Pharmaceutical Pediatric Formulations

Flavorants plays an important role in patient acceptability especially for pediatric oral liquid formulations. The selection of flavorants should be clearly described and justified as some flavorants has toxic effect especially in pediatric preparation. The safety concerns must be recognized including the risk of allergies and sensitization [2].

Peppermint oil

Peppermint oil is important flavoring agent used different oral liquid preparation especially for pediatrics as it has favorable taste and odour for them. But, different unwanted effects such as atrial fibrillation, muscle pain and cooling or burning sensations are occurred commonly in pediatric populations due to peppermint oil [30].

Coloring agents and dyes

Coloring agents have different roles in pharmaceutical as well as cosmetics and food industries. From these, attracting of consumers, identification of products and protecting effect of products are some of the functions of coloring agents. Especially coloring agents (mostly bright color) are highly important for pediatric formulations to attract them with their medications. Most coloring agents used in pharmaceutical oral preparations grouped to one of the following groups: azo dyes (tartrazine), triphenylmethane dyes, xanthene dyes (erythrosine) and quinoline dyes (quinoline yellow).

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The numbers of coloring agents that are globally acceptable from a regulatory perspective are limited as many coloring agents have been associated with hypersensitivity and other adverse reactions for pediatric populations [39].

Anaphylactic reactions, asthma, urticaria, angioedema, hyperkinesis, cross-sensitivity with acetylsalicylic acid, sodium benzoate and indomethacin is common in pediatrics when they take azo dyes [27]. Due to this, azo-dyes are recommended to avoid from pediatric medications or risk benefit assessments should be done before including them in the formulation.

Contact dermatitis is common because of quinoline dyes. Triphenylmethane dyes also might cause bronchoconstriction, skin rash, erythema, angioedema and anaphylaxis. Xanthine dyes might also cause photosensitization and carcinogenicity on children [40].

Fillers (Diluents)

Diluents are chemically inactive excipients, mostly used to make up the required bulk of solid dosage form and used up to 80 % in a formulation. Many studies reported that fillers used in the solid dosage forms such as tablets and hard gelatin capsules show several unwanted effects to pediatrics on long-term as well as short duration therapy. So, it is necessary to categorize the safety of diluents before preparation of a pharmaceutical formulation to reduce the adverse effects [41].

Lactose

More than 20% of all solid dosage forms found in the market contain lactose as binder and filler. It is a disaccharide of glucose and galactose and is absorbed after hydrolysis by intestinal lactase. It can cause hypersensitivity reactions in children and young infants when it used in pediatric formulations. Because of immature intestine, preterm infants have reduced levels of lactase enzyme to hydrolyze lactose. In infants with lactose intolerance (lactase deficiency), lactose is not readily metabolized by lactase leading to the buildup of lactic acid, hydrogen and carbon dioxide. Abdominal pain, distention or bloating, flatulence, diarrhea, muscle and joint pain and eczema are common toxicities of lactose in infants and children [18].

Sometimes children have serious and prolonged reactions to lactose might lead to complications such as metabolic acidosis, jaundice, dehydration and bacterial proliferation [3]. Moreover, the unabsorbed lactose may raise the osmotic pressure in the colon which may prevent water and other important nutrients and drugs from re absorption and causing laxative effect. WHO recommended to not using more than 3g per day [25].

Mannitol

Mannitol is widely used as filler in several pharmaceutical formulations especially in chewable and orodispersible tablets as it has good mouth filling property. Comparing to sugars, it is comparatively less cariogenic. In some case, hypersensitivity reactions and anaphylactic reactions are reported after the intravenous infusion of 10 % or 20 % (w/v) which contain mannitol [41]. Direct action of mannitol on mast cells is responsible to anaphylactic reactions. Its absorbtion is not more than 20 % when taken orally. Due to its high osmotic pressure creating ability it's also responsible to severe diarrhea in turn decrease the transit time of small intestine leads to decreasing the absorbtion of some drugs [42].

Surfactants

Polysorbates

Polysorbate is a surfactant commonly used in protein parenteral formulations to minimize denaturation at the air-water interface. It is also sometimes used in injectable solutions of small molecules for the purpose of solubility enhancement due to its ability micelle formation [41].

It causes several serious adverse effects on pediatrics such as hypersensitivity, thrombocytopenia, cholestasis, ascites, hypotension, renal dysfunction, hepatomegaly, and severe metabolic acidosis which may leads to death. Because of these adverse effects, WHO recommended acceptable to be no more than 25 mg/kg [30]. It also inhibits the activity of P-glycoproteins [42].

Carrageenan

Carrageenan is used as suspending and wetting agent for suspension and cream preparations. It is identified by causing severe inflammatory reactions in animal trials and should not recommend including in pediatric preparations [12].