2)中的4h的药物累计释放率却只有50％.结论:本文所制备的羧甲基壳聚糖pH敏感性水凝胶具有良好的孔隙率和pH响应性能,在口服药物传输体系中有一定的应用前景.     

Evaluation of indomethacin percutaneous absorption from nanostructured lipid carriers (NLC): in vitro and in vivo studies

The aim of this study was the evaluation, in vitro and in vivo, of indomethacin (IND) release through the skin from nanostructured lipid carriers (NLC). NLC were prepared by ultrasonication, and were characterized in order to determine drug content, and particle size; finally the NLC were processed to hydrogels (A and B). The IND release pattern from NLC hydrogels was evaluated in vitro, to determine its percutaneous absorption through excised human skin (stratum corneum and epidermis, SCE), and in vivo. To evaluate the in vivo IND release, two methods were employed: (1) the IND topical anti-inflammatory activity was determined at different time-points after its cutaneous application; in this case, the UVB-induced erythema on healthy human volunteers, chosen as inflammatory model, was monitored by reflectance visible spectrophotometry; (2) the extent of IND absorption into human skin was performed by the tape-stripping technique. The in vitro percutaneous absorption studies showed lower fluxes of IND through SCE membranes from NLC hydrogels (A and B) in comparison to an aqueous dispersion (C) and a hydro-alcoholic gel (D) both containing free IND. The findings from the former in vivo method showed that the anti-inflammatory effect, following IND topical application, was more prolonged with IND-loaded NLC gel formulation (A) if compared to formulation C and D. The results from tape stripping technique confirmed the trend obtained by the former in vivo method and indicated that IND topical bioavailability in the stratum corneum varied substantially depending upon the formulations (A-D).