Ex Vivo Conjunctival Retention and Transconjunctival Transport of Poorly Soluble Drugs Using Polymeric Micelles
Silvia PescinaLetícia Grolli LuccaPaolo GovoniCristina PadulaElena Del FaveroLaura CantùPatrizia SantiSara Nicoli
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This paper addresses the problem of ocular delivery of lipophilic drugs. The aim of the paper is the evaluation of polymeric micelles, prepared using TPGS (d-α-Tocopheryl polyethylene glycol 1000 succinate), a water-soluble derivative of Vitamin E and/or poloxamer 407, as a vehicle for the ocular delivery of dexamethasone, cyclosporine, and econazole nitrate. The research steps were: (1) characterize polymeric micelles by dynamic light scattering (DLS) and X-ray scattering; (2) evaluate the solubility increase of the three drugs; (3) measure the in vitro transport and conjunctiva retention, in comparison to conventional vehicles; (4) investigate the mechanisms of enhancement, by studying drug release from the micelles and transconjunctival permeation of TPGS; and (5) study the effect of micelles application on the histology of conjunctiva. The data obtained demonstrate the application potential of polymeric micelles in ocular delivery, due to their ability to increase the solubility of lipophilic drugs and enhance transport in and across the conjunctival epithelium. The best-performing formulation was the one made of TPGS alone (micelles size ≈ 12 nm), probably because of the higher mobility of these micelles, an enhanced interaction with the conjunctival epithelium, and, possibly, the penetration of intact micelles.Keywords:
Penetration (warfare)
Poloxamer 407
Objective:To prepare a Breviscapine in situ nasal thermoreversible gel.Methods:With Poloxamer 407 and Poloxamer 188 as gel base,the gelation temperature was investigated by stirrer.Results:19% Poloxamer 407 and 4% Poloxamer 188 were established as the best compositions of the gel base,and its gelation temperature was 32.9 ℃,which was suitable for drug delivery system of nasal.Conclusion:The temperature of Brethermosensitive gel was close to the temperature of asal cavity,so it is suitable for drug delivery system of nasal cavity.
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Poloxamer 407 has shown clinical promise in suppressing surgically related adhesion formation. The mechanisms by which this occurs are not well understood. Since poloxamer 188 has rather dramatic fibrin altering properties, the present study was performed to evaluate the effects of poloxamer 407 on fibrin assembly, structure and dissolution. Studies were performed in platelet-rich plasma (PRP), platelet-poor plasma (PPP) and a purified protein system. Poloxamer 407 enhanced the rate of fibrin assembly, and increased final gel turbidity. As poloxamer 407 concentration rose from 0 to 20 mg/ml in the purified protein system, the final gel optical density (OD) increased from 0.30 to 0.95, and fiber size (mass/length ratio [mu]) increased from 2.4 to 13.4 x 10(13) daltons/cm. Precipitation was noted in the purified system at poloxamer 407 concentrations > or = 20 mg/ml. Over a poloxamer 407 range of 0-20 mg/ml, mu increased from 2.64 to 13.2 x 10(13) daltons/cm in PRP. In PPP, mu increased from 2.95 to 9.25 x 10(13) daltons/cm. In contrast to results with poloxamer 188, clot lysis with tPA (43 IU/ml) was prolonged in the presence of poloxamer 407. At 20 mg of poloxamer 407 per ml, clot lysis was less than 18% complete after 3000 s. For the control, lysis was 50% complete after 1350 s. Poloxamer 407 inhibition of fibrinolysis was due to inhibition of plasminogen activation or plasmin activity. The fibrin altering properties of poloxamer 407 may partially explain some of this agent's interesting clinical properties.
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Sustained delivery of proteins from polymer-based thermosensitive gel has achieved considerable attention since last decade. In our previous work, we developed a formulation for sustained delivery of IL-1Ra-loaded poloxamer 407 formulation and investigated its in vitro and in vivo characteristics. In the present work, we extended this approach to investigate stability of IL-1Ra from poloxamer 407 formulation stored at 4 °C, 25 °C and 40 °C for 3 months. Samples were taken and in vitro drug release kinetics was studied. Percent of drug content was measured using the BCA method. DSC and SDS-PAGE were used to assess the conformational stability of IL-1Ra. FTIR spectroscopy was performed to investigate the drug–polymer interaction. From the results, it was found that gelation temperature, viscosity and in vitro release pattern of IL-1Ra from poloxamer 407 formulation at 4 °C were almost same throughout the stability study period. DSC profiles of IL-1Ra loaded in poloxamer 407 formulation increased the thermostability of IL-1Ra significantly in poloxamer 407 formulation. There were no apparent changes in the entire FTIR spectrum of the IL-1Ra that would suggest that there was no effect of the polymer on the structure of IL-1Ra. Moreover, results of SDS-PAGE confirmed the stability of IL-1Ra in poloxamer 407 formulation. These results provided evidence that poloxamer 407 is a promising polymer not only for sustained delivery of IL-1Ra but also provides conformational stability for extended time.
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Objective To prepare poloxamer 407-based in situ gel and to discover the relationship between temperature and concentration of polaxamer 407.Methods The pilocarpine-loaded in situ gel was prepared based on poloxamer 407,and the best concentration of poloxamer 407 was chosen according to the phase transfer temperature.Results Phase transfer temperature of gel with 18~20% polaxamer 407 was below human temperature,and the pH≈7.The in vitro release experiment showed that the drug release velocity of 18%,19%,20% in situ gels were 0.462,0.393,and 0.294 mg·min-1.Conclusion Dissolution of 18~20% poloxamer solution was suitable for ophthalmic drug delivery as the thermosensitive gel.
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In this review, we describe the application of thermosensitive hydrogels composed of poloxamer in medicine, especially for oral cavities. Thermosensitive hydrogels remain fluid at room temperature; at body temperature, they become more viscous gels. In this manner, the gelling system can remain localized for considerable durations and control and prolong drug release. The chemical structure of the poloxamer triblock copolymer leads to an amphiphilic aqueous solution and an active surface. Moreover, the poloxamer can gel by forming micelles in an aqueous solution, depending on its critical micelle concentration and critical micelle temperature. Owing to its controlled-release effect, a thermosensitive gel based on poloxamer 407 (P407) is used to deliver drugs with different characteristics. As demonstrated in studies on poloxamer formulations, an increase in gelling viscosity decreases the drug release rate and gel dissolution time to the extent that it prolongs the drug’s duration of action in disease treatment. This property is used for drug delivery and different therapeutic applications. Its unique route of administration, for many oral diseases, is advantageous over traditional routes of administration, such as direct application and systemic treatment. In conclusion, thermosensitive gels based on poloxamers are suitable and have great potential for oral disease treatment.
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【Objective】 Hyperlipidemia is a well-established risk factor for cardiovascular morbidity.We attempted to develop a chemically-induced hyperlipidemic animal model in Kunming mice,using poloxamer 407.【Methods】 Male Kunming mice were randomly divided into 2 groups:control group without any intervention and poloxamer 407 group.After fasted overnight,a bolus of poloxamer 407(0.3 g/kg) was intraperitoneally injected into mice,and blood triglyceride and cholesterol were measured at 0,3,6,24,48 and 72 h after the injection.【Results】 Poloxamer 407 caused the increase of blood triglyceride more than 40-fold and cholesterol 5-fold.And this hyperlipidemic effect of poloxamer 407 lasted up to 72 h after injection.【Conclusions】 Poloxamer 407 induced Kunming mice may be used as a new hyperlipidemic animal model.
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The study's goal was to create an in situ intrarectal mucoadhesive gel of sumatriptan (SMT) combining mucoadhesive polymer (xyloglucan) and thermosensitive polymers (poloxamer 407 and poloxamer 188) to prolong rectal residence time for treatment of migraines. Nine SMT mucoadhesive rectal in situ gel (RIG) formulas were created by mixing poloxamer 407 (18%, 19%, or 20%) with poloxamer 188 (5%), a mucoadhesive polymer at various doses (0.1, 0.2, and 0.3) as well as SMT (25 mg/ml). The prepared suppositories underwent for mucoadhesive force, gelation temperature, and gelation time. When SMT and mucoadhesive polymer were added to the poloxamer mixture, the gelation temperature dropped; however, poloxamer 188 had the opposite effect. These polymers supported the prepared liquids' ability to adhere to mucous membranes and form a strong gel. The transition gelation temperature of the poloxamer solution rose as a result of the addition of poloxamer 188. The findings showed that the formula RIG5 which is composed of poloxamer 407 (19%), poloxamer 188 (5%), and xyloglucan (0.2%) had an ideal transition temperature of 36.33°C, gel strength of 44.66°C, mucoadhesive force of 6409°C, and in vitro drug release of 93.98% over an 8-hour period. In light of this, it can be said that SMT was successfully manufactured as RIG without causing any chemical reaction with its additives.
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Poloxamer 407 수용액은 저온에서는 용액상태를 유지하고 있어도 온도가 증가하면 겔을 형성하는 것으로 알려져있다. Poloxamer 407은 낮은 온도범위에서는 단량체로 존재하다가, 온도가 증가하면 단량체와 미셀간에 평형상태가 되고 더 높은 온도에서는 집합체가 형성되었다. 형광분석기와 점도 측정계를 사용하여 이런 상...
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To enhance the physical stability of two model proteins during solution agitation, we investigated the interaction of the nonionic surfactant poloxamer 407 (Pluronic F-127) with each protein. Vigorous agitation of aqueous solutions of interleukin-2 and urease which contained no poloxamer 407 and were maintained at 4 degrees C resulted in a greater than 50% loss in the biological activity at 12 and 24 hours, respectively. Similar aqueous solutions which were maintained at 4 degrees C and contained either urease or interleukin-2 and poloxamer 407 at a concentration of 10% w/w and 0.5% w/w, respectively lost negligible biological activity when left undisturbed for 96 hours. Moreover, when aqueous solutions of urease and interleukin-2 which contained poloxamer 407 at a concentration of 10% w/w and 0.5% w/w, respectively were maintained at 4 degrees C and subjected to agitation for 96 hours, no significant loss in the biological activity was observed for either protein. In addition, urease was observed to have increased enzymatic activity at early time points regardless of the hydrodynamic solution conditions and poloxamer 407 concentrations evaluated. In contrast, a negligible enhancement in the biological activity of interleukin-2 was observed when aqueous solutions of the protein were exposed to similar hydrodynamic conditions employed for urease solutions, but different poloxamer concentrations (0% w/w vs. 0.5% w/w). Results of molar ellipticity, [theta], versus wavelength, lambda, profiles using CD spectropolarimetry on individual aqueous solutions of both proteins containing 2% w/w poloxamer 407 were in close agreement to spectrum obtained with each protein in pH = 7 phosphate buffer (PB).(ABSTRACT TRUNCATED AT 250 WORDS)
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Poloxamer (Pluronic®) nonionic surfactant vehicles are a series of chemically-related block copolymers finding widespread use in parenteral formulations as solubilizing and wetting agents for traditional, low-molecular weight organic drug molecules, as well as stabilizing agents for proteins and polypeptide drugs. We report the effects of poloxamer 407 (Pluronic® F-127) on plasma cholesterol and triglyceride concentrations in rats. Poloxamer 407 injected into rats by intraperitoneal injection (dose = 1.5 gm/kg) resulted in sustained (greater than 96 hour) hypercholesterolemia and hypertriglyceridemia. A larger dose of poloxamer 407 was required to elevate plasma triglyceride relative to total cholesterol. Ingestion of commercial rat chow had a negligible effect on plasma cholesterol and triglycerides levels in control (no poloxamer injection) animals, but consumption of food by animals that received an intraperitoneal injection of poloxamer 407 (30% w/w) resulted in significantly (p
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