Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations

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Pharmaceutical Development
Training Workshop on Pharmaceutical Development
with focus on Paediatric Formulations Protea
Hotel Victoria Junction, Waterfront Cape Town,
South Africa Date 16 to 20 April 2007
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Pharmaceutical Development

• Suitable dosage forms for pediatric medicine
• Presenter Jean-Marc AIACHE
• Emeritus Professor,
• Auvergne University,
• Faculty of Pharmacy,
• 28 Place Henri Dunant
• 63000 Clermont-Ferrand, France
• jm.aiache_at_wanadoo.fr

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Pharmaceutical Development

• Outline and Objectives of presentation
• What are the problems?
• 1) Children characteristics
• 2) Prescription and administration of drug
  products
• Are there suitable dosage forms for paediatric
  medicines?
• 1) Specific dosage forms for long or chronic
  diseases
• 2) Specific dosage forms for acute or common
  illness
• a) D.F to help the parents for drug
  administration
• b) To help the parents for drug acceptance by
  children
• c) To help the child to take his medicine

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What are the problems?

• 1) Children characteristics
• Children are SPECIFIC patients, and not small
  ADULTS
• Classification

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What are the problems?

• Their metabolism is different from adults
• Their reaction to drugs may be also different
  (pharmacokinetics, pharmacodynamic..)
• Their preference in term of taste or colour is
  quite fundamentally different of adults

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What are the problems?

• 2) Prescription and administration of drug
  products
• The drug product prescription is done by
  Paediatricians (for heavy diseases or long or
  chronic diseases) or more often by a General
  Practitioner (for common or acute diseases)
• The administration of drug products to children
  is made by their PARENTS
• So their role is of most importance in the
  drug product acceptability, size, colour, shape,
  aspect, taste.
• Furthermore it is compulsory to treat their
  stress!
• ALL THESE FACTORS CANNOT BE DISSOCIATED

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Are there suitable dosage forms for paediatric
medicines?

• There are two different issues in relation to the
  type of diseases to be treated.
• Specific dosage forms for long or chronic
  diseases
• Specific dosage forms for acute or common illness

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Specific dosage forms for long or chronic
diseases

• In a decreasing order
• Cancers, Aids, Pain
• Pulmonary diseases, Asthma
• Epilepsies, Depression, psychiatric troubles
• Cardiovascular, Metabolic diseases (diabetes)
• Virus, Orphan diseases

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Example Cancers

• Cancers are rare Disease in the child (1-2 cases/
  10000 lt 15 years old)
• The main treatment is made of Cytostatics drugs,
  largely used in the treatment of adults cancer,
  but without any evaluation in Children neither
  for conditions of use nor for safety, furthermore
  they are not registered for this use(off label
  use).

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Example cancers

• Dosage forms used
• 1)The majority are presented in injectable dosage
  form containing a dose for adult treatment and
  MUST be DILUTED before injection or
  infusion.This is done in the Hospital Pharmacy,
  until now most generally manually.Risks!!!
• The injection or infusion is painful.

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Example cancers

• 2)Some solid oral dosage form have been developed
  for adult use tablets or hard gelatin capsules
• i.e. Méthotrexate tablet 2.5 mg The usual
  maintenance dose is 15 mg per m²!! How many
  units to be administered??
• Some capsules are open and diluted to be
  administered as solutions ,but the taste is very
  Bad.

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Improvements

• Better system of catheter to avoid risk of burn
  by Cytostatics
• More precise pump to select the most adapted
  dilution for children before infusion.
• During their illness the most important for
  children is their pain and they are afraid of all
  that could be an aggression (injection,
  perfusion.)
• Use of nitrogen protoxide or  fentanyl patch
  (manually dose-area adapted!!) to prevent pain.
• Morphine micro pellets are used also as
  suspension in milk or juice or waterbut the
  capsules must be opened and the pellets
  transferred.

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2nd example Asthma

• The main treatment AEROSOLS of anti-asthmatic
  drugs.
• They are administered with devices ,the aim of
  which is to obtain the good number of small
  particles able to reach the good lung sites.

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2nd example Asthma

• Pressurized Metered Dose Inhaler5 (pM.D.I.)
• 1)First issue for child Identify the way of
  use.
• 2) Second issue coordination hand and lung
  and disuse of actuator.
• So the need for spacer is quite compulsory, if
  it is accepted by the child!!

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2nd example Asthma

• DRUG POWDER INHALERS (D.P.I.)
• 1)No issue of coordination hand and lung and
  disuse of actuator.
• 2) But issue of inspiration pressure to obtain
  the full dose.
• Despite the progress, children have
  difficulties to use .
• New systems, between pMDI and DPI, which delete
  inspiration pressure are proposed

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2nd example Asthma

• NEBULIZATION with jet or ultrasonic nebulizer.
• They are made from a solution (no specific
  children formula!), more or less diluted and the
  device( some are child specific in size and
  material) is prepared and applied by the parents
  who can watch precisely the value and time of
  administration duration.The child has to be
  occupied during the 10 to 15 minutes of
  administration.
• ORAL TREATMENT Theophyllin solutions cannot be
  used as alcohol is the main solvent.
• Tablets or capsules SR but to be swallowed .

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Other examples

• Epilepsies, Depression, psychiatric troubles
  solutions administered as drops in? Water, juice
  ,taste
• Cardiovascular drops, crushed tablets" Viagra
  in newborn infant.
• Metabolic diseases (diabetes) injection of
  insulin or use of implanted pumps, but
  difficult. Perhaps the Exhubera
• Virus, Orphan diseases Solutions for injection
  or oral route as simple as possible..
• Ocular systematic control at birth ocular insert

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Acute or common illness The most important
prescriptions
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Acute or common illness

• For of these prescribed drugs,80 are reported to
  be used in accordance with their label and with
  conventional DF, not at all specifically adapted
  to the children use.
• The dose of API is fixed by using empirically
  established dosage regimen and the dose
  combination is sometimes largely used, which is
  not really convenient.
• The DF used and the ones to be developed in the
  future can be classified according to their use
  by the parents or the children compliance
  (patient-child, age, kind of illness, etc)

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Dosage forms for newborns, infants ,toddlers
(0-23 months)

• a) D.F to help the parents for drug
  administration
• Passive administration to i.e. drugs in powder
  form or encapsulated, suspended in milk in the
  baby bottle, eventually with sugar,
• Issues milk and drugs (adsorption,
  precipitation), taste
• Suppositories size and dose adapted.

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Dosage forms for newborns, infants ,toddlers

• a) D.F to help the parents for drug
  administration
• Active administration powders, solutions,
  suspensions introduced in pacifiers, teats,
  double teat or pacifier (reservoir) with which
  the child can play and in the same time takes a
  dose of drug.
• BIG ISSUE these devices have to be different
  or to present a special design to be different of
  the common device .
• The issue of the choice of dilution liquid
  remains!!!!

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Dosage forms for newborns, infants ,toddlers

• The majority of D.F for Respiratory diseases
  (common cold, cough, etc )as well as for
  Digestive tract, Metabolism ,and Fever or small
  pains are liquids.They are presented as
  solutions containing sugar or sweeteners, as
  suspensions or suspensions easy to prepare from
  powders or granulates.
• Another issue is the method of delivery of
  the liquids and the accuracy of the device used
  for measuring the dose. In the EP an essay has to
  be done.
• Graduated Glasses, Syringes, Burettes for dosing
  oral liquids, Med-T-Spoon, Intelligent single
  doses. The graduations are presented in Kg, body
  area in m²,age (day ,month, years)

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Dosage forms for children(2-11 years)

• b) TO HELP THE PARENTS FOR DRUG ACCEPTANCE BY
  CHILDREN
• Passive Administration to children with a taste
  not completely elaborated or to children who
  refuse systematically every new taste
• Examples Suppositories or powder for mixing
  with food basic (and quite compulsory) dosage
  forms !

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Dosage forms for children(2-11 years)

• Active Administration
• Its goal is to increase the interest of the
  child for the drug administration system.
• For other routes of administration than oral, the
  D.F are conventional, with doses adapted to
  children, improvements come from packaging.
• But for the route ,oral route, the taste will
  represent the main issue of all the developed
  D.F..

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Dosage forms for children(2-11 years)

• The problem of the TASTE has to be solved.
• 2 issues
• 1)The use of specific tasty and masking
  substances used for children or special
  techniques for coating the bitter substances. It
  has been proposed special new dosage form adapted
  to a quick release of the drug in solution or
  suspension form.

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Dosage forms for children(2-11 years)

• 2) Taste evaluation studies in children have to
  be improved for evaluation and above all, have
  to be allowed and done systematically for every
  new drug under ethical comity supervision with
  large group of subjects.
• Creation of taste class-room to teach the
  taste..

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Dosage forms for children(2-11 years)

• So for active administration ,the dosage form
  could be presented as
• a special (and delicious) food
• a very famous sweet
• a toy or something which tell a story

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Dosage forms for adolescents(12-16-18 years)

• To help the child to take his medicine (from
  teenager to young adult)
• Passive administration the drug is contained in
  a reservoir or neutral device implantable or
  hidden so that the child receive the drug in a
  constant and regular way but overall does not
  show at school or in a stadium that he is ill .He
  must look like a normal child as his school
  friends.!

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Dosage forms for adolescents(12-16-18 years)

• Active Administration
• The child is responsible (as far as he can !!)
  of the time of the drug product administration
• either by a memory recall, which tells the
  evolution of the illness
• either by his toy, an intelligent Game-Boy,
  which by a bell, indicates the precise time of
  dosing

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• But all these developments must be under the
  control of two very important factors

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Pharmaceutical Development

• Summary and conclusion
• A very big effort has to be made for changing
  the mentality, and also the methods of drug
  development in view of adapting the dosage to the
  right patients by taking in account all their
  physiologic and pathologic conditions.

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References

• Symposium Médicament pédiatrique et ses
  spécificités - Design moi un médicament.
  21-22/03/2002, Vichy, France
• Dr. J-L STEPHAN, Difficulté de la prescription
  pédiatrique en cancérologie
• Pr J-M AIACHE, Médicaments et enfants, point de
  vue du formulateur galénique
• F. JEGOU, Médicaments et enfants, avis du
  designer
• P. GAUTHIER, Résultats dune enquête réalisée
  auprès des pédiatres

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References

• EMEA GUIDELINES
• Reflection Paper Formulations of Choice for the
  Paediatric Population (Sept 2006)Guideline on
  conduct of Pharmacovigilance for medicines used
  by the paediatric population (June 2006)
  Guideline on the Role of Pharmacokinetics in the
  Development of Medicinal Products in the
  Paediatric Population (June 2006) Discussion
  paper on the impact of renal immaturity when
  investigating medicinal products intended for
  paediatric use (Dec 2004) Note for guidance on
  evaluation of anticancer medicinal products in
  man (addendum on paediatric oncology) (Jan 2004)
  . Better Medicines for Children. European
  Commission on-line 2002 http//pharmacos.eudra.
  org/F2/pharmacos/medchild.htm (November 2002,
  date last accessed).
• FDA publications
• . Guidance for industry. Pediatric oncology
  studies, in response to a written request. Food
  and Drug AdministrationCenter for Drug
  Evaluation and Research on-line 2001
  http//www.fda.gov/cder/guidance/3756dft.htm
  (November 2002, date last accessed).
• . Food and Drug Administration Modernization Act
  of 1997. Food and Drug AdministrationCenter for
  Drug Evaluation and Research on-line 1997
  http//www.fda.gov/cder/guidance/105-115.htm
  (November 2002, date last accessed).