Poloxamer Gel Research Articles

Preparation and Evaluation of Chloramphenicol as Thermosensitive Ocular in- situ Gel

The purpose of this study was to develop poloxamer-based in-situ gel of chloramphenicol aiming to increase bioavailability and prolong corneal contact time, controlling drug release, and enhancing ocular bioavailability. The in-situ gel was prepared using different concentrations of poloxamer 407 combined with hydroxypropyl methyl cellulose (HPMC) or carbapol 940 to achieve gelation temperature about physiological temperature and improve rheological behavior and gelling properties of poloxamer gel. The prepared formulations were evaluated for their appearance, pH, and sol-gel transition temperature. The formulations F2, F3, and F5 have a gelation temperature within the accepted range 35-370C and were evaluated for their isotonicity, rheological studies, ocular irritation test, sterility and release studies. The selected formulations (F2,F3, and F5) isotonic, pseudoplastic, non irritant, pass sterility test, and the in vitro release demonstrated a diffusion-erosion controlled release of chloramphenicol over a period of 4 hr., 6 hr., and 6 hr. respectively.
 Key words: Chloramphenicol, in-situ gel, ocular dosage form, poloxamer.

Influence of Testing Parameters on In Vitro Tramadol Release from Poloxamer Thermogels using the Immersion Cell Method.

The immersion cell is an in vitro performance test of drug release from semisolids. Several studies made use of immersion cells to investigate drug release from thermosensitive Poloxamer-based gels; however, specifications on the parameter setting are not yet available. Therefore, the aim of this study was to evaluate the influence of testing parameters on tramadol (a model drug) release, release rate, and dissolution efficiency (DE) from Poloxamer gels, using immersion cells. The thermosensitive gelling formulation showed batch-to-batch uniformity of gelling behavior, drug content, and drug release. The use of a membrane in the immersion cell resulted in slower drug release as compared to the absence of a membrane. Moreover, the faster the paddle rotation, the faster the drug release was. Membrane thickness showed a strong and significant linear relationship with corresponding DE values (Pearson's correlation coefficient, r=-0.9470; p=0.004). Factors that did not influence drug release include paddle position, i.e., distance between paddle and membrane, as well as membrane mean pore size. This study sets forth the importance of carefully controlling the following parameters including presence/absence of membrane, paddle rotation speed, and membrane thickness during the setup of release experiments from gels using immersion cells.

Poloxamer-Based Thermoreversible Gel for Topical Delivery of Emodin: Influence of P407 and P188 on Solubility of Emodin and Its Application in Cellular Activity Screening.

Emodin is a component in a Chinese herb, Rheum officinale Baill, traditionally used for diabetes and anticancer. Its poor solubility is one of the major challenges to pharmaceutical scientists. We previously reported on thermoreversible gel formulations based on poloxamer for the topical delivery of emodin. The present study was to understand the effect of poloxamer type on emodin solubility and its application in cellular activity screening. Various gel formulations composed of poloxamer 407 (P407), poloxamer 188 (P188) and PEG400 were prepared and evaluated. Major evaluation parameters were the gelation temperature (Tgel) and solubility of emodin. The emodin solubility increased with increasing poloxamer concentration and the Tgel was modulated by the proper combination of P407. In particular, this study showed that the amount of P407 in thermoreversible poloxamer gel (PG) was the dominant factor in enhancing solubility and P188 was effective at fixing gelation temperature in the desired range. A thermoreversible emodin PG was selected as the proper composition with the liquid state at room temperature and gel state at body temperature. The gel showed the solubility enhancement of emodin at least 100-fold compared to 10% ethanol or water. The thermoreversible formulation was applied for in vitro cellular activity screening in the human dermal fibroblast cell line and DLD-1 colon cancer cell line after dilution with cell culture media. The thermoreversible gel formulation remained as a clear solution in the microplate, which allowed reliable cellular activity screening. In contrast, emodin solution in ethanol or DMSO showed precipitation at the corresponding emodin concentration, complicating data interpretation. In conclusion, the gel formulation is proposed as a useful prototype topical formulation for testing emodin in vivo as well as in vitro.

Development and evaluation of midazolam in situ nasal gel properties in presence of solubility enhancers at cilia-friendly pH

Midazolam (MDZ) is a short acting benzodiazepine not only used in treatment of pediatric status epilepticus but also is the most common preoperative sedative-agent in many surgical processes especially in children. According to MDZ hydrophobic characteristics at physiological-pH, its commercial parenteral aqueous solution is formulated in acidic pH that may cause pain and inflammation at administration-site. Alternatively, it is administered orally especially in children, however its bitter taste results low patient-compliance. Nasal route shows better acceptance than oral route. Considering fast clearance and frequent administration of nasal solutions, the mucoadhesive gels are considerable. According to MDZ poor aqueous solubility at physiologic pH (≈6) and nasal dose volume limitation, MDZ solubility enhancement techniques evaluation seems to be necessary in mucoadhesive gel formulation. Solubilized MDZ gel at physiologic pH -as a replacement of commercial acidic parenteral formulations- not only can improve MDZ residence-time in nasal-cavity but also reduces nasal administered volume. In this study, thermosensitive Poloxamer407 used as in situ gel-forming agent in various concentrations in presence of different solubility enhancers such as propylene glycol (P.G), polyethylene glycol400 (PEG400) and β-cyclodextrin (β-CD) in various amounts. MDZ solubility and gelation properties of different gel formulations were evaluated. Results showed Poloxamer gel containing P.G, enhanced MDZ solubility at nasal physiologic-pH up to 15.1 fold. Optimized nasal gel formulation indicated acceptable gelation-temperature (34±0.5 °C), gelation-capacity (1.5±0.10 min) with shearthinning pattern, which released MDZ within 1hour. Rat nasal histopathological showed no damage within 3 hours after nasal administration of MDZ nasal-gel. Stability tests of MDZ nasal-gel were acceptable over 90 days.

Evaluation of the Performance of an Ophthalmic Thermosensitive Hydrogel Containing Combination of Suramin and Bevacizumab.

Suramab (SUM) is a new pharmaceutical combination made up of suramine (SUR) and bevacizumab (BVM), which showed a high synergistic effect when administered jointly. As the pharmaceutical vehicle, poloxamer aqueous dispersions were used since this system is able to maintain their fluidity at low temperatures (<15ºC) but which become gel in the corporal environment (>35ºC). In the present study we aimed at evaluating the effect of Poloxamer to prolong the effect of SUM. These formulations were characterized using rheological, biopharmaceutical (drug release) and morphological (SEM) technique. Corneal NV was induced in Sprague Dawley rats Corneal. At 15 days of follow up animals were sacrificed and perfused with black drawing ink. Digital photographs were taken and the area of neovascularisation (ANV) was calculated using the image programmed. The rheological behavior was influenced by the addition of drugs, resulting in a decrease in the gelation temperature (Tsol/gel). Both drugs were released from poloxamer gels by means of an anomalous mechanism. However, BVM was released faster than SUR, with their combination (SUM) to appearing to reduce delivery, probably due to interactions between the drugs or with the polymeric matrix. The in vivo studies showed that SUM-poloxamer gel was able to increase the corneal antiangiogenic effect compared to the SUM solution and BVM alone at 15 days of follow-up. Furthermore no injurious effects were observed in the histological tissue examination after drug administration. The presence of Poloxamer, known to modulate control release of biological agents, seems to have a favorable effect on SUM subconjunctival administered.

Development and validation of an analytical method using High Performance Liquid Chromatography (HPLC) to determine ethyl butylacetylaminopropionate in topical repellent formulations

ABSTRACT Diseases caused by insects are frequent in poor countries, leading to epidemic scenarios in urban areas; e.g., Dengue, Zika and Chikungunya. For this reason, the development of a safe and efficient topical formulation is essential. Ethyl butylacetylaminopropionate (EB) is a mosquito repellent developed by Merck, which is used in products for adults, children and especially babies, due to its low allergenic potential. The aim of this work was to validate an analytical methodology to quantify EB in a new poloxamer-based formulation by high-performance liquid chromatography (HPLC). The quantification methodology was performed at 40 oC using a Kromasil reverse-phase column (C18), with the dimensions of 250 x 4.6 mm. The mobile phase was acetonitrile:water (1:1) at a 1.0 mL/min flow-rate. The detector wavelength was set at 218 nm to detect EB. The methodology was considered validated since the results indicated linearity (R2>0.99), specificity, selectivity, precision and accuracy (active recovery between 98% and 102%). It also presented limits of detection and quantification of 0.255 µg/mL and 0.849 µg/mL, respectively. The present study demonstrated the EB vehiculated in poloxamer gel is promising as a new insect repellent formulation, since it could be quantified and quality control evaluated.

Subconjunctival antimicrobial poloxamer gel for treatment of corneal ulceration in stranded California sea lions (Zalophus californianus).

Corneal ulcers are commonly encountered in pinnipeds. Prolonged oral antibiotics and topical ophthalmic solutions may not be practical to administer, and novel treatment techniques are desired. Thermodynamic gels are a potential solution because they hold antimicrobials at the site of injection, slowly releasing drug. This study investigated the clinical efficacy of antibiotic-impregnated poloxamer gel in management of corneal ulceration. Twenty-six California sea lions undergoing rehabilitation at The Marine Mammal Center. A poloxamer gel mixed with 2% enrofloxacin was subconjunctivally injected in the treatment group. Control animals received oral doxycycline. Systemic anti-inflammatories and analgesics were administered as needed. Corneal examinations under general anesthesia were repeated weekly, and included sampling for bacterial culture and corneal cytology, collection of high-quality corneal images, and treatment administration until the ulcers were healed. There was no gross or histologic evidence of a localized tissue reaction to the gel administration in the conjunctiva, and no evidence of systemic reaction to therapy in animals that died due to unrelated causes during the study period (n = 17). In animals that experienced a superficial corneal ulcer involving only epithelium or superficial stroma (n = 12), all lesions resolved completely, in both treatment and control groups. Of those animals with deeper or more complex ulcers involving keratomalacia or descemetoceles (n = 15), four demonstrated complete lesion resolution (all four received gel treatment). This study demonstrates that subconjunctival antibiotic poloxamer gel administration is a safe and effective alternative therapeutic option to traditional treatments for superficial corneal ulceration in pinnipeds.

Controlled release ibuprofen-poloxamer gel for epidural use – A pharmacokinetic study using microdialysis in pigs

In order to avoid the risks of sideeffects of epidural local anesthetics and opioids, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) epidurally would be an interesting option of analgesic therapy. The fairly short duration of action of spinally administered NSAIDs, e.g., ibuprofen, may be prolonged by using controlled release poloxamer gel formulation. Using a microdialysis technique we studied the epidural and intrathecal pharmacokinetics of ibuprofen after its epidural administration as a poloxamer 407 formulation or a solution formulation. In addition, plasma ibuprofen concentrations were analyzed from central venous blood samples. Ibuprofen concentrations in the epidural space were significantly higher and longer lasting after the epidural gel injection compared with the epidural solution injection. The epidural AUC of ibuprofen was over threefold greater after epidural ibuprofen gel injection compared with the ibuprofen solution injection (p<0.001). The systemic absorption of ibuprofen from 25% poloxamer 407 gel was very low. The in situ forming poloxamer gel acted as a reservoir allowing targeted ibuprofen release at the epidural injection site and restricted ibuprofen molecules to a smaller spinal area. Ibuprofen diffusion from the epidural space to the intrathecal space was steady and prolonged. These results demonstrate that the use of epidurally injectable poloxamer gel can increase and prolong ibuprofen delivery from epidural space to the CSF enhancing thus ibuprofen entry into the central neuroaxis for spinal analgesia. Further toxicological and dose-finding studies are justified.

Optimization of thermoreversible poloxamer gel system using QbD principle

The objective of this study was to optimize thermoreversible gel formulations with respect to their gelation temperature and solubilizing capacity, using quality by design (QbD) principles based on design of experiment (DoE). Independent variables, X1, X2 and X3, represent the weight percentages of poloxamer 407 (P407), poloxamer 188 (P188) and the polyethylene glycol 400, respectively (these polymers are either thermoreversible gelling agents or solubilizers). Emodin, a poorly water-soluble compound, was used as a model drug. Fifteen gel formulations were prepared based on the compositions generated by an extreme vertices type of mixture design using a DoE software, in which their gelation temperatures (Y1) and emodin solubility (Y2) were measured. The gelation temperature and emodin solubility were each described adequately using a full cubic model and a quadratic model, respectively. Theoretical and experimental responses showed linearity with R2=0.9943 for the gelation temperature and R2=0.9629 for emodin solubility. The design space was established from the models describing the gelation temperature (test accuracy: 104.5%) and emodin solubility (test accuracy: 96.6%). This study demonstrates successful application of DoE for prediction of gelation temperature and solubility of emodin thermoreversible poloxamer gel (PG). In conclusion, the present DoE approach has led to the establishment of a design space and manufacturing control strategy for gel formulations.

Fluconazole-loaded niosomal gels as a topical ocular drug delivery system for corneal fungal infections

Non-ionic surfactant vesicles containing fluconazole (FLZ) were prepared using, span 60 or span 80 and cholesterol in weight ratios of 1:1, 2:1 and 1:2. The prepared vesicles were characterized for size, entrapment efficiency, and in vitro drug release. The drug encapsulation efficiencies varied from 40.0% to 84.35%. The particle size ranged from 140 to 280 nm. Higher encapsulation was obtained by the span 60: cholesterol ratio of 2:1, which showed the best drug release. The selected niosomal formulations were incorporated into poloxamer 407 and chitosan gel formulations. Drug release from niosomal dispersions and niosomal gels, permeation of drug from niosomal gels through goat cornea and its antifungal activity were evaluated. Results showed that the surfactant: cholesterol ratio had a significant effect on the encapsulation efficiency and the size of vesicles. The niosomes prepared with 2:1 surfactant: cholesterol showed superior release over the other niosomal formulations. The drug release and permeation from poloxamer gel were higher than that from chitosan gel. Permeation study showed that, the flux of drug was dependent on the viscosity of the gel. The selected niosomal gels had excellent antifungal activity where the poloxamer niosomal gel was more effective compared to chitosan niosomal gel.

Effect of mechanical properties on the release of meloxicam from poloxamer gel bases.

Thermoreversible gel of meloxicam, efficient for the treatment of joint diseases, was aimed to prepare for night application available for chronotherapy in this study. Poloxamer 407 and 188 polymers were used at 20-30% w/w as a vehicle in combination with different additives (polyvinylmethylether maleic anhydride copolymer, hydroxypropyl methylcellulose, polyethylene glycol 400, dimethyl sulfoxide, sodium chloride). Characterisation of prepared gels was evaluated by viscosity and texture analysis, and the effect of formulation variables on the gel formulations were evaluated by in vitro drug release and erosion studies. Between the investigated gel bases, Poloxamer 407-hydroxypropyl methylcellulose gel was found to be ideal due to its gel strength (1.560±0.0135 N), viscosity (312.3±2.06 cP) and release characteristics. These promising results could be encouraging for further studies to make it an alternative to commercial dosage forms.

Radiolabeling and cell incorporation studies of gemcitabine HCl microspheres on bladder cancer and papilloma cell line

In the present study incorporation differences between the developed formulations for treatment for bladder cancer was investigated by radioactive cell culture studies. Developed bioadhesive microspheres (MS) and gemcitabinehydrochloride loaded MS (GHCl-MS) were radiolabeled. After observing the optimum labeling conditions, 99mTc-MS and 99mTc-GHCl-MS were loaded to the chitosan gel (CG) and poloxamer gel. The in vitro cell incorporation affinity of newly developed formulations to bladder papilloma (RT4) and the carcinoma (T24) cell lines was investigated. Cell culture studies results indicate that the use of prolonged release bioadhesive CG formulation was highly improved the targeting of the GHCl to the cancer cells.

Chitosan-clodronate nanoparticles loaded in poloxamer gel for intra-articular administration

This work was based on the study of an intra-articular delivery system constituted by a poloxamer gel vehiculating clodronate in chitosan nanoparticles. This system has been conceived to obtain a specific and controlled release of clodronate in the joints to reduce the arthritis rheumatoid degenerative effect. Clodronate (CLO) is a first-generation bisphosphonate with anti-inflammatory properties, inhibiting the cytokine and NO secretion from macrophages, therefore causing apoptosis in these cells. This is related to its ability to be metabolized by cells and converted into a cytotoxic intermediate as a non-hydrolysable analogue of ATP. Chitosan (CHI) was used to develop nanosystems, by ionotropic gelation induced by clodronate itself. A fractional factorial experimental design allowed us to obtain nanoparticles, the diameter of which ranged from 200 to 300nm. Glutaraldehyde was used to increase nanoparticle stability and modify the drug release profile. The zeta potential value of crosslinked nanopaparticles was 21.0mV±1.3, while drug loading was 31.0%±5.4 w/w; nanoparticle yield was 18.2%±1.8 w/w, the encapsulation efficiency was 48.8%±9.9 w/w. Nanoparticles were homogenously loaded in a poloxamer sol, and the drug delivery system is produced in-situ after local administration, when sol become gel at physiological temperature. The properties of poloxamer gels containing CHI-CLO nanoparticles, such as viscosity, gelation temperature and drug release properties, were evaluated. In vitro studies were conducted to evaluate the effects of these nanoparticles on a human monocytic cell line (THP1). The results showed that this drug delivery system is more efficient, with respect to the free drug, to counteract the inflammatory process characteristic of several degenerative diseases.

Design and evaluation of an intravesical delivery system for superficial bladder cancer: preparation of gemcitabine HCl-loaded chitosan-thioglycolic acid nanoparticles and comparison of chitosan/poloxamer gels as carriers.

This study aimed to develop an intravesical delivery system of gemcitabine HCl for superficial bladder cancer in order to provide a controlled release profile, to prolong the residence time, and to avoid drug elimination via urination. For this aim, bioadhesive nanoparticles were prepared with thiolated chitosan (chitosan–thioglycolic acid conjugate) and were dispersed in bioadhesive chitosan gel or in an in situ gelling poloxamer formulation in order to improve intravesical residence time. In addition, nanoparticle-loaded gels were diluted with artificial urine to mimic in vivo conditions in the bladder and were characterized regarding changes in gel structure. The obtained results showed that chitosanthioglycolic acid nanoparticles with a mean diameter of 174.5±3.762 nm and zeta potential of 32.100±0.575 mV were successfully developed via ionotropic gelation and that the encapsulation efficiency of gemcitabine HCl was nearly 20%. In vitro/ex vivo characterization studies demonstrated that both nanoparticles and nanoparticle-loaded chitosan and poloxamer gels might be alternative carriers for intravesical administration of gemcitabine HCl, prolonging its residence time in the bladder and hence improving treatment efficacy. However, when the gel formulations were diluted with artificial urine, poloxamer gels lost their in situ gelling properties at body temperature, which is in conflict with the aimed formulation property. Therefore, 2% chitosan gel formulation was found to be a more promising carrier system for intravesical administration of nanoparticles.

Terbinafine hydrochloride loaded liposome film formulation for treatment of onychomycosis: in vitro and in vivo evaluation

Onychomycosis is a fungal infection of nail unit that is caused by dermatophytes. Oral Terbinafine hydrochloride (TBF-HCl) is being used for the treatment of onychomycosis since 24 years. The side effects caused by the systemic application and limitations of topical administration of this drug regarding the diffusion through nail lead to the development of a new formulation based on, TBF-HCl-loaded liposome. The newly obtained film formulations were prepared and characterized via several parameters, such as physical appearance, drug content, thickness, bioadhesive properties and tensile strength. In vitro and ex vivo permeation studies were performed to select an optimum film formulation for antifungal activity to show the efficiency of formulations regarding the treatment of onychomycosis. The in vitro release percentages of drug were found 71.6 ± 3.28, 54.4 ± 4.26, 56.1 ± 7.48 and 46.0 ± 2.43 for liposome loaded pullulan films (LI-P, LII-P) and liposome loaded Eudragit films (LI-E, LII-E), respectively. The accumulated drug in the nail plates were found 31.16 ± 4.22, 24.81 ± 5.35, 8.17 ± 1.81 and 8.92 ± 3.37 for LI-P, LII-P, LI-E and LII-E, respectively, which within therapeutic range for all film formulations. The accumulated drug in the nail plate was found within therapeutic range for all film formulations. The efficacy of the selected TBF-HCl-loaded liposome film formulation was compared with TBF-HCl-loaded liposome, ethosome, liposome poloxamer gel and ethosome chitosan gel formulations. It was found that TBF-HCl-loaded liposome film formulation had better antifungal activity on fungal nails which make this liposome film formulation promising for ungual therapy of fungal nail infection.

Preparation of SLN-containing Thermoresponsive In-situ Forming Gel as a Controlled Nanoparticle Delivery System and Investigating its Rheological, Thermal and Erosion Behavior.

Various nanoparticles have been investigated as novel drug delivery systems, including solid lipid nanoparticles (SLNs). Due to their rapid clearance from systemic circulation, nanoparticles do not provide sustained action in most cases. Different strategies have been employed to overcome this problem. In this direction, the present study introduces erodible in-situ forming gel systems as potential vehicles for prolonged release of SLNs. SLNs were prepared by solidification of an oil-in-water microemulsion containing stearic acid, surfactants and co-surfactants. Nanoparticles were then dispersed in a thermosensitive Poloxamer 407 aqueous solution (sol) at 4 °C and their effects on gel forming ability, sol-gel transition and rheological behavior of the system were investigated over 5-50 °C. Thermal behavior of the system was investigated by differential scanning calorimetry too. Erosion rate of the gel in the presence and absence of SLN was measured by gravimetric method. Integrity of SLNs in the system was investigated by scanning electron microscopy (SEM) and particle size analysis. SLN showed particle size and zeta potential of 130 ± 1.39 nm and - 44 ± 2.1 mV respectively. Particle size analysis and SEM studies after gel erosion revealed presence of intact SLN in the hydrogel. SLN reduced erosion rate of Poloxamer gel and increased its sol-gel transition temperature from 26 to 29 °C. However, gelling kinetic did not change significantly after addition of SLN. Damping factor <1 indicated stability of the SLN-containing system. Present results indicate potential of sol-gel systems for controlled nanoparticle delivery and show that SLN affects properties of the system.

Anti-inflammatory effects of a novel ricinoleic acid poloxamer gel system for transdermal delivery

Our previous study showed that the use of ricinoleic acid as an oil phase resulted in the formation of a stable pluronic lecithin organogel (PLO gel) with better thixotropic properties and higher permeation of ketoprofen than the isopropyl palmitate PLO gel. This study aims to evaluate and compare the in vitro and in vivo anti-inflammatory effects of the ricinoleic acid PLO gel system with isopropyl palmitate PLO gel. Ketoprofen was used as a model drug. In vitro anti-inflammatory activity and cell viability tests were performed in human rheumatoid arthritis synovial fibroblast cell line using a blank ricinoleic acid PLO gel and compared to that of the isopropyl palmitate PLO gel. In vivo anti-inflammatory activity of ricinoleic acid PLO gel containing 10% ketoprofen was evaluated and compared with the isopropyl palmitate PLO gel in a carrageenan-induced rat paw edema model. The results from the in vitro study showed that the blank ricinoleic acid PLO gel possessed significantly higher anti-inflammatory activity than isopropyl palmitate PLO gel at 1mM concentration (p<0.05), while both the gel formulations had no significant cytotoxic activity. Further in vivo testing of the formulation showed that the ricinoleic acid PLO gel formulation was significantly more effective in reducing pain and edema when compared to the isopropyl palmitate PLO gel. In addition, the ricinoleic acid PLO gel formulation markedly inhibited the synthesis of prostaglandin E2. In conclusion, the efficacy of PLO gels used in pain management may be enhanced by using ricinoleic acid instead of isopropyl palmitate as an oil phase.

Hemostatic effect and distribution of new rhThrombin formulations in rats.

Recombinant human thrombin (rhThrombin) is a potential hemostatic alternative to bovine and human plasma-derived thrombin. Hemostatic, liver regeneration effect and plasma concentrations of rhThrombin (SCILL) tested in the form of solution and hydrogels (thermo-sensitive poloxamer gel and carbomer gel; hameln rds) were evaluated.In the bleeding model, rhThrombin was applied locally on the bleeding site. The time to hemostasis was measured. The rhThrombin in liquid form as well as the thermo-sensitive gel forming formulation significantly reduced the bleeding time in comparison to saline. In the regeneration model, a cut in the form “V” was made on the liver and rhThrombin in both formulations was applied at defined concentrations to the wound for 5 min. The rats survived 1, 3 and 5 days after the injury and treatment. Histological examination showed better results in the group treated with rh Thrombin gel in comparison to the liquid form – solution; differences were insignificant.Low [125I]-rhThrombin radioactivity was evaluated in plasma after topical application (solution and both hydrogels) at hemostatic effective doses to partial hepatectomy in rats. Locally applied rh Thrombin on the rat damaged liver tissue never reached pharmacologically active systemic levels. The plasmatic levels and the content of this active protein in injured liver tissue were lower after application of its hydrogels versus solution.

Preclinical evaluation of a ricinoleic acid poloxamer gel system for transdermal eyelid delivery.

Our previous study has shown that pluronic lecithin organogel (PLO gel) made of ricinoleic acid has the potential for use as a transdermal eyelid delivery system. The present study deals with the evaluation of ocular tissue concentrations of dexamethasone in a rabbit model following topical application of the gel formulation onto the eyelids. The PLO gel formulation containing dexamethasone was applied to the outside of the eyelid skin. Rabbits were sacrificed at regular time intervals of 2, 4, 8, 12, 20 and 24h. Maxidex(®) eye drops were used as a control. Rabbits were sacrificed and dexamethasone concentrations were analyzed in anterior segment tissues such as the cornea, conjunctiva, aqueous humor, lens, and iris-ciliary body by liquid chromatography tandem mass spectrometry (LC-MS/MS). Rabbit eyes were also examined for ocular irritation and scored using the modified Draize scoring system. No significant irritation or redness was observed in the eyes as compared to the control rabbit eyes. PLO gel formulation resulted in constant dexamethasone concentrations in the anterior segment tissues for up to 24h, which was equivalent or higher than Maxidex(®) eye drops. The findings of this investigation indicate that the ricinoleic acid PLO gel formulation may be clinically effective as a new treatment modality for anterior segment diseases.

Development and characterization of a ricinoleic acid poloxamer gel system for transdermal eyelid delivery

Objective: This study deals with the preparation and evaluation of a pluronic lecithin organogel (PLO gel) containing ricinoleic acid for the transdermal eyelid delivery of dexamethasone and tobramycin.Methods: Five different PLO gel formulations (F1, F2, F3, F4 and F5) containing tobramycin (0.3%) and dexamethasone (0.1%) were prepared and compared to a conventional PLO gel (light mineral oil PLO gel, F6) with respect to physical appearance and viscosity. The optimized ricinoleic acid PLO gel formulation (F2) was further characterized for pH, gelation temperature, morphology and drug content. Ex vivo permeability of dexamethasone and bactericidal activity of tobramycin from formulation F2 was tested, and values were compared to the marketed Tobradex® eye ointment.Results: No apparent changes in the physical appearance and consistency were observed when ricinoleic acid was used as the oil phase. The pH of the optimized ricinoleic acid PLO gel (formulation F2) was found to be 6.54 with a gelation temperature of 31 °C. The drug content of tobramycin and dexamethasone were found to be 102.8% and 100.14%, respectively. The penetration profile of dexamethasone from formulation F2 was found to be much higher than the marketed Tobradex® eye ointment. F2 showed a better antimicrobial activity and higher zones of inhibition when compared to the marketed Tobradex® eye ointment.Conclusion: The findings of this investigation indicate that the ricinoleic acid PLO gel has the potential for use as a transdermal eyelid delivery system.