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POLOXAMER 188
Poloxamers are polymers used for drug delivery as formulation excipients. They are used in pharmaceutical formulations as surfactants, emulsifying agents, solubilizing agent, dispersing agents, and as in vivo absorbance enhancers. They are also used in topical dosage forms and rectal suppositories. The common available grades are; poloxamer 68, 88, 98, 108, 124, 188, 237, 338, and 407.
Cas no.: 9003-11-6
EC no.: 618-355-0
SYNONYMS:
Poloxalene, Poloxamer 188, Pluronic, POLOXAMER, Poloxalkol, 9003-11-6, Poloxamer 407, Pluronic L 61, Pluronic L-81, Detalan, Pluracare, Therabloat, Tergitol XH, Lutrol F, Adeka Pluronic F 108, Epan 485, Epan 710, Epan 785, Cirrasol ALN-WS, 106392-12-5, Pluronic L44, Polyoxamer 108, Pluronic F 38, Pluronic F108, Pluronic F127, Tergitol nonionic XH, Antarox 17R4, Antarox 25R2, Antarox B 25, Antarox F 68, Antarox F 88, Antarox F 88FL, Antarox L 72, Antarox P 84, Daltocel F 460, Slovanik M-640, Antarox F 108, Antarox P 104, Antarox SC 138, Emulgen PP 230, Adeka 25R1, Adeka 25R2, Adeka L 61, Dehypon KE 3557, Empilan P 7068, Proxanol, Arcol E 351, D 500 (polyglycol), Polyethylene-polypropylene glycol, Arco Polyol R 2633, Epan 450, Crisvon Assistor SD 14, Pluronic L, Breox BL 19-10, Epan U 108, Proxanol Tsl-3, Pluronic F77, Pluronic F87, Pluronic F88, Pluronic L62, Pluronic L64, Pluronic P65, Pluronic P84, Pluronic P85, Meroxapol 105, Poloxamer 101, Crl 1005, Pluronic P103, Pluronic P104, Pluronic P105, BASF-L 101, Pluronic L 122, Polyethylene glycol, propoxylated, Ethylene oxide-propylene oxide block polymer, Glycols, polyethylene-polypropylene, BSP 5000, CRL 1605, CRL 8131, CRL 8142, Oxirane, methyl-, polymer with oxirane, block, RC 102, Oxirane, methyl-, polymer with oxirane, Methyloxirane polymer with oxirane block, SK&F 18,667, F 77, F 87, F 88, P 84, P 85, B 053, F 108, F 127, P 103, P 104, P 105, P 123, PEG/PPG-125/30 Copolymer, HSDB 7222, NSC 63908, Polyethylene oxide-polypropylene oxide, Vepoloxamer (USAN), Vepoloxamer [USAN], Polyoxyethylene-oxy-propylene [French], Poly(ethylene oxide-co-propylene oxide), Polyoxyethylene - polyoxypropylene copolymer, F-108, Ethylene oxide-propylene oxide block copolymer dipropylene glycol ether, Ethylene oxide-propylene oxide block copolymer ether with ethylene glycol, Polyoxyethylene - polyoxypropylene block copolymer, alpha-Hydro-omega, hydroxypoly(oxyethylene)(sub a)-poly(oxopropylene)(sub b)-poly(oxyethylene)(sub a) block copolymer, alpha-Hydro-omega-hydroxypoly(oxyethylene)a-poly(oxopropylene)b-poly(oxyethylene)a block copolymer, 75-H-1400, C10H22O3, 2-methyloxirane; oxirane, Poloxamer [USAN:INN:BAN], Pluracol V, Pluriol PE, component of Casakol, Pluronic L122, Lutrol F (TN), oxirane-propylene oxide, 2-methyloxirane;oxirane, Pluriol PE 6810, PEG-PPG-PEG, ETS9O8IMRZ, UNII-ETS9O8IMRZ, Eban 710, Epan 750, Epon 420, UNII-66UUC8WX0D, 66UUC8WX0D, Niax 16-46, UNII-199SZS8E2Q, UNII-JP0CK963E0, UNII-P5QZM4T259, SCHEMBL11737, ethylene oxide propylene oxide, Oxirane, polymer with oxirane, UNII-1AZW43116L, UNII-52901V8XAR, Propylene Oxide Ethylene Oxide, TsL 431, ADEKA PLURONIC F-108, 199SZS8E2Q, JP0CK963E0, P5QZM4T259, UNII-68T8I45V23, CHEBI:32026, MST-188, TVM 370, 1AZW43116L, 52901V8XAR, Peg/ppg-24/34 triblock copolymer, Poloxalene [USAN:USP:INN:BAN], NSC63908, NSC-63908, WS 661, AKOS015912614, Oxirane, 2-methyl-, polymer with oxirane, ether with 1,2-propanediol (2:1), Oxirane, methyl-, polymer with oxirane, ether with 1,2-propanediol (2:1), 68T8I45V23, DB11451, SK&F-18667, LS-72949, SK & F 18,667, LS-101081, N 480, D01941,D10680, M 90/20, 75H90000, alpha.Hydro.omega.hydroxypoly(oxyethylene)poly(oxypropylene)poly(oxyethylene) block copolymer.
REGULATORY PROCESS NAMES:
Oxirane, 2-methyl-, polymer with oxirane, Poloxalene
IUPAC NAMES:
2-methyloxirane, Agent I122, EO-PO block co-polymer, Ethylene oxyd and prophylene oxyd block copolymer, methyl-oxirane polymer with oxirane, Oxirane methyl polymer with oxirane, Oxirane, 2-methyl-, polymer with oxirane, OXIRANE, METHYL-, POLYMER WITH OXIRANE, Oxirane, methyl-, polymer with oxirane, oxirane, methyl-,polymer with oxirane, Poloxalene, polyalkylene glycol, Polyethylene-polypropylene glycol, Polyoxyethylene-polyoxypropylene glycol
OTHER NAMES:
2-methyloxirane; oxirane, ethylene oxide / propylene oxide block copolymer, Ethylene oxide/propylene oxide co-polymer, Poloxamer 101
POLOXAMER 188:
Poloxamer 188, is a useful surfactant for the formulation of cosmetics and pharmaceuticals because it increases miscibility. All Spectrum Chemical NF products are manufactured, packaged and stored under current Good Manufacturing Practices (cGMP) per 21CFR part 211 in FDA registered and inspected facilities.
White to slightly yellowish waxy substance in the form of micropearls; weak odor.
Poloxamer 188 (P188) is a triblock copolymer of the form polyethylene oxide–polypropylene oxide–polyethylene oxide (PEO–PPO–PEO). The center PPO block is hydrophobic, and the side PEO blocks are hydrophilic, resulting in surface-active properties. P188 has been used in the pharmaceutical industry as an excipient in various formulations and drug delivery systems. Although the chemical stability of P188 in the solid state has been reported, there are very few reports detailing the solution state stability.
Usage: Improve Solubility, Absorption And Bioa-Vailability
Application: Pharmaceutical industry, issolution enhancer, lubricant & wetting agent, drug solubilizer, plasticizer, thermoreversible gelling effect, others…
Work As: A Plasticizing Agent, A Solubilizer And An Emulsifier
Supports: Both Solid And Liquid Dispersion
Suitable For: Skin Delivery Applications
Technical Advantage: Specialized for use in insect cell culture Poloxamer 188 is a surfactant used in cell culture to protect cells in suspension against possible damage during transfer, freezing and thawing, and stirring. It is a non-ionic detergent with an average molecular weight of 8400Da consisting of a central polyoxypropylene flanked by two polyoxyethylene molecules.
Manufacture of biologics in suspension cell culture causes damage to the cell membranes (shear stress). The majority of the damage occurs due to agitation from the impellor, and during gas sparging at the bubble layer, regardless of the bioreactor size that is used. Damaged cells in the culture lowers the overall health of the culture, and will ultimately affect the protein production yield.
Many different compounds have been screened for use in protecting the cells from this shear stress, including animal serum, cellulosic derivatives, dextran sulfate, polyethelyne glycols (PEGs), polyvinyl alcohol (PVA) and poloxamers. The most widely used additive to protect against shear stress is poloxamer 188 (P 188, often referred to as Pluronic F-68). Impurities present in poloxamer 188 preparations can have toxic effects on the cell culture, so it is very important to use the most pure and consistent poloxamer 188 which has been designed for use in cell culture systems.
Description:
This compound belongs to the class of organic compounds known as epoxides. These are compounds containing a cyclic ether with three ring atoms(one oxygen and two carbon atoms).
Used to reduce foaming in stirred cultures and reduce cell attachment to glass.
Provided at concentration of 10% and effective at working concentration of 0.1%
Manufactured at a cGMP compliant facility, located in Grand Island, New York, registered with the FDA as a medical device manufacturer and certified to ISO 13485 standards
Poloxamer 188 is a non-ionic surfactant used to reduce shear forces in suspension cultures. The solution can also be used to reduce foaming in stirred cultures and reduce cell attachment to glass. Poloxamer 188 is effective at a working concentration of 0.1%. However the concentration depends on the process and cultures.
Polyethylene-polypropylene glycol is nonionic polyoxyethylene–polyoxypropylene copolymers used primarily in pharmaceutical formulations as emulsifying or solubilizing agents.The polyoxyethylene segment is hydrophilic while the polyoxypropylene segment is hydrophobic. All of the Polyethylene-polypropylene glycol is chemically similar in composition, differing only in the relative amounts of propylene and ethylene oxides added during manufacture. Their physical and surface-active properties vary over a wide range and a number of different types are commercially available;
Polyethylene-polypropylene glycol is used as emulsifying agents in intravenous fat emulsions, and as solubilizing and stabilizing agents to maintain the clarity of elixirs and syrups. Polyethylene-polypropylene glycol may also be used as wetting agents; in ointments, suppository bases, and gels; and as tablet binders and coatings.
Poloxamer 188 has also been used as an emulsifying agent for fluorocarbons used as artificial blood substitutes, and in the preparation of solid-dispersion systems. More recently,Polyethylene-polypropylene glycol has found use in drug-delivery systems.
Therapeutically, poloxamer 188 is administered orally as a wetting agent and stool lubricant in the treatment of constipation; it is usually used in combination with a laxative such as danthron. Polyethylene-polypropylene glycol may also be used therapeutically as wetting agents in eye-drop formulations, in the treatment of kidney stones, and as skin-wound cleansers.
Poloxamer 338 and 407 are used in solutions for contact lens care.
Application:
Used as an emulsifying agent in intravenous fat emulsions, and as solubilizing agent to maintain the clarity of elixirs and syrups. May also be used as a wetting agent in eye drops, ointments, suppository bases, gels, and as tablet binders and coatings.
Solubility:
Readily soluble in ethanol, dissolves readily in water to give an opalescent solution, and is insoluble in diethyl ether, paraffin and fatty oils.
Packaging:
Fibreboard drums with a content of 23 kgs (50 lbs) and 102 kgs (225 lbs).
Storage/Stability:
Meets specification after at least 2 years stored in the unopened original containers at room temperature.
Formula: (C₃H₆O.C₂H₄O)x
MW: 8400 g/mol
Storage Temperature: Ambient
Physicochemical Information:
Boiling point >149 °C
Density 1.06 g/cm3 (25 °C)
Melting Point 52 °C
pH value 6.0 - 7 (H₂O)
Vapor pressure <0.1 hPa (25 °C)
Bulk density 1050 kg/m3
Solubility >100 g/l
Safety Information according to GHS
Storage class 10 - 13 Other liquids and solids
WGK WGK 1 slightly hazardous to water
Disposal 3
Relatively unreactive organic reagents should be collected in container A. If halogenated, they should be collected in container B. For solid residues use container C.
Storage and Shipping Information:
Storage: Store at +2°C to +25°C.
Poloxamer 188 (P188) is a nonionic block linear copolymer that exhibits rheologic, anti-thrombotic, anti-inflammatory, and cytoprotective activities in various tissue injury models. Composed of two hydrophilic side-chains attached to a hydrophobic center core, its average molecular weight is 8400 Daltons. POLOXAMER 188 has been approved by the FDA for more than 50 years as a therapeutic agent to reduce viscosity in the blood before transfusions. Due to its sufactant properties, POLOXAMER 188 may also be found in over-the-counter (OTC) products such as toothpaste, laxatives and mouthwash, and used in various cosmetic, industrial and pharmaceutical applications. There is an evidence of POLOXAMER 188 increasing the structural stability and resealing of the plasma membrane via direct incorporation into the phospholipid bilayer. The ability of POLOXAMER 188 in attenuating membrane damage and cell injury has been demonstrated in a variety of in vivo and in vitro models. The use of POLOXAMER 188 as a potential treatment in different pathological conditions, such as chronic microvascular diseases and skeletal muscle deficiencies, is under investigation.
Because of their amphiphilic structures, the polymers have surfactant properties that make them useful in industrial applications. Among other things, they can be used to increase the water solubility of hydrophobic, oily substances or otherwise increase the miscibility of two substances with different hydrophobicities. For this reason, these polymers are commonly used in industrial applications, cosmetics, and pharmaceuticals. They have also been evaluated for various drug delivery applications and were shown to sensitize drug-resistant cancers to chemotherapy.
In bioprocess applications, poloxamers are used in cell culture media for their cell cushioning effects because their addition leads to less stressful shear conditions for cells in reactors.
When mixed with water, concentrated solutions of poloxamers can form hydrogels. These gels can be extruded easily, acting as a carrier for other particles, and used for robocasting.
Pharmacodynamics
Poloxamer 188 exerts a protective action against oxidative stress and inflammation in tissue injury in various experimental models. In the rat model of excitotoxic injury, immediate intrathecal administration of POLOXAMER 188 reduced neuronal loss, indicated by smaller spherical excitotoxic lesions. In a murine hind-limb model, POLOXAMER 188 mediated a protective action against ischemia-reperfusion injury as indicated by decreased myocyte injury, preserved tissue adenosine 5'-triphosphate levels, and improved survival rates, suggesting that POLOXAMER 188 can seal defects in cell membranes and attenuate damage induced by reactive oxygen species. POLOXAMER 188 was shown to elicit protective effects against excitotoxic injury, and trauma-induced necrotic and apoptotic cell death in cultured neurons. In the mouse stroke models, POLOXAMER 188 exerted a neuroprotective effect in brain ischemia-reperfusion induced acute injury by significantly reducing infarct volume and water content in brain edema and ameliorating the neurological symptoms 24 h after ischemia or reperfusion injury. POLOXAMER 188 also significantly inhibited inflammatory, coagulation, and apoptotic responses resulting from superior mesenteric artery occlusion. In the experimental model of striatum injury in rats, POLOXAMER 188 was shown to reduce excitotoxicity-induced tissue loss and macrophage infiltrate.
Mechanism of Action
POLOXAMER 188 seals stable defects in cell membranes induced by skeletal muscle cell membranes rupture induced by ischemia-reperfusion injury, electroporation, irradiation, and heat damage. The full mechanism of action of POLOXAMER 188 in inducing cytoprotective effects is not clear; however, based on in vitro experiments and the structural similarity to plasmalemma, POLOXAMER 188 may be directly incorporated into the phospholipid bilayer to attenuate the extent of tissue injury. Its high surface activity facilitates POLOXAMER 188 to be inserted into lipid monolayers. POLOXAMER 188 is proposed to exert localized actions by only interacting with damaged and compromised bilayers where the local lipid packing density is reduced. In addition to the direct interaction with the membrane, POLOXAMER 188 was shown to inhibit MMP-9 protein levels and activity, as well as the NF-κb signal pathway, in the model of acute cerebral ischemia, which is associated with increased BBB permeability leading to cerebral edema and increased penetration. MMP-9 is a key factor in extracellular matrix (ECM) degradation and BBB disruption.
Absorption
Following a 48-hour continuous intravenous infusion of purified POLOXAMER 188 in healthy volunteers, the mean concentration of POLOXAMER 188 at steady state concentration (Css) was 522 ± 118 mg/L and the maximum concentration occurring at the end of the loading dose was approximately 909 ± 165 mg/L. The plasma concentrations were dose-proportional.
Volume of distribution
The volume of distribution at steady state (Vss) after a continuous intravenous infusion of 500 mg/kg of POLOXAMER 188 on day 7 was approximately 2.13 ml/kg in pregnant female rats. Vss was 876 ml/kg in dogs receiving a dose of 720 mg/kg/day.
Protein binding
The exact protein binding profile of POLOXAMER 188 has not been determined due to the apparent formation of micelles that caused excessive non-specific binding to ultrafiltration and dialysis membranes. Based on the findings of a protein binding interaction studies, POLOXAMER 188 displayed no clinically significant human plasma binding characteristics.
Metabolism
A single metabolite, HW1, with a molecular weight of approximately 16000 Daltons was detected in a pharmacokinetic study in dogs and man. HW1 was present in 10-20 and 40% of the parent compound at steady state in dogs and humans, respectively. However, it is suggested that block polymers are not metabolized and are excreted unchanged in the urine and feces, and HW1 may be a component of the higher molecular weight distribution of POLOXAMER 188 that concentrates in the plasma due to its lower clearance rate.
Route of elimination
Renal clearance accounted for 90% of total plasma clearance in healthy male subjects.
Half-life
In humans, POLOXAMER 188 has half-life of 18 hours. The terminal plasma elimination half-life was approximately 7.65 ± 1.10 hours in healthy volunteers receiving a 48-hour continuous intravenous infusion of purified POLOXAMER 188.
Toxicity
In an acute oral toxicity study in rat, the LD50 was 9380 mg/kg. POLOXAMER 188 has been demonstrated to be safe when given for up to 72 hours.
Poloxamer 188 is a nonionic linear copolymer with surfactant properties. Poloxamer 188 exhibits anti-thrombotic, anti-inflammatory, and cytoprotective activities in various tissue injury models.
Poloxamer 188 is an poloxamer that enables and enhances a wide range of functional applications. For instant and modified release applications, Poloxamer 188 can act as a stabilizer in oral suspensions. In formulations that include poorly soluble actives, Poloxamer 188 can improve solubility, absorption and bioavailability. Corresponding dosage forms can then be processed by melting or granulation. Poloxamer 188 serves as a plasticizing agent, a solubilizer and an emulsifier, supporting both solid and liquid dispersions, as well as emulsions and micro-emulsions. Poloxamer 188 can also act as a co-emulsifier in creams and emulsions for skin delivery applications.
Poloxamer 188 can be used as an emulsifier and solubilizer, as a dispersing and wetting agent for solid dispersions and also to improve solubility, absorption and bioavailability of poorly soluble actives. It also is utilized as a co-emulsifier in creams, emulsions and as a suspension stabilizer and tablet lubricant. As dissolution enhancer, lubricant and wetting agent it is particularly suitable for wet granulation.
Therapeutic Uses
Mechanical cleansing of a wound with a sponge soaked in a surfactant has prevented the development of experimental wound infection. The surfactant utilized for wound cleansing is Pluronic F-68 (poloxalene; I), a member of a family of block copolymers called Pluronic polyls. Long term toxicity studies and clinical trials suggest that this surfactant is safe for human use. I is a nonionic detergent that does not have any intrinsic antibacterial activity. Although mechanical cleansing with saline-soaked sponges effectively removes bacteria, it damages the wound and impairs its resistance to infection. The severity of the damage to the skin exerted by the sponge can be correlated with its porosity. Sponges with a low porosity are abrasive and exert more damage to skin than do sponges with a higher porosity. The addition of I to even the most abrasive sponges ensures that the bacterial removal efficiency of the sponge scrub is maintained, while tissue trauma is minimized. This dual effect of the surfactant results in a dramatic reduction in the infection rate of contaminated wounds.
Drug Warnings
A randomized, double blind, placebo controlled, dose escalation study of the toxicity and pharmacokinetics of poloxamer 188 (rheothrx) was conducted in 36 healthy male subjects (ages 19-35 yr) who received iv injections of 10-90 mg/kg/hr poloxamer or placebo. The most common adverse effects were pain, injection site abnormality, and nausea. Eight subjects discontinued treatment with poloxamer due to adverse events.
This chemical is not considered hazardous by the 2012 OSHA Hazard Communication Standard (29 CFR 1910.1200)
Not a dangerous substance or mixture according to the Globally Harmonized System (GHS).
Identity (IR spectrum) passes test
Hydroxyl value 11 - 15
Molecular weight 7,680 - 9,510
Water, % Û 1
Ph (2.5 % in water) 6.0 - 7.5
Ethylene oxide, ppm Û 1
Propylene oxide, ppm Û 5
1,4-Dioxan, ppm Û 5
Polyoxyethylene, % wt. 79.9 - 83.7
Unsaturation, meq/g 0.018 - 0.034
Heavy metals, ppm Û 10
Melting point, °C Û 52 - 57
Appearance of the solution
(20 % in water) clear, not darker than G6
Sulfated ash, % Û 0.4
Lutrol F 68 meets the requirements of the current USP/NF family monograph, “Poloxamer”.
