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Method of Manufacture

Poloxamer polymers are prepared by reacting propylene oxide with propylene glycol to form polyoxypropylene glycol. Ethylene oxide is then added to form the block copolymer.

Safety

Poloxamers are used in a variety of oral, parenteral, and topical pharmaceutical formulations and are generally regarded as nontoxic and nonirritant materials. Poloxamers are not metabolized in the body.

Animal toxicity studies, with dogs and rabbits, have shown poloxamers to be nonirritating and nonsensitizing when applied in 5% w/v and 10% w/v concentration to the eyes, gums, and skin.

In a 14-day study of intravenous administration at concentrations up to 0.5 g/kg/day to rabbits, no overt adverse effects were noted. A similar study with dogs also showed no adverse effects at dosage levels up to 0.5 g/kg/day. In a longer- term study, rats fed 3% w/w or 5% w/w of poloxamer in food for up to 2 years did not exhibit any significant symptoms of toxicity. However, rats receiving 7.5% w/w of poloxamer in their diet showed some decrease in growth rate.

No hemolysis of human blood cells was observed over 18 hours at 258C, with 0.001–10% w/v poloxamer solutions.

Acute animal toxicity data for poloxamer 188:(15)

LD50 (mouse, IV): 1 g/kg LD50 (mouse, oral): 15 g/kg LD50 (mouse, SC): 5.5 g/kg LD50 (rat, IV): 7.5 g/kg LD50 (rat, oral): 9.4 g/kg

Handling Precautions

Similarly, with many of the trade names used for polox- amers, e.g. Pluronic F-68 (BASF Corp), the first digit arbitrarily represents the molecular weight of the polyoxypropylene portion and the second digit represents the weight percent of the oxyethylene portion. The letters ‘L’, ‘P’, and ‘F’, stand for the physical form of the poloxamer: liquid, paste, or flakes; see also Table V.

Table V: Nonproprietary name and corresponding commercial grade.

Nonproprietary name Commercial grade

Note that in the USA the trade name Pluronic is used by BASF Corp. for pharmaceutical-grade and industrial-grade poloxamers, while in Europe the trade name Lutrol is used by BASF Corp. for the pharmaceutical-grade material.

Poloxamers for use in the cosmetic industry as oil-in-water emulsifiers, cleansers for mild facial products, and dispersing agents are marketed by BASF Corp. as Pluracare. The grades available are listed in Table VI. Poloxamer has been used in a poly(lactic-co-glycolic acid) (PLGA):poloxamer and PLGA:po- loxamine blend nanoparticle composition as novel carriers for gene delivery.(16) A specification for poloxamer is contained in the Food Chemicals Codex (FCC).

Table VI: Nonproprietary name and corresponding Pluracare grade (BASF Corp.).

Observe normal precautions appropriate to the circumstances and quantity of material handled. Eye protection and gloves are

pH of 2.5% w/v aqueous solution

recommended.

Regulatory Status

Included in the FDA Inactive Ingredients Guide (IV injections; inhalations, ophthalmic preparations; oral powders, solutions, suspensions, and syrups; topical preparations). Included in nonparenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.

Related Substances

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Comments

Although the USPNF 23 contains specifications for five poloxamer grades, many more different poloxamers are commercially available that vary in their molecular weight and the proportion of oxyethylene present in the polymer. A series of poloxamers with greatly varying physical properties are thus available.

The nonproprietary name ‘poloxamer’ is followed by a number, the first two digits of which, when multiplied by 100, correspond to the approximate average molecular weight of the polyoxypropylene portion of the copolymer and the third digit, when multiplied by 10, corresponds to the percentage by weight of the polyoxyethylene portion.

Poloxamer 184 L-64 12–18 5–7.5

Poloxamer 185 P-65 12–18 6–7.4

Poloxamer 407 F-127 18–23 6–7.4

Specific References

Suh H, Jun HW. Physicochemical and release studies of naproxen in poloxamer gels. Int J Pharm 1996; 129: 13–20.

Pandit NK, Wang D. Salt effects on the diffusion and release rate of propranolol from poloxamer 407 gels. Int J Pharm 1998; 167: 183–189.

Wanka G, Hoffman H, Ulbricht W. Phase diagrams and aggregation behaviour of poly(oxyethylene)-poly(oxypropylene)- poly(oxyethylene) triblock copolymers in aqueous solutions. Macromolecules 1994; 27: 4151–4159.

Kabanov AV, Nazarova IR, Astafieva IV, et al. Micelle formation and solubilization of fluorescent probes in poly-(oxyethylene-b- oxypropylene-b-oxyethylene) solutions. Macromolecules 1995; 28: 2303–2314.

Lee JW, Park ES, Chi SC. Solubilization of ibuprofen in aqueous solution. J Korean Pharm Sci 1997; 27(4): 279–286.

Alakhov V, Pietrzynski G, Patel K, et al. Pluronic block copolymers and Pluronic poly(acrylic acid) microgels in oral delivery of megestrol acetate. J Pharm Pharmacol 2004; 56: 1233–1241.

Cabana A, Ait-Kadi A, Juhasz J. Study of the gelation process of polyethylene oxide copolymer (Poloxamer 407) aqueous solutions. J Colloid Interface Sci 1997; 190: 307–312.

538 Poloxamer

Bohorquez M, Koch C, Trygstad T, Pandit N. A study of the temperature-dependent micellizatin of Pluronic F127. J Colloid Interface Sci 1999; 216: 34–40.

Lu G, Jun HW. Diffusion studies of methotrexate in carbopol and poloxamer gels. Int J Pharm 1998; 160: 1–9.

Oh T, Bronich TK, Kabanov AV. Micellar formulations for drug delivery based on mixtures of hydrophobic and hydrophilic Pluronic (R) block copolymers. J Control Release 2004; 94(10): 411–422.

Bochot A, Fattal E, Gulik A, et al. Liposomes dispersed within a thermosensitive gel: a new dosage form for ocular delivery. Pharm Res 1998; 15: 1364–1369.

Kim EK, Gao Z, Park J, et al. rhEGF/HP-b-CD complex in poloxamer gel for ophthalmic delivery. Int J Pharm 2002; 233: 159–167.

Anderson BC, Pandit NK, Mallapragada SK. Understanding drug release from poly(ethylene oxide)-b-(propylene oxide)-b-poly(eth- lene oxide) gels. J Control Release 2001; 70: 157–167.

Moore T, Croy S, Mallapragada SK, Pandit NK. Experimental investigation and mathematical modelling of Pluromic F127 gel dissolution: drug release in stirred systems. J Control Release 2000; 67: 191–202.

Sweet DV, ed. Registry of Toxic Effects of Chemical Substances, Cincinnati: US Department of Health, 1987.

Csaba N, Caamaro P, Sanchez A, Dominguez F, Alonso MJ. PLGA:poloxamer and PLGA:poloxamine blend nanoparticles: new carriers for gene delivery. Biomacromolecules 2005; 6(1): 271–278.

Chemical Name and CAS Registry Number

Polycarbophil [9003-01-4]

Empirical Formula and Molecular Weight

Polycarbophils are polymers of acrylic acid crosslinked with divinyl glycol. The molecular weight of these polymers is theoretically estimated to range from 700 000 to 3–4 billion. However, there are no methods currently available to measure the actual molecular weight of a crosslinked (i.e. three- dimensional) polymer of this type.

Structural Formula

See Section 4.

Functional Category

Adsorbent; bioadhesive; controlled-release tablet binder; emul- sifying agent; thickening agent; suspending agent.

Applications in Pharmaceutical Formulation or Technology

Conventionally, polycarbophil is used as a thickening agent at very low concentrations (less than 1%) to produce a wide range of 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.

Polycarbophil is an excellent bioadhesive in buccal, ophthalmic, intestinal, nasal, vaginal, and rectal applications. Buccal tablets prepared using polycarbophil have shown high bioadhesive force and prolonged residence time and proved to be nonirritative in in vivo trials with human buccal mucosa.(1) It is also useful in designing controlled-release formulations(2) and for drugs that undergo first-pass metabolism.(3) Polycarbophil buccoadhesive disks have also been developed in formulations increasing the bioavailability(4) and transmucosal absorption of poorly water-soluble drugs.(5) Sublingual tablets of buprenor- phine formulated using polycarbophil have shown superior mucoadhesive strength when compared to those using carbo- mer.(6)

Polycarbophil gels have been used for delivering bioactive substances for local application to gingival,(7) oropharyngeal(8) and periodontal(9,10) areas and also for ocular drug delivery.(11) The nasal retention of plasmid DNA is highly prolonged with the use of polycarbophil as the gelling agent.(12) Polycarbophil has also been used to design an insulin liquid suppository for rectal application.(13,14) A vaginal gel of econazole has shown

improved therapeutic benefit on topical application in vaginal candidiasis.(15) Mucoadhesive vaginal vaccine delivery systems using polycarbophil have proved to be effective in the induction of mucosal and systemic immune responses.(16) Polycarbophil gels have been used to deliver granulocyte-macrophage colony- stimulating factor (GM-CSF) effectively to genital preneoplastic lesions.(17) Polycarbophil microspheres have been formulated for drug delivery to oral(18,19) and nasal(20) cavities. Floating- bioadhesive microspheres coated with polycarbophil have been found to be a useful gastroretentive drug delivery system for the treatment of Helicobacter pylori.(21) Conjugation with L-cysteine greatly enhances the mucoadhesive properties of polycarbophil(22) and can be used as a platform for oral polypeptide delivery(23) (e.g. heparin,(24) insulin,(25) antigens for oral protein vaccination(26)) and for ocular(27) and transdermal drug delivery systems.(28) Polycarbophil has been reported to act as a permeation enhancer by triggering the reversible opening of the tight junctions between the cells, thereby allowing the paracellular transport of peptides, in addition to locally deactivating the most important enzymes of the gastrointestinal tract.(29) Polycarbophil promotes bowel regularity and is used therapeutically for chronic constipation, diverticulosis, and irritable bowel syndrome.

Description

Polycarbophil occurs as fluffy, white to off-white, mildly acidic polymer powder with slightly acetic odor.

Pharmacopeial Specifications

See Table I.

Table I: Pharmacopeial specifications for polycarbophil.

Test USP 28

Identification +

pH (1% dispersion) 44.0

Loss on drying 41.5%

Absorbing power 562 g/g

Limit of acrylic acid 40.3%

Limit of ethyl acetate 40.45%

Organic volatile impurities +

Residue on ignition 44.0%

Typical Properties

Acidity/alkalinity: pH = 2.5–3.0 (1.0% w/v aqueous disper- sion); pH = 2.7–3.5 (0.5% w/v aqueous dispersion).

Ash content: 0.009 ppm

Density (bulk): 0. 19–0.24 g/cm3

Dissociation constant: pKa = 6.0 0.5

Equilibrium moisture content: 8–10% (at 50% relative humidity)

Glass transition temperature: 100–1058C

Moisture content: 2.0% maximum

540 Polycarbophil

Solubility: polycarbophil polymers can swell in water to around 1000 times their original volume (and ten times their original diameter) to form gels when exposed to a pH environment above 4–6. Since the pKa of these polymers is

6.0 0.5, the carboxylate groups on the polymer backbone ionize, resulting in electrostatic repulsion between the negative particles, which extends the molecule, adding to the swelling of the polymer.

Particle size distribution: polycarbophils are produced from primary polymer particles of an average diameter of about

0.2 mm. These polymers are then flocculated, resulting in powders averaging 2–7 mm in diameter. Once formed, the flocculated agglomerates cannot be broken down into their primary particles.

Specific gravity: 1.41

Stability and Storage Conditions

Polycarbophil polymers are stable, hygroscopic materials. They do not undergo hydrolysis or oxidation under normal conditions. Heat aging at temperatures below 1048C for up to 2 hours does not affect the efficiency of the dry polymer. However, prolonged exposure to excessive temperatures can result in discoloration, reduced stability, and in some cases plasticization of the polymer. Complete decomposition occurs with heating for 30 minutes at 2608C.

Polycarbophil polymers do not support bacteria, mold, or fungal growth in dry powder form. Microbial growth may occur in mucilages of the polymer solution. Although the gel properties are not affected by such growth, this phenomenon is usually unacceptable. The addition of appropriate preservatives prevents mold and bacterial growth in these mucilages. Exposure of polycarbophil mucilages to high temperatures results in a drop in viscosity.

Polycarbophil polymers are very hygroscopic and should be packed in air-tight, corrosion-resistant containers. They should be stored in a cool, dry place, and the container should be kept closed when not in use. Moisture pickup does not affect the efficiency of the resins, but resin containing high levels of moisture is more difficult to disperse and weigh accurately. Glass, plastic, or resin-lined containers are recommended for products containing polycarbophil. Packaging in aluminum tubes usually requires formulations to have a pH less than 6.5, and packaging in other metallic tubes or containers necessitates a pH greater than 7.7 to prolong polycarbophil stability.

Incompatibilities

Heat may be generated if polycarbophil comes into contact with strong basic materials such as ammonia, sodium hydro- xide, potassium hydroxide, or strongly basic amines. Poly- carbophil polymers are not compatible with cationic polymers, strong acids, and high levels of electrolytes, as electrolytes tend to reduce the viscosity of polycarbophil-based gels.

Method of Manufacture

Polycarbophils are synthetic, high-molecular-weight, cross- linked polymers of acrylic acid. These poly(acrylic acid) polymers are crosslinked with divinyl glycol. They are synthesized via precipitation polymerization in ethyl acetate and then dried.

Safety

Polycarbophil polymers have a long history of safe and effective use in topical gels, creams, lotions, and ointments. They have been shown to have extremely low irritancy properties and are nonsensitizing with repeated usage.

The use of these polymers is supported by extensive toxicological studies.(30)

LD50 (guinea pig, oral): 2.0 g/kg LD50 (mouse, IP): 0.039 g/kg LD50 (mouse, IV): 0.070 g/kg LD50 (mouse, oral): 4.6 g/kg LD50 (rat, oral): >2.5 g/kg

LD50 (rabbit, skin): >3.0 g/kg

Handling Precautions

Observe normal precautions appropriate to the circumstances and quantity of material handled. Excessive dust generation should be minimized to avoid the risk of explosion (lowest explosive concentration is 130 g/m3). Polycarbophil dust is an irritant to eyes, mucous membranes, and the respiratory tract. Powder/dust eye irritation is a physical, not a chemical effect. Solid particles on the eye (powder/dust) may cause pain and be accompanied by irritation. Saline should be used for irrigation purposes. Dust inhalation may cause coughing, mucus produc- tion, and shortness of breath. Contact dermatitis may occur in individuals under extreme conditions of prolonged and repeated contact, high exposure, high temperature, and occlusion (being held onto the skin) by clothing. Gloves, eye protection, and a dust respirator are recommended during handling. Polycarbophil should be used in well-ventilated conditions.

Regulatory Status

GRAS listed. Included in the FDA Inactive Ingredients Guide (vaginal gel; oral, troche). Included in nonparenteral medicines licensed in the UK.

Related Substances

Calcium polycarbophil; carbomer.

Calcium polycarbophil

Empirical formula: calcium polycarbophil is the calcium salt of polyacrylic acid crosslinked with divinyl glycol.

Molecular weight: the molecular weight of these polymers is theoretically estimated to range from 700 000 to 3–4 billion. There are, however, no methods currently available to measure the actual molecular weight of a crosslinked (i.e. three-dimensional) polymer of this type.

CAS number: [9003-97-8]

Synonyms: Noveon CA-1; Noveon CA-2.

Appearance: white powder with slightly acetic odor.

Acidity/alkalinity: pH = 6.0–8.0 (1% w/v aqueous dispersion).

Density (bulk): 0.86 g/cm3 (Noveon CA-1); 0.55 g/cm3 (Noveon CA-2).

Moisture content: <10%

Pharmacopeial specifications: see Table II.

Comments: Noveon CA-1 is a coarsely ground grade of calcium polycarbophil and is ideally suited for formulating swallowable bulk laxative tablets, while Noveon CA-2 is a finely ground grade and is designed for formulating chewable or swallowable bulk laxative tablets. Both grades swell in the intestinal tract, taking advantage of the natural

Polycarbophil 541

Table II: Pharmacopeial specifications for calcium polycarbophil.

Test USP 28

Identification +

Loss on drying 410%

Absorbing power 535 g/g

Organic volatile impurities +

Calcium content (on dried basis) 18–22%

water absorbency of polycarbophil. The swollen polycarbo- phil gel then acts as a bulk laxative as it moves through the gastrointestinal tract.

Comments

—

Specific References

Nafee NA, Ismail FA, Boraie NA, Mortada LM. Mucoadhesive delivery systems. I. Evaluation of mucoadhesive polymers for buccal tablet formulation. Drug Dev Ind Pharm 2004; 30(9): 985–

993.

Jain AC, Aungst BJ, Adeyeye MC. Development and in vivo evaluation of buccal tablets prepared using danazol–sulfobuty- lether 7 beta-cyclodextrin (SBE 7) complexes. J Pharm Sci 2002; 91(7): 1659–1668.

Akbari J, Nokhodchi A, Farid D, et al. Development and evaluation of buccoadhesive propranolol hydrochloride tablet formulations: effect of fillers. Farmaco 2004; 59(2): 155–161.

El-Samaligy MS, Yahia SA, Basalious EB. Formulation and evaluation of diclofenac sodium buccoadhesive discs. Int J Pharm 2004; 286(1–2): 27–39.

Jay S, Fountain W, Cui Z, Mumper RJ. Transmucosal delivery of testosterone in rabbits using novel bi-layer mucoadhesive wax-film composite disks. J Pharm Sci 2002; 91(9): 2016–2025.

Das NG, Das SK. Development of mucoadhesive dosage forms of buprenorphine for sublingual drug delivery. Drug Deliv 2004; 11(2): 89–95.

Jones DS, Irwin CR, Woolfson AD, et al. Physicochemical characterization and preliminary in vivo efficacy of bioadhesive, semisolid formulations containing flurbiprofen for the treatment of gingivitis. J Pharm Sci 1999; 88(6): 592–598.

Jones DS, Woolfson AD, Brown AF. Viscoelastic properties of bioadhesive, chlorhexidine-containing semi-solids for topical application to the oropharynx. Pharm Res 1998; 15(7): 1131–

1136.

Jones DS, Woolfson AD, Djokic J, Coulter WA. Development and mechanical characterization of bioadhesive semi-solid, polymeric systems containing tetracycline for the treatment of periodontal diseases. Pharm Res 1996; 13(11): 1734–1738.

Jones DS, Woolfson AD, Brown AF, et al. Design, characterisation and preliminary clinical evaluation of a novel mucoadhesive topical formulation containing tetracycline for the treatment of periodontal disease. J Control Release 2000; 67(2–3): 357–368.

Nagarsenker MS, Londhe VY, Nadkarni GD. Preparation and evaluation of liposomal formulations of tropicamide for ocular delivery. Int J Pharm 1999; 190(1): 63–71.

Park JS, Oh YK, Yoon H, et al. In situ gelling and mucoadhesive polymer vehicles for controlled intranasal delivery of plasmid DNA. J Biomed Mater Res 2002; 59(1): 144–151.

Yun M, Choi H, Jung J, Kim C. Development of a thermo- reversible insulin liquid suppository with bioavailability enhance- ment. Int J Pharm 1999; 189(2): 137–145.

Hosny EA. Relative hypoglycemia of rectal insulin suppositories containing deoxycholic acid, sodium taurocholate, polycarbophil,

and their combinations in diabetic rabbits. Drug Dev Ind Pharm

1999; 25(6): 745–752.

Ghelardi E, Tavanti A, Lupetti A, et al. Control of Candida albicans murine vaginitis by topical administration of polycarbo- phil–econazole complex. Antimicrob Agents Chemother 1998; 42(9): 2434–2436.

Oh YK, Park JS, Yoon H, Kim CK. Enhanced mucosal and systemic immune responses to a vaginal vaccine coadministered with RANTES-expressing plasmid DNA using in situ-gelling mucoadhesive delivery system. Vaccine 2003; 21(17–18): 1980–

1988.

Hubert P, Evrard B, Maillard C, et al. Delivery of granulocyte- macrophage colony-stimulating factor in bioadhesive hydrogel stimulates migration of dendritic cells in models of human papillomavirus-associated (pre)neoplastic epithelial lesions. Anti- microb Agents Chemother 2004; 48(11): 4342–4348.

Kockisch S, Rees GD, Young SA, et al. Polymeric microspheres for drug delivery to the oral cavity: an in vitro evaluation of mucoadhesive potential. J Pharm Sci 2003; 92(8): 1614–1623.

Kockisch S, Rees GD, Young SA, et al. In situ evaluation of drug- loaded microspheres on a mucosal surface under dynamic test conditions. Int J Pharm 2004; 276(1–2): 51–58.

Leitner VM, Guggi D, Krauland AH, Bernkop-Schnurch A. Nasal delivery of human growth hormone: in vitro and in vivo evaluation of a thiomer/glutathione microparticulate delivery system. J Control Release 2004; 100(1): 87–95.

Umamaheswari RB, Jain S, Tripathi PK, et al. Floating-bioadhesive microspheres containing acetohydroxamic acid for clearance of Helicobacter pylori. Drug Deliv 2002; 9(4): 223–231.

Langoth N, Kalbe J, Bernkop-Schnurch A. Development of buccal drug delivery systems based on a thiolated polymer. Int J Pharm 2003; 252(1–2): 141–148.

Bernkop-Schnurch A, Thaler SC. Polycarbophil–cysteine conju- gates as platforms for oral polypeptide delivery systems. J Pharm Sci 2000; 89(7): 901–909.

Kast CE, Guggi D, Langoth N, Bernkop-Schnurch A. Development and in vivo evaluation of an oral delivery system for low molecular weight heparin based on thiolated polycarbophil. Pharm Res 2003; 20(6): 931–936.

Marschutz MK, Caliceti P, Bernkop-Schnurch A. Design and in vivo evaluation of an oral delivery system for insulin. Pharm Res 2000; 17(12): 1468–1474.

Marschutz MK, Puttipipatkhachorn S, Bernkop-Schnurch A. Design and in vitro evaluation of a mucoadhesive oral delivery system for a model polypeptide antigen. Pharmazie 2001; 56(9): 724–729.

Hornof MD, Bernkop-Schnurch A. In vitro evaluation of the permeation enhancing effect of polycarbophil–cysteine conjugates on the cornea of rabbits. J Pharm Sci 2002; 91(12): 2588–2592.

Valenta C, Walzer A, Clausen AE, Bernkop-Schnurch A. Thiolated polymers: development and evaluation of transdermal delivery systems for progesterone. Pharm Res 2001; 18(2): 211–216.

Junginger HE, Verhoef JC. Macromolecules as safe penetration enhancers for hydrophilic drugs—a fiction? Pharm Sci Tech Today 1998; 1: 370–375.

The Registry of Toxic Effects of Chemical Substances. Atlanta: National Institute for Occupational Safety and Health, 2004.

General References

Noveon Inc. Polycarbophil. http://www.pharma.noveon.com/ literature/msds/msdaa1.pdf (accessed 18 May 2005).

E1200; Litesse; polydextrose A; polydextrose K.

Chemical Name and CAS Registry Number

Polydextrose [68424-04-4]

Empirical Formula and Molecular Weight

(C6H12O6)x 1200–2000 (average)

Structural Formula

See Section 18.

Functional Category

Base for medicated confectionery; coating agent; granulation aid; tablet binder; viscosity-increasing agent.

Applications in Pharmaceutical Formulation or Technology

Polydextrose is used in pharmaceutical formulations and food products. In food products it is used as a bulking agent; it also has texturizing and humectant properties.

Although polydextrose can be used in a wide range of pharmaceutical formulations, its primary use is in solid-dosage forms.

In tableting, polydextrose solutions are used as binders in wet-granulation processes. Polydextrose is also used in the manufacture of directly compressible tableting excipients. Polydextrose solutions may also be used, in conjunction with other materials, as a film and tablet coating agent.

Polydextrose acts as a bulking agent in the formulation of ‘sugar-free’ confectionery-type dosage forms. In conjunction with isomalt, lactitol, or maltitol, polydextrose can be used in the manufacture of ‘sugar-free’ hard-boiled candies and acacia lozenges or pastilles.

The combination of high water solubility and high viscosity of polydextrose facilitates the processing of sugar-free candies

of excellent quality. Polydextrose is amorphous and does not crystallize at low temperatures or high concentrations, so it can be used to control the crystallization of polyols and sugars and therefore the structure and texture of the final product.

Description

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