Pediatric drug development: formulation considerations.

http://informahealthcare.com/ddi ISSN: 0363-9045 (print), 1520-5762 (electronic) Drug Dev Ind Pharm, Early Online: 1–17 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2013.850713

REVIEW ARTICLE

Drug Development and Industrial Pharmacy Downloaded from informahealthcare.com by University of Texas at Austin on 06/15/14 For personal use only.

Pediatric drug development: formulation considerations Areeg Anwer Ali1, Naseem Ahmad Charoo2, and Daud Baraka Abdallah3 1

Department of Clinical Pharmacy and Pharmacology, RAKCOPS, RAK Medical and Health Sciences University, Ras Al Khaimah, UAE, 2Xepa, Soul Pattinson Sdn Bhd, Melaka, Malaysia, and 3Department of Pharmaceutics, Faculty of Pharmacy, Al Ribat University, Khartoum, Sudan

Abstract

Keywords

Absence of safe, effective and appropriate treatment is one of the main causes of high mortality and morbidity rates among the pediatric group. This review provides an overview of pharmacokinetic differences between pediatric and adult population and their implications in pharmaceutical development. Different pediatric dosage forms, their merits and demerits are discussed. Food and Drug Administration Act of 1997 and the Best Pharmaceuticals for Children Act 2002 added 6 months patent extension and exclusivity incentives to pharmaceutical companies for evaluation of medicinal products in children. Prescription Drug User Fee Act and Food and Drug Administration Amendments Act of 2007 made it mandatory for pharmaceutical companies to perform pediatric clinical studies on new drug products. Drug development program should include additional clinical bridge studies to evaluate differences in pharmacokinetics and pharmacodynamics of drugs in adult and child populations. Additionally, pharmaceutical development should consider ease of administration, palatability, appropriate excipients, stability and therapeutic equivalency of pediatric dosage forms. Pediatric population is diverse with individual preferences and demand for custom made dosage formulations. Practically it is not feasible to have different pharmaceutical dosage forms for each group. Hence, an appropriate dosage form that can be administered across pediatric population is warranted.

Clinical studies, excipients, formulation development, pediatric formulations, pharmacokinetics, taste masking

Introduction In the absence of specific pediatric medicines, their huge demand is met by extemporaneously prepared products. Upward shift in such prescriptions justifies the ‘‘Make Medicine Child Size’’ initiative. It resonated well with the wishes of the wider scientific community that children should benefit from recent scientific developments and improving access to medicines can be a leap forward. Extemporaneously prepared preparations are generally viscous dispersions prepared from tablets by incorporating other excipients like antimicrobial preservatives and viscosity modifiers. With little or no regard for drug – excipient compatibility and effect of these additional excipients or processes on critical quality attributes, such preparations are a threat to safety, efficacy and quality. The pediatric age group is so diverse that due to their individual preferences, it is challenging to develop a single formulation which is accepted across this group. Adding further to this complexity are rapid anatomical and physiological changes that this group undergoes making it further difficult to find the right dose. The group being highly vulnerable presents several ethical challenges in performing clinical studies on children. Clinical studies must be balanced to obtain needed information against the ethical obligations to protect children through the

Address for correspondence: Naseem Ahmad Charoo, Xepa, Soul Pattinson Sdn Bhd, 1-5 Cheng Industrial Estate, 75250 Melaka, Malaysia. Tel: +606 335 1515. Fax: +606 335 5829. E-mail: naseem102@yahoo .com

History Received 22 June 2013 Revised 16 September 2013 Accepted 19 September 2013 Published online 31 January 2014

study. The products to be studied in the pediatric population are categorized into four classes1, as shown in Figure 1. Oral route is by far the most preferred route for children 46 years. The target product profile of pediatric formulations by this route of administration will have additional critical quality attributes (CQAs) in the form of organoleptic characteristics, palatability, dosing flexibility, safety, ease of administration, pharmacokinetics and stability. Liquid dosage forms are preferred among children 55 years of age for their ease in swallowing and dose adjustment. Children in school age can be administered solid dosage forms. The dose accuracy and ease with which taste can be masked makes tablets and capsules popular among children and caregivers. Taste needs a special mention, for good medication with disagreeable taste will lead to noncompliance with the dosing regimen. Therefore, organoleptic additives form an integral component of pediatric formulations.

Regulatory perspective The number of product labels not bearing pediatric use information has gone down from 76% to 67%, during 1997–2012 period, respectively2. Yet, two-third of medicinal products prescribed to children have not been evaluated clinically and labeled for pediatric use (Figure 1). As a consequence, off-label use of these medicines has resulted in their use for unapproved indications. The widespread use of unauthorized medicinal products in children was a precursor for release of concept paper ‘‘Better medicines for children – proposed regulatory actions on pediatric medicinal products’’3.


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Drug Dev Ind Pharm, Early Online: 1–17

Figure 1. Clinical studies in pediatric population.

The adoption of the4 Food and Drug Administration (FDA) Modernization Act of 1997 and the Best Pharmaceuticals for Children Act in 2002 (BPA 2002)5 added incentives for pharmaceutical companies in terms of market exclusivity extension to 6 months and/or patent extension for performing additional clinical studies to evaluate these medicinal products in pediatric population. Similarly, the European Commission also took the initiative in 1997 by introducing incentives for pediatric formulation development6. ICH (International Conference on Harmonisation) guidance document E11 on7 ‘‘Clinical investigation of medicinal products in the pediatric population’’ was finalized in 2000. Pediatric Research Equity Act in 2003 authorized FDA to make pediatric studies mandatory for products that would be used in pediatric patients and extend clinical data obtained in adults to approve pediatric medicines in certain situations8. Prescription Drug User Fee Act and Food and Drug Administration Amendments Act (FDAAA) of 2007 (FDA2007) further encouraged the pediatric drug development (US Govt accountability office) by extending incentives and improving review process for pediatric studies9. Food and Drug Administration Amendments Act (FDAAA) of 2007 required future applications to be submitted with safety and efficacy data in all pediatric age groups with provision for extrapolation of clinical findings from studies performed on adults or from one pediatric age group to another when appropriate. In Europe, pediatric regulation governing development and authorization of medicines for pediatric use was implemented10 in 2007. These acts made it mandatory for pharmaceutical companies to perform clinical studies in pediatric population on new drug products to evaluate the feasibility of their use in children11.

Pharmacokinetics differences between pediatric population and adults Absorption The oral route is the most common and preferred route of drug administration. pH-mediated drug diffusion, gastric emptying time and intestinal transit time are essential characteristics that

determine drug absorption through this route. The developmental differences in gastrointestinal conditions between child and adult population groups can manifest in drug bioavailability difference in these two groups. The changes in gastric pH taking place during the development stages of a child are shown in Table 1. In infants, the gastric pH ranges from 6 to 8 but reaches to adult value by the age of 3 years23. This difference is manifested in faster absorption of acid labile drugs (penicillin) in neonates and infants as compared to adult population24–26. The absorption of weak acid drugs (Phenobarbital)27 is decreased whereas absorption of basic drugs is increased13. Gastric emptying is slow and reaches adult value within 6–8 months28. The small intestine is the major site for absorption and slow gastric emptying decreases the absorption of drugs (chloramphenicol and amoxicillin) in infants29,30. Fatty foods such as children formulas/milk further reduce gastric emptying and may delay onset of drug action31. Solid and liquid foods trigger peristaltic waves and increase the gastric emptying rate. Generally, liquids empty faster than solids and this may be one important criterion for selecting suspension dosage formulation over tablet dosage forms31,32. Faster intestinal transit time in children may result in incomplete absorption of some controlled release dosage forms33. Distribution In addition to the physiological factors, the drug distribution is determined by its physicochemical properties such as pKa, partition coefficient, molecular weight and solubility. When compared to adults, plasma protein binding and partitioning are different in the pediatric population and fluctuate continuously during the early years. The high volume of distribution of water-soluble drugs (linezolid and gentamicin) is caused by high extracellular and total body water16,17. Further, the concentration of binding proteins, their binding capacity and affinity to drug molecules is low in neonates and infants34,35. The plasma protein binding of drugs such as phenobarbital18, salicylates and phenytoin is significantly reduced in neonates36. Consequently, these drugs need a higher loading dose to achieve therapeutic

Inadequate [fat soluble substances (Vitamins D and E)-poorly absorbed]

Blood Brain Barrier: higher permeability

Unbound drug fraction: high

80–90% body weight; low fat content water soluble drugs: large volume of distribution, e.g. phenobarbital

Low

Activities increase

Develop rapidly

Reduced

5–6% of cardiac output

Bile salt pool

Membrane permeability

Plasma protein binding

Body water

Hepatic enzyme activity

Microsomal enzymatic systems

Hepatic phase I reactions

Phase II reactions

Renal blood flow

Reaches to adult value

Prolonged –Intestinal motility and proteolytic enzymatic activity: low –IgA secretion: low –Intestinal permeability: high –Protein digestion: incomplete –Protein, carbohydrate absorption: high

Intestinal transit

15–20% of cardiac output

Slow and linear

6–8

10–30th day

Gastric emptying

1–3

24 h

6–8

Birth

Gastric pH

Physiological parameter

Table 1. Summary of developmental changes in physiological and pharmacokinetic parameters.

[22]

[17,19–21]

[16–18]

[16]

[15]

[14]

[12,13]

References

Reduced (incomplete absorption of sustained release formulations)

1–3.5

Adults

[12]

1–2 (same as adults)

3rd year

Similar to adult biphasic (rapid and slow phase)

1–2

1st year


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plasma/serum concentration37,38. However, higher level of free drug in plasma has the potential to cause toxic effects39. The permeability of blood brain barrier (BBB) in neonates is also superior which many low penetrating drugs can easily breach to elicit serious adverse effects15.


Metabolism In metabolism, the structure of the drug is changed to the form that can be easily eliminated by the body. The main organ responsible for metabolism of drugs is the liver and it also undergoes developmental changes with age. Newborn neonates metabolize drugs at a rate several times lower than adults due to the relative lack of mature metabolic enzymes (phase I), particularly oxidative and conjugative systems. For example, the oxidative metabolism of phenobarbital and phenytoin is severely impaired in infants21. The glucuronidation pathway (phase II enzyme reactions) is also relatively un-developed in newborns. The insufficient metabolism of chloramphenicol by glucuronyl transferases to the inactive glucuronide metabolite caused famous Gray Baby Syndrome in newborn infants19 and the low activity of cytochrome P-450 3A resulted in higher midazolam blood levels in term infants40. Low first pass metabolism in neonates may lead to higher blood levels of certain drugs such as zidovudine20. Although most drugs are metabolized to less active forms, some may be transformed to active metabolites. An example is the conversion of theophylline to caffeine by the methylation reaction which is generally low in adults but high in term infants41. Sulfate conjugation reactions are well developed in infants and children39. Hepatotoxicity of acetaminophen, excreted via sulfate conjugation pathway in children, is considerably reduced in comparison to adults (adults use glucuronide conjugate pathway for its excretion)42. Excretion Elimination of drugs generally depends on kidney function, which also undergoes developmental changes in early childhood. Decreased clearance of drugs in newborn babies relative to adults is primarily caused by reduced renal tubular function, blood flow and the glomerular filtration22. The immature renal elimination system leads to accumulation of aminoglycosides and penicillins which necessitates less frequent dosing intervals43. Overall kidney function increases with age. Therefore, as the kidney function matures, there may be a shift from potential drug over-dose to potential under-dose for some drugs, such as theophylline. Urinary pH values differ too which may influence re-absorption of drugs22.

Formulation development The focus area of a drug in a clinical set up is its clinical effect, dose, drug interaction and adverse effects. The mode of its delivery to the pediatric patient is paid less attention. The path to dosage formulation development for adults is straightforward in that solid dosage forms are acceptable to the majority of adult patients. Pediatric population is diverse (neonates, newborn, toddlers, young children and adolescents) with individual preferences and demand for custom made dosage formulations. The desired attributes for these pharmaceutical dosage forms tailoring to individual pediatric population group needs are varied. However, practically, it is not feasible to have different pharmaceutical dosage forms for each group. Hence, an appropriate dosage form that can be administered across pediatric population is warranted.


The oral route is the preferred mode of drug administration in adults and children 46 years of age. Children 56 years find it difficult to swallow a solid dosage form and therefore liquid dosage formulations are used to administer drugs to this group. Their preference for oral route can be gaged by the fact that over 90% of pediatric dosage forms are administered by oral route. The majority of these are supplied as liquid dosage forms44 because they are easy to swallow and their dose can be easily adjusted according to the body weight or surface area. Further, the drug being already in solution form facilitates faster onset of action. The desired features and challenges offered by solid and liquid dosage forms are shown in Figure 2. The Biopharmaceutics Classification System (BCS) based on solubility and permeability categorizes drugs into four main classes45. Class I drugs (High soluble/high permeable), class II (low soluble/high permeable), class III (high soluble/low permeable) and class IV (low soluble/low permeable). High soluble drug has dose/solubility ratio 250 ml in aqueous media at 37 C over the pH range of 1.2–6.8 and high permeable drug shows extent of absorption over 90%. WHO (World Health Organisation) technical report series provides the BCS classification of drugs present in the WHO Model List of Essential Medicines46. BCS is an important pharmaceutical tool used in developing bioequivalent formulations and obtaining science based biowaivers for dosage forms. However, its application in pediatric population is questionable mainly due to the higher permeability of the intestinal mucosa of infants and young children in comparison to adults. Also physiological parameters like gastrointestinal pH, gastrointestinal motility, gastric emptying time and intestinal transport systems are different in children and adult population12,18,23. Due to their low solubility, the absorption of Class II and IV drugs is dissolution rate limited. Various strategies such as particle size reduction, polymorphic form and addition of solubility enhancer to overcome poor solubility are considered. The quality target product profile (QTPP) for a typical pediatric oral solid dosage formulation is depicted in Table 2. Critical quality attributes based on QTPP for a pediatric dosage formulation will be appearance, identification, weight/dosing volume, assay, content uniformity, taste, stability (physical, chemical, microbiological), impurities and dissolution. Liquid formulations Liquid formulations contain drug either in solution or in dispersion form in the vehicle and may be supplied as solutions, suspensions, emulsions, elixirs, syrups, spirits, tinctures, liniments, sprays, aromatic waters or aerosols. Water is physiologically compatible, devoid of toxicity and has high dielectric constant which is essential for dissolution of ionizable drugs. Therefore, water is the preferred vehicle for drug substances with high solubility and agreeable taste. Other solvents/vehicles that are used include mineral oil, polyethylene glycol, glycerine and alcohols. Usually, alcohols are avoided in pediatric formulations due to their toxicity. FDA recommends an alcohol limit of 0.5% and 5% for patients under 6 years of age and between 6 and 12 years of age, respectively47. There are safety concerns with the use of other solvents which are listed in Table 3. The intrinsic solubility of many drugs is low and cannot be formulated in liquid dosage forms at the required dosage strength. Many approaches are available to increase the aqueous solubility including pH control48, use of cosolvents49–52, complexation53, solubilization52, chemical modification54,55 and particle size reduction56. Suspension formulations should be considered when solubility cannot be modulated. By minimizing drug in solution form, suspensions improve palatability and allow increased drug load in reduced dose volume. The drug release can also be modified in

Pediatric drug development

5


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Figure 2. Features of solid and liquid dosage forms.

suspension formulations. The oral bioavailability of efavirenz is only 40–45% and administration of higher doses is required to achieve therapeutic effect. A concentrated, taste masked stable aqueous formulation of efavirenz was developed for the management of pediatric anti-HIV therapy and to prevent mouth burning syndrome associated with its use57. In certain instances presence of drug in solid state in suspension formulations imparts more chemical stability to drug substances such as acetazolamide and chlorothiazide than the solution form58,59. However, there are other factors that determine

the drug stability. For example, the hydrolysis of furosemide is pH dependent. In spite of being present in solid state, it hydrolyzed in acidic conditions but was more stable in alkaline conditions even though it was present in solution form60. The liquid dosage forms have several limitations. They are bulky and difficult to transport, require careful handling and have special storage requirements. In liquid state drug is more susceptible to degradation and has a lesser shelf life than solid dosage forms. Also, liquid dosage forms are prone to microbial growth. In addition to being a risk to the health, microbial

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Table 2. Quality target product profile of pediatric dosage form.


QTPP (quality target product profile) Attribute

TPP (target product profile)

Dosage form

Weight/dosing volumes

Liquid dosage form Dispersible tablet Powder for oral suspension ODT Chewable tablets Ingestible

Appearance

Elegant

Strength

–

Route of administration

Oral

Indications Impurities Bioavailability/Bioequivalence

Disease treatment – –

Stability

Physical, chemical and microbial stability

TPQP (target product quality profile) Palatable DT (53 min) Palatable, redispersible, stable DT 530 s, palatable, mouth feel Palatable, mouth feel 51000 mg in fixed dose combinations 53 mm in mini tabs 55 ml (children 55 years) and 510 ml (children over 5 years). Attractive color, shape, size, flavor and taste Identification, assay, compliance to content uniformity limits Palatable Dissolution, bioavailability and bioequivalence Comply with necessary guidance documents Bioequivalent to reference listed drug (for generics) 424 months

contamination may cause changes in pH, appearance, odor, smell and palatability of the preparation. Therefore, preservatives are usually added. The accurate dose measurement is another serious concern especially with potent drugs. In order to be measurable, the dose volume for liquid formulations are generally kept 55 ml (children 55 years) and 510 ml (children over 5 years)61. Bad taste is more pronounced in liquid formulations and thus sweeteners are required. The stability problems encountered in liquid dosage forms are color change, decrease in potency, increase in degradation impurities, clarity changes, difficulty in re-dispersion of settled particles in suspension, polymorph changes, microbial growth, creaming and breaking in emulsions. The instability is primarily caused by pH of the solution, type of solvent, light, temperature and excipients. pH-solubility and pH-stability profile are evaluated during formulation development to obtain optimum pH62,63. Drugs undergoing hydrolysis in a liquid dosage form can be stabilized by formulating them with buffers at pH of maximum stability. However, sometimes the components of buffer system can themselves lead to hydrolytic degradation. Codeine buffered at pH 7 using 0.05 M phosphate buffer hydrolyzed 20 times faster than un-buffered solution at the same pH62. Due to its effect on oxidation reduction potential of the drug, pH may also influence the oxidative degradation of drugs. Drugs undergoing oxidative degradation may be stabilized by antioxidants and/or stored in containers containing nitrogen or carbon dioxide. Temperature can enhance the hydrolysis rate of drugs. Photolabile drugs are stored in amber glass containers and protected from light exposure. Elastomeric and plastic containers and closures may leach nitrosamines, monomers, plasticizers, antioxidants and vulcanizing agents into the liquid dosage form. Therefore, the stability of product is determined in the final container closure system62,63. Extemporaneously prepared formulations In spite of many initiatives that have been undertaken in improving the availability of drug products to children, the demand for pediatric medicines still remains huge. The medical

Significance Ensures complete dispersion, release of drug, efficacy and ease of administration

Ease of swallowing

Patient acceptability and compliance Efficacy Ease of dosing and Patient compliance to therapy Ensure therapeutic efficacy Safety Safety and efficacy To be commerciable

practitioners usually fill this gap by extemporaneously preparing products to suit pediatric patients. Through the use of these unlicensed preparations the prescribers try to overcome the shortage of approved medicines for children63. However, there is a serious concern about their safety, efficacy and quality. These preparations are generally prepared by modifying commercially available dosage forms. The most commonly prepared extemporaneous preparations are suspensions usually prepared from tablets with the use of excipients such as antimicrobial preservatives, suspending agents and flavoring agents. Such preparations should be easily and uniformly dispersible with gentle shaking. The selection of vehicle is of primary importance in achieving this critical quality attribute. Methyl cellulose in syrup or glycerol base is commonly used vehicle. Sometimes alcohol is used if the drug is poorly soluble in water. However, it is difficult to prepare methyl cellulose suspensions which have caused a surge in the use of ready to use suspensions in USA. Ora-Plus and Ora-Sweet have been used as suspending and sweetening agents, respectively, for many extemporaneously prepared formulations. The possible adverse effects of excipients should be considered while preparing these formulations. Sucrose is known to promote dental caries on chronic use and parabens can cause hypersensitivity reactions64. These preparations should remain within their physical, chemical and microbiological specifications during storage for a specified time62. The shelf lives of extemporaneous preparations are empirically assigned or may be based on published information65. The drug is readily available for a chemical reaction in liquid dosage forms which is one of the primary reasons for using the conservative expiration date for extemporaneously prepared liquid dosage forms. The stability of excipients such as preservatives, organoleptic additives, solubilizers and viscosity enhancers used in liquid dosage forms is equally important. Extemporaneously prepared liquid dosage forms of lisinopril prepared in 1% methylcellulose, simple syrup NF (1:13) and Ora Plus-Ora sweet (1:1) was found stable for at least 13 weeks under refrigerated conditions and 8 weeks at room temperature66. Folic acid was found to retain its potency at pH 5.0–5.5 in liquid dosage formulations. Degradation rate was higher in water as

– – – Induces bronchospasm Wheezing Toxicity, banned for use in pediatric medicines

Sodium benzoate

Methyl paraben

Propyl paraben

Sorbic acid Benzalkonium chloride Sulphite Thiomersal

Benzoic acid

–Neurotoxicity, metabolic acidosis –Contraindicated in neonates and should be avoided in children 53 years Allergic reactions, increase risk of jaundice Urticaria, dermatitis

Benzyl alcohol

Preservative

–

Stearic acid

Silicon dioxide

–

–

Crospovidone

Magnesium strearate

–

Croscarmellose sodium

Celiac disease

Laxative effect

Sorbitol

Starch

–

Microcrystalline cellulose

–

Allergic reactions

Mannitol

Povidone

Induces diarrhea

Toxicities

Lactose

Excipient

Glidant

Lubricant

Disintegrant

Binder

Diluent

Function

Granisetron HCl oral solution, Ondansetron HCl orla solution, Ribavirin oral solution, Desloratadine syrup, Zidovudine syrup, Ranitidine effervescent tablets, Cefadroxil powder for suspension, Amoxicilline for oral suspension, Cefdinir for oral suspension, Cefixime for oral suspension Famotidine powder for suspension, Mycophenolate Mofetil powder for suspension, Abacavir Sulfate solution, Emtricitabine oral solution, Galantamine oral solution, Lamivudine oral solution Abacavir Sulfate solution, Emtricitabine oral solution, Galantamine oral solution, Lamivudine oral solution Oxcarbazepine oral suspension – – –

Pediatric drug development (continued )

25 * * *

10

10

5

5

5

–

Efavirenz oral solution, Fluoxetine oral solution

*

*

*

*

*

*

25

*

*

*

*

ADI (mg/kg/day)

Amoxicillin and Clavulanate Potassium powder for suspension, Cefdinir powder for suspension, Cefixime powder for suspension, Ceftibuten powder for suspension, Linezolid powder for suspension

Mefloquine HCl tablets for suspension, Thiabendazole suspension, Amoxicillin chewable tablets, Carbamazepine chewable tablets, Cetirizine chewable tablets, Lamotrigine chewable tablets, Desloratadine ODT, Loratadine ODT Cefuroxime axetil powder for oral suspension, Carbamazepine chewable tablets

Montelukast sodium chewable tablets, Loratadine ODT, Fexofenadine HCl tablets, Cefpodoxime Proxetil for oral suspension Granisetron HCl chewable tablets, desloratadine ODT, Nelfinavir Mesylate oral powder, Mefloquine HCl tablets for suspension

Lamotrigine chewable tablets, Atovaquone and Proguanil tablets, Cefuroxime Axetil powder for suspension, Clarithromycin for suspension –

Thiabendazole suspension and chewable tablets, Cetirizine HCl chewable tablets, Lansoprazole ODT, Ondansetron ODT, Busulfan tablets, Dextroamphetamine Sulfate, Dextrostat tablets, Cefpodoxime Proxetil for oral suspension, Deferasirox tablets for oral suspension, Mefloquine HCl/Lariam tablets for suspension Thiabendazole suspension, Amoxicillin chewable tablets, Cetirizine chewable tablets, Thiabendazole chewable tablets, Desloaratadine ODT, Ondansetron ODT, Amoxicillin and Clavulanate powder for suspension, Linezolid powder for suspension Mefloquine HCl tablets for suspension; Acyclovir suspension, Cetirizine chewable tablets, Desloratadine ODT Oseltamivir phosphate powder for suspension, Granisetron HCl oral solution

Marketed formulations containing these excipients

Table 3. Commonly used excipients for solid dosage formulations with their associated toxicities and acceptable daily intake (ADI)*.


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Azo dyes (tartrazine, sunset yellow and new coccine)

Should be avoided in children. Negative effect on children behavior, urticaria, bronchoconstriction, angioedema

Neurotoxicity, drug interactions CNS adverse effects Seizures, neurotoxicity, contact dermatitis, laxative effect, CNS depression, should not be administered in children 54 years

Ethanol

Propylene glycol

–

Should be avoided in pediatric patients suffering from fructose intolerance, high amounts should be avoided in patients with diabetes, chronic use may promote dental caries Contraindicated in patients with hypoglycaemia or fructose intolerance May cause osmotic diarrhea, contraindicated in hypoglycaemic patients and diabetics, IV use should be avoided Induces headaches, cross reactivity with sulphonamides, contraindicated in homozygous autosomal recessive patients, may be harmful to patients with phenylketonuria Cross sensitivity reactions with sulphonamides, poor after taste, allergic reaction (urticaria, pruritis)

Toxicities

Water

Saccharine

Aspartame

Sorbitol/xylitol

Fructose

Sucrose

Excipient

*

40

2.5

Lamivudine oral solution, Granisetron HCl oral solution, Ondansetron HCl oral solution, Ribavirin oral solution, Amantadine HCl syrup

Amoxicilline chewable tablets, Methylphenidate HCL chewable tablets, Desloratadine ODT, Ondansetron free base ODT, Ranitidine effervescent tablets, Amoxicillin and Clavulanate Potassium powder for oral suspension, Cefprozil powder for suspension, Cefuroxime axetil powder for suspension, Linezolid powder for suspension

Oseltamivir phosphate powder for suspension, Abacavir Sulfate oral solution, Amprenavir oral solution, Galantamine HBr oral solution, Lopinavir and Ritonavir oral solution, Nizatidine oral solution

–

Carbamazepine suspension, Dextromethorphan Polistirex suspension, Oxcarbamazepine suspension, Cefpodoxime Proxetil for oral suspension, Benazepril HCl tablets for suspension, Imatinib Mesylate tablets for suspension

25

*

*

*

Lopinavir solution, Dextromethorphan Polistirex suspension

Methylphenidate HCL oral solution, Nizatidine oral solution, Ondansetron HCl oral solution, Ribavirin oral solution, Ritonavir oral solution, Cetirizine HCl syrup, Desloratadine syrup, Ranitidine HCl syrup Dextromethorphan Polistirex suspension, Oxcarbazepine suspension, Ritonavir oral solution

*

ADI (mg/kg/day)

Lamivudine oral solution, Nizatidine oral solution, Ribavirin oral solution, Hydrocodone Bitartrate syrup, valproic acid syrup, Zidovudine syrup, Carbamazepine suspension, Nevirapine suspension, Carbamazepine chewable tablets, Dextroamphetamine Sulfate tablets, Stavudine powder for suspension

Marketed formulations containing these excipients

A. A. Ali et al.

Coloring agent

Solvent

Sweetener

Function

Table 3. Continued


8 Drug Dev Ind Pharm, Early Online: 1–17

– – – – –

Xanthan gum

Acacia gum

Guar gum Hydroxypropyl cellulose

Hydroxypropyl methyl cellulose

– – – –

Sodium hydroxide Hydrochloric acid Magnesium phosphate Magnesium carbonate

Suspending agent

– – –

Ascorbic acid Acetic acid Citric acid

Carbamazepine suspension, Dextromethorphan Polistirex suspension, Phenylephrine Tannate suspension, Thiabendazole chewable tablets, Amoxicillin and Clavulanate Potassium powder for suspension, Azithromycin for oral suspension Nitazoxanide powder for suspension, Thiabendazole suspension, Thiabendazole chewable tablets, Dextroamphetamine Sulfate tablets Cefdinir powder for suspension, Methylphenidate HCL chewable tablets Azithromycin for oral suspension, Cefpodoxime Proxetil for oral suspension, Atovaquone and Proguanil HCl tablets Nelfinavir Mesylate oral powder for suspension

Didanosine powder for suspension, Azithromycin for suspension, Emtricitabine oral solution, Ranitidine HCl syrup Oxcarbazepine oral suspension Cetirizine HCl syrup Amantadine HCl syrup, Desloratadine syrup, ranitidine HCl syrup, Zidovudine syrup, Carbamazepine suspension, Desloratadien ODT, Cefdinir powder for suspension Galantamine HBr/oral solution, Nevirapine suspension – – Lansoprazole ODT delayed release

Topiramate sprinkle capsules Clarithromycin powder for suspension, Nevirapine suspension –

– – – –

Lansoprazole ODT delayed release, Ciprofloxacin microcapsules for suspension Dexmethyl-phenidate sprinkle powder in capsules

– –

Sodium phosphate

Desloratadine ODT

–

pH modifier

–

– – – – – –

Mint Tutti fruiti Peppermint Vanilla Buble gum Strawberry

Abacavir sulfate oral solution, Lamivudine oral solution, Cetirizine syrup, Acyclovir suspension, Amoxicilline chewable tablets, Azithromycin for oral suspension Lamotrigine chewable tablets Azithromycin for oral suspension, Cefprozil powder for suspension, Amoxicilline chewable tablets Efavirenz oral solution, Fluoxetine HCl oral solution, Loratadine ODT – Amprenavir oral solution, Lopinavir and Ritonavir oral solution, Amoxicilline chewable tablets Azithromycin for oral suspension Nizatidine oral solution, Desloratadine syrup, Amoxicillin drops for suspension Ondansetron HCl oral solution, Lansoprazole ODT, Cefdinir powder for suspension, Cefixime powder for suspension, Ciprofloxacin microcapsules for suspension, Nitazoxanide powder for suspension

*

–

Pediatric drug development (continued )

*

1500

*

10.0

* * * *

* * *

*

* * *

* *

*

*

* * * * * *

* *

*

*

* *

– –

Fibrosing colonopathy

– –

Blackcurrent Cherry

Methacrylic acid and ethylacrylate copolymer Butylated methacrylate copolymer Methacrylic acid Ammonium methacrylate copolymer Cellulose acetate carbomer Ethyl cellulsoe

–

Banana

–

–

Coating material

Flavoring agent

Quinoline dyes (quinoline yellow) Triphenylmethane dyes (e.g. FD&C blue) Erythrosine dyes


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9

* –

*The ADI levels are either not specified or the levels necessary to achieve a desired effect were not considered to represent a hazard to health by WHO. *References: [124–130].

Lansoprazole delayed release for oral suspension

– –

* * Ciprofloxacin microcapsules for suspension, Mycophenolate Mofetil powder for suspension Lopinavir and Ritonavir oral solution

– –

Sodium lauryl sulphate Polyoxyl 35 castor oil (Cremophor EL) Lecithin Polyoxyl 40 hydrogenated castor oil (Cremophor Docusate sodium

* *

Dextromethorphan Polistirex suspension, Nevirapine suspension, Cefadroxil powder for suspension, Cefprozil powder for suspension, Ceftibuten powder for suspension Topiramate sprinkle capsules, Deferasirox tablets for suspension Ritonavir oral solution Liver/kidney failure

25.0

compared to sorbitol, glycerine and propylene glycol67. Similarly, Enalpril maleate liquid formulations prepared from tablets were found to retain 98% of the initial enalpril maleate concentration in sugar containing and sugar free vehicles at 4 C and 25 C for 30 days68. Many extemporaneously prepared suspensions have demonstrated therapeutically effective concentration and were found stable69. Solid dosage forms

Polysorbate 20/80

–

– –

Tragacanth Carboxymethyl cellulose sodium Sodium alginate


Surfactant

*

Dextromethorphan Polistirex suspension Famotidine powder for suspension, Linezolid powder for suspension, Nitazoxanide powder for suspension, Acyclovir suspension Nizatidine oral solution

Marketed formulations containing these excipients Toxicities Excipient Function

Table 3. Continued


* *

A. A. Ali et al. ADI (mg/kg/day)

10

Tablets and capsules are portable, show better stability profile and dose accuracy as compared to the liquid dosage formulations. Taste can be easily masked by film or sugar coating. Usually children 56 years of age do not accept them easily whereas children 46 years may experience swallowing difficulty which necessitates control over tablet size. Scoring/breakline on tablets facilitate in breaking/splitting them into smaller fractions for dose adjustment and ease in swallowing. Each fraction should deliver the minimum therapeutic dose as indicated on the approved drug product labeling. This is ensured by compliance of each portion to the ‘‘Uniformity of Dosage Units’’ test70. Food and Drug Administration (FDA) recently issued a draft guidance document on tablet scoring to address the need for consistent scoring between generic and Reference Listed drug (RLD) product71. Thomson et al. observed that pre-school children were able to swallow mini-tablets of 53 mm diameter with some water72. Similarly, mini-tablets and multiparticulate formulations permit flexible dosing, drug release modification and taste masking opportunities. They can be consumed with or without water and may be mixed with some food. However, sophisticated technology needed for their manufacturing increases their cost significantly. Different types of tablet dosage forms are available each with specific characteristics as depicted in Figure 2. Orally disintegrating tablets (ODTs) disperse or melt within seconds on coming in contact with saliva and thus overcome swallowing problems73. No water is needed for their administration74. A post marketing surveillance carried from 2008 to 2010 in Japan indicated improved efficacy, safety and palatability of amlodipine ODT75. Ondansetron ODT was found useful for the treatment of gastroenteritis and dehydration in 6 months old children76. Approximately 90% of the patients aged 5–11 years undergoing adenotonsillectomy dosed preoperatively ondansetraon ODT found its taste good with significant reduction in incidence of vomiting77. These dosage forms consist of either soft porous matrix or low hardness tablets with high amount of superdisintegrants. They are highly moisture sensitive and require specialized peel off packaging to ensure physical integrity and stability. Such specialized packaging needs are met by using sophisticated packaging equipment such as robotic hand in Cima’s PakSolv technology78. Blister and bottle packaging is the most commonly used. However, the regular push through blister packaging may not work in most of the ODTs and hence peelable closures are used. Rigid multilayer foil based materials are commonly used to protect dosage form integrity79. The challenges in developing ODT are palatability79, mechanical strength80,81, fast disintegration, hygroscopicity82, drug solubility83, drug loading84, size of tablets85 and packaging. Mannitol is an excipient of choice in ODT and chewable tablets for its good compressibility, sweetness, low hygroscopicity and slower dissolution kinetics. It is also available as directly compressible material. Mannitol based ready to use excipients LudiflashÕ (BASF SE, Ludwigshafen, Germany), Parteck ODTÕ (Merck Millipore, Darmstadt, Germany), Pearlitol FlashÕ (Roquette Pharma, France), Pharmaburst 500Õ (SPI Pharma, Les Vallons, France) and Prosolv ODTÕ (JRS Pharma, Rosenberg, Germany), were used to prepare directly compressed



DOI: 10.3109/03639045.2013.850713

mini-tablets for pediatric use. ODT could be produced with all the excipients studied. Ludiflash showed better crushing strength and wetting results86. In another study pellets prepared from Ludiflash improved the swallowing and palatability of ibuprofen and paracetamol ODTs87. Solid dispersions of water soluble highly bitter drug pryidostigmine bromide were prepared using eudragit EPO and incorporated into the ODTs. The bitter taste was masked below the threshold value and tablets disintegrated rapidly in the oral cavity88. The USP apparatus 2 with a paddle speed of 50 rpm is considered most suitable apparatus for dissolution testing of ODT89. The pH sensitivity of polymer coatings should be considered in dissolution method development. The effect of taste masking approaches such as complexation and coating on dissolution and pharmacokinetic profile of ODT’s should be evaluated89. Orally disintegrating tablets of various drugs are available commercially, e.g. ZydisÔ (R. P. Scherer Inc., Somerset, NV), OraSolvÔ (Cima Labs Inc., Brooklyn Park, MN), WOWTABÔ (Yamanouchi Pharma Technologies Inc., Palo Alto, CA) and Films (LTS Lohmann, West Caldwell, NJ). The technologies for preparing ODT include Freeze-Drying/Lyophilization (ZydisÔ (Catalent, Somerset, NJ), QuicksolvÔ (Janssen Pharmaceutica, Titusville, NJ)), Molding (Fast meltÔ (Athena Pharmaceutiques SAS, Saint Cloud, France), ZipletsÔ (Eurand-Aptalis Pharmaceutical Technologies Inc, Bridgewater, NJ)), Compaction (OrasolvÔ (Cima Labs Inc., Brooklyn Park, MN), DurasolvÔ (Cima Labs Inc., Brooklyn Park, MN)), disintegrant addition, Sublimation, Spray Drying, Mass Extrusion, Cottoncandy process (FlashDoseÔ, Fuisz Technologies, Chantilly, VA) and NanoCrystalÔ (Elan Pharmaceutical Technologies, PA) technology. These technologies are complex and proprietary which increase the cost of their production in comparison to conventional tablets. Advantages and disadvantages of these technologies were listed comprehensively by Hirani et al.90. Fast dissolving films also known as oral wafers have quickly emerged as an alternative to the OTC medicines. They are also placed directly on the tongue where they disintegrate in seconds. They stick to the oral mucosa and hence are unlikely to be spat out. Usually they range from 2 to 8 cm2 area with a thickness of 20–500 mm76. Their size confers many advantages including dose accuracy, portability, less choking risk, improved bioavailability and can be consumed without water. These attributes make them suitable for pediatric population. These films should be robust enough to handle wear and tear during transportation. Polymers and plasticizers form the backbone of these films. Ondansetron 4 and 8 mg (ZuplenzÕ , Monosol Rx, LLC, Warren, NJ), fast dissolving films are available commercially for use in children of 44 years of age. Other products available in fast dissolving films are Orajel Kids (Menthol/pectin, product for dental pain), Sudafed (phenylephrine or pseudoephedrine product for nasal congestion), Suppress (Menthol), TheraFlu (combination product of pain reliever, anti-pyretic and decongestant), Triaminic (children’s anti-tussive product)76,91,92. Dispersible tablets are manufactured with commonly available technology and packaging. These tablets must disintegrate within 3 min in water into a uniform dispersion. Dispersible tablets of anti-retroviral therapy were preferred by caregivers and children and preference increased with the passage of therapy93. Dispersible tablets for WHO recommended zinc treatment for childhood diarrhea were received well94. Taste of these tablets should be adequate for acceptability. They have relatively less physical strength and are more sensitive to moisture. Hence tablets should be packed in stronger packaging such as polyvinylidene chloride, polychlorotrifluoroethylene and aluminium foil.

11

Effervescent tablets like dispersible tablets are dissolved or dispersed in water before administration95,96. They contain acid and carbonates or bicarbonates which react in the presence of water to release carbon dioxide96. Effervescence creates a palatable sparkling solution which may enhance the drug permeability due to carbon dioxide bubbling effect on the intestinal epithelium97. Ekenved et al.98 found that the absorption of acetylsalicylic acid form effervescent tablets was rapid. These tablets should be stored in tightly closed containers and desiccants may be needed in some cases. Excipients used should have low moisture, good solubility and wetting properties. These tablets have to be manufactured at low humidity (530% RH) and temperature (525 C)99. Chewable tablets are also used to administer drugs to children of 2 years or older under elderly supervision to ensure tablets are chewed not ingested100. They are safe, well tolerated, palatable, stable, portable, can be precisely dosed and do not need water for administration100. Didanosine chewable tablets allowed higher dosing precision in children as compared to zidovudine capsules101. Safety of chewable tablets in children of 42 years old is documented100. The critical quality attributes of chewable tablets among other attributes include taste and mouth feel. Different grades of microcrystalline cellulose such as Avicel CE-15 are available as directly compressible material102. Microcrystalline cellulose along with mannitol enhance smooth feel, eliminate grittiness and reduce tooth packing. More than 60 chewable tablet formulations are approved for use in USA. Aspiration injury due to chewable tablets is rare100. These tablets may be swallowed by the patient without chewing and hence they should be formulated such that on chewing or swallowing they meet the quality control test requirements for conventional tablets including dissolution test103. Chewing gums have been developed for dimenhydrate and fluoride104. The minimum chewing time required to ensure complete drug release should be determined and mentioned in the label. Since they are not meant to be swallowed they can be recommended for children 46 years. Children tend to confuse them with candies and carry a risk of consuming a large number of these dosage forms. Parents or caregivers should be adequately warned about the danger of excessive consumption of these tablets. Marked increase in retinol and retinyl palmitate concentration was noted after overdose of vitamin A chewable tablets105. Buccal and sublingual tablets are usually not recommended for children because their contact time with saliva is long. Powders (or granules) for oral suspensions are dispersed in the prescribed amount of water prior to oral administration. Powder (granules) can also be sprinkled on food or sauce before administering it. The excipients usually present in these formulations include sweeteners, colorants, stabilizing agents, suspending agents and preservatives. Single dose sachets are meant to be consumed immediately whereas multiple dose bottle packs are usually stored at 5–8 C till the complete consumption of medicine. Multiple dose formulations may need antimicrobial preservatives and should be evaluated for in-use stability1,10.

Excipients Taste of medication is an important CQA for pediatric formulations. The organoleptic appeal of a pediatric formulation is usually enhanced by the addition of flavorants, colorants and sweeteners. Risk of non-compliance to the dosage regimen due to unacceptable taste increases significantly in therapies for chronic ailments. The flavor should be compatible with the color and taste in conveying the correct message such as lemon tasting formulation should be colored yellow and lemon flavored106. Colorants are added to make medication attractive. Like other excipients,


12

A. A. Ali et al.

they should be thoroughly evaluated for their compatibility with other formulation components as incompatibility of certain dyes with calcium, magnesium and aluminium containing substances is known107. The shade and stability of dyes is affected by pH, microbial activity and exposure to light107. The use of colorants is regulated by the amendments effected in 1960 in Federal Food, Drug and Cosmetic Act of 1938108. The preference for a flavor varies with individual and age. Children seem to like sweet candy fruit flavors whereas adults like sweet tart flavored preparations. A bulk portion of liquid dosage forms consists of sweetening agents. Most commonly used sweetener, sucrose, when used 465% w/w inhibits the microbial growth. It is stable at pH 4.0–8.0, however it tends to crystallize around the neck of bottles leading to ‘‘Cap Lock’’109. Sorbitol and glycerine reduce its tendency to crystallize. Long term use of sucrose is discouraged as it may cause dental caries and may complicate the management of diabetes. Liquid glucose is another commonly used sweetener consisting of dextrose, dextrins, maltose and water. It is obtained by incomplete hydrolysis of starch and has a characteristic odor and flavor. Its method of manufacture is easily controllable and hence batch to batch variability is insignificant. A new generation of sweeteners such as sucralose, acesulfame and stevia overcome the issues of metabolism and toxicity associated with traditional sweeteners saccharine, aspartame and cyclamates (Table 3). Sucralose, acesulfame and stevia are 600, 130 and 30 times sweeter than sucrose, respectively. These sweeteners are heat stable and exhibit stability over wide pH range110. Besides enhancing organoleptic properties, excipients are incorporated to ensure physical/chemical stability, precision and accuracy of dosing, improve bioavailability, control release and aid in manufacturing. Antimicrobial preservatives are usually required in aqueous liquid preparation such as syrups, emulsions, suspensions and some semisolid preparations. Preparations containing high alcoholic or hydro-alcoholic content may not require preservatives. The preservatives selected should be safe, stable, compatible with other formulation ingredients including container closure system and have enough water solubility to achieve required concentration in the aqueous phase in a multiphase system. The un-dissociated form responsible for preservative action depends on the pH of the formulation. Benzoic acid and other acidic preservatives are un-dissociated in acidic pH whereas alkaline preservative remain un-dissociated in alkaline pH111. Some excipients may physically hold preservatives and make them unavailable for action112. Pediatric formulations are often more complex due to taste masking, dose volume, delivery and aesthetic requirements which demand incorporation of a broad range of excipients. For instance, a typical liquid dosage forms may contain solvent/vehicle, cosolvent, preservatives, viscosity enhancers, wetting agents, bulking agents, taste masking agents and other excipients as dictated by the drug characteristics. Higher number of excipients results in increased potential for drug-excipient and excipientexcipient incompatibility. Preferably, formulation should contain as minimum excipients as possible. One opportunity to achieve this is by sprinkling the medication on juice, sauce or cocktail of children’s choice thereby obviating the need for adding taste masking agents. Dose volume in such instances may be minimized by increasing the solid fraction of the formulation113 for achieving suitable dilution. The stability of drug in recommended diluents must be proven and such diluents must have been shown to improve the taste of formulations. Excipients are classified into GRAS (Generally regarded as safe) approved, intermediate and newer compounds114. GRAS excipients have been used in the pharmaceutical industry for a


long time. Intermediate represent the structural modification of the existing approved excipients whereas newer compounds have never been used before. Pharmacokinetic variations between pediatric and adult population should be considered in the selection of excipients for pediatric formulations. The acceptable daily intake (ADI) expressed as mg/kg/day is determined by dividing NOEL (no observed effect level) by safety factors taking into consideration inter individual variation within the same species and difference between tested animals and humans115–129. PDE (permitted daily exposure) determined by similar approach for solvents, is used together with ADI for risk assessment of excipients in drugs. The high permeability of BBB in neonates and infants resulted in higher concentration of propylene glycol causing several fatalities in pediatric population116,117. The higher blood level of benzoic acid (oxidation product of benzyl alcohol) due to its poor conjugation with glycine caused Gasping Syndrome complications like metabolic acidosis, seizures, encephalopathy, thrombocytopenia, renal dysfunction and deaths in pediatric patients118,119. Oral liquid with ethanol should not be given to neonates. The ICH limit for residual solvents like ethanol may not be acceptable to children. Allergic reactions such as asthmatic reactions, rashes and abdominal upset due to sulfites are not uncommon120. Aluminium containing salts or substances accumulate in patients with reduced kidney function121. The toxicological risk associated with excipients used in liquid formulations is higher than the excipients used in solid formulations. Like drug substances excipients may also degrade and contain trace amounts of their degradation products which may be carried over to the drug product. The stability of the formulations may be impacted due to these degradants and hence should be considered during product development. Povidone and lactose are known to contain trace amount of peroxides and aldehydes, respectively. N-oxide degradation product of raloxefen was increased in presence of povidone122. Maillard’s reaction leading to browning color of the product is well known interaction of lactose with drugs containing primary and secondary amine123.

Taste masking Each taste bud contains 50–100 taste cells130,131. Taste sensation is elicited when drugs dissolve in saliva and interact with taste receptors (surface proteins) or ion channels (pore like proteins)132. Salt and sour tastes interact with ion channels and sweet and bitter trigger surface protein responses. The concentration of positive ions increases due to the taste receptor stimulation. The varying ion concentration initiates electrical changes in the negatively charged taste cells causing generation of chemical signals. Neurotransmitters are released due to this process and are perceived by brain as taste130,131,133,134. Several observations have been made to correlate taste of the drug to its functional group. (Table 4) The adults and children perceive taste differently134,135. Therefore, the taste of a pediatric formulation should ideally be evaluated in children. The cultural, regional and age differences in taste perception are not uncommon. For example in USA, bubble gum and grape flavors are preferred whereas the majority of population in Europe likes citrus and red berry flavors. These differences should be considered while selecting flavoring and sweetening agents. According to EU adhoc committee, the taste masking studies should be performed in adults wherever possible. Though phase I clinical studies performed in adults provide useful information but the data cannot be directly extended to children136–138. However, healthy children can participate in palatability testing for a new


DOI: 10.3109/03639045.2013.850713

13

Table 4. Relationship of drug functional group to the taste and preferred taste masking flavors used.


Active pharmaceutical ingredient with functional group

Taste observed

–Cl

Salty taste

–Br

Bitter and salty

–OH

Sweetness

–RCOOR’ (alcohols, and aldehydes) –N –COOH Iron containing preparations

Pleasant taste and odor Bitter and sweet Acid Metallic

General observation Low molecular weight salts – salty High molecular weight salts – bitter Increase in –OH groups increases the sweetness – Alkaloids (quinine) – bitterAspartame – sweet

flavored medicine when the study is ‘‘swill and spit’’ type taste testing for drugs with known safety profile139. There are many practical and technical challenges in performing taste testing in children including designing questionnaire, reliability of pediatric response and interpretation of results140. Different approaches used in masking the unpleasant taste are; adding sweeteners, flavorants, complexation141, particle coating142, ion exchange143, multiple unit coated system and encapsulation of drug144,145. Fluid bed coating is usually used to prepare multi-particulate granules or pellets146. Taste perception can be suppressed either at mouth or at brain level147. Alternatively, source of undesirable taste can be eliminated by techniques like encapsulation. Two different substances may compete for the same taste receptors or interfere with taste transduction mechanism and enhance or suppress each other’s taste. Sodium and zinc salts when used at certain concentrations, suppress bitter tasting substances148–150. Strong tastant such as angelica oil aroma can completely mask weaker sweet tasting substances by suppressing their taste perception in brain149. Cooling sensation of some flavoring agents may numb taste buds which can mask bitterness of certain drugs151. Flavors with different mechanisms of action may be combined to achieve the synergetic taste masking effect. Taste receptor desensitizer, sodium phenolate, was used with chocolate flavor to mask aspirin taste152. Flavoring and sweetening agents are effective taste masking excipients for less to moderately bitter drugs. For highly bitter drugs these must be used along with other taste masking approaches. The nature of the ODT dosage form demands use of minimal quantity of excipients which makes taste masking a major challenge in these dosage forms. Flavoring and sweetening agents alone may be of little value in these dosage forms hence other taste masking strategies such as, complexation, particle coating, microencapsulation and use of insoluble salt may be considered for preventing exposure of the drug to the tongue151. Taste masking strategies used in ODT have been reviewed153. Children are fond of sweetness. Sweetened formulations can increase the compliance to dosage regimen. Due to the risk of developing dental caries, sucrose should be replaced in chronic therapies with sugar free formulations. Neohesperidine dihydrochalone extracted from Citrus aurantium is effective bitterness suppressor154. Children are attracted to bright colors and when used with right flavors and sweeteners will further enhance compliance. However, many colors are known to elicit hypersensitivity reactions and these should not be used unless necessary and product label should clearly list them125,155.

Taste masking flavors Cinnamon, orange, raspberry, apple, vanilla, apricot Cocoa-flavored vehicles, cherry, walnut Berry, vanilla, grapefruit – Cocoa-flavored vehicles Citrus, orange, cherry mint, barries, gurana

Poor mouth feel (grittiness) can make otherwise excellent preparation unacceptable. The texture can be improved by using correct viscosity modifiers. The coating prevents physical contact of the drug with the taste receptors. Due to the inherent complexity of the process, it should be resorted to only when other simpler taste masking approaches do not work. Microencapsulation is the process of coating drug with polymeric film using coacervation and spray drying techniques. Coating materials used for this purpose are starch; eudragits, povidone, hydroxypropyl cellulose, gelatin, methylcellulose, ethyl cellulose and hydroxyl propyl methyl cellulose156–161,144. The polymers which are insoluble at salivary pH 6.8 but dissolve at gastric pH 1.2 or at higher pH 47.5 are ideal candidates. Eudragit E100 coated indinavir microparticles prepared by double emulsion solvent diffusion considerably improved the taste of a bitter drug162. The polymer coated microparticles dissolved in the gastric medium while remaining unchanged above pH 7. Besides their use in sustained release and drug stabilization, ion exchange resins have found application also in taste masking. The taste of ranitidine and paroxetine was masked using this technique163,164. These are synthetic inert organic polymers to which insoluble groups are attached. They exchange their labile ions with the drug ions present in solution and form insoluble drug resonates with virtually no taste. Copolymer of styrene and divinylbenzene are most commonly used polymers165. Cyclodextrins provide host cavities for the guest drug molecules in inclusion complexation process166. In addition to decrease in drug solubility, the drug–cyclodextrin complex minimizes its contact with the saliva. The strength of drug– cyclodextrin complex determines the effectiveness of taste masking. An association constant value of 101–104 mol is ideal. Sucrose potentiated the effect of hydroxypropyl-beta-cyclodextrin (HP-b-CD) by increasing the stability constant of the complex167. Bitter taste of bromoisovaleryl urea was successfully masked by this approach168. Complexation of atorvastatin with hydroxypropyl-beta cyclodextrin improved its stability, bioavailability and mouth feel169. Insoluble drugs are generally tasteless unless they are extremely bitter so much so that they elicit taste sensation in parts per million (PPM) levels. In case of prodrugs, chemical modification of drug molecule alters its interaction with taste receptors besides affecting solubility. Taste evaluation techniques include panel testing in humans, frog taste nerve response measurement, taste sensor (artificial tongue) and spectrophotometric evaluation. An electronic tongue provides information on bitterness levels and global taste


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fingerprint170. The sensor system of an electronic tongue was found to detect small changes in the concentrations of commonly used sweeteners, sucrose, aspartame, sucralose and neohesperidin dihydrochalcone171.

10.

Summary

11.

There is an urgent need to extend recent pharmaceutical developments to pediatric population. ‘‘Make Medicine Child Size’’ like initiatives together with other relevant guidance documents from USFDA and EMA (European Medicine Agency) have provided the necessary impetus to the pediatric drug development program, a step forward in mitigating risk by reducing reliance on extemporaneously prepared preparations. The diversity of the pediatric age group, special taste preferences, anatomical and physiological differences between children and adults, ethical challenges in clinical studies and producing stable and therapeutically effective dosage formulation present complexity in pharmaceutical development. Oral route is the preferred mode of administration with liquid and solid dosage formulations vastly preferred over other dosage forms. Appropriate consideration should be given to ease of dosing, dose flexibility, dosing volume, selection of safe excipients and their quantities with an objective to prepare stable, palatable and therapeutically effective formulation.

12. 13.

14.

15. 16. 17. 18.

Declaration of interest

19.

The authors report no declarations of interest for this article content. This review received no specific grant from any funding agency in the public, commercial or not-for-profit sectors

20. 21.

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