Poloxamers

Poloxamers are block copolymers from ethylene oxide and propylene oxide. Poloxamers are also known as Pluronic (28). Poloxamers can be subdivided into 3 categories, namely emulsion forming, micelle forming, and water soluble poloxamers. 

Various factors, which determine the poloxamer characteristics and behavior are the molecular weight, the ratio of poly(phenyl-ene oxide) to poly(ethylene oxide), temperature conditions, concentration, and the presence of ionic materials. There is thus a wide range of characteristics in existing commercially available poloxamers which can be exploited in formulating the compositions of the present disclosure, especially where the composition further includes a medicinal agent and is utilized for drug delivery purposes (29). 

Particularly useful for these purposes are triblock copol5mers of the formula HO(C2H4o)a(C3H6o)b(C2H4o)cH, wherein a and c are independently from 1-150 units and b ranges from 10-200 units, with the overall molecular weight ranging from 1-50 k D. 

A biocompatible, biodegradable polymer can be produced as follows. A poloxamer (Pluronic F68) (30) is dried in vacuo at about 105°C for 14 h. Afterwards, glycolide and then -caprolactone are added. As a catalyst stannous octoate is used (29). 

The reaction is allowed to proceed at 178°C for some 4 h. After completition of the reaction, the bioabsorbable polymer is extruded and allowed to cool for a minimum of 16 h. The resulting bioabsorbable terpolymer contains about 40% Pluronic F68, 51% of caprolactoyl groups, 9% of glycoyl groups, and less than 1% of residual caprolactone monomer (29). The resulting composition may be utilized to form medical devices, drug delivery devices, or coatings for other medical devices. 

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Several other examples of modified mobile phases are given in Figs. 13.58 and 13.59 using 90/5/5 TEIF/MeOH/ACN and 95/5 chloroform/w-butylamine for the SEC analysis of poloxamer and nitrile-butadiene rubber samples, respectively. 

The term poloxamer is widely used to describe a series of ABA block coploymers of polyethylene oxide and polypropylene oxide, extensively used in industry as antifoams, emulsifiers, wetting agents, rinse aids, and in numerous other applications [1-5]. Poloxamers are amphiphilic in character, being comprised of a central polypropylene oxide (PO) block, which is hydrophobic, sandwiched between two hydrophilic polyethylene oxide (EO) blocks as shown below ... 

For the central PO block to serve as an effective hydrophobe, the value of n must be at least 15 the value of m in commercially manufactured poloxamers is such that the EO blocks constitute between 10-80% of the total polymer mass. The absolute and relative masses of the hydrophilic and hydrophobic blocks, on which the physico-chemical properties of the polymers depend, can be controlled during manufacture, enabling the production of poloxamers tailored to specific applications. 

The poloxamers manufactured by BASF (Cheadle, UK) are known as Pluronic PE block copolymers those manufactured by ICl (Cleveland, UK) as Synperonic PE nonionic surfactants. 

The initiator usually constitutes less than 1% of the final product, and since starting the process with such a small amount of material in the reaction vessel may be difficult, it is often reacted with propylene oxide to produce a precursor compound, which may be stored until required [6]. The yield of poloxamer is essentially stoichiometric the lengths of the PO and EO blocks are determined by the amount of epoxide fed into the reactor at each stage. Upon completion of the reaction, the mixture is cooled and the alkaline catalyst neutralized. The neutral salt may then be removed or allowed to remain in the product, in which case it is present at a level of 0.5-1.0%. The catalyst may, alternatively, be removed by adsorption on acidic clays or with ion exchangers [7]. Exact maintenance of temperature, pressure, agitation speed, and other parameters are required if the products are to be reproducible, thus poloxamers from different suppliers may exhibit some difference in properties. 

It is important to recognize that the following analytical methods essentially determine EO-PO ratio ( H NMR, IR, cleavage methods) or even simply alkylene oxide content (compleximetric methods) of the analyte, and as such are not specific quantitative or qualitative methods for poloxamers, since EO-PO copolymers of a different structure (for instance, random copolymers, or PO-EO-PO block copolymers) may respond to the methods in a way indistinguishable from poloxamers. The principal technique that permits definitive identification of a sample as a poloxamer is C NMR, which allows structural details, such as the distribution of EO and PO units along the polymer chain, to be elucidated [10]. 

IR analysis can also be used quantitatively to determine the EO-PO ratio [12]. Using mixtures of polyethylene glycol and polypropyene glycol as calibration standards, the ratio of two absorbances, one due to the methyl group of the PO unit (e.g., the C-H stretch band at 2975 cm ) and one due to the methylene group (e.g., the C-H stretch band at 2870 cm ), are plotted against percent of PO content. The ratio of the same two absorbances taken from the IR spectrum of a poloxamer may then be used to determine its percent of PO content by interpolation. 

Poloxamers are used primarily in aqueous solution and may be quantified in the aqueous phase by the use of compleximetric methods. However, a major limitation is that these techniques are essentially only capable of quantifying alkylene oxide groups and are by no means selective for poloxamers. The basis of these methods is the formation of a complex between a metal ion and the oxygen atoms that form the ether linkages. Reaction of this complex with an anion leads to the formation of a salt that, after precipitation or extraction, may be used for quantitation. A method reported to be rapid, simple, and consistently reproducible [18] involves a two-phase titration, which eliminates interferences from anionic surfactants. The poloxamer is complexed with potassium ions in an alkaline aqueous solution and extracted into dichloromethane as an ion pair with the titrant, tet-rakis (4-fluorophenyl) borate. The end point is defined by a color change resulting from the complexation of the indicator, Victoria Blue B, with excess titrant. The Wickbold [19] method, widely used to determine nonionic surfactants, has been applied to poloxamer type surfactants 120]. Essentially the method involves the formation in the presence of barium ions of a complex be-... 

Purification of poloxamers has been extensively investigated due to their use in medical applications, the intention often being to remove potentially toxic components. Supercritical fluid fractionation and liquid fractionation have been used successfully to remove low-molecular weight impurities and antioxidants from poloxamers. Gel filtration, high-performance liquid chromatography (HPLC), and ultrafiltration through membranes are among the other techniques examined [5]. 

A summary of the physical properties of poloxamers follows, with the emphasis on those properties most relevant to commercial applications. An extensive review (277 references) [4] provides a wealth of specific exam-... 

Poloxamers suppress the formation of foam by forming an insoluble monolayer, thus the antifoaming action of poloxamers depends on the cloud point, above which the polymer becomes insoluble. For the poloxamer to... 

Table 3 Techniques Used to Characterize the Aggregation Behavior of Poloxamers...

Poloxamers are most important commercially as anti-foams, wetting agents, and emulsifiers, but have also been found to have numerous potential applications in the medical field. 

The potential use of poloxamers in the medical field has been extensively investigated [5,35]. The use of poloxamers in drug delivery, as gels in the controlled release of drugs and in solid form in the targetting of drugs at specific sites in the body, has received significant atten-... 

Although poloxamers show poor biodegradability, they exhibit very low acute toxicity [92] and are reported as having low potential for causing irritation and skin sensitization [26]. Toxicity decreases as ethylene oxide content increases, and the least toxic poloxamers are approved as food additives [80]. 

I. R. Schmolka, Poloxamers, The Versatile Surfactants for Medical Investigations. Conference Paper, 2nd Inter-... 

The formation of peroxides and formaldehyde in the high-purity polyoxyethylene surfactants in toiletries has been shown to lead to contact dermatitis [31], Peroxides in hydrogenated castor oil can cause autoxidation of miconazole [32], Oxidative decomposition of the polyoxyethylene chains occurs at elevated temperature, leading to the formation of ethylene glycol, which may then be oxidized to formaldehyde. When polyethylene glycol and poloxamer were used to prepare solid dispersions of bendroflumethiazide, a potent, lipophilic diuretic drug, the drug reacted with the formaldehyde to produce hydroflumethiazide [33],... 

Polyoxyethylerie-polyoxypropylene block copolymers (Pluronics or Poloxamer) 29.0... 

Emulsifiers. Natural lecithin is one of the most widely used emulsifiers because it is metabolized in the body. However, type I allergic reaction to soybean lecithin emulsified in lipid solutions has been observed [195], Among the synthetic emulsifying agents, block copolymers of polyoxyethylene-polyoxypropylene (poloxamer) have attracted increasing interest for parenteral emulsions. Other examples of emulsifiers commonly found in parenteral formulations are given in Table 9 [190]. 

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