oral solid dosage forms for children
TRANSCRIPT
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ORAL SOLID DOSAGE FORMS FOR CHILDREN
PRESENTED BY
DIPESH KHANAL
M.PHARM
1st year 2nd semester
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Overview Infants and children are far different from
adults in terms of societal, psychosocial, behavioral, and medical perspectives.
More than 100 years ago Dr. Abraham Jacobi, the father of American pediatrics, recognized the importance of and need for age-appropriate pharmacotherapy when he wrote, “Pediatrics does not deal with miniature men and women, with reduced doses and the same class of disease in smaller bodies, but . . . has its own independent range and horizon.”[1]
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OVERVIEW CONTD.. Moving back to historical dates associated to
drug therapy, plenty of adverse drug reactions has been reported, as summarized.
In 1937, 107 people– primarily children–died after taking elixir of sulphanilamide to treat streptococcal infection. Sulphanilamide was not very water soluble, a chemist at Massengill Co. found that it dissolved well in diethylene glycol (more commonly known as antifreeze), which is now known to be highly toxic.
Retinoic acid embryopathy
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OVERVIEW CONTD.. In 1956, an excessive mortality rate and an
increased incidence of kernicterus among premature babies receiving a sulfonamide antibiotic compared with those receiving chlortetracycline.
low birth weight infants exposed to a parenteral vitamin E formulation.
The gasping syndrome, in infants who received excessive amount of benzyl alcohol [2]
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GROWTH AND DEVELOPMENTAL ASPECTS
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AGE CLASSIFICATION Based on the guideline on clinical investigation of medicinal products in paediatric population age group can be classified as Pre-term newborn infants (<37 weeks of gestational age);Term newborn infants (0–27 days);Infants and toddlers (1 month to 23 months);Children (2–11 years);Adolescents (12–18 years).
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Contd.. These age ranges reflect biological changes
the changes after birth; the early growth spurt; gradual growth from 2-12 years; the pubertal and
Adolescent growth spurt and development towards adult maturity. The age group 2-11 years could be further subdivided in terms of the child’s ability to accept and use different dosage forms, e.g. into pre-school children (2-5 years) and school children (6-11 years),[3]
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MAJOR DEVELOPMENTAL PERIOD
Prenatal development / prematurity Birth - Rapid postnatal development Prepuberty Puberty Postpubertal adolescence
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Variations in the pattern of pubertal changes in girls
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Variations in the pattern of pubertal changes in boys [4]
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VARIATIONS AMONG AGE GROUP The category of preterm newborn infants is
not a homogeneous group of patients. A 25-week gestation, 500-gram (g)
newborn is very different from a 30-week gestation newborn weighing 1,500 g.
A distinction should also be made for low-birth-weight babies as to whether they are immature or growth retarded.
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Important points to be considered in these patients Gestational age at birth and age after birth. Immaturity of renal and hepatic clearance mechanisms Protein binding and displacement issues (particularly bilirubin). Penetration of medicinal products into the central nervous system Rapid and variable maturation of all physiologic and pharmacologic processes leading to different dosing regimens with chronic exposure. Small blood volumes (a 500-g infant has 40 mL of blood)
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PHARMACOKINETIC ISSUESABSORPTION A therapeutic agent administered by means
of any extravascular route must overcome chemical, physical, mechanical, and biologic barriers in order to be absorbed.
Developmental changes in absorptive surfaces such as the gastrointestinal tract, skin, and pulmonary tree can influence the rate and extent of the bioavailability of a drug.
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At birth, newborns have an alkaline gastric pH (pH 6–8).
Gastric acid production increases over the next 24–48 h to achieve adult pH levels (pH 1–3).
Following this initial burst of hydrochloric acid secretion, gastric acid production declines and gastric acidity remains relatively low in the first months of life.
Postnatal increases in gastric acid production generally correlate with postnatal age and, on a per kg basis, adult levels are approached by 2 years of age.
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Thus enhanced bioavailability of weakly basic compounds, but reduced bioavailabilities of weakly acidic compounds.
Certain compounds require pancreatic exocrine and biliary function for adequate absorption.
New-born have immature pancreatic and biliary function at birth.
The levels of most pancreatic enzymes are significantly reduced , and bile formation, bile acid pool size (50% adult values), bile acid synthesis and metabolism, and bile acid intestinal absorption are all reduced in the newborn.[5]
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Gastro-intestinal transit Little is known about how any formulation, let
alone multiparticulates would transit through the paediatric gastric-intestinal tract.
most of the gastric emptying data available are from infants suffering from Gastro-Oesophageal Reflux Disease (GORD) and much of the intestinal transit information is from paediatric patients under investigation for constipation.
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Swallowing There are a number of anatomical differences which
contribute to young children’s difficulty of swallowing solids.
Before 4 or 5 months of age, infants possess an extrusion reflex that enables them to swallow only liquids. This is a protective mechanism where the tongue is thrust forward to prevent any nonliquid food or objects from entering the oral cavity.
Anatomical factors (the neuromuscular coordination development is not sufficient to allow infants to eat solid foods) but also nutritional factors (there can be an increased risk of infections and allergies with early introduction of solids but it has to be balanced with infant’s developmental nutrient and energy requirements.
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A gag reflex of varying degrees is apparent up until about seven to nine months of age.
Hence from birth, liquid medicines seem to be the dosage form of choice whereas by 6months of age, children can physiologically and anatomically swallow thick/liquid semi-solid formulations which may include e.g. multi-particulates in soft food or beverages.
There is no clear evidence based answer for the age at which children can swallow a monolithic dosage form.
Five to six years of age is often mentioned although younger children can do it with some training or if the tablet is small e.g. with a diameter of 3mm.
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Oesophageal transit
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Gastric emptying time The structure of the stomach is largely
developed by 14 weeks of gestation and motility and secretion by around 20 weeks
Gastric motility and emptying develop further when the infant swallows amniotic fluid from around 28 weeks of gestation.
There are no contractions of the stomach to propel solids during the first few days of life and hence gastric emptying can be delayed immediately after birth in both term and pre-term infants.
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Intestinal transit Pre-term infants generally have longer intestinal
transit times than infants born at term. The intestinal transit time of a pre-term infant
decreases with enteral feeding (milk) and on increasing gestational age.
Despite the fact the intestine grows, the issue of when intestinal transit time reaches adult values is less clear.
No difference in intestinal transit time are found in children aged from 2 months to 3 years versus 3 to 12 years (with large pellets of 5mm which were swallowed with milk having an average whole-gut-transit-time of 23.7±3.08 and 25.4±3.7 h
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[6]
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Distribution Body water/fat The proportion of body water per kg of body weight
is high in the first weeks of life and gradually declines whilst proportion of body fat is low (especially in pre-term neonates)
and increases until maximum proportion is reached at about 1 year of age.
A greater proportion of body water is extracellular in young infants. Thus, water soluble substances (e.g. aminoglycosides) will have a higher volume of distribution in the very young whilst fat soluble substances (e.g. diazepam) may be expected to have their greatest volume of distribution in older infants and toddlers.
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Protein binding Protein binding is generally reduced in
neonates and infants so that a greater proportion of highly protein-bound drugs are free and active in plasma.
During the neonatal period competing substances such as bilirubin and free fatty acids may also influence or be affected by drug-protein binding.
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Metabolism In general, clearance of substances metabolised in
the liver is greater in children than in adults, requiring higher doses per kg body weight.
The main pathway for phase 1 reactions is oxidation using the cytochrome P450 dependent (CYP) enzymes and these enzymes are generally immature at birth reaching maximum values at about 2 years of age.
Hepatic clearance of some substances will be greater on a per kg body weight basis than for adults e.g. carbamazepine, theophylline.
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Phase 2 reactions include glucuronidation and sulphation.
Enzymes involved develop at different rates such that metabolism of substances may vary considerably in infancy both qualitatively and quantitatively.
Neonates are unable to conjugate benzoic acid efficiently and this is of great importance to the use of benzyl alcohol as an excipient in this age group since its metabolite benzoic acid can accumulate and is toxic.
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Renal elimination Maturation of renal function is a dynamic process
that begins during fetal organogenesis and is complete by early childhood.
The glomerular filtration rate is approximately 2 to 4 ml per minute per 1.73 m2 in term neonates, but it may be as low as 0.6 to 0.8 ml per minute per 1.73 m2 in preterm neonates.
The glomerular filtration rate increases rapidly during the first two weeks of life and then rises steadily until adult values are reached at 8 to 12 months of age.
Similarly, tubular secretion is immature at birth and reaches adult capacity during the first year of life.[1]
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Physiologic changes in multiple organs and organ systems during development are responsible for age-related differences in drug disposition.
As reflected by Panel A, the activity of many cytochrome P-450 (CYP) isoforms and a single glucuronosyltransferase (UGT) isoform is markedly diminished during the first two months of life.
In addition, the acquisition of adult activity over time is enzyme- and isoform-specific.
Panel B shows age-dependent changes in body composition, which influence the apparent volume of distribution for drugs.
Infants in the first six months of life have markedly expanded total-body water and extracellular water, expressed as a percentage of total body weight, as compared with older infants and adults.
Panel C shows the age-dependent changes in both the structure and function of the gastrointestinal tract. As with hepatic drug-metabolizing enzymes (Panel A), the activity of cytochrome P-450 1A1 (CYP1A1) in the intestine is low during early life.
Panel D summarizes the effect of postnatal development on the processes of active tubular secretion, represented by the clearance of para-aminohippuric acid and the glomerular filtration rate, both of which approximate adult activity by 6 to 12 months of age.
Panel E shows age dependence in the thickness, extent of perfusion, and extent of hydration of the skin and the relative size of the skin-surface area (reflected by the ratio of body-surface area to body weight). Although skin thickness is similar in infants and adults, the extent of perfusion and hydration diminishes from infancy to adulthood.
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EXCIPIENTS CONSIDERATION As indicated excipients should be
pharmacologically inactive, they may cause adverse effects when used in paediatric formulation.
It has to be kept in mind that the physiology of neonates and infants differs considerably from that of adults.
They may not be able to metabolise or eliminate an ingredient in a pharmaceutical product in the same manner as an adult
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Preservatives (benzyl alcohol/ benzoic acid/ benzoates)
Benzyl alcohol is commonly used as a preservative in many injectable drugs and solutions.
It must not be given to neonates due to their immature metabolism.
A number of neonatal deaths and severe respiratory and metabolic complications in low-birth-weight premature infants have been associated with use of this agent in bacteriostatic saline intravascular flush and endotracheal tube lavage solutions.
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ARTIFICIAL SWEETNERS Sucrose: Sucrose is the most commonly used
sweetening agent. It is a disaccharide that is readily hydrolysed in the intestine to the absorbable mono-saccharides fructose and glucose.
It should be avoided for paediatric patients suffering from hereditary fructose intolerance.
It should be avoided in patients suffering with diabetes.
Sucrose causes a decrease in dental plaque pH, dissolving tooth enamel and promoting dental caries.
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Fructose: causes an elevation in blood glucose concentration and should therefore be avoided in patients suffering from diabetes.
It is also contraindicated in patients with hypoglycaemia or hereditary fructose intolerance.
It may cause laxative effects when administered orally at high doses.
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Sorbitol, Xylitol Sorbitol and xylitol may cause osmotic
diarrhea. Sorbitol is metabolised to fructose, it is
contraindicated in paediatric patients with hereditary fructose intolerance and hypoglycaemia.
In severe cases it may cause damage of the liver accompanied with coma resulting in death of those patients. Especially intravenous administration of sorbitol should be avoided.
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Aspartame: Aspartame, a dipeptide of aspartic acid and a
methyl ester of phenylalanine, is 150-200 times as sweet as sucrose.
The phenylalanine component may be harmful in patients with phenylketonuria and
contra-indicated in homozygous autosomal recessive patients.
Rare hypersensitivity reactions have been reported.
Cross-reactivity with sulfonamides can occur.[3}
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Saccharin Associated with a significantly increased risk for the
development of bladder cancer. Banned in Canada due to carcinogenic potential. Most widely used in Nepal. Saccharin is an o-toluene sulfonamide derivative and
causes similar dermatologic reactions. Crosssensitivity with sulfonamides has been demonstrated;
therefore, children with “sulfa” allergy should also avoid saccharin.
pruritus and urticaria are the most common reactions, followed by eczema, photosensitivity, and prurigo.
Other reactions include wheezing, nausea, diarrhea, tongue blisters, tachycardia, fixed eruptions, headache, diuresis, and sensory neuropathy.[7]
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FillersLactose Lactose is a disaccharide of glucose and galactose,
and is absorbed after hydrolysis by intestinal lactase.
In infants and young children lactose intolerance may be associated with severe prolonged diarrhea, dehydration, and metabolic acidosis. Although it is difficult to attribute these symptoms
sensitivity to lactose varies widely in severity and the intake of considerably less than 3 g may provoke the described symptoms
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Microcrystalline cellulose: It may result in intestinal persorption. It shouldn’t be used in children below 2yrs of age.SOLVENTSEthanol co-administration of ethanol may alter drug
adsorption or metabolism and may result in drug interaction.
Adverse effects to the Central Nervous System are commonly reported, arising with blood ethanol concentrations in the range of 1 – 100 mg/100 ml
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Propylene Glycol Paediatric patients below 4 years have a
limited metabolic pathway (alcohol dehydrogenase).
Main toxic action is depression of the central nervous system.
High osmotic pressure may cause laxative effects.
Topical administration has been reported to cause contact dermatitis
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Colouring Agents Pediatric patients prefer brightly coloured
preparations. However, colouring agents should be avoided in pediatric formulations unless necessary.
The azo dye tartrazine (FD&C Yellow No. 5) is known to be potentially dangerous in aspirin-intolerant individuals.
Patients with recurrent allergic vascular purpura may experience exacerbations after exposure to azo dyes, such as tartrazine, sunset yellow, and new coccine
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Gastrointestinal intolerance, with abdominal pain, vomiting, and indigestion, has been associated with sunset yellow.
dermatologic reactions, including photosensitivity, erythroderma, and desquamation, have been attributed to erythrosine, an iodine-containing dye.
Contact dermatitis has been associated with neutral red,126,127 D&C Yellow No. 11,128,129 indigo carmine (FD&C Blue No. 2),130 quinoline yellow,129 and gentian violet.
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Coating material Cases of fibrosing colonopathy in children
have been reported for high-strength pancreatic enzyme formulations coated with a methacrylic acid and ethylacrylate copolymer.
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TASTE, SMELL AND TEXTURE These factors influence in the acceptability of the
dosage form. The human foetus appears to have specialized
taste cells at about the 7th or 8th week of gestation, with structurally mature taste buds visible at 13 to 15 weeks.
In contrast, olfaction develops postnatally. Odours are detected within hours of birth. Changes
in respiration and salivation can be observed, and responses become more robust during the first few days after birth.
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The affective responses to pleasant or unpleasant odours do not appear in children until the age of about 5; after age of 6 the adult pattern may be observed.
Children have greater difficulties to recognize tastes in mixtures than adults due to their limited analytical skills in perceptual tasks.
Their ability to recognize a flavour may also be affected by the concentration of the flavour in the formulation and the appearance of the medication itself.
For example, a strawberry flavour-containing formulation was identified as chocolate because of its brown colour, indicating a strong association between colour and flavour.
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Acceptance issues of flavour Market research has revealed standard
combinations of specific sweeteners with relevant flavours, which may vary by country and target market.
“bubble-gum” and “grape” in the United States, “citrus” and “red berries” in Europe and “liquorice” in Scandinavia. A bubble-gum or cherry flavour in combination with
a high intensity sweetener may suit the US paediatric market, while a less intense sweetness may be more appropriate for Japan.
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Table: Highlighting different flavour tytpes
Table: flavour preference in Europe for target disease population
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CHILDREN’S ARE NOT EQUAL TO SMALL ADULTS
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Risk associated with manipulation of adult dosage forms Splitting tablets into segments. Crushing tablets Opening capsules Dispersing tablets/ capsules and taking
proportions
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SOLID ORAL DOSAGE FORMTABLETS AND CAPSULES Solid oral dosage forms such as tablets and
capsules can offer advantages of greater stability, accuracy of dosing and improved portability over liquid formulations.
Formulation taste is rarely an issue, with film and/or sugar coats used to improve palatability.
The primary limitation for paediatric use is that solid oral dosage forms can present significant problems for young children and adolescents who have difficulty swallowing
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The size of tablets and capsules should be kept as small as possible.
One of the key advantages of solid dosage forms is that they do offer the opportunity for the development of modified-release formulations,
Scored tablets can be used for individual therapy when breaking them into subunits.
However consideration must be made to ensure uniform dose distribution.
Recently snap-tab technology has been used where a tablet can be uniformly divided into four parts.
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Another innovation is an anti-malarial tablet which can be divided into eight equal parts.
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Oro Dispersible Dosage forms Orodispersible dosage forms may comprise
orodispersible tablets, lyophilised wafers and thin films and are placed in the mouth where they disperse or “melt” on the tongue.
Orodispersible dosage forms hold great promise for children as they are easy to administer, do not require additional water and, as long as dispersion is rapid, are difficult to spit out and could provide a range of dosages appropriate for use in younger children.
Some patented technology as Zydis technology, Orasolv technology, Durasolv technology, Wow tab technology, Cotton candy technology are used to prepare this sort of dosage forms.
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Oral wafers: They are strips of typically 2-8 cm2 with 20-
500 µm thick. It usually contains less than 50 mg of API. They can dissolve or disintegrate in mouth
within a few seconds without water. Example: Triaminic thin strip is available in
USA for preschool children.
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Oral effervescent dosage forms Oral effervescent dosage forms include tablets,
granules and powders that are dissolved in water prior to administration.
Effervescent products should always be fully dissolved prior to administration, and large volumes of diluent may be required to do so which can be problematic for children.
To minimise the possibility of ingesting bicarbonate, children should be instructed not to drink the solution until the effervescence has subsided.
As effervescent tablets normally contain high sodium and/or potassium ion concentrations,
They may not be suitable for all patients, e.g. those with renal insufficiency.
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Chewable tablets: Chewable tablets are a valuable paediatric
dosage form for children of 2 years and older. They are considered to be safe in younger age
groups if administration is supervised to ensure thorough chewing to reduce the risk of inhalation or ingestion of tablet fragments.
Chewable tablets should have a smooth, rapid disintegration. Ideally, the formulation should contain non-carcinogenic sweeteners.
Antacids, antibiotics, anticonvulsants, analgesics, anti-asthmatics, vitamins and cold/allergy preparations are available as this form.
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Chewing gums Medical chewing gum has only been used for relatively few
paediatric formulations such as dimenhydrinate and fluoride. It may be a suitable dosage form for children as most
children of age 6 years or older are familiar with chewing gum.
Chewing gum is easy to administer, does not require additional water and may be taken anywhere.
It may be possible to mask the unpleasant taste of active substances by sweeteners and flavours added to the chewing gum.
The release of the active substances is controlled by various means such as solubilisers, ion exchange, encapsulation and the amount of gum base.
The minimum chewing time needed to ensure complete release of the required dose should be determined usually take 10-20 minutes[8].
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Multiparticulate dosage forms For substances that are not stable or cannot be
taste masked in liquid preparations, powders or multiparticulate formulations (e.g. pellets, granules and mini tablets) can be formulated.
These can be dosed directly into the mouth of the paediatric patient, or by mixing the prescribed dose with a small amount of soft food or with a drink prior to administration.
Formulations can be provided in a bottle with dosing scoop, or in single-dose sachets.
They may also be supplied in the form of capsules the contents of which can be sprinkled onto food.
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The product information should specify which commonly available foods are suitable for mixing with the preparation, and also list foods that should be avoided due to stability, compatibility or taste issues.
In all cases a device is needed to select or extract a predefined volume or to choose a specific number of dosage units from the multi-dose container.[3][9]
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Fig: showing Dosing spoon for determining and withdrawing small-sized solid drug car- riers from multi-dose containers
Fig: showing pellet dispenser
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Specialized formulationGummy bears Gummy bears are a small, rubbery-textured candies
shaped in the form of bears. They are just slightly less than an inch in length (closer to 2 centimeters).
Usually suitable for children above 2 years.
Lollipop It is suitable for children above 3 years. It is in trend in US compounding pharmacies. They are formulated depending upon individual
taste preference.
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Conclusion Formulating solid oral dosage form and
other dosage forms intended for paediatric purpose is a critical issue as lots of research works has not occurred in this field.
Due to the lack of information of factors influencing the fate of drug in the body of children, still dosage forms and excipients safety issues and acceptance is a matter of study.
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REFERENCES1. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL et al. Developmental
Pharmacology – drug disposition, action, and therapy in infants and children. N Engl J Med 2003; 349: 1157-67.
2. N.Y. Rakhmanina, J.N. van den Anker / Advanced Drug Delivery Reviews 58 (2006) 4–14
3. EMEA/CHMP/PEG/194810/2005; Reflection paper: formulation of choice for the paediatric population.
4. Marshall WA, Tanner JM. Arch Dis Child 1970;45(239):13-235. Jane Alcorna , Patrick J. McNamara, P harmacokinetics in the newborn; Advanced
Drug Delivery Reviews 55 (2003) 667–6866. Alexandra Bowlesa, Joanne Keaneb, Terry Ernestc, David Claphamd, Catherine
Tuleua,e, , Specific aspects of gastro-intestinal transit in children for drug delivery ∗design; International Journal of Pharmaceutics 395 (2010) 37–43
7. "Inactive" Ingredients in Pharmaceutical Products: Update (Subject Review); http://www.pediatrics.org/cgi/content/full/99/2/268, 15th Nov 2010
8. Ines Sttotenberg, Gesine Winzenberg, Jorg Brettkreutz, Solid Oral Dosage forms for children, formulations, excipients, and acceptance issues; Journal of applied therapeutic research; Vol 7, 4, 2010.
9. Klaus Wening, Jörg Breitkreutz; Oral drug delivery in personalized medicine: Unmet needs and novel approaches; International JournalofPharmaceutics (2010); article in press.
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THANK YOU ALL FOR YOUR KIND ATTENTION