Table 3 Excipients known to be harmful and potentially harmful to neonates used in study population, their applications and safety concerns
From: Hospitalised neonates in Estonia commonly receive potentially harmful excipients
Excipient | Functional category† | Applications and typical concentration ranges† | Safety concern |
|---|---|---|---|
Known to be harmful to neonates | |||
Parabens (methyl- and propyl parahydroxybenzoate) | Antimicrobial | Antimicrobial activity against yeasts and molds. Combination of Methyparaben (0.18%) and propylparaben (0.02%) for parenteral formulations. In combinations with propylene glycol (2-5%)/ imidurea | Hyperbilirubinemia in neonates. Irritant in injections / ophthalmic drugs. Hypersensitivity reactions. [18, 19] |
Saccharin sodium | Sweetening | 0.02-0.5% w/w* | Urticaria with pruritus and photosensitivity reactions. [14] |
Sodium benzoate | Antimicrobial, tablet / capsule lubricant | 0.02-0.5% in oral medicines; 0.5% in parenteral medicines; 2-5% w/w tablet lubricant | Contact urticaria. [21] Topical irritant. Increased risk of hyperbilirubinaemia in neonates. |
Benzyl alcohol | Antimicrobial, solvent | Up to 2% v/v* in parenteral/oral preparations, typically 1% v/v. 5% v/v and up used as solubilisers. 10% v/v local anaesthetic properties (parenterals, ophthalmic solutions, oitments) | Headache, vertigo, nausea, vomiting, diarrhea, metabolic acidosis, seizures, gasping. Hypersensitivity; fatal toxic syndrome in premature infants. Pain on injection, [8, 18–20] |
Benzalkonium chloride | Antimicrobial, antiseptic, solubilising, wetting | Ophthalmic preparations – preservative, 0.01-0.02% w/v*; In combination with other preservatives | Ototoxic when applied to ear, skin irritation and hypersensitivity Bronchoconstriction in asthmatics. Eye irritation. [18–20] |
Propylene glycol | Antimicrobial, humectant, plasticizer, solvent, stabilizing, water-miscible cosolvent | Humectant – topical – approx.15%. Preservative –solutions / semisolids – 15-30%. Solvent or cosolvent: aerosol solutions 10-30%, oral solutions 10-25%, parenterals 10-60%, topical 5-80% | Skin irritation. Central nervous system (CNS) depression. High doses - cardiovascular, hepatic, respiratory adverse events. [18–20] |
Polysorbate 80 | Dispersing, emulsifying, non-ionic surfactant, solubilising, suspending, wetting | Emulsifying: alone in oil-in-water emulsions 1-15%; in combination 1-10%. To increase water-holding prop of ointments 1-10%. Solubilising: poorly soluble API*s in lipophilic bases 1-5%; insoluble APIs in lipophilic bases 0.1-3% | E-Ferol syndrome - thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension, metabolic acidosis. [18] |
Ethanol | Solvent | In the USA, the max quantity of alcohol included in over the counter (OTC) medicines 0.5% v/v for products for use by children under 6 years of age. Parenteral products containing up to 50% of alcohol (e 95 or 96% v/v) | CNS depression - muscle incoordination, visual impairment. Negative synergic effects on CNS when associated with dextromethorfan. Chronic toxicity [8, 18, 20] |
Potentially harmful excipients | |||
Sodium metabisulphite | Antimicrobial, antioxidant | Antioxidant in oral, parenteral, and topical formulations: 0.01–1.0% w/v, intramuscular 27% w/v. Antimicrobial: syrups. | Hypersensitivity. Paradoxical bronchospasm, wheezing, dyspnoe and chest tightness in asthmatic children.[18–20] |
Colloidal anhydrous silica | Adsorbent; anticaking; emulsion stabilizer; glidant; suspending; tablet disintegrant; thermal stabilizer; viscosity-increasing | Improves flow properties of dry powders (0.1-0.5%) (tabletting); stabilizes emulsions (1.0-5.0%); thixotropic thickening/ suspending (2.0-10.0%); in aerosols to promote particulate suspension, eliminate hard settling, minimize clogging of spray nozzles (0.5-2.0%) | A possible sarcoidosis-inducing antigen [22] |
Anhydrous sodium hydrogen phosphate (monobasic, dibasic) | Buffering; emulsifying; sequestering. | Buffering agent; sequestering agent. Concentrations are dependent on the formulation. | Gastrointestinal (GI) disturbances including diarrhea, nausea, and vomiting [18] |
Sodium bicarbonate | Alkalizing; therapeutic. | To produce or maintain an alkaline pH in a preparation | Exacerbation of chronic heart failure in elderly [18] |
Macrogols - polyethylene glycol | Ointment base; plasticizer; solvent; suppository base; tablet and capsule lubricant. | High molecular weight macrogols can be used as lubricants in tablet formulations; water solubility and bad penetration through skin makes them useful as ointment bases | Hypersensitivity reactions, hyperosmolarity, metabolic acidosis, and renal failure in burn patients. [18] |
Trometamol | Buffering | Buffering agent, buffer range from 7.1–9 | Hypersensitivity reactions. [23] |
Cetostearyl alcohol | Emollient; emulsifying; viscosity-increasing. | Increasing viscosity; stabilizes emulsions; co-emulsifier; decreasing the amount of surfactant required | |
Sodium lauryl sulphate | Anionic surfactant; detergent; emulsifying; skin penetrant; tablet and capsule lubricant, wetting | Tablet lubricant (1.0-2.0%) | Irritation to the skin, eyes, mucous membranes, upper respiratory tract, and stomach. [18] |
Sorbitan stearate | Dispersing; emulsifying; nonionic surfactant; solubilizing; suspending; wetting | When used alone produces water-in-oil emulsions / microemulsions. In combination with polysorbate produces water-in-oil or oil-in-water emulsions / creams. | Hypersensitive reactions.[18] |
Lactic acid | Acidulant | In injections in the form of lactate as a source of bicarbonate (0.012-1.16%) | Neonates have difficulty in metabolizing R-lactic acid, and this isomer and the racemate should therefore not be used in infants aged less than 3 months old. [18] |
Sodium cyclamate | Sweetening | 0.17% w/v as sweeter, in combination with saccharin | Photosensitivity. [18] |
Disodium edetate | Chelating | Forms stable water-soluble complexes with alkaline earth and heavy-metal ions; concentrations 0.005-0.1% | Local inflammatory reactions. [18] |
Gelatin | Coating; film-forming; gelling; suspending; tablet binder; viscosity-increasing | Tablet binder; microencapsulation | Local irritation. Hypersensitivity reactions, including serious anaphylactoid reactions [21] |
Povidone | Disintegrant; dissolution enhancer; suspending; tablet binder | Binder in wet-granulation process; coating; solubilizer for poorly soluble drugs (0.5-5%) | Subcutaneous granulomas at the injection site. [21] |
Trolamine | Alkalizing; emulsifying | When mixed in equimolar proportions with a fatty acid an emulsifying agent to produce fine-grained, stable oil-in-water emulsions will be formed (2-4%) | Hypersensitivity, skin irritant. [18] |
Cresol | Antimicrobial preservative; disinfectant. | Antimicrobial preservative in parenteral formulations (0.15-0.3%) | Skin hypersensitivity reactions. [18] |
Maltose | Sweetening; tablet diluent | Osmotic - ophthalmic drops and parenteral inf. | Single report of hyponatremia in a liver transplantation patient. [18] |
Sorbic acid | Antimicrobial | As antimicrobial preservative (0.05-0.2%) | Irritant and allergic hypersensitivity skin reactions. [18, 19] |
Boric acid | Antimicrobial, buffering | As antimicrobial preservative in eye drops. Good buffering capacity to control pH. | Poisoning - abdominal pain, vomiting, diarrhea, erythematous rash, CNS depression. Convulsions, hyperpyrexia, and renal tubular damage. [18] |
Borax | Alkalizing; antimicrobial; buffering; disinfectant; emulsifying; stabilizing | Antimicrobial preservative in eye preparations | Vomiting, diarrhea, erythema, CNS depression, and kidney damage. [18] |
Glycine | Buffering; bulking; freeze-drying; tablet disintegrant; wetting | Cofreeze-dried excipient in injectable formulations | Disturbances of fluid and electrolyte balance; cardiovascular and pulmonary disorders. [18] |
Calcium chloride dihydrate | Antimicrobial, water-absorbing. | Dehydrating properties | Stomach and heart disturbances. Eye irritant, dermatitis. [18] |
Leucine | Antiadherent; flavoring; lubricant | As antiadherent to improve the deagglomeration | Moderately toxic by the s/c route.[18] |
Titanium dioxide | Coating as opacifier, pigment | As a white pigment and opacifier | Possibly carcinogenic [24] |
Benzethonium chloride | Surfactant, antiseptic, wetting and/or solubilizing | As an antimicrobial preservative (0.01-0.02% w/v) | Probably neurotoxic [25] |
Erythrosine | Cherry-pink/red synthetic coal tar dye | Dye | Toxic to human lymphocytes in vitro, binds directly to DNA. [26] |
Sodium cetate trihydrate | Antimicrobial; buffering; flavoring, stabilizing | As a buffering agent and as an antimicrobial preservative | Poisonous if injected i/v, an irritant to the skin and eyes. [18] |
Ethylendiamine | Counter ion | Counter ion of theophylline | Hypersensitivity reactions [27] |
Macrogol cetostearyl ether | Emulsifying; penetration enhancer; solubilizing; wetting | Solubilizing agent, enhancing effect on the skin permeation | Moderately toxic. [18] |
Copovidone | Film-forming; granulation aid; tablet binder | As a film-forming agent (0.5-5%); tablet binder (direct compression and wet granulation) (2.0-5.0%) | Moderately toxic by ingestion, gastric disturbances. [18] |
Sodium formaldehyde sulfoxylate | Antioxidant | Antioxidant in parental, rectal solutions | Moderately toxic by ingestion, when heated to decomposition it emits toxic fumes. [18] |
Castor oil | Emollient; oleaginous vehicle; solvent. | extended release agent | Contact dermatitis. [18] |
Acacia | Emulsifying; stabilizing; suspending; tablet binder; viscosity-increasing. | Viscosity increasing agent (as it is in powder for oral suspensions) | Hypersensitivity reactions. [18] |