506 Poloxamer

physicochemical properties of the resin matrix. The functional See also Section 18. groups introduced on the matrix confer the property of ion exchange. Depending upon the acidity or basicity of the functional groups, strongly acidic to strongly basic types of ion-exchange 18 Comments resins may be produced. A number of other polacrilin (Amberlite) resins are commercially available that have a variety of industrial and pharmaceutical 14 Safety applications; see Table II. Polacrilin potassium and other polacrilin resins are used in oral pharmaceutical formulations and are generally regarded as 19 Specific References nontoxic and nonirritant materials. However, excessive ingestion 1 Van Abbe´ NJ, Rees JT. Amberlite resin XE-88 as a tablet disintegrant. J of polacrilin resins may disturb the electrolyte balance of the body. Am Pharm Assoc (Sci) 1958; 47: 487–489. 2 Khan KA, Rhodes CT. Effect of disintegrant concentration on 15 Handling Precautions disintegration and compression characteristics of two insoluble direct Observe normal precautions appropriate to the circumstances and compression systems. Can J Pharm Sci 1973; 8: 77–80. quantity of material handled. Polacrilin potassium may be irritating 3 Rudnic EM et al. Evaluation of the mechanism of disintegrant action. to the eyes; eye protection and gloves are recommended. Drug Dev Ind Pharm 1982; 8: 87–109. 4 Smith HA et al. The development of a liquid antihistaminic preparation with sustained release properties. J Am Pharm Assoc (Sci) 1960; 49: 94– 16 Regulatory Status 97. Included in the FDA Inactive Ingredients Database (oral capsules 5 Borodkin S, Yunker MH. Interaction of amine drugs with a and tablets). Included in non-parenteral medicines licensed in the polycarboxylic acid ion-exchange resin. J Pharm Sci 1970; 59: 481– UK. Included in the Canadian List of Acceptable Non-medicinal 486. Ingredients. 20 General References 17 Related Substances — Polacrilin. Polacrilin 21 Author CAS number [54182-62-6] A Palmieri. Synonyms Amberlite IRP-64; methacrylic acid polymer with divinylben- zene; 2-methyl-2-propenoic acid polymer with divinylben- 22 Date of Revision zene. 10 February 2009.

P Poloxamer

1 Nonproprietary Names Table I: Typical poloxamer grades. BP: Poloxamers Poloxamer Physical abAverage molecular PhEur: Poloxamers form weight USP-NF: Poloxamer 124 Liquid 12 20 2 090–2 360 188 Solid 80 27 7 680–9 510 2 Synonyms 237 Solid 64 37 6 840–8 830 Lutrol; Monolan; Pluronic; poloxalkol; poloxamera; polyethylene– 338 Solid 141 44 12 700–17 400 propylene glycol copolymer; polyoxyethylene–polyoxypropylene 407 Solid 101 56 9 840–14 600 copolymer; Supronic; Synperonic.

3 Chemical Name and CAS Registry Number a-Hydro-o-hydroxypoly(oxyethylene)poly(oxypropylene) poly- (oxyethylene) block copolymer [9003-11-6] 5 Structural Formula

4 Empirical Formula and Molecular Weight The poloxamer polyols are a series of closely related block copolymers of ethylene oxide and propylene oxide conforming to the general formula HO(C2H4O)a(C3H6O)b(C2H4O)aH. The grades included in the PhEur 6.0 and USP32–NF27 are shown in Table I. The PhEur 6.0 states that a suitable antioxidant may be added. Poloxamer 507

6 Functional Category Table III: Pharmacopeial specifications for poloxamer. Dispersing agent; emulsifying agent; solubilizing agent; tablet lubricant; wetting agent. Test PhEur 6.0 USP32–NF27 Identification þþ 7 Applications in Pharmaceutical Formulation or Characters þ — þ Technology Appearance of solution — Average molecular weight Poloxamers are nonionic polyoxyethylene–polyoxypropylene co- For poloxamer 124 2 090–2 360 2 090–2 360 polymers used primarily in pharmaceutical formulations as emul- For poloxamer 188 7 680–9 510 7 680–9 510 sifying or solubilizing agents.(1-8) The polyoxyethylene segment is For poloxamer 237 6 840–8 830 6 840–8 830 hydrophilic while the polyoxypropylene segment is hydrophobic. For poloxamer 338 12 700–17 400 12 700–17 400 All of the poloxamers are chemically similar in composition, For poloxamer 407 9 840–14 600 9 840–14 600 differing only in the relative amounts of propylene and ethylene Weight percent oxyethylene For poloxamer 124 44.8–48.6 46.7 1.9 oxides added during manufacture. Their physical and surface-active For poloxamer 188 79.9–83.7 81.8 1.9 properties vary over a wide range and a number of different types For poloxamer 237 70.5–74.3 72.4 1.9 are commercially available; see Sections 4, 9, 10 and 18. For poloxamer 338 81.4–84.9 83.1 1.7 Poloxamers are used as emulsifying agents in intravenous fat For poloxamer 407 71.5–74.9 73.2 1.7 emulsions, and as solubilizing and stabilizing agents to maintain the pH (aqueous solution) 5.0–7.5 5.0–7.5 Unsaturation (mEq/g) clarity of elixirs and syrups. Poloxamers may also be used as wetting agents; in ointments, suppository bases, and gels; and as tablet For poloxamer 124 — 0.020 0.008 For poloxamer 188 — 0.026 0.008 binders and coatings. For poloxamer 237 — 0.034 0.008 Poloxamer 188 has also been used as an emulsifying agent for For poloxamer 338 — 0.031 0.008 fluorocarbons used as artificial blood substitutes, and in the For poloxamer 407 — 0.048 0.017 preparation of solid-dispersion systems. Oxypropylene : oxyethylene ratio þ — More recently, poloxamers have found use in drug-delivery Total ash 40.4% — (9–14) Heavy metals — 40.002% systems. 4 Therapeutically, poloxamer 188 is administered orally as a Water 1.0% — Free ethylene oxide, propylene oxide þþ wetting agent and stool lubricant in the treatment of constipation; it and 1,4-dioxane is usually used in combination with a laxative such as danthron. Ethylene oxide — 41 ppm Poloxamers may also be used therapeutically as wetting agents in Propylene oxide — 45 ppm eye-drop formulations, in the treatment of kidney stones, and as 1,4-Dioxane — 45 ppm skin-wound cleansers. Poloxamer 338 and 407 are used in solutions for contact lens care. See Table II. Melting point 168C for poloxamer 124; Table II: Uses of poloxamer. 52–578C for poloxamer 188; Use Concentration (%) 498C for poloxamer 237; 8 P Fat emulsifier 0.3 57 C for poloxamer 338; Flavor solubilizer 0.3 52–578C for poloxamer 407. Fluorocarbon emulsifier 2.5 Moisture content Poloxamers generally contain less than 0.5% Gelling agent 15–50 w/w water and are hygroscopic only at relative humidity greater Spreading agent 1 than 80%. See also Figure 1. Stabilizing agent 1–5 Solubility varies according to the poloxamer type; see Suppository base 4–6 or 90 Solubility Tablet coating 10 also Table IV. Tablet excipient 5–10 Surface tension Wetting agent 0.01–5 19.8 mN/m (19.8 dynes/cm) for a 0.1% w/v aqueous poloxamer 188 solution at 258C; 24.0 mN/m (24.0 dynes/cm) for a 0.01% w/v aqueous polox- 8 Description amer 188 solution at 258C; Poloxamers generally occur as white, waxy, free-flowing prilled 26.0 mN/m (26.0 dynes/cm) for a 0.001% w/v aqueous polox- granules, or as cast solids. They are practically odorless and amer solution at 258C. tasteless. At room temperature, poloxamer 124 occurs as a colorless Viscosity (dynamic) 1000 mPa s (1000 cP) as a melt at 778C for liquid. poloxamer 188.

9 Pharmacopeial Specifications 11 Stability and Storage Conditions See Table III. Poloxamers are stable materials. Aqueous solutions are stable in the presence of acids, alkalis, and metal ions. However, aqueous 10 Typical Properties solutions support mold growth. Acidity/alkalinity pH = 5.0–7.4 for a 2.5% w/v aqueous solution. The bulk material should be stored in a well-closed container in a Cloud point >1008C for a 1% w/v aqueous solution, and a 10% cool, dry place. w/v aqueous solution of poloxamer 188. Density 1.06 g/cm3 at 258C Flash point 2608C 12 Incompatibilities Flowability Solid poloxamers are free flowing. Depending on the relative concentrations, poloxamer 188 is HLB value 0.5–30; 29 for poloxamer 188. incompatible with phenols and parabens. 508 Poloxamer

50 LD50 (mouse, IV): 1 g/kg

LD50 (mouse, oral): 15 g/kg

LD50 (mouse, SC): 5.5 g/kg

40 LD50 (rat, IV): 7.5 g/kg

LD50 (rat, oral): 9.4 g/kg

30 15 Handling Precautions Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are recommended. 20 16 Regulatory Status Included in the FDA Inactive Ingredients Database (IV injections; 10 inhalations, ophthalmic preparations; oral powders, solutions,

Equilibrium moisture at 25ºC (%) suspensions, and syrups; topical preparations). Included in non- parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. 0 20100 90807060504030 100 Relative humidity (%) 17 Related Substances — Figure 1: Equilibrium moisture content of poloxamer 188 (Pluronic F-68, BASF Corp.). 18 Comments Although the USP32–NF27 contains specifications for five polox- 8 Table IV: Solubility at 20 C for various types of poloxamer in different amer grades, many more different poloxamers are commercially solvents. available that vary in their molecular weight and the proportion of Type Solvent oxyethylene present in the polymer. A series of poloxamers with greatly varying physical properties are thus available. Ethanol Propan-2- Propylene Water Xylene The nonproprietary name ‘poloxamer’ is followed by a number, (95%) ol glycol the first two digits of which, when multiplied by 100, correspond to Poloxamer Freely Freely Freely Freely Freely the approximate average molecular weight of the polyoxypropylene 124 soluble soluble soluble soluble soluble portion of the copolymer and the third digit, when multiplied by 10, Poloxamer Freely — — Freely — corresponds to the percentage by weight of the polyoxyethylene 188 soluble soluble portion. Poloxamer Freely Sparingly — Freely Sparingly Similarly, with many of the trade names used for poloxamers, 237 soluble soluble soluble soluble e.g. Pluronic F-68 (BASF Corp.), the first digit arbitrarily represents P Poloxamer Freely — Sparingly Freely — the molecular weight of the polyoxypropylene portion and the 338 soluble soluble soluble second digit represents the weight percent of the oxyethylene Poloxamer Freely Freely — Freely — ‘ ’ ‘ ’ ‘ ’ 407 soluble soluble soluble portion. The letters L , P , and F , stand for the physical form of the poloxamer: liquid, paste, or flakes; see also Table V.

13 Method of Manufacture Table V: Nonproprietary name and corresponding commercial grade. Poloxamer polymers are prepared by reacting propylene oxide with Nonproprietary name Commercial grade propylene glycol to form polyoxypropylene glycol. Ethylene oxide is then added to form the block copolymer. Poloxamer 124 L-44 Poloxamer 188 F-68 Poloxamer 237 F-87 14 Safety Poloxamer 338 F-108 Poloxamers are used in a variety of oral, parenteral, and topical Poloxamer 407 F-127 pharmaceutical formulations, and are generally regarded as nontoxic and nonirritant materials. Poloxamers are not metabo- Note that in the USA the trade name Pluronic is used by BASF lized in the body. Corp. for pharmaceutical-grade and industrial-grade poloxamers, Animal toxicity studies, with dogs and rabbits, have shown while in Europe the trade name Lutrol is used by BASF Corp. for the poloxamers to be nonirritating and nonsensitizing when applied in pharmaceutical-grade material. 5% w/v and 10% w/v concentration to the eyes, gums, and skin. Poloxamers for use in the cosmetic industry as oil-in-water In a 14-day study of intravenous administration at concentra- emulsifiers, cleansers for mild facial products, and dispersing agents tions up to 0.5 g/kg/day to rabbits, no overt adverse effects were are marketed by BASF Corp. as Pluracare; the grades available are noted. A similar study with dogs also showed no adverse effects at listed in Table VI. Studies on poloxamer 407, which shows dosage levels up to 0.5 g/kg/day. In a longer-term study, rats fed 3% thermoreversible properties for optimizing drug formulation w/w or 5% w/w of poloxamer in food for up to 2 years did not temperature, have demonstrated immunomodulation and cytotoxi- exhibit any significant symptoms of toxicity. However, rats city promoting properties.(16) Poloxamer has been used in a receiving 7.5% w/w of poloxamer in their diet showed some poly(lactic-co-glycolic acid) (PLGA) : poloxamer and PLGA : polox- decrease in growth rate. amine blend nanoparticle composition as novel carriers for gene No hemolysis of human blood cells was observed over 18 hours delivery.(17) Specifications for poloxamer 331 and poloxamer 407 at 258C, with 0.001–10% w/v poloxamer solutions. are contained in the Food Chemicals Codex (FCC).(18) Acute animal toxicity data for poloxamer 188:(15) The PubChem Compound ID (CID) for poloxamer is 24751. Polycarbophil 509

10 Oh T et al. Micellar formulations for drug delivery based on mixtures of Table VI: Nonproprietary name and corresponding Pluracare grade hydrophobic and hydrophilic Pluronic (R) block copolymers. J Control (BASF Corp.). Release 2004; 94(10): 411–422. Nonproprietary Commercial HLB value pH of 2.5% w/v 11 Bochot A et al. Liposomes dispersed within a thermosensitive gel: a new name grade aqueous solution dosage form for ocular delivery. Pharm Res 1998; 15: 1364–1369. 12 Kim EK et al. rhEGF/HP-b-CD complex in poloxamer gel for Poloxamer 184 L-64 12–18 5–7.5 ophthalmic delivery. Int J Pharm 2002; 233: 159–167. Poloxamer 185 P-65 12–18 6–7.4 13 Anderson BC et al. Understanding drug release from poly(ethylene Poloxamer 407 F-127 18–23 6–7.4 oxide)-b-(propylene oxide)-b-poly(ethlene oxide) gels. J Control Release 2001; 70: 157–167. 14 Moore T et al. Experimental investigation and mathematical modelling of Pluromic F127 gel dissolution: drug release in stirred systems. 19 Specific References J Control Release 2000; 67: 191–202. 1OhIet al. Fluorescence spectroscopy studies on micellization of 15 Sweet DV, ed. Registry of Toxic Effects of Chemical Substances. poloxamer 407 solution. Arch Pharm Res 2003; 26: 653–658. Cincinnati: US Department of Health, 1987. 2 Mata JP et al. Concentration, temperature and salt induced micelliza- 16 Dumortier G et al. A review of poloxamer 407 pharmaceutical and tion of a triblock copolymer Pluronic L64 in aqueous media. J Colloid pharmacological characteristics. Pharm Res 2006; 23(12): 2709–2728. Interface Sci 2005; 292: 548–556. 17 Csaba N et al. PLGA : poloxamer and PLGA:poloxamine blend 3 Jebari MM et al. Aggregation behaviour of Pluronic L64 surfactant at nanoparticles: new carriers for gene delivery. Biomacromolecules various temperatures and concentrations examined by dynamic light 2005; 6(1): 271–278. scattering and viscosity measurements. Polym Int 2006; 55: 176–183. 18 Food Chemicals Codex, 6th edn. Bethesda, MD: United States 4 Dumortier G et al. Development of a thermogelling ophthalmic Pharmacopeia, 2008; 768–770. formulation of cysteine. Drug Dev Ind Pharm 2006; 32: 72. 5QiHet al. Development of poloxamer analogs/carbopol-based in situ gelling and mucoadhesive ophthalmic delivery system for puerarin. Int 20 General References J Pharm 2007; 337: 178–187. — 6 Darwish AM et al. Evaluation of a novel vaginal bromocriptine mesylate formulation. Fertil Steril 2005; 83(4): 1053–1055. 7 El-Kamel A, El-Khatib M. Thermally reversible in situ gelling 21 Author carbamazepine liquid suppository. Drug Deliv 2006; 13: 143–148. JH Collett. 8 Wang Y et al. A novel method for viral gene delivery in solid tumours. Cancer Res 2005; 65: 7541–7545. 22 Date of Revision 9 Lu G, Jun HW. Diffusion studies of methotrexate in carbopol and poloxamer gels. Int J Pharm 1998; 160(1): 1–9. 18 February 2009.

Polycarbophil P

1 Nonproprietary Names 7 Applications in Pharmaceutical Formulation or USP: Polycarbophil Technology Conventionally, polycarbophil is used as a thickening agent at very 2 Synonyms low concentrations (less than 1%) to produce a wide range of Noveon AA-1. viscosities and flow properties in topical lotions, creams, and gels, in oral suspensions, and in transdermal gel reservoirs. It is also used as an emulsifying agent in topical oil-in-water systems. 3 Chemical Name and CAS Registry Number Polycarbophil is an excellent bioadhesive in buccal, ophthalmic, Polycarbophil [9003-97-8] intestinal, nasal, vaginal, and rectal applications. Buccal tablets prepared using polycarbophil have shown high bioadhesive force 4 Empirical Formula and Molecular Weight and prolonged residence time, and proved to be nonirritative in in (1) Polycarbophil is a high molecular weight acrylic acid polymer vivo trials with human buccal mucosa. Polycarbophil has been crosslinked with divinyl glycol. The molecular weight of this used in combination with hydroxypropyl methylcellulose to polymer is theoretically estimated to range from 700 000 to 3–4 develop a bilayered buccal bioadhesive film formulation of nicotine (2) billion. However, there are no methods currently available to hydrogen tartrate for smoking cessation therapy. It is also useful (3) measure the actual molecular weight of a crosslinked (i.e. three- in designing controlled-release formulations and for drugs that (4) dimensional) polymer of this type. undergo first-pass metabolism. Polycarbophil buccoadhesive disks have also been developed in formulations increasing the (5) 5 Structural Formula bioavailability and transmucosal absorption of poorly water- soluble drugs.(6) Sublingual tablets of buprenorphine formulated See Section 4. using polycarbophil have shown superior mucoadhesive strength when compared to those using carbomer.(7) 6 Functional Category Polycarbophil gels have been used for delivering bioactive Adsorbent; bioadhesive material; controlled-release agent; emulsi- substances for local application to gingival,(8) oropharyngeal(9) fying agent; suspending agent; tablet binder; thickening agent. and periodontal(10,11) areas, and also for ocular drug delivery.(12)