"Maximum bolus dose not causing laxation—data for adults.

All the polyols presented are considered as food additive or GRAS in the United States. Source: Adapted from Ref. 61.

"Maximum bolus dose not causing laxation—data for adults.

All the polyols presented are considered as food additive or GRAS in the United States. Source: Adapted from Ref. 61.

glucose and thus provide less energy per unit mass to the consumer and have lower glycemic and insulinemic indices. Sugar alcohols reaching the large intestine are almost completely digested by the colonic flora, which can cause certain side effects as fermentation of unabsorbed sugar leads to flatulence. In addition, as they are osmotically active, diarrhea may occur when the fermentation capacity is exceeded. Their main characteristics are resumed in Table 4, adapted from (61). In a survey of 129 oral liquid dosage forms stocked at a large university teaching hospital, 42% contained sorbitol (62). The sorbitol concentration in the identified products varied from 3.5% to 72% w/v (0.175-3.6 g/mL). In a recent review of pediatric oral formulations commercially available in the United States, 44% of the liquids contained sorbitol (57). The other polyols found were xylitol, mannitol, maltitol, and, in many, glycerol.

Artificial or intense sweeteners are often used not only to restrict the sugar intake in food and beverages but also to boost the degree of sweetness to mask bitter notes. Only few are approved for use in over 80 countries (e.g., saccharin, aspartame, sucralose, and acesulfame potassium). There is some ongoing controversy over whether artificial sweeteners are health risks despite lack of scientifically controlled peer-reviewed studies in general consistently to produce clear evidence. It is to be noted that if an acceptable daily intake (ADI) value is available, most of the time it is for a general adult population and not specifically for pediatric and geriatric population.

Both solid and liquid dosage forms may contain saccharin. Saccharin (E954) is a nonnutritive sweetening agent, which is 250 to 500 times as sweet as sucrose. In a survey of sweetener content of pediatric medications, seven of nine chewable tablets contained saccharin (0.45-8.0 mg/tablet) and sucrose or mannitol. Of 150 liquid preparations investigated, 74 contained saccharin (1.25-33 mg/5 mL) (56). Saccharin is a sulfanamide derivative that should be avoided in children with sulfa allergies (47). It is recommended that daily saccharin intake be maintained below 1 g because of a risk of bladder cancer. A lifetime daily diet containing 5% to 7.5% saccharin has induced bladder tumors in rats (63). However, it is probable that saccharin is only a very weak carcinogen in humans. The amount contained in pharmaceutical preparations is well below the recommended maximum human daily intake. It is not approved in Canada but is in the United States and in Europe, only for children older than three years. It was found in combination or alone in 10 of the 12 commercially available liquids containing intense sweeteners in a recent American review of the commercially available pediatric dosage forms (57).

Aspartame (E951), a phenylalanine derivative, is incorporated in many chewable tablets and sugar-free dosage forms. Aspartame-containing products should be avoided in children with autosomal recessive phenylketonuria (47). Neotame is a derivative of aspartame but is 7000 to 13,000 times sweeter than sucrose, with greater stability at higher and neutral pH as well as higher temperatures than aspartame. It has a clean sweet taste (no off-tastes) and is not metabolized into phenylalanine. It is generally recognized as safe (GRAS) listed and approved as a food in over 25 countries but is not yet widely used.

Acesulfam K (E950) is an oxathiazinone sweetener; it is widely used, as it is stable during typical manufacturing and storage conditions of many pharmaceutical dosage forms. It can be used on its own (-200 times sweeter than sucrose) but has interesting synergistic properties with other intense sweeteners as well as bulk sweeteners such as sugar alcohols. It is similar to sucralose (E955), which is the only intense sweetener made from sugar (chlorination). It is approximately 600 times sweeter than sugar, with a clean sugar-like taste with just a sweet aftertaste. Presently 1 of 32 oral liquid formulations on the American market contains sucralose (57).

Vehicle Selection

Ethanol has long been employed as a solvent in pharmaceuticals and is still prevalent; in a recent survey in America, it was found that 5 of the 32 pediatric liquids commercially available still contain alcohol (57). Since it also acts as a preservative, it is second only to water in its use in liquid preparations. It has also been suggested that it may enhance the oral absorption of some active ingredients (64).

There are severe acute and chronic concerns around pediatric medicines containing ethanol. Hepatic metabolism of ethanol involves a nonlinear saturable pathway. Young children have a limited ability to metabolize and thereby detoxify ethanol. Ethanol intoxication has been recorded in children with blood levels as low as 25 mg/dL. Alcohol has a volume of distribution of approximately 0.65 L/kg. Ingestion of 20 mL of a 10% alcohol solution will produce a blood level of 25 mg/dL in a 30-lb. child. The American Academy of Pediatrics (AAP) Committee on Drugs recommends that pharmaceutical formulations intended for use in children should not produce ethanol blood levels of >25 mg/dL after a single dose. In general, manufacturers have voluntarily complied with the recommendations. In 1992 the Nonprescription Drug Manufacturers Association established voluntary limits for alcohol content of nonprescription products (65).

1. A maximum of 10% alcohol in products for adults and teens, 12 years and older

2. A maximum of 5% alcohol in products intended for children aged 6 to 12 years

3. Less than 0.5% alcohol content for products intended for children less than 6 years

Extemporaneous production of pediatric dosage forms is commonly undertaken in hospitals. Without the sophisticated formulation capabilities of pharmaceutical manufacturers, alcohol-based vehicles have been recommended for extemporaneous preparation of liquid dosage forms (66). There is a critical need to conduct research studies to assist the pharmacist in replacing current formulations with stable, alcohol-free preparations.

Propylene glycol is used as solvents in many formulations (e.g., oral, topical, and parenteral routes) for poorly soluble compounds such as phenobarbital, phenytoin, diazepam, and multivitamin concentrates. Because of the limited metabolic pathways in children younger than four years, number of adverse events has been described (laxative effects per os, contact dermatitis) but mainly serious systemic CNS depression. Seven of the thirty-two liquids (solution, suspension, syrup) commercially available for children in America contained propylene glycol (57).

Administration Considerations in Dosage Form Development

Limited evidence-based information around acceptability and preference of dosage forms in children are available, despite the fact that the therapeutic outcomes are closely linked to it (67).

An ideal formulation should suit all subsets of the pediatric population, have minimum administration frequency, be palatable, contain nontoxic excipients, provide easy and accurate dose administration, and have minimal impact on lifestyle (68,69).

Oral administration Oral administration is the preferred route of administration. There is a general consensus among pediatricians and parents that children younger that five years have great difficulty with, or are unable to swallow, a solid oral dosage form. Manufacturers, therefore, tend to favor liquid formulations. It allows dosing flexibility for the heterogenous pediatric population (varying weight, PK/PD, physical abilities, and developmental capacity). Liquid dosage forms, however, are not free of problems. They are often less stable and have shorter expiration dates; accurate measurement depends on device used, and administration of the prescribed dose can also be a problem, especially in infants. Dose volumes are critical, and it is considered that children younger than five years should not receive more than 5 mL and that older children should not be dosed with more than 10 mL. It is evident that the less palatable the drug is, the smaller should this volume be. Appropriate administration devices have to be used (70). They should also be easy to use even with an uncooperative child. To achieve satisfactory dispensing of drops, usually concentrated liquids, carers should hold the dropper vertically (71). Formulating liquids can be more challenging, as they require a greater quantity and type of excipients, which are limited in choice and concentration for pediatric patients (43,72).

To overcome insufficient stability in liquid state, dispersible tablets and effervescent dosage forms provide a "dry" alternative to liquid but are not without inherent issues (large volume of diluent, bicarbonate ingestion, sodium and/or potassium content not suitable for renally impaired patients, difficult taste masking).

In adults, tablets and capsules are the most popular dosage forms because of the accuracy of dose, taste maskability, stability, portability, low-cost production, and modifiable drug delivery release. Nevertheless, their main disadvantage for children is the nonflexibility of dose and the difficulty or inability to be swallowed by the very young. This is frequently often overcome by crushing tablets or opening capsules and adding the powder to water or soft food or beverages despite proof of accurate dose and bioequivalence (73). In some instance the resulting powder is further diluted with powder excipients and repackaged in sachets or capsules for extemporaneous dispensing with few, if any, compatibility/stability consideration.

When tablets are not scored but yet cut to obtain the appropriate dose or to facilitate swallowing, dose accuracy cannot always be ensured: the weight of a split tablet can range from 50% to 150% of the actual half-tablet weight (74). Splitting tablets into segments is not recommended with narrow therapeutic index drugs, potent or cytotoxics drugs, or small tablets. Some tablets (e.g., coated, multilayered, modified release) cannot be manipulated without affecting taste, release properties, and possible therapeutic effects, unless especially stated by the manufacturer (75). A potentially very fruitful area for future research and development is sprinkle multiparticulates formulations as they offer a solution to many of the limitations highlighted above and have been very well received by both patients and their parents. They can be dosed intraorally or in a vehicle the child likes, from a bottle (dosing scoop), or from individual sachets or capsules.

Chewable tablets are considered to be safe for use in children with full dentition (2-3 years) (76-78) and under supervision. Orodispersible preparations in the oral cavity (e.g., tablets, films, wafers) stand also on the periphery of solids and liquids, with the extra challenge that the quantity of excipients available to improve the palatability is limited.

It is to be noted that few studies have been performed to assess age, development, and oral dosage forms of choice (i.e., applicability, acceptability, preference).

Buccal and sublingual administration Oromucosal drug administration is possible, although mainly limited by ability and compliance concerns in the younger age group. It might be difficult in babies due to feeding patterns. Safety needs to be established in children.

Rectal administration The administration of drugs by a solid rectal dosage form (i.e., suppositories) can result in a wide variability in the rate and extent of absorption in children (79). Rectal administration of a drug is not favored by adolescents, carers, and various ethnic groups and can sometime be difficult (premature loss of the dose) in the very young. These facts, coupled with the inflexibility of a dose, make this a route difficult to promote for pediatric patients with chronic conditions. Nevertheless it can be an alternative route if the oral route is not available or local effects or immediate systemic effects (epileptic seizures) are required.

Transdermal administration The development of the stratum corneum is complete at birth but is more perfused and hydrated than in adults. It is considered to have permeability similar to that of adults, except in preterm infants (80). Preterm neonates and infants have an underdeveloped epidermal barrier and are subject to excessive absorption of potentially toxic ingredients from topically applied products. Once matured (3-5 months after birth), infant skin presents less variability, but the ratio of surface area to weight is higher in children, when compared with that of adults.

Only few transdermal products (e.g., steroidal hormone, caffeine, theophylline, fentanyl, scopolamine, nicotine, methylphenidate) have been tested or marketed for use in the pediatric population. The development of transdermal products in pediatric doses could be very beneficial for children who are unable to tolerate oral medications. The need for several sizes of patches to cover different doses needed by different subsets of the pediatric population and to avoid accidents with cutting adult patches can be a limitation. The younger, the better permeation. Hence a compromise between topical versus transdermal efficacy and safety should be sought.

Parenteral administration Absorption of medication following an intramuscular (IM) injection is often erratic in neonates owing to their small muscle mass and an inadequate perfusion of the IM site (81,82). In a study of infants and children aged 28 days to 6 years, the IM administration of chloramphenicol succinate produced serum levels that were not significantly different from those produced in intravenous (IV) administration (83). However, the bioavailability of most drugs administered intramuscularly has not been evaluated in the pediatric population. In addition to bioavailability issues, there are other concerns specific to pediatrics with the IM administration of drugs. The volume of solution injected is directly related to the degree of pain and discomfort associated with an IM injection. Manufacturers' recommendations for reconstitution of IM products often result in a final volume that is excessive for a single injection site in a child's smaller muscle mass, thereby requiring multiple injections and a significant degree of discomfort for the patient. If a smaller volume is used for reconstitution, the problems of drug solubility and high osmotic load at the site of injection must be addressed (84,85). The inclusion of a local anesthetic, such as lidocaine, as part of the reconstituted product is often necessary (84-86).

In a report from the Boston Collaborative Drug Surveillance Program, pediatric nurses have reported a much higher frequency of complications from IM injections than that observed in the adult population. Twenty-three percent of pediatric nurses surveyed had observed complications (e.g., local pain, abscess, hematoma) versus a rate of 0.4% reported in adult patients (87). Serious complications, such as paralysis from infiltration of the sciatic nerve, quadriceps myofibrosis, and accidental intra-arterial injection, are usually the result of the difficulty in placement of an IM injection in children.

In hospital, many patients have a venous cannula, and systemic drugs not given orally are usually given intravenously rather than subcutaneously or intramuscularly.

The major problem with the IV route in children is dosing errors. Because of the unavailability of stock solutions prepared for pediatric doses, errors in dilution of an adult stock solution have resulted in 10- to 20-fold errors in administered doses (88,89). A secondary problem is the maintenance of patient IV lines in infants and nonsedated children.

Intranasal drug delivery This drug delivery provides fast and direct access to systemic circulation without first-pass metabolism. Administration is not easy especially with uncooperative children, but small volumes involved, rapidity of execution, feasibility at home has made it more attractive, particularly for no-needle approach to acute illnesses. Aerosols with an appropriate device can avoid swallowing and is more precise in terms of dose. Drugs such as benzodiazepines, fentanyl, diamorphine, and ketamine have been used successfully via this route (90).

Pulmonary drug delivery Endotracheal drug delivery is a very effective method of administering emergency medications (i.e., epinephrine, atropine, lidocaine, naloxone) to children when an IV line is not available. To optimize drug delivery to the distal portions of the airway, the drug must be administered rapidly, using an adequate volume of diluent: 5 to 10 mL in young children; 10 to 20 mL for adolescents (91).

Pressurized inhalation products have also been very successfully employed in the pediatric population to provide a drug directly to the desired site of action, the lung. These products are designed to deliver a unit dose at high velocity with small particle size, the ideal conditions for drug delivery to distal airways (92). Self-administration is difficult for younger patients without coordination.

The choice of inhalation devices is crucial and is made in relation to age. Pressured metered-dose inhaler (pMDI) can only be used by older children. Environmentally friendly chlorofluorocarbon (CFC)-free formulations, using hydrofluoroalkane (HFA) as the propellant, are now replacing CFCs, except for formulaic exemptions. To decrease oropharyngeal impaction and optimize and widen pMDI utilization, spacers can be used (93). With a face mask, it even enables pMDI for very young infants. Dry-powder inhaler (DPI) is for children with enough inspiratory flow to trigger particles' release and transport the particles deep in the lung. Nebulizers are applicable for all ages but very few are portable yet. Guidance for use of different inhaler types (i.e., nebulizers, pMDI, and DPI) has been established by the Global Initiative on Asthma (GINA), a panel of clinical experts who look at the various inhaler types, their features, and patient experience. Their guidance has been incorporated in national regulatory guidance throughout the world. The most appropriate device should be selected for each child.

• Children younger than four years should use a pMDI plus a spacer with face mask or a nebulizer with face mask.

• Children aged four to six years should use a pMDI plus a spacer with mouthpiece, a DPI, or, if necessary, a nebulizer with face mask.

• For children using spacers, the spacer must fit the inhaler, and attention should be paid to ensure that the spacer fits the child's face.

• Children of any age older than six years who have difficulty using pMDIs should use a pMDI with a spacer, breath-actuated inhaler, DPI, or nebulizer. DPIs require an inspiratory effort that may be difficult to achieve during severe attacks.

• Children having severe attacks should use a pMDI with a spacer or a nebulizer.

• Particularly among children younger than five years, inhaler techniques may be poor and should be monitored closely.

The use of the aerosol route for delivery of antibiotics for pulmonary infections remains controversial. The majority of pediatric studies have been conducted in children with cystic fibrosis. In these patients distribution of the antibiotic to the desired tissue site is impeded because of the viscosity of the sputum in patients with acute exacerbations of their pulmonary infections (94,95). Long-term studies have demonstrated preventive benefits of aerosolized antibiotics in children with cystic fibrosis who are colonizing Pseudomonas aeruginosa in their lungs but are not acutely ill (96,97). Cyclic administration of tobramycin administered by nebulizer has received FDA approval (98).

Systemic treatment via the respiratory tract needs further study to determine its usefulness.

Compliance Issues: Taste Preference and Palatability

Compliance and concordance issues have multivariate complex origins but an acceptable taste especially with pediatric patients (99). Two factors make taste preference and palatability critical considerations in pediatric adherence. The dosage forms most commonly employed for pediatric formulations are liquids and chewable tablets. A perceived unpleasant taste is much more evident with these dosage forms than when a drug is administered as a conventional solid oral dosage form. It is widely believed that children younger than six years have more acute taste perception than older children and adults. Taste buds and olfactory receptors are fully developed in early infancy. Different taste acuity and preferences occur between teenagers and infants, as well as between boys and girls (100-102). Loss of taste perception accompanies the aging process. Children's adherence to therapy is affected by their cognitive skills, their acceptability or ability to swallow, and their own taste perception, affected or not by their disease.

Smell, taste, texture, and aftertaste, therefore, are important factors in the development of pediatric dosage forms. In a study of six brands of OTC chewable vitamins, flavor type and intensity, soft texture, and short aftertaste were critical factors in product preference. The flavor and texture attributes of the best-selling product were significantly different from that of the other brands (103).

Flavoring standardization would be an ideal global development of formulation but is complex as it depends on many factors such as the geographical and sociocultural background and the health condition of the target population. There are at least 26 different flavorings used in pediatric antimicrobial preparations (104). In America, cherry is a very common flavoring, although a blind taste comparison found that other flavorings, such as orange, strawberry, and bubble gum, were well accepted in pediatric antimicrobial suspensions (105). In many circumstances it may be difficult to mask the unpleasant taste of the active ingredient. Regardless of the flavoring used, parents consistently report that children prefer cephalosporin products to penicillin suspensions (105).

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