Poloxamers and their applications

Karmarkar A. B.

The use of polymers in pharmaceutical, biomedical as well as engineering fields has solved many aspects of these fields. The polymers of differing arrangements are useful in various pharmaceutical formulations.

The functional polymers like poloxamers are extensively used in the pharmaceutical industry due their characteristic nature of themoreversibility. These high viscosity hydromiscible vehicles provide controlled delivery of drugs. Due to broad compatibility with drug candidates of diverse nature and ingredients in formulations, poloxamers serve to be excellent vehicle for drug delivery for different routes of administration. This review describes the characteristic features of poloxamers along with its applicability in various drug delivery systems and also its biomedical applications.

Introduction:

Polymers are the substances of high molecular weight made up of repeating monomer units. These are widely used in pharmaceutical systems as adjuvants, suspending and emulsifying agents, adhesives, packaging and coating materials and increasingly, components of controlled and site specific drug delivery systems. The chemical reactivity of polymers depends upon the chemistry of their monomer units, but their properties depend to large extent on the way the monomers are put together. Polymer molecules may be linear or branched, and separate linear or branched chains may be joined by crosslinks. Polymers in which all the monomeric units are identical are referred to as homopolymers; those formed from more than one monomer type are called copolymers. Various arrangements of monomers, say A and B lead to formation of varieties of copolymers. Copolymers may be described as alternating copolymers, block copolymers, or graft copolymers. Pluronic is one of the most widely used block copolymer and forms heterogels.¹ The use of pluronic block copolymers in experimental medicine and pharmaceutical sciences has a long history. Several excellent articles are available that provide detailed information about pluronic based formulations, particularly gels, w/o and o/w emulsions, nanoparticles coated with block copolymer and solid polymer blends.^2-3 The use of pluronic micelles in drug delivery, including issues of solubilization of water insoluble drugs, preparation of stable micellar formulations and specific applications in cancer, gene therapy and other areas, has been recently reviewed.⁴ The concept of pharmaceutical excipients as non-active formulation ingredients has undergone substantial evolution.⁵ This is because many excipient considered ‘inert’, in actuality display important and sometimes very useful activities, making them essential constituents of the formulation. As a result, these formulation components are referred to as ‘functional excipients’. Pluronic block copolymers fall into this functional excipient category having demonstrable effects.

Characteristic And Properties Of Poloxamers:

Poloxamers or pluronic (marketed by BASF Corporation) are the series of commercially available difunctional triblock copolymers of non-ionic nature.⁶ They comprise of a central block of relatively hydrophobic polypropylene oxide surrounded on both sides by the blocks of relatively hydrophilic poly ethylene oxide.^7-8 Due to the PEO/PPO ration of 2:1, when these molecules are immersed into the aqueous solvents, they form micellar structures above critical micellar concentration.^9-10 They are regarded as PEO-PPO-PEO copolymers. Chemically they are Oxirane, methyl-, polymer with oxirane OR α-Hydro-ω-hydroxypoly(oxyethylene)_a poly(oxypropylene)_b poly(oxyethylene)_a block copolymer. Generally, these are waxy, white granules of free-flowing nature and are practically odorless and tasteless.¹¹ Aqueous solutions of pluronic in presence of acids, alkalis, and metal ions are very stable. The poloxamers are readily soluble in aqueous, polar and non-polar organic solvents and due to this fact they have established themselves as a preferred molecule in the formulation techniques. The pluronic triblock copolymers are available in various grades differing in molecular weights and physical forms. Depending upon the physical designation for the grades are assigned, as F for flakes, P for paste, L for liquid. The general structure for the pluronic can be stated as follows:

Fig. 1: General Structure of Pluronic

The above figure ‘a’ represents ethylene oxide portion and ‘b’ represents propylene oxide portion. Various properties of pluronic grades along with their specifications are given below:

Table No. 1: Pluronic grades and their chemical composition ^12-13

Table No.2: Specifications of Poloxamers ¹²

Apart from these forms, micronized poloxamers are also developed. These have been micronized to an average particle size of approximately 50 µm whereas particle size of prill material is 1000 µm. Lutrol ^® micro 68 (Micronized Poloxamer 188) and Lutrol ^® micro 127 (Micronized poloxamer 407) are the products marketed by BASF and both contain BHT.

Micellar Behavior Of Poloxamers:

Poloxamers, like other surfactants when dispersed in the liquid, at low concentrations, exist individually as monomolecular micelles. This leads to decrease in the surface tension as well as surface free energy. But as the concentration of the pluronic in the system increases, this results in the formation of multimolecular aggregates.¹⁴ Polypropylene oxide (PPO) forms central hydrophobic core wherein methyl groups interact via Van der waals forces with substance undergoing solubilization. However, water solubility is believed to be due to the polyethylene oxide (PEO) block by hydrogen bonding interactions of ether oxygen with water molecules. Due to these interactions, pluronic are readily soluble in and non-polar organic solvents and established themselves in formulation of dosage forms.¹⁵ In contrast to low molecular weight surfactants,¹⁶ pluronic like block copolymers have shown different aggregate forms, depending on the molecular weight, block sizes, solvent composition, and temperature. Micellar behavior of different block copolymers is found to be dependent upon solvent composition and temperature.^17-19 Micelle structure consist of hydrophobic PPO block^19-21 lying in the micelle core and the PEO block in the corona.²² Bockstahl et al.²³ studied the micellar behavior in case of pluronic P84 in 12.5 % w/w solutions. They determined the size and shape of the micelle using Positron Annihilation Lifetime Spectroscopy experiments (PALS). This study can give information about normal micelle. Fourier transform infrared (FTIR) spectroscopy was used by Su et al.²⁴ to study association behavior of PEO-PPO-PEO block copolymer in water or organic solvents. Formation of polymolecular aggregates can be evident from light scattering and fluorescence spectroscopy experiments.

Oh et al. ²⁵ used fluorescence spectroscopy to study the micelle formation of the poloxamer 407 in aqueous solution. The excitation and emission spectra of pyrene, a fluorescence probe, were measured as a function of the concentration of poloxamer 407 and temperature. A blue shift in the emission spectrum and a red shift in the excitation spectrum were observed as pyrene transferred from an aqueous to a hydrophobic micellar environment. From the results, critical micelle concentration (CMC) and critical micelle temperature (CMT) were determined. Also, from the fluorescence spectra of the probe molecules such as 8-anilino-1-naphthalene sulfonic acid and 1-pyrenecarboxaldehyde, the blue shift of the lmax was observed. These results suggest a decrease in the polarity of the microenvironment around probe because of micelle formation. The poloxamer 407 above CMC is strongly complexed with hydrophobic fluorescent probes and the binding constant of complex increased with increasing the hydrophobicity of the probe.

Effect Of Additives On Micellar Behavior:

It was reported by many workers that the various salts and additives added, surfactants, polymers, cosolvents have marked effect on micellization, clouding, solubilization behavior of pluronic solutions. According to Desai et al.²⁶, addition of sodium chloride, lowers the CMC due to fact that it develops the hydrophobicity in PPO moiety and hydrophilicity of PEO moiety is reduced. On the other hand, addition of urea increases the CMC due to increased solubility of semipolar PPO as well as PEO moiety. While the addition of sodium dodecyl sulphate causes formation of polymer–sodium dodecyl sulphate complex or mixed micelle indicating polyelectrolyte nature. Pandit et al.²⁷ studied the effect of NaCl, Na₂SO₄, Na₃PO₄, and NaSCN on pluronic F-127 solutions. The structure making salts lower the critical micellar temperature significantly, following Hofmeister series as Na₃PO₄ > Na₂SO₄ > NaCl. Whereas, NaSCN, which is water structure breaker, increases critical micellar temperature. Apart from this, various parameters studied include cloud point, solubilization, CMC, etc. The techniques employed are static light scattering and pyrene fluorescence. Ivanova et al.²⁸ examined ternary isothermal (25C) systems of pluronic F127 in presence of various cosolvents such as water and polar water immiscible solvents like glycerol, propylene glycol or ethanol, a partially water immiscible solvent like glycerol triacetate and in presence of surfactants like sodium dodecyl sulphate and cetyl trimethyl ammonium bromide using Small Angle X-ray Scattering (SAXS). Micellar behavior upon addition of sodium chloride solution and temperature range of 25-50 C in pluronic P85, P65 and F88 are studied.²⁹ This was determined by cloud point, surface tension, dye spectral change, fluorescence and viscosity measurements. Pandit et al.³⁰, have shown that salts with multivalent cations when added in specified concentrations, inhibit formation of gel in case of pluronic F 127. Temperatures at gel formation (T₁), gel melting (T₂) and at cloud point (T_cp) were examined for 20% w/w gels in presence of some salts.

Anti-inflammatory drugs like indomethacin and naproxen which are hydrophobic show decrease in micellar size. These drugs cause decrease in the aggregation numbers leading to the decrease in the number of micelles. It is also observed that they cause reduction in boundaries in between liquid-to-gel and gel-to-liquid. Micelle-water partition coefficient of indomethacin was found to be grater than naproxen due to drug-water hydrophobic interactions.³¹

Phase Behavior Of Poloxamers:

PEO/PPO ratio determines the phase behavior of pluronic like triblock copolymers. Modification of the structure and introduction of additional degree of freedom can be brought about by addition of solvents which are selective for block copolymers. The phase behavior that results depends upon relative volumes of polar PEO rich domains and of relatively nonpolar PPO rich domains. If water is the solvent used in making the solutions, it swells PEO blocks and causes formation of structures of higher curvature. As concentration of water increases, the hexagonal structure reverts to micellar cubic structure and melts to form micellar water-rich solution. Polar water-miscible solvents maintain microstructure to high solvent/water ratios. Large varieties of lyotropic liquid crystalline structures are observed in partially water miscible solvents. These solvents show fewer types of structures in contrast to non-polar solvents.²⁸

Temperature Dependence And Behavior Of Poloxamer Micelle:

Various studies showed that critical micellar concentration (CMC) of solutions decreases with increasing temperature.^32-34,21 However, it was found that micellar growth increases at 25 C, for pluronic L64.³⁵ For pluronic P85, the micellar growth occurred with increasing temperature, as investigated by Brown et al.³⁴ using static and Dynamic Light Scattering (DLS). By the use of same technique, Zhou and Chou³² studied the temperature dependence on micellar behavior of pluronic F68. They found three temperature regions, as unimer, transition and micelle regions. Alexandridis et al.²¹ by making use of hydrophobic fluorescence probe (Diphenylhexatriene) demonstrated the onset of formation of micelle for various pluronic members in aqueous media. In hydrophilic and hydrophobic environments, fluorescence efficiency of Diphenylhexatriene was found to be zero and one, respectively. This gives indication about formation of micelle with temperature increase and concentration. From that the critical micellar concentration and critical micellar temperature were obtained and are correlated with pluronic molecular weight and PPO/PEO ratio. Jain et al.³⁶ studied extensively structures of micelle and micelle interactions of pluronic P84 and pluronic P104 in aqueous solutions using Small Angle Neutron Scattering (SANS). According to work of various workers, it is clear that critical micellar concentration is strongly dependent on temperature. This has been led to the concept called critical micellization temperature. The temperature at which micelles appear in PEO/PPO/PEO solution at certain concentration is critical micellization temperature. When temperature approaches to critical micellization temperature, in aqueous solution, the antisymmetric C-H stretching vibration of methyl groups shifts towards lower wavenumber.²⁴ This indicates that methyl groups are experiencing less polar environment and the interaction of methyl groups with water molecules is weakened by heat. Symmetric deformation vibration of methyl groups is composed of two bands which are observed at higher temperatures and these bands can be related to hydrated and dehydrated state. As temperature increases, the proportion of dehydrated methyl groups of pluronic increases. Higher proportion of dehydrated methyl groups, more hydrophobic the polymer will be. Results of FTIR showed that, for pluronic P104, PPO blocks are hydrated at conditions of lower temperature and lower polymer concentration. Jebari et al.³⁷ studied aggregation behavior of pluronic L64 at various temperature values. The temperature range used was 34-52 C and with L-64 aqueous solution in the concentration range of 33-67 mg/mL. The two regimes separated by one critical temperature of about 45 C, and one critical concentration of 50 mg/mL was obtained using Dynamic light scattering (DLS) by ‘Photon beat’ technique. With the use of Electron Spin Resonance (ESR) technique, Zhou and Schlick³⁸ demonstrated aggregation behaviour in case of pluronic L64 (EO₁₃PO₃₀EO₁₃). Linder et al.³⁹ demonstrated dynamic and static properties of pluronic P94 in its concentrated micellar solution and gel phase. They characterized the system by using dynamic and static light scattering along with small angle X- Ray scattering. Also NMR and Ultrasonic studies have shown micellar arrangement in pluronic F127.⁴⁰

Thermoreversible Behavior Of Poloxamers:

Pluronics, as are ABA type of copolymers, show characteristic property of thermoreversible gelation. The reversible thermal behavior of pluronic F127 in case of dilute as well as concentrated solutions was studied extensively.^41-43 Generally, this type of behavior is observed in aqueous solutions of concentration range 20-30% w/w.⁴⁴ They are liquid when refrigerated (4-5 C) but turn into gel form when at room temperature. The gel thus formed is reversible on again cooling.¹⁹ When the pluronic is placed into cold water, at low concentrations; hydration layer surrounds the poloxamer molecule and hydrophobic portions are separated due to hydrogen bonding. With increasing temperature, desolvation of the hydrophilic chains occurs as the result of breakage of hydrogen bonds. This results into hydrophobic interactions amongst the polyoxypropylene domains and gel gets formed. Hydroxyl groups of the copolymer become more accessible due to hydration.⁴⁵ The gel formed is micellar and the liquid micellar phase which is stable at low temperature undergoes conversion into cubic structure as the temperature increases.⁴⁶ While the hexagonally packed cylinders are formed with increasing temperatures.⁴⁷ The molecular weight and percentage of hydrophobic portion are determinant factors for gelling behavior. The gel formation occurs only when concentration is above critical micellar concentration.⁴⁸ Reverse thermal gelation is the unique property of pluronic copolymers and due to this extensive research has taken place. This property is useful in the various drug delivery systems such as oral, ocular, nasal, topical, dental, and other biomedical fields.

Adsorption Measurements:

Kormany et al.⁴⁹, carried out adsorption measurements of triblock copolymer, pluronic of various grades (P6400 13/30/13; P6800 76/30/76; P10500 37/56/37; P12700 100/66/100). Whilmey type tensiometer was used to determine wettability of solid surfaces. By use of this method, adsorption of Pluronics on hydrophobic surface was studied effectively. Decrease in Solid-Liquid interfacial tensions while increase in Solid-Gas interfacial tensions was observed due to presence adsorbed layer. From stability point of view, different stability is shown by adsorbed layers and this gives good correlation of molecular weight/HLB indicating solubility of surfactants.

Kiss et al.⁵⁰ studied adsorption of four different poly (ethylene oxide)/poly (propylene oxide)/poly (ethylene oxide) triblock copolymers (pluronics) onto the hydrophobized surface of the sensor with the help of Optical Waveguide Lightmode Spectroscopy (OWLS). Adsorbed amounts of pluronic PE10300, PE10500, PE6400, and PE6800 determined follow the order of the hydrophobicity of the pluronic compounds characterized by their hydrophile-lipophile balance (HLB) values. Dynamic tensiometric method was used to determine the wettability of two hydrophobic surfaces, the poly (lactide-co-glycolide), PLGA70/30 copolymer and silylated glass, in aqueous solutions of the above pluronic grades. Marked increase in wetting tension was observed after the adsorption of surfactants, and decrease in apparent contact angle as the indication of the wetting effect on both the biopolymer and the hydrophobic glass, was correlated to the poly(ethylene oxide) (PEO) content of the adsorbed layer obtained on the hydrophobized sensor surface by the OWLS method.

Applications Of Poloxamers:

Various grades of Poloxamers serve to be efficient way for the drug delivery as well as other biomedical applications.

Ophthalmic Applications:

Poloxamer in the form of its hydrogel was used as lens refilling material for injectable intraocular lens. In this, air vinyl was used as in vitro model, for checking transparency of the hydrogel. At low temperatures, poloxamer hydrogel was easy to inject and for high temperatures, showed no leaking after injections. It was found that 25% poloxamer hydrogel is suitable for lens refilling procedure. In the in vivo study on rabbits, no ocular inflammation or posterior capsular opacification was observed.⁵¹ In situ gelling solutions of alginate and pluronic were prepared as the vehicle for ophthalmic drug delivery. Rheological studies and in vitro release as well as in vivo studies were also carried out. Optimum concentration for in situ gelling of pluronic was found to be 14% w/w. Marked increase in gel strength was found in solutions containing mixture of 0.1% w/w alginate and 14% w/w Pluronic. This combination was found to be used as in situ gelling drug delivery for enhancing ocular bioavailability.⁵² Similar type of study was carried out by Lin et al by using carbopol and pluronic combinations. They prepared a series of solutions of carbopol, pluronic and their mixtures. The most suitable concentration was found to be 0.3% for Carbopol and 14% for pluronic.⁵³

Biodegradable nanocapsules of pilocarpine made up of polyisobutylcyanoacrylate (PIBCA) containing pluronic F127 were prepared by using interfacial polymerization method for efficient ocular delivery. Scanning electron microscopy (SEM), particle size analysis and measurement of pilocarpine loading were used and physicochemical characterization of colloidal dispersion of PIBCA nanocapsules was done. Amount of pilocarpine loaded into nanocapsules is about 13.5%. Comparison was made between PIBCA-nanocapsules dispersion of 1% pilocarpine only and after incorporation of it into pluronic F127 gel system and 1% pilocarpine added into pluronic F-127 gel containing 5% methylcellulose alone. Miotic response was measured in the albino rabbit eye and statistical analysis for duration and intensity of miosis were also carried out. From these studies, it was found that the pluronic F127 enhances contact time of the model drug, pilocarpine with absorbing tissue in the eye. ⁵⁴

Commercially available 1.0% aqueous solutions of tropicamide are adjusted to acidic pH of 4.4-5.0. But these formulations cause eye irritation and induce copious lachrimation, causing reduction in bioavailability. Carmignani et al. developed ophthalimic vehicles containing polymer solubilized tropicamide. The tested solubilizers were tyloxapol and cremophor and one polymer, pluronic P85. Four stable 1% tropicamide formulations, containing 3% tyloxapol, 7.5% cremophor, 15% pluronic P85, or 5% cremophor and 10% pluronic were submitted to mydriatic activity tests in rabbits. This was resulted into statistically significant improvement in area under curve of tropicamide in test rabbits as compared to commercial 1.0% tropicamide eyedrops.⁵⁵ Indomethacin in the form of aqueous solution of was developed based on pluronic F68 in 15% concentration and pluronic F127 in the concentration of 10%. They showed some practical advantages over the models prepared with polyols and polysorbate 80, which were used for comparison. Both pluronics that were used in the formulation acted effectively as solubilizers, created appropriate viscosity, and formed thermoreversible gels at higher temperatures. This was resulted into chemical stability of indomethacin and cause prolonged in vitro diffusion. Also high physiological tolerance was found on rabbit eyes. Moreover, indomethacin stability and solution viscosity in the presence of pluronics did not change after heat sterilization (i.e., the samples can bear heat sterilization).⁵⁶ Preliminary studies carried out with cysteine 2% solution showed that pH adjusted to isoelectrical pH (i.e., 4.9) led to enhance stability during autoclaving and ensured no significant degradation during at least 14 days if stored at 2-8°C protected from light. Optimized formulations combined either cysteine(2%)/poloxamer407(16.5%) or cysteine(2%)/poloxamer407(20%)/poloxamer188(5%) and were characterized by an adequate temperature of gelification (TG) (25.9°C and 26.9°C, respectively), an important gel strength (5.1daN and 5.3daN, respectively) and a drastic increase in the apparent viscosity between 24°C and 32°C (multiplication factor of 78 and 77-fold, respectively). Cysteine addition produced only slight but significant decrease in temperature of gelification and increase in gel strength.⁵⁷

A novel approach for designing an ocular delivery system based on the dispersion of liposomes into a thermosensitive gel made of a copolymer of ethylene oxide and propylene oxide (poloxamer 407). At high concentration of 20-30% and temperature of about 20C, poloxamer 407 passes from a solution to a gel. For stabilization of liposomes in the gel, PEG2000-DSPE was introduced in their composition. Adsorption studies investigated by size and ζ-potential measurements have shown that the adsorption was higher for positively charged or neutral non-sterically stabilized liposomes. Poloxamer 407 adsorbed to a lower extent with negatively charged or PEG-DSPE containing liposomes. Furthermore, using a fluorescent aqueous marker, it was shown that liposome permeability was dramatically reduced in the presence of poloxamer 407 when PEG-DSPE was incorporated into the liposomes. This data suggests that poloxamer 407 could adsorb, at different extents, to all types of vesicles but that bilayer destabilization by the copolymer was reduced when liposomes were sterically stabilized. This was explained by the poor accessibility of the poloxamer to the phospholipidic which is the possible consequence of the steric repulsion effect induced by polyethylene glycol. Finally, it was shown that the thermosensitivity of poloxamer 407 was maintained after introducing the liposomes into the gel.⁵⁸

Bochot et al.⁵⁹ developed an ocular controlled release formulation of a model oligonucleotide (pdT16), contained within liposomes dispersed within a thermosensitive gel comprised of poloxamer 407. Also the effect of the poloxamer concentration 2% or 27% on the stability of the liposomes (PC: CHOL and PC: CHOL: PEG-DSPE) was studied. The in vitro release profiles of pdT16 from various poloxamer formulations (free pdT16 dispersed within 20% and 27% poloxamer gels, pdT16 encapsulated within liposomes dispersed within 20% and 27% poloxamer gels) were realized using a membrane-free release model. A great leakage of pdT16 from liposomes was observed within a dilute 2% poloxamer solution. The destabilization effect of poloxamer was reduced when higher concentration (27%) was used. Poloxamer dissolution was found to control the release process of pdT16, whereas the dispersion of liposomes within 27% poloxamer gel was shown to slow down the diffusion of pdT16 out from the gel. Thus this system containing dispersion of liposomes within a 27% poloxamer gel represents an interesting system to control the release of a model oligonucleotide compare to a simple gel.

Qi et al.⁶⁰ developed a thermosensitive in situ gelling and mucoadhesive ophthalmic drug delivery system composed of puerarin based on poloxamer analogs [21% (w/v) poloxamer 407 / 5% (w/v) poloxamer 188] and carbopol [0.1% (w/v) or 0.2% (w/v) carbopol 1342P NF].These combined solutions convert to firm gels under physiological condition and attach to the ocular mucosal surface for a relatively long period of time. In vitro release studies showed diffusion-controlled release of puerarin from the combined solutions over a period of 8 hrs. In vivo studies (the elimination of puerarin in tear and intraocular pressure-lowering effect) indicated that combined solutions had better ability to retain drug than poloxamer analogs or carbopol alone. Thus it can be concluded that ocular bioavailability of puerarin can be increased by using in situ gelling and mucoadhesive vehicle.

Intranasal Applications:

When the mucociliary clearance is rapid, it is important criteria for the bioavailability. Zhou and Donovan⁶¹ used putative bioadhesive polymers such as methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, carbopol 934P, chitosan glutamate and pluronic F127 for the study of mucociliary clearance with the use of rat model. The mucociliary clearance for these polymer gels from nasal cavity was determined by following removal of microspheres which are fluorescently labeled and incorporated in the formulation. It was found that the pluronic F127 and other polymer gel formulations have longer residence times and hence decrease mucociliary clearance.

Effect of mucosal administration of tetanus toxoid, in presence of pluronic F127, with chitosan or lysophosphatidylcholine on systemic and mucosal immune response was studied by Westerink et al.⁶² Balb/c mice immunized by intraperitoneal route with tetanus toxoid and boosted intranasally with tetanus toxoid in pluronic F127/chitosan, showed significant increase in the systemic antitetanus toxoid antibody response compared to mice boosted intranasally with tetanus toxoid in PBS or mice boosted intranasally in pluronic F127/lysophosphatidylcholine. Marked increase in antitetanus toxoid mucosal IgA response in the group boosted with the tetanus toxoid in pluronic F127/chitosan was observed from the study of antigen specific IgA response in the nasal and lung washes of these animals. Significant increase in antitetanus toxoid IgG and mucosal IgA antibody responses was observed in mice immunized and boosted intranasally with tetanus toxoid in pluronic F127/chitosan as compared to the animals immunized and boosted intranasally with the tetanus toxoid in PBS or tetanus toxoid in pluronic F127/ lysophosphatidylcholine. From these studies, it is confirmed that pluronic F127/chitosan serves to be novel mucosal vaccine delivery system comprising two components which exert synergistic effect on immune response.

Csaba et al.⁶³ prepared new type of nanoparticles using various polymer blends. In vitro cellular uptake (HEK 293 cell line) of FITC-labelled plasmid DNA nanoencapsulated in PLGA: pluronic F68 and PLGA: tetronic T904 particles were studied by confocal microscopy. In vitro cell culture studies showed that nanoparticles enter the cells and cause transportation of DNA across the membrane. Fluorescent nanoparticles in in vivo studies showed that they are able to overcome nasal mucosal barrier. In the case of immunization studies, DNA-loaded nanoparticles show fast and strong response, more marked than naked plasmid DNA for up to 6 weeks. This shows that these nanoparticles serve to be efficient carriers for delivery of DNA across the nasal mucosa.

Pluronic F127 thermoreversible gels of Vitamin B₁₂ were formulated to improve absorption and patient compliance. Cold process is used for the preparation of pluronic F127 gels. Gelation temperature was found to decrease while gel melting temperature increased with Vitamin and pluronic F127 concentration. Linearity was observed for semilogarithmic plot of pluronic F127 concentration and 1/T₂ that shows interaction of both at gel melting.⁶⁴

Thermoreversible pluronic gel for nasal administration of Melatonin for use in case of sleep disorders was formulated. With the use of cold method, aqueous pluronic gels containing drug (0.5 mg/0.1ml), PEG 400 and PEG 15000 were studied for gelation and gel melting. Melatonin shifted gelation range to higher temperature while PEG narrowed the gel range. It was observed that increase in pluronic concentration, flux of diffusion decreased. Bimodal pattern was observed with pluronic gel (20%w/w, 1mg/0.1 ml) showing a desired peak flux (0.248µg/min./cm²) at 300min. Nasal gels prepared showed fast onset of action and induced sleep within fifteen minutes. This has proved that melatonin gels can be used in the treatment of circadian cycle sleep disorders.⁶⁵

Majithiya et al.⁶⁶ prepared thermoreversible-mucoadhesive gel formulation for intranasal delivery of sumatriptan using thermoreversible polymer pluronic F127 and mucoadhesive polymer carbopol 934P. Formulations were developed so as to have gelation temperature below 34C so that gelation will be at physiological temperature after intranasal administration. Physical appearance and rheological measurement were used for determination of gelation temperature. Gelation temperature of formulations decreases as the concentration of carbopol increases (that is from 29C for 18% pluronic F127 to 23.9C for pluronic F127, 0.5% carbopol). Mucoadhesive force in terms of detachment stress, determined using sheep mucosal membrane was found to increase with increasing concentration of carbopol. From the results of in vitro drug permeation studies, it was clear that effective permeation coefficient could be significantly increased by using in situ gelling formulation having concentration of carbopol 0.3% or greater. Also the histopathological examination did not detect any damage during in vitro permeation studies. From this, it was now clear that in situ gelling and mucoadhesive nasal formulation of sumatriptan prepared from pluronic F127 represents efficient way for prolongation of nasal residence and nasal absorption.

Thermosensitive nasal gel of dextromethorphan hydrobromide was prepared and also in vitro drug release was studied. The thermosensitive polymer used for the preparation of nasal drop was poloxamer 407. Vertical diffusion cell was used for in vitro drug release study. The poloxamer solution of 20% w/w concentration and 2.5% w/w PEG 6000 is liquid at room temperature, then undergoes a phase transition to a semisolid gel when being heated up to 33 C.

Higuchi equation kinetics(r>0.99) is followed by drug release form poloxamer vehicle. This formulation thus proves to be efficient than traditional nasal preparations.⁶⁷ Also Jain et al. studied nasal absorption of metoprolol tartarate by using poloxamer 407.

Gonjari and Kasture⁶⁸ developed nasal controlled release formulation of a model drug propranolol hydrochloride contained within liposomes dispersed in a thermoreversible gel prepared by using polymer like poloxamer 407 and combination of poloxamer 407 with bioadhesive polymer like carbopol 934P. Liposomes were prepared by reverse phase evaporation method using soya lecithin and cholesterol in different ratios. The combination of soya lecithin and cholesterol showing maximum percentage entrapment was used for further dispersion into gel prepared by using thermoreversible polymer and thermoreversible gel containing a mucoadhesive. The results showed that gel is having capacity to accommodate the liposomes without losing its gelation property. Also formulation showed a satisfactory result. This formulation is supposed to be useful in prolonging the nasal residence time of the encapsulated drug, in controlling its release and subsequently improving nasal bioavailability.

Vaginal Delivery:

Bromocriptine when taken orally has been found to give side effects. Therefore attempt has been made to formulate it in the form of vaginal suppositories. Darwish et al.⁶⁹ prepared two formulas of vaginal bromocriptine suppositories for comparision with vaginal application of bromocriptine tablets. The study was carried out in two phases. In pharmaceutical phase, firstly, vaginal suppositories incorporating 2.5 mg of bromocriptine mesylate were prepared using fusion method. Then physical characteristics were tested like weight variation, content uniformity, hardness, melting point, liquefaction time, and disintegration time. In vitro drug release studies were also performed for examination of type of base, partition coefficient of the drug, melting point of the base, hydroxyl number of the base, presence of additives, and concentration of additives. After this, interaction between drug and suppository base was studied using DSC and X-ray diffractometer infrared spectroscopy (IR). Formulation A contains drug and bas comprising of 80% propylene glycol and 20% polyethylene glycol 20000 whereas formulation B comprising of formulation A with solid dispersion with pluronic F 127 prepared by solvent evaporation method. The clinical phase was conducted on 54 hyperprolactinemic patients. The results of pharmaceutical phase showed an increased dissolution rate of bromocriptine/pluronic F127 that was 39-fold greater than that of the pure drug alone. First-order release kinetic mechanisms were examined for formulations A and B. Formula B was found to give higher release rate constant (k = 0.51 min^-1) than formula A (k =0.048 min^-1). Therefore, bromocriptine vaginal suppositories containing pluronic F127 served to be effective in lowering serum prolactin and this formulation was better tolerated by most of the patients, had minimal local irritative vaginal effects, and were proved to be more convenient for vaginal use than the tablet form.

Bilensoy et al.⁷⁰ formulated new mucoadhesive, thermoreversible, and prolonged release vaginal gel for the treatment of vaginitis. Clotrimazole (1%) has been formulated in a vaginal gel using pluronic F 127 (in 20% concentration) which is a thermosensitive polymeric material along with mucoadhesive polymers like carbopol 934P and hydroxypropyl methyl cellulose (0.2% for both). For increasing solubility, clotrimazole was incorporated in the form of inclusion complex with 1:1 molar ratio with β-cyclodextrin. Characterization was done with the ¹H NMR spectroscopy, FTIR spectrophotometry, DSC, scanning electron microscopy, phase solubility studies, and determination of stability constant (k_1:1). In vitro release profiles were also studied. Thus this formulation represents better therapeutic efficacy and patient compliance for vaginitis treatment.

Similarly, mucoadhesive, thermosensitive gel (MTG) were prepared by Chang et al.⁷¹ The MTG were composed of poloxamer 407, 188 and polycarbophil (PC). Poloxamer 188 and PC increased mucoadhesiveness but reduced syringebility of liquid forms of gels. MTG containing poloxamer 407/poloxamer188/PC (15/15/0.2 or 15/20/0.2) were prepared and studied. Of these two MTG, the formulation with 15% poloxamer 188 gelled at higher temperature and showed low value of elastic modulus. MTG cause the sustained release of the drug clotrimazole. In vivo studies were carried out on Candida albicans vaginitis in female rats and MTG cause release of clotrimazole for prolonged time period. These results suggest that mucoadhesive thermosensitive vaginal gel of clotrimazole was found to be effective and convenient for the treatment of vaginal candidasis with reduced dosing interval. However, cell viability and morphology data support that MTG are safe for vaginal application.

Rectal Applications:

Surface active triblock copolymers like Pluronics were evaluated as a vehicle for rectal administration of indomethacin. The effects of the concentration of pluronic F127, temperature and drug concentration on the drug release were studied by means of an in vitro release method using a cellulose membrane. As the concentration of pluronic in the vehicle increases, corresponding decrease in the drug release occurs. Apparent release rate increased with increasing temperature from 20 to 44C. Increase in drug concentration increased the drug release rate. Indomethacin gel preparations made by dissolving the drug in pluronic F127 aqueous gel were administered rectally to rabbits and the drug plasma levels were obtained and compared to those after rectal administration of commercial suppositories. After rectal administration of commercial suppositories, plasma concentration reached the maximum after 30 min. Whereas, gel preparation did not show a sharp peak of plasma concentration and produced a sustained plateau level of indomethacin.⁷² Choi et al.⁷³ developed novel, in situ gelling rectal liquid suppository containing acetaminophen. The gelation temperature was adjusted to be at 30-36C. Poloxamer 407 and / or poloxamer 188 were used for thermosensitive gelation property. Bioadhesive polymers were used to impart gel strength and bioadhesive force. Also the bioavailability of acetaminophen was determined.

Derick et al.⁷⁴ studied the use of pluronic polyols in the development of sustained release rectal suppository formulations. Solid and liquid pluronic polyols (pluronic L61, F68, L101, and F108) were combined in a weight ratio ranging from 80:20 (solid to liquid) to 70:30 to prepare the bases. The USP standard basket dissolution apparatus was used for the study of release behavior of the drug riboflavin. The control polybase suppository which released 50% of the drug (t50) in about 7.23 minutes but pluronic F68/L61 suppositories at an 80:20 weight ratio exhibited a t50 of 86.5 minutes (1.44 hours). Riboflavin release from suppositories made with pluronic F108/L101 was even further delayed. The t50 of riboflavin from pluronic F108/L101 suppositories at an 80:20 weight ratio, for instance, was 274.4 minutes (4.6 hours). The results of this showed that specific combinations of pluronic can be made to prepare sustained release formulations that can deliver the drugs within minutes to hours. This flexibility of compounding sustained-release suppositories is beneficial, especially for the management of chronic pain in cancer patients.

Charrueau et al.⁷⁵ made use of poloxamer 407 for rectal administration of short chain fatty acids. Five thermogels were prepared with poloxamer 407 at concentrations ranging from 17% to 20% and viscosities were measured at room temperature and 37°C, and their gelling temperatures were determined. From the threshold concentration of 17.5%, the solutions exhibit Newtonian character at room temperature (50-80 mPa.s), gelled at 37°C. The higher the concentration, the higher the viscosity (1750 to 49,000 mPa.s), the lower the gelling temperature (27.6°C to 23.4°C), and the stronger the work of adhesion (2.2 to 4.5 mJ). Short chain fatty acid release from the 18% polymer gel was decreased by 60% compared to the rectal solution. The 18% poloxamer 407 concentration provided a solution that was liquid at room temperature that gelled at 37°C, possessed adhesive properties, and controlled short-chain fatty acid release.

Two quinine rectal gel formulations for pediatric use were prepared and evaluated. These two were mucoadhesive gel and thermosensitive gels containing 20 mg quinine base/g were evaluated in vitro and in vivo in rabbit. The mucoadhesive and the thermosensitive gels contained hydroxypropyl methylcellulose 4000 (HPMC) and poloxamer 407, respectively. The calculated in vitro release exponent (n) values suggested that drug was released from both gels by non-Fickian diffusion. Both gels exhibit practically similar efficient of dissolution (ED%) which was not reflected in the plasma and, therefore, quinine bioavailability from mucoadhesive gel was found to be higher than that obtained from thermosensitive gel and their AUC_0–∞ were statistically different (P = 0.0006). The t_1/2 values of quinine were significantly higher for hydrogels than for IV and rectal solutions. MRT values displayed by thermosensitive gel and mucoadhesive gel were not statistically different but were about 3.8- and 1.3-fold, respectively, larger than those obtained for IV solution and rectal solution, respectively. No damage to the rectal mucosa of the rabbit was observed in the tolerability studies.⁷⁶

A novel clotrimazole-loaded poloxamer-based suppository with enhanced anti-tumor activity and alleviated hepatotoxicity, the melting point of various formulations composed of P 188 and propylene glycol was developed by Yong et al.⁷⁷ dissolution as well as anti-tumor activity of clotrimazole was also studied. Hepatotoxicity of clotrimazole was carried out after its rectal administration compared to oral administration in mice. The poloxamer mixture composed of poloxamer 188/propylene glycol in 70%/30% with the melting point of about 32 °C was a solid form at room temperature and instantly melted at physiological temperature. Poloxamer 188: propylene glycol ration greatly affect the dissolution rates of clotrimazole from poloxamer-based suppository. The results of dissolution testing states that the dissolution rate of clotrimazole from poloxamer-based suppositories was independent of the time. It was found that poloxamer188-propylene glycol based suppository with loaded clotrimazole showed no sign of irritation or damage to rectal tissues of rats and also improved anti-tumor activity was observed in the case of mouse. Furthermore, its rectal administration decreased the hepatotoxicity compared to oral administration. Thus, the poloxamer-based solid suppository system with clotrimazole/poloxamer 188/propylene glycol was an effective rectal dosage form for the treatment of tumors with alleviated adverse effects.

El-Kamel et al.⁷⁸ made the use of thermoreversible property of pluronic to formulate liquid suppository of carbamazepine having characteristic property of in situ gelling. Carbamazepine (CBZ), an anti-epileptic drug, undergoes extensive hepatic first pass metabolism when administered orally. Rectal dosage form of CBZ is not commercially available, although it is of particular interest when oral administration is impossible. Conventional suppositories can cause patient discomfort and may reach the end of the colon; consequently, the drug can undergo the first-pass effect. Mucoadhesive liquid suppositories of CBZ were prepared by adding carbopol to formulation of thermally gelling suppositories that contain 20% poloxamer 407 and either 15% poloxamer 188 or 1% methylcellulose. Reasonable gelation temperature, gel strength and bioadhesive force was observed in the formulation composed of 20% poloxamer 407, 1% methylcellulose, and 0.5% carbopol. Fickian diffusion pattern was observed in the CBZ release mechanism analysis. In vivo evaluation of the same formulation showed higher peak plasma concentration of CBZ compared with the orally administered suspension containing the equivalent amount of drug. No observed statistical significant difference (p > 0.05) in extent of bioavailability between the liquid suppository and oral suspension as indicated by the values of AUC_0–∞, 17.9 and 18.8 g.h/ml respectively. From these results, it was confirmed that mucoadhesive in situ gelling liquid suppository could be an effective and convenient delivery system of carbamazepine.

Barichello et al.⁷⁹ developed and evaluated pluronic F127 gel containing unsaturated fatty acids like oleic acid (18:1), eicosapentaenoic acid (20:5) and docosahexaenoic acid (22:6) as a potential formulation for the rectal delivery of insulin. Pluronic gels were prepared by cold method and unsaturated fatty acids were dispersed in it. Male Wistar rats were used for the in vivo absorption experiments and serum insulin levels were measures by making use of insulin enzyme imuunoassay kit. The hypoglycemic effect of was studied following rectal administration of various formulations in normal rats. Rectal absorption of insulin was significantly enhanced, and marked hypoglycemia was induced by all pluronic F127 gels of insulin (Dose: 5U/kg) containing different unsaturated fatty acids. Low t_max mean values are observed from pluronic gels containing unsaturated fatty acids that indicate absorption of insulin occurred very rapidly in the rectum. The relative hypoglycemic efficacy of pluronic F127 gel formulations containing fatty acids such as oleic acid, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were found to be 28.4±8.1, 26.8±14.3 and 23.1±5.7% respectively. Therefore it was confirmed that 20% pluronic F127 gels containing unsaturated fatty acids are the potential formulations for the rectal delivery of insulin.

Mebeverine hydrochloride (MbHCl) suffers from extensive first pass effect. The bioavailability of it can be improved and its absorption can be restricted to lower rectum only by using rectal solution having gelation temperature range of 30-37 C. Mixtures of poloxamer 407 and poloxamer 188 were used for the temperature sensitive gelation property. The cold method was used for the preparation of rectal solutions. Hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), methyl cellulose (MC) and polyvinylpyrrolidone K-25 (PVP K-25) were used to modulate gel strength and to impart mucoadhesive force to MbHCl-poloxamer rectal solution. Addition of 10% MbHCl in rectal solution was found to increase gelation temperature of poloxamer mixtures while the effect was reversed upon the addition of mucoadhesive polymers. On the other hand, these polymers reinforced the gel strength and the mucoadhesive force of the prepared solutions. The effect was most pronounced with MC. As the concentration of cellulosic bioadhesive polymers increases, the release of MbHCl was retarded to the different extents and it was possible to sustain drug release over a period of 8 hrs. Order of polymers according to their release retarding effect was found to be MC > HPMC > HEC. However, it was found that PVP K-25 had no effect on the drug release. Pretreatment of guinea pigs with MbHCl rectal solution [poloxamer 407/poloxamer 188/ MC/ MbHCl (23/ 7/ 1.5/ 10% w/w)], having satisfactory gel strength, mucoadhesive properties and acceptable sustained release profile with zero order release kinetics, showed a significant extended spasmolytic effect to spasmogens-induced contractions on guinea pig ileum and did not cause any histological damage to the rectal tissues.⁸⁰

Yong et al.⁸¹ prepared ibuprofen-loaded liquid suppository using eutectic mixture with menthol, and investigated the effects of menthol and poloxamer 188 (P188) on the aqueous solubility of ibuprofen. The physicochemical properties such as gelation temperature, gel strength and bioadhesive force of various formulations composed of ibuprofen, menthol and poloxamer 188 were investigated. The pharmacokinetic study of ibuprofen delivered by the liquid suppositories composed of poloxamer 188 and menthol were then performed. The solubility of ibuprofen increased in absence of poloxamer 188 until the ratio of menthol to ibuprofen increased from 0:10 to 4:6 followed by an abrupt decrease in solubility above the ratio of 4:6. This indicated that four parts of ibuprofen formed eutectic mixture with six parts of menthol. The solutions with the same ratio showed abrupt increase in solubility in presence of poloxamer 188. Furthermore, the solution with ratio of 4:6 showed more than 2.5- and 6-fold increase in the solubility of ibuprofen compared with that without additives and that without menthol, respectively. The poloxamer gel with menthol/ibuprofen ratio of 1:9 and higher than 15% poloxamer 188 showed the maximum solubility of ibuprofen, 1.2 mg/ml. It was found that ibuprofen increases gelation temperature whereas weakened the gel strength and bioadhesive force of liquid suppositories. However menthol shows reverse behavior due to formation of eutectic mixture with ibuprofen. The ibuprofen-loaded liquid suppositories [P 188/menthol/ibuprofen (15/0.25/2.5%)] with the maximum ibuprofen solubility of 1.2 mg/ml were administered easily to the anus and remain at the administered site without leakage after the dose. Higher initial plasma concentrations, C_max and area under curve were observed than that of solid suppository that indicates the drug from poloxamer gel could be more absorbed than that from solid one in rats. The liquid suppository system with P 188 and menthol serves to be more effective and convenient dosage form for rectal administration and will be expected to enhance the rectal bioavailability of ibuprofen.

A thermoreversible insulin liquid suppository was developed by Yun et al.⁸² This undergoes a phase transition to bioadhesive gels at body temperature and enhances the bioavailability of insulin. The effects of insulin and sodium salicylate on the physicochemical properties of a liquid suppository composed of poloxamer 407, poloxamer 188 and polycarbophil were also examined. The pharmacodynamic study and quantitative histological assessment of the rectal mucosa of rats were carried out after the dose of insulin-loaded liquid suppositories with different amounts of sodium salicylate into streptozotocin-treated rats. Only thermo-reversible insulin liquid suppository composed of insulin/poloxamer 407/poloxamer188/polycarbophil/sodium salicylate (100 (IU/g)/15/20/0.2/10%) showed the optimal physicochemical properties and good safety in rats. It was observed that significantly lower plasma glucose levels, AUC_0→4h (the area below basal glucose level) and C_nadir (the plasma glucose levels at the nadir) than did the solid and liquid suppositories without sodium salicylate in rats, indicating that the insulin from liquid suppository with sodium salicylate could be well absorbed in rats due to the absorption enhancing effect of sodium salicylate. It is concluded that thermoreversible insulin liquid suppository [insulin/P 407/P 188/polycarbophil/sodium salicylate (100 (IU/g)/15/20/0.2/10%)], which was easy to administer without any pain during insertion and remained at the administered sites, could have a potential to be developed as a more convenient, safe and effective rectal delivery system of insulin.

Paek et al.⁸³ formulated rectal suppository using poloxamer 188 and propylene glycol that enhances the anticancer effect of 5-fluorouracil (5-FU) in Mice. The rectal suppository was made with 70% poloxamer 188 and 30% propylene glycol, which was a solid phase at room temperature and instantly melted at physiological temperature. The treatment with the 5-FU suppository was more effective than the oral route in decreasing the volume of rectal cancer in mice. Also it was found that survival rate of the mice with rectal cancer was higher in the group treated with the 5-FU suppository than in the group treated with 5-FU orally. Furthermore, in mice skin cancers induced by inoculation of murine CT-26 colon carcinoma cells, the anticancer effect of 5-FU was significantly enhanced by the rectal administration of the suppository than by oral treatment. From these results it was confirmed that poloxamer gel system with 5-FU/poloxamer 188/propylene glycol is an effective rectal dosage form for the treatment of both rectal and non-rectal cancers.

Ear Applications:

Lee et al.⁸⁴ prepared the formulation for the local delivery of vancomycin with the use of pluronic F127 for the effective treatment of otitis media caused by methicillin resistant Staphylococcus aureus (MRSA). The phase transition property of pluronic F127, which is liquid at room temperature and becomes solid at body temperature, made injection convenient and hence reduced the side effects of the potent antibiotic. The temperature responsive polymer–vancomycin matrix system was also shown to effectively deliver vancomycin locally to the infected inner ear, plus the MRSA growth was inhibited by the formulation. From in vivo studies it was clear that otitis media was cured from sustained local delivery of vancomycin. Accordingly, this system has potential clinical application for treating chronic otitis media with improved patient compliance and better therapeutic efficacy.

Kamil et al.⁸⁵ created human sized and shaped auricle using the technique of tissue engineering. Mixtures of autogenous chondrocytes and biodegradable polymers were used inside a perforated, auricle shaped hollow gold mold. Three biodegradable polymers (calcium alginate, pluronic F127, and polyglycolic acid) were used to retain the seeded chondrocytes inside the mold. These molds, along with a control, were implanted subcutaneously in the abdominal area of 10 animals (pigs and sheep). The constructs were removed after 8 to 20 weeks and were assessed by gross morphology and histology. All the gold implants were well tolerated by the animals. The implants using calcium alginate generated constructs of the exact shape and size of a normal human ear, the histology demonstrated mostly normal cartilage with some persistent alginate. The implants with pluronic F127 resulted in cartilage with essentially normal histology, although leakage outside the molds and external cartilage generation was noted.

Dental Applications:

Maheshwari et al.⁸⁶ developed the tetracycline-serratiopeptidase containing periodontal gel formulation. Attempt has been made to reduce polymer concentration and to obtain reasonable viscosity at the lower concentration of pluronic by addition of a viscosity modifier. Cold method was used to formulate gel of pluronic in 20% w/w concentration. The effect of the amount of tetracycline and aerosil on gel properties was studied. Different parameters used for the evaluation of gel were polarizing microscopy, gelation, gel melting, bioadhesion, viscosity, drug release, and stability of enzyme. An in vivo study was performed to evaluate the clinical efficiency of the liquid crystalline gel. A total of 30 subjects of both sexes who were more than 21 years old and had been diagnosed as suffering from chronic localized or generalized periodontitis were considered for the study. Addition of aerosil to the gel favored hexagonal phase formation. Viscosity and bioadhesivity increased with an increase in the concentration of aerosil. Release of tetracycline was sustained as the concentration of aerosil increased. Various clinical parameters confirmed the acceptability and efficiency of this gel system.

Buccal Applications:

A polymeric film composed of carbopol, poloxamer and hydroxypropyl methylcellulose was prepared to develop a buccal patch and the effects of composition of the film on adhesion time, swelling ratio, and dissolution of the film were studied by Chun et al.⁸⁷ The effects of plasticizers or penetration enhancers on the release of triamcinolone acetonide (TAA) were also studied. The hydrogen bonding between carbopol and poloxamer played important role in reducing swelling ratio and dissolution rate of polymer film and increasing adhesion time. The swelling ratio of the composite film was significantly reduced and the adhesion time was increased when compared with carbopol film. As the ratio of pluronic to hydroxypropyl methylcellulose increased from 0/66 to 33/33, the release rate of TAA decreased. However, no further significant decrease of release rate was observed beyond the ratio of 33/33. The release rate of TAA in the polymeric film containing polyethylene glycol 400, a plasticizer, showed the highest release rate followed by triethyl citrate, and castor oil. The release rate of TAA from the polymeric film containing permeation enhancers was slower than that from the control without enhancers. From these observations it was clear that buccal patch composed of polymeric film of cabopol, poloxamer and hydropropyl methylcellulose was effective in the buccal delivery of triamcinolone acetonide.

Using the same drug Shin et al.⁸⁸ developed the bioadhesive gels with the use of carbopol 934 and pluronic F127. The release profiles of drug were studied as the function of drug concentration and temperature. Bile salts, glycols and non-ionic surface active were used as enhancer for effective permeation through buccal mucosa. Among these enhancers sodium deoxycholate is used as best enhancer. The pluronic F127 and carbopol 934 can be used as a reservoir which release triamcinolone acetonide or other drugs when applied topically by forming soft bioadhesive gel at body temperature.

Bourre et al.⁸⁹ developed 5-aminolevulinic acid ( ALA ) thermosetting gel composed of pluronic F127 gel. The evaluation of formulation was done in an in vivo mouse model for potential use in photodynamic therapy of Barrett’s mucosa. In vitro studies of the influence of pluronic F127 percentage on thermosetting gel temperature, followed by the influence of ALA concentration on thermosetting temperature and ALA-gel stability as a function of time or temperature were studied. In vivo relationships between ALA doses and fluorescence were studied to determine the optimal concentration. Fluorescence measurement in in vivo studies showed that ALA concentration and time had a nonlinear influence on protoporphyrin IX synthesis. ALA-pluronic F127 is a suitable formulation for treatment of Barrett’s esophagus, allowing easy application in liquid form at 4C and good adhesion in the esophagus in gel form, with efficient diffusion of ALA into treated mucosa.

Pluronic polyol effects on Human Gingival Fibroblast (HGF) attachment and growth were studied. The purpose of this study was to determine the in vitro effects of pluronic polyols, a family of widely used surfactants currently used as drug carriers for antibiotic, anti-inflammatory, and antineoplastic agents, on the attachment and growth of human gingival fibroblasts (HGF) to dentin and plastic surfaces using established tissue culture techniques. Plastic culture wells containing Eagle's minimal essential media (EMEM) with 10% fetal calf serum and pluronic F68 or F127 in concentrations from 1.2 x 10(-2) to 1.2 x 10(-10) M were incubated with HGF and run in replicates of ten. Attached cells were quantified by measuring the optical density of methylene blue-stained cells. The results thus showed that pluronic was beneficial in the very low amount of dosages in early post-surgical wound healing by facilitating early attachment and enhancing the growth rate of human gingival fibroblasts.⁹⁰

Morishita et al.⁹¹ studied the release of insulin from pluronic F127 (PF 127) gel composed of unsaturated fatty acids such as oleic acid (18:1), eicosapentaenoic acid (20:5) or docosahexaenoic acid (22:6) and the hypoglycemic effect of insulin following the buccal administration of the gel formulations in normal rats. A weighed amount of PF 127 was slowly added to a cold (5–10°C) phosphate buffer solution (PBS) of pH 7.4, with gentle mixing until there was complete dissolution of the polymer. Insulin (porcine insulin, 27.0 IU: mg) was dissolved in 0.1 N HC1, then diluted with PBS and adjusted with 0.1 N NaOH to pH 7.4. The insulin solution was added with gentle stirring to the PF127 solution. Male Wistar rats were used for the in vivo studies. In the presence of unsaturated fatty acids, insulin release was found to decrease. Remarkable and continuous hypoglycemia was induced by all PF 127 gels (insulin dose, 25 IU/kg) containing unsaturated fatty acids. PF 127 gels containing oleic acid showed the highest pharmacological availability. These results showed that 20% pluronic F127 gels containing unsaturated fatty acids are potential and effective formulations for the buccal delivery of insulin.

Transdermal And Topical Applications:

Much amount of work had been carried out by various workers for the use of pluronic as valued ingredient in the topical drug delivery systems. Cappel et al.⁹² studied the effect of poloxamer 188, poloxamer 407, poloxamer 338 and poloxamer 184 as well as poloxamine [poloxamine 304 (Tetronic 304), poloxamine 904 (Tetronic 904), and poloxamine 908 (Tetronic 908)] surfactants on transdermal drug delivery. The permeability of octanol decreased with increasing surfactant concentration. Determination of thermodynamic activity revealed that the effects observed were due to entrapment of the lipophilic test permeant in micelles, a finding which was in excellent agreement with the permeation data obtained with silicone elastomer sheeting. No negative effect on the permeability of octanol through hairless mouse skin was observed due to poloxamer 188. All effects of poloxamer or poloxamine surfactants on full thickness hairless mouse skin as well as silicone rubber membrane were totally reversible when the respective surfactant solution was removed from the donor compartment. In conclusion, neither differences in molecular weight nor varying HLB values of poloxamers and poloxamines appeared to play a major role in affecting the barrier properties of hairless mouse skin.

Thermoreversible gels of pluronic F127 as the vehicles for the percutaneous administration of indomethacin were studied and evaluated by Miyazaki et al.⁹³ Rat, model was for the in vivo studies and it was found that 20% gel in water was suitable for the topical administration of the drug. Improved percutaneous absorption was observed after addition of isopropyl myristate or limonene to the formulation, especially when the gel was applied using occlusive dressing technique.

A new synthetic capsaicin analog (CA) modified with 4-hydroxyl and alkyl chain of capsaicin was synthesized as a potent anti-inflammatory analgesic drug. Lee et al.⁹⁴ studied the percutaneous absorption and histopathology of a poloxamer-based formulation of CA. Vertical Franz type diffusion cells were used for skin penetration of drug against receptor phase filled with about 10 ml of 0.9% isotonic saline at 32°C. The concentration of drug was determined by the reverse phased HPLC (C18, Symmetry^®) with fluorometeric detector. Total amount of CA free base permeated was higher than that of the CA salt form. Percutaneous absorption of CA was greatly enhanced in ethanol and propylene glycol than that in water, 2-hydroxypropy-β-cyclodextrin and PEG400. The flux rate of CA increased slightly when propylene glycol was added to ethanol solution. The marked enhancing effect of the 5% fatty acid IPM in cosolvents was also noted on the percutaneous absorption of a poloxamer-based formulation of CA. Addition of 5% OA and 5% LA into the gel containing 5% IPM resulted in a slight increase in skin permeation. No significant difference in skin permeation was observed as a function of poloxamer content (20, 25 and 30%). The buffer system of 30% poloxamer-based gel slightly changed the cumulative amounts of CA penetrated for 24 h. The flux of poloxamer-based gels increased linearly as the drug concentration increased. There was a variation of percutaneous absorption of the drug, depending on the species used. The flux of a poloxamer-based formulation of CA was the highest in case of hairless mice but the lowest in hamsters. No skin erythema and histopathologic changes were observed on the dorsal site of hairless mice in six groups after a week or two months application, suggesting no skin toxicity of the poloxamer-based gel. Based on these findings, the current poloxamer-based formulation appears useful in the systemic delivery of CA as topical or transdermal patch formulations.

Pople and Singh⁹⁵ prepared the topical formulation containing solid lipid nanoparticles of vitamin A palmitate to study beneficial effects on skin. Topical gels enriched with solid lipid nanoparticles of vitamin A were prepared. Gels were prepared using polymers like carbopol 940 (1%), pemulen TR-1 (1%), xanthan gum (1%), and poloxamer F127 (15%). For the preparation of the gel, glycerol (10%), nanoparticulate dispersion (20%), and water were weighed in a beaker and stirred. Required quantity of gelling agent was dispersed in the aqueous phase under continuous stirring. Solid lipid nanoparticulate dispersion was prepared with the help of high pressure homogenization technique. The nanoparticulate dispersion and its gels were evaluated for various parameters such as particle size, in vitro drug release, in vitro penetration, in vivo skin hydration, and skin irritation. In vivo skin hydration studies in albino rats revealed increase in the thickness of the stratum corneum with improved skin hydration. The developed formulation was nonirritant to the skin with no erythema or edema and had primary irritation index of 0.00. Thus it is clear that solid lipid nanoparticulate dispersion gel composed of polymers is efficient delivery system.

Fang et al.⁹⁶ correlated in vitro topical application of nonivamide hydrogel with in vivo pharmacodynamic responses using Wistar rat animal model. The incorporation of pluronic F127 polymer into hydrogels resulted in retarded release of nonivamide. Chitosan and carboxymethylcellulose hydrogels produced higher levels of in vitro nonivamide permeation and skin distribution. Depending on dose and duration after topical application, in vivo effects of nonivamide on skin perturbation and vasodilation were found to differ. Quantification of transepidermal water loss was demonstrated to correlate with the measured in vitro skin distribution of nonivamide.

Gels serve as the efficient vehicle for the iontophoresis. These can be easily amalgamated with the iontophoretic delivery system and can also match the contours of the skin. Insulin was used as a model peptide for large peptides in the molecular weight range of 3-7 kDa. Pillai et al.⁹⁷, with the use of poloxamer 407 prepared a gel formulation and evaluated by ex vivo and in vivo skin permeation studies in rat with chemical enhancer and/or iontophoresis. During the storage period, poloxamer gel was found physically and chemically stable. In ex vivo studies, both linoleic acid and menthone in combination with iontophoresis showed a synergistic enhancement of insulin permeation. The plasma insulin concentration was highest with linoleic acid pre-treatment, in agreement with ex vivo permeation studies, but the reduction in plasma glucose levels was comparable to iontophoresis. Menthone pre-treatment resulted in rapid attainment of peak plasma insulin concentration, but the reduction in plasma glucose levels was less than other treatment groups. There was no direct relation between plasma insulin concentration and plasma glucose levels and is attributed to the fact that the action of insulin in mediated by a cascade of cellular mechanisms, before a reduction in plasma glucose levels is observed. Iontophoresis either alone or in combination with linoleic acid produced a reduction in plasma glucose levels to the extent of 36-40%.

Escobar-Chávez et al.⁹⁸ prepared pluronic F127 gels containing Azone^® and Transcutol^® as penetration enhancers and determined the penetration of sodium naproxen through human skin in vivo. Sodium naproxen penetration was found to be enhanced with the combination of Azone^® and Transcutol^® in pluronic F127 gels. The enhancement ratios were found up to two fold compared with the formulation containing only Transcutol^®. The confirmation of the results was done by TEWL and ATR-FTIR spectroscopy, suggesting a synergic action for Azone^® and Transcutol^®. The thermoreversible behavior of pluronic gels, the influence of the components added to the gel formulations on viscosity, as a function of temperature, was also studied.

Hepatic first pass metabolism of NSAIDs (non steroidal anti-inflammatory drugs) can be avoided if they are given via percutaneous delivery and drug can delivered for extended period of time at a sustained, concentrated level at the inflammation site that mainly acts at the joint and the related regions. By using hydroxypropyl methylcellulose (HPMC) and poloxamer 407, the new topical formulations having suitable adhesion were prepared. The effects of temperature on drug release was performed at 32^oC, 37^oC and 42^oC according to drug concentration of 0.04%, 0.08%, 0.12%, 0.16%, and 0.2% (w/w) using synthetic cellulose membrane. The increase of temperature showed the increased drug release. The activation energy (Ea), which were calculated from the slope of lop P versus 1000/T plots was 11.22 kcal/ mol for 0.04%, 10.79 kcal/mol for 0.08%, 10.41 kcal/mol for 0.12% and 8.88 kcal/mol for 0.16% loading dose from the pranoprofen gel. For enhancing permeation of the drug, penetration enhancers like propylene glycol, ethylene glycol, glycerides, non-ionic surfactants, and fatty acids were incorporated in the gel formuluation. Among the various enhancers used, propylene glycol mono laurate showed the highest enhancing effects with the enhancement factor of 2.74. The results of this study suggest that development of topical gel formulation of pranoprofen containing an enhancer is feasible.⁹⁹

El-Kattan et al.¹⁰⁰ studied the effect of formulation variables on the percutaneous permeation of ketoprofen from gel formulations. The aim of the study was to evaluate the effect of four terpene enhancers, enhancer lipophilicity, and ethanol concentration using hydroxypropyl cellulose (HPC) and two pluronic F127 gel formulations on the percutaneous permeation of ketoprofen. Hairless mouse skin was used for the all experiments as in vitro study model. Comparison was made with the data recorded within 24 hrs and the control gels (containing no terpene) using Franz diffusion cells. Out of the three gel formulations, the highest increase in the ketoprofen permeation was observed using limonene followed by nerolidol, fenchone, and thymol. Relationships were established between terpene lipophilicity, enhancement ratios for ketoprofen flux (ER_flux), and the cumulative amount of ketoprofen after 24 hrs from the three gel formulations.

The potential of gels formed in situ by dilute aqueous solutions of a xyloglucan polysaccharide derived from tamarind seed as sustained release vehicles for percutaneous administration of non-steroidal anti-inflammatory drugs was assessed by Takahashi et al.¹⁰¹ Chilled aqueous solutions of xyloglucan that had been partially degraded by β-galactosidase formed gels at concentrations of 1–2% w/w when warmed to 37 °C. The in vitro release of ibuprofen and ketoprofen at pH 7.4 from the enzyme degraded xyloglucan gels and the subsequent permeation of these fully ionized drugs through cellulose membranes followed root-time kinetics over a period of 12 h after an initial lag period. Diffusion coefficients were appreciably higher when the drugs were released from 1.5% w/w xyloglucan gels than when released from 25% w/w pluronic F127 gels formed in situ under identical conditions. Plasma concentrations of ibuprofen and ketoprofen from gels formed in situ following topical application of chilled aqueous solutions of xyloglucan and pluronic F127 to the abdominal skin of rats were compared. The bioavailabilities of ibuprofen and ketoprofen were significantly higher when released from xyloglucan gels compared to pluronic F127 gels.

Injectable Routes:

Katakam et al.¹⁰² studied and evaluated the use of poloxamer in developing a sustained release formulation of recombinant human growth hormone (rhGH). Due to characteristic property of thermoreversibility, poloxamer exists as solution but undergoes gel formation at body temperature. In vitro release studies were conducted at 37°C for 72 h. HPLC assay shows the zero order release profile. Iodination of rhGH was then performed for the release of ¹²⁵I-rhGH from poloxamer gel. In vivo studies in rats were then conducted using the poloxamer gel formulation for controlled release of rhGH with the administration via intramuscular and subcutaneous routes. 60–72 h was required for the controlled release formulation to release rhGH and for a week in vivo following intramuscular and subcutaneous injections. No significant difference (P<0.05) was observed following administration by either route.

For treatment of severe pain, epidural administration of drugs is more common way and for improvement of this therapy, a long-acting single-dose gel injection appears to be beneficial. Paavola et al.¹⁰³ studied the use of three different as additives in the injectable poloxamer gel formulation in controlling drug release. The release of lidocaine hydrochloride and ibuprofen sodium from 25% poloxamer (PO) gel and poloxamer gel with hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (CMC), or dextran (DE) was studied in vitro. Ibuprofen release is prolonged by cellulose additives significantly. However, additives were found to have a slight release-increasing effect on lidocaine as compared with the PO gel. Structural differences of the gels, more than the macroviscosity, seem to regulate the release of drugs. The drug permeation-prolonging effect of the respective gels, along with the control solutions, was evaluated in vitro using porcine dura mater membrane. Rate limiting step was found to be compact gel depot and significantly prolonged the dural permeation of both drugs in comparison with control solutions. Possibility of interactions between dural membrane and the gel was demonstrated by difference in the drug release and permeation-reducing effects of the gels. These results were found to be efficient and useful for further in vivo animal testing of these injectable poloxamer-based gels.

In another study, Paavola at al.¹⁰⁴ studied the possibility of using liposomes to control the release and dural ibuprofen permeation in vitro. Ibuprofen release in controlled manner was found to be from the liposomal gel. In vitro permeation pattern was found to be suitable in maintaining constant drug levels. Liposomal solutions of ibuprofen (20 mg/ml) were prepared by high-pressure homogenization from egg phosphatidylcholine. The liposomal gel consisted of poloxamer 407 and the liposomal solution. No signs in the ¹H-NMR spectroscopy of line broadenings or chemical shifts were observed. The liposomal formulations were reproducible and stable. Ibuprofen release in phosphate buffer, pH 7.4, at 37°C from the liposomal solution and the liposomal gel were prolonged significantly compared with their respective solution and gel controls. The liposomal gel controlled ibuprofen release and dural permeation in vitro and showed a permeation pattern favorable for maintaining constant drug levels. Thus the liposomal gel formulation of poloxamer serves to be new promising approach to increase the local epidural availability.

Subcutaneous Route:

Ricci et al.¹⁰⁵ studied sustained release of lidocaine from poloxamer 407 gels and showed that alteration of poloxamer 407 gel content can affect drug release rates. Rate of drug release can also be affected due to inorganic salts and PEG400 included in poloxamer 407 gel. The use of poloxamer 407 gels cause prolongation in residence time of lidocaine at the injection site, sustain its release and increases therapeutic efficacy. Diffusion system was used to study release study and it was found to follow Higuchi square root law time kinetic (r>0.98). As the polymer concentration increases there occurs reduction in lidocaine release rates and diffusion coefficients via extended gel dissolution time and prolonged drug diffusion through gel matrix. In vivo studies were carried out on male rats and given subcutaneous injection of 300µl of formulation and the control group is treated with only saline. The results indicate in the support that the possibility of using poloxamer gel as sustained release, injectable extravascular formulation. Poloxamer 407 proved to be promising carrier for sustaining release of lidocaine.

Morishita et al.¹⁰⁶ evaluated the use of pluronic F127 (PF127) gels, polylactic-co-glycolic acid (PLGA) nanoparticles and their combination for parenteral delivery of peptides and proteins having short half-lives using insulin as a model drug. In vitro release study was carried out using membraneless in vitro model, at 37C. Wistar rats as the animal model for in vivo studies and evaluation of serum glucose and insulin was performed following subcutaneous administration of various insulin formulations. It was found from in vitro release studies that as the concentration of pluronic in the gel increases, insulin is slowly released from matrices, independent of vehicle used. Acute hypoglycemic peak resulting from administration of insulin was obtained between 0.2 and 2.0 hr after administration (peak at 1 h) is replaced after administration of insulin–PLGA nanoparticles by an almost constant hypoglycemic effect with a slower recovery of the serum glucose levels at about 2 h after administration. By loading insulin into pluronic gels, more prolonged hypoglycemic effect of insulin was obtained in inverse proportion to the polymer concentration. Pluronic F127 gel formulations containing insulin–PLGA nanoparticles had the most long-lasting hypoglycemic effects of all formulations. From this study in vitro and in vivo type, it was clear that pluronic F127 gel formulations containing drug or nanoparticles containing drug could be very efficient form of controlled delivery system for peptides and proteins which have short half lives.

Intramuscular Route:

Wang et al.¹⁰⁷ developed and evaluated potential sustained-release recombinant interleukin-2 (rlL-2) formulation by using the intramuscular injection in rats. The triblock copolymer, pluronic F127 showing the property of reverse thermo gelation was used for preparation of the formulation. The rlL-2/poloxamer 407 preparation was injected intramuscularly in rats as a viscous mobile solution with subsequent gelation in vivo. Resultant plasma rlL-2 concentration-time data indicated absorption rate-limited disposition of rlL-2 following intramuscular injection. The mean values of absorption rate constant (k_a) were found to be 0.64 ± 0.073 for an rlL-2 aqueous solution and 0.21 ± 0.019 h^-1 for the rIL-2 gel formulation. The mean values of the elimination rate constant (k_elim) were 1.76 ± 0.22 and 1.21 ± 0.079 h^-1 following administration of rlL-2 as an aqueous solution or gel formulation, respectively. The blood sampling time point at which the greatest plasma rlL-2 concentration (C_max) was observed was 2 h for rats injected intramuscularly with rlL-2 formulated in poloxamer 407 compared to 1 h for rats injected intramuscularly with an rlL-2 aqueous solution.

The mean value of the Cm~ was significantly (p < 0.05) less in rats injected intramuscularly with the rlL-2 gel formulation (C_max = 12500 ± 1450 pg/ml) compared to rats injected intramuscularly with an aqueous solution of rlL-2 (C_max = 19 600 ± 2650 pg/ml). The bioavailability of rlL-2 when injected intramuscularly as an rlL-2/poloxamer gel formulation relative to an intramuscular injection of an rlL-2 aqueous solution was approx. 1.0. Cumulative amounts of rlL-2 recovered in the urine 48 h after an intramuscular injection of either an rlL-2 aqueous solution or rlL-2 gel formulation were found to be less than 1 percent of the administered dose. Since the rlL-2/poloxamer formulation evaluated in this study resulted in a decrease in the maximum blood concentration of rlL-2 achieved and an increase in the time required to reach a maximum blood concentration, without a reduction in the bioavailability of the protein, the rlL-2 gel formulation may represent an alternative, sustained-release mode of rIL-2 administration.

Wenzel et al.¹⁰⁸ carried out the comparison of the effectiveness of intramuscular sustained release pluronic F127 (PF127) gel formulations of deslorelin, a potent GnRH agonist, and GnRH to their solution formulations in inducing the release of luteinizing hormone (LH) and formation of luteal tissue in cattle. Pluronic F127 in the concentration of 25%w/w was used for the preparation of injectable formulations of deslorelin and GnRH. Pluronic F127 gels sustained the in vitro release of deslorelin as well as GnRH at similar rates and reduced drug degradation in muscle tissue when compared to the solution formulations. The cows were treated with 100 µg deslorelin or 100 µg GnRH in solution or in PF127. Deslorelin and GnRH showed desirable elevations in plasma LH and progesterone concentrations in vivo. The gel formulations of both drugs induced broader peak of LH. Also, the peak LH levels were lower and the peak times were delayed with the gel formulations compared to the solution formulations. Similar responses were showed by solution dosage form of both of these drugs. Peak LH levels were observed at an earlier time (3 hr for deslorelin versus 5.25 hr for GnRH); in case of pluronic F127 gel formulation. These results indicate that deslorelin exerts a pharmacological effect in cattle. The response of LH to deslorelin and GnRH can be altered by controlling input or release rate of the drug. From these results it was clear that Pluronic gel formulations can sustain peptide release and reduce peptide degradation.

Intravenous route:

Pluronic F38 (Poloxamer 108) has been used experimentally in a new fractionation procedure for plasma proteins. Residual amounts of this copolymer might be administered intravenously with a plasma fraction; its toxicity was evaluated following intravenous administration. Pluronic F38 was injected intravenously in the amount of 0.15, 1, 2, and 4 gm/kg at five times a week for two weeks to Sprague-Dawley rats. Light microscopical examination revealed that pluronic F38 caused early and prominent vacuolization of epithelial cells in the proximal renal tubules and of hepatocytes and a gradual accumulation of vacuoles in Type II macrophages in the lung. These alterations in morphology were dose dependent and increased in severity during the period of administration. The lesions were slowly reversible; there was a moderate decrease in vacuolization 14 days after the last injection. Vacuoles were probably distended lysosomes, as indicated by transmission electron microscopy. The paucity of additional cellular changes suggests that, although pluronic F38 may be rapidly phagocytized, it is well tolerated even when administered intravenously in large doses.¹⁰⁹

With the intravenous administration, small colloidal (150 nm and below, in diameter) can be redirected specifically to the rabbit bone marrow by coating their surface with the block co-polymer poloxamer 407. The coated colloids are sequestered by the sinusoidal endothelial cells of the bone marrow and are accumulated in dense bodies within these cells. The uptake of poloxamer 407-coated colloids by marrow eondothelial cells suggests that the steric repulsive barrier, imposed by the polyoxyethylene segment of the polymer, to particle-cell interaction can apparently be overcome by a specific interaction mechanism(s) with the cell surface. This type of uptake can not be achieved by other diblock copolymer having structure similar to pluronic. Porter et al.¹¹⁰ studied the application of the current model for the site-specific targeting or drug carriers to bone marrow and the prevention of the adherence of metastases of tumors which selectively colonize the bone marrow endothelium.

Lee et al.¹¹¹ compared inverse-targeting of reticuloendothelial system (RES)-rich organs after intravenous (i.v.) injection of free adriamycin, ADM (treatment I) and ADM-loaded neutral proliposomes containing poloxamer 407 (treatment II), 16 mg per kg as free ADM, to rats using the HPLC assay. The amount of ADM remaining per g tissue at 30 min after i.v. administration, and the tissue-to-plasma ratio of ADM in the spleen, a RES-rich organ, were significantly lower. While in non-RES organs such as the Kidney, stomach small intestine, large intestine, lung, heart, muscle and mesentery, values were found markedly higher in treatment II than in treatment I. After 1 min i.v. infusion, the terminal half-life (65.2 vs 406 min), mean residence time (27.5 vs 318 min) and the apparent volume of distribution at steady state (2480 vs 22800 ml kg⁻¹) were significantly higher, but the renal clearance (9.81 vs 0.138 ml min⁻¹ kg⁻¹), and the amount of ADM excreted in 48 h urine (496 vs 39.5 μg) were significantly lower in treatment II than in treatment I.

Poloxamer 407 was adsorbed onto the surface of model colloidal drug carriers, polystyrene nanoparticles of 40, 70 and 137 nm in diameter, and the effect of the degree of surface coverage and the conformation of the poly (ethylene oxide) (PEO) chains on biological fate was studied by Stolnik et al.¹¹² The in vitro interaction of the nanoparticles with different degrees of poloxamer 407 surface coverage with serum components and the in vivo biodistribution in the rat model were assessed. Following the intravenous administration to rats, even the nanoparticles with the lowest degree of surface coverage (approx. 5%) showed improved circulation profiles relative to the uncoated nanoparticles. The effect was more pronounced for the 40 nm nanoparticles. A further increase in the surface coverage to approx. 25% resulted in a significant increase in circulation time, as compared to uncoated and 5% coated systems, for all sizes of nanoparticles. Also it was important that a long in vivo blood circulation time could be achieved for nanoparticles with a relatively low degree of surface coverage with PEO chains.

With the use of poloxamer and poloxamine 908, solid lipid nanoparticles were prepared. The protein adsorption pattern acquired on the surface of these particles after intravenous injection is the key factor determining the organ distribution. Here, Goppert et al.¹¹³ studied changes in the plasma protein adsorption patterns in the course of variation of the polymers stabilizing the solid lipid nanoparticles. The protein adsorption pattern and total protein mass adsorbed to the nanoparticles was evaluated using the bicinchoninic acid (BCA)-protein assay. The results indicate that in vivo well-tolerable SLN are a promising site-specific drug delivery system for intravenous injection.

Other Phrmaceutical Applications:

Pluronic copolymers have wide range of applications in pharmaceutical industry as a featured excipient. Various grades of them were used as emulsifier, suspension stabilizer in liquid orals, parenteral and topical dosage forms and also as solubilizer for hydrophobic drugs. In solid dosage forms, they act as wetting agent, plasticizer, tablet lubricant and has wide application in formulation of gels due to thermoreversible gelation behavior. Desai et al.¹¹⁴ evaluated the micronized poloxamer 188 and micronized poloxamer 407 as a tablet lubricants in comparison with magnesium stearate and stearic acid using conventional caffeine formulation and to evaluate the effect of lubricant mixing time on tablet properties using acetaminophen direct compressible formulation. From the results it was concluded that micronized poloxamer 188 and micronized poloxamer 407 has lubrication property and have no negative effect on tablet properties. However, lubricant mixing time may not be a critical parameter when poloxamers are used as a lubricant.

Ruchatz et al.¹¹⁵ studied the effects of pluronic F68 added in different ratios to pluronic F127 solutions for developing novel delivery formulations. Here the investigation of the influence of mucoadhesive compound and model drug. Also sol-gel transition temperature and assessment of rheological behavior were also studied. From these results, combination of pluronic F127 and F68 serves to be promising for the development of liquid controlled release systems thermogelling at body temperature.

Batrakova et al.¹¹⁶ examined the effect of novel drug delivery system, pluronic P85, on P-glycoprotein-mediated efflux from the brain using in vitro and in vivo methods. The effect of pluronic P85 on the directional flux across an in vitro blood brain barrier (BBB) was also characterized. It was found that Pluronic increased the cellular accumulation of digoxin three fold in porcine kidney epithelial cells (LLC-PK1) and five fold in the LLC-PK1-MDR1-transfected cells. A prototypical P-glycoprotein substrate rhodamine-123 also has similar effects. The coadministration of pluronic P85 in concentration of 1% with radiolabeled digoxin in wild -type increased the brain penetration of digoxin three fold. These data gives indication that Pluronic P85 can enhance the delivery of digoxin to the brain through inhibition of P-glycoprotein mediated efflux mechanism.

Coeshott et al.¹¹⁷ formulated a new vaccine delivery system based on pluronic F127 combined with immunostimulants. They evaluated the potential use of pluronic F127 as component of systemic as well as mucosal adjuvant / delivery vehicles. Protein antigens (tetanus toxoid (TT), diphtheria toxoid (DT) and anthrax recombinant protective antigen (rPA) were formulated with F127 in combination with CpG motifs or chitosan, as examples of immunomodulators, and were compared to more traditional adjuvants in mice. After systemic administration of protein antigens, IgG antibody responses were markedly enhanced by Pluronic F127 / CpG and F127/chitosan combinations compared to antigens mixed with CpGs or chitosan alone. From these studies, pluronic block-copolymer approach could enhance the delivery of a variety of clinically useful antigens in vaccination schemes.

Biomedical And Other Applications:

The marketed formulation by RheothRx^® injection is the intravenous formulation of poloxamer 188 which is used in the clinical studies like during thrombolysis in acute myocardial infarction. Lechmann and Reinhart studied the effect of above formulation on plasma and whole blood viscosity of healthy individuals in vitro. Increase in high and low shear viscosity was observed at highest RheothRx^® concentration. Erythrocyte morphology remained unchanged. These results indicate that poloxamer 188 increases plasma and whole blood viscosity.¹¹⁸

Pluronic F127 was used by Ohta et al.¹¹⁹ to simulate embolization and dissolution of embolism in the renal artery and superior mesenteric artery (SMA). The embolic effect was evaluatd by angiography immediately after initial injection and every 15 minutes for 2.5 hr. after embolization and using female Japanese rats as the animal model for in vivo study. Pathologic changes of renal parenchyma and embolic effect for SMA and ischemic changes of intestine were also evaluated. Pluronic F127 thus works as temporary embolic material and dissolves before severe ischemic tissue damage can ensured. This property therefore makes it as a potentially safe substance to use as temporary embolic material in medicine.

Witt et al.¹²⁰ examined pluronic P85 and its potential to enhance opiod peptide analgesia. Two opioid peptides, [D-Pen², D-Pen⁵]-enkephalin (DPDPE) and biphalin, were studied as to the benefits of P85 coadministration, above (1.0%) and below (0.01%) the critical micelle concentration, with morphine as a nonpeptide control. Pluronic P85 was examined in vitro to assess blood brain barrier uptake in association with P-glycoprotein effect, DPDPE and morphine being P-glycoprotein substrates. This indicates that, in addition to P-glycoprotein inhibition, 0.01% P85 increased ¹²⁵I-DPDPE and [³H] morphine uptake.

Intratumoral infusions pose to the problem of dissemination. To reduce this problem, a novel method based on poloxamer 407 was developed. This formulation could significantly increase the viscosity of virus suspension when the temperature was changed from 4C to 37C. By using this method, significant increase transgene expression in solid tumors was observed and reduction in virus dissemination by 2 orders of magnitude after intratumoral infusion of adenoviral vectors occurs. The mechanism of reduction was likely to be that the viscous poloxamer solution blocked convection of viral vectors in the interstitial space and the lumen of microvessels in the vicinity of the infusion site. For reducing toxicity and enhancing efficacy in viral gene therapy, this method can be used in the clinical practice.¹²¹

Frim et al.¹²² studied poloxamer 188 mediated neuroprotection in rat model of glutamate toxicity. Quinolinate was infused into the striatum followed 10min and 4 hr later by poloxamer 188 administered either intravenously or intracisternally, or by vehicle. Mean neuronal loss examined volumetrically 7 days later in control animals was 50% greater (Po0.01) than after intracisternal poloxamer 188 treatment; control lesion volumes were 38% greater than lesion volumes after intravenous poloxamer188 treatment. These results confirm that poloxamer 188 protects against glutamate toxicity in the rat brain.

Summary:

Difunctional block copolymer, pluronic exhibits various desirable characteristics of pharmaceutical formulations. Its micellar behavior, temperature dependent gelation property provides solubility to the systems and desirable delivery rate. Thermoresponsive nature of pluronic makes it excellent candidate for the delivery of drugs at the various site of application. Apart from these pluronic serves to be suitable for various biomedical and engineering fields. There has been remarkable progress in development of pluronic based formulations. The new wave of pharmaceutical products will definitely make use of this polymer and various formulation problems incurred will get solved.

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